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    • 专利摘要:
    tetracycline topical compositions and method of use thereof, the present invention is a brittle topical hydrophobic therapeutic composition comprising a carrier comprising (a) from approximately 60% to 99% by weight of at least one hydrophobic oil ; (b) at least one viscosity modifying agent selected from a group consisting of fatty alcohol, fatty acid and wax, and; (c) a tetracycline antibiotic, wherein at least a portion of the tetracycline antibiotic is suspended in the composition; the viscosity of the composition is at least 30% higher than the viscosity of the vehicle without the tetracycline antibiotic; and is higher than the viscosity of hydrophobic oil and tetracycline antibiotic without viscosity modifying agents; and the amount of viscosity modifying agents may optionally be reduced by at least an amount by weight that could increase the viscosity of the vehicle without the tetracycline antibiotic by at least 30%; wherein tetracycline is chemically stable in the composition for at least six months; more than approximately 90% of tetracycline does not collapse; and when packaged in an aerosol container with the addition of liquefied or compressed propellant gas, the composition generates upon release of the container a friable foam of at least good quality which breaks easily upon application of shear force.
    公开号:BR112012007473A2
    申请号:R112012007473
    申请日:2010-10-01
    公开日:2019-05-07
    发明作者:Elana Gazal；Yohan Hazot；Rita Keynan；Irakliy Papiashvili；David Schuz；Dov Tamarkin
    申请人:Foamix Ltd；
    IPC主号:
    专利说明:

    “TOPICAL COMPOSITIONS OF TETRACYCLINE AND ITS METHOD OF USE”
    Cross Reference to Related Patent Applications
    This patent application claims the priority benefit, under Title 35 of the United States Code, section 119 (e), of United States Provisional Patent Application Series Number 61 / 248,144 filed on October 2, 2009, whose Possible translation of the title would be: FOAM COMPOSITIONS FREE OF SURFACTANT AND FREE OF WATER, BREAKING FOAMS AND THEIR METHODS OF USE; United States Provisional Patent Application No. 61 / 322,148 filed on April 8, 2010, whose possible translation of the title would be: FOAM-FREE SURFACTANT COMPOSITIONS AND WATER-FREE FOAMS, BREAKING FOAMS AND THEIR METHODS OF USE; United States Provisional Patent Application No. 61 / 349,911 filed on May 31, 2010, whose possible translation of the title would be: FOAM COMPOSITIONS FREE OF SURFACTANT AND FREE OF WATER, BREAKING FOAMS AND THEIR METHODS OF USE; United States Provisional Patent Application No. 61 / 385,385 filed on September 22, 2010, whose possible translation of the title would be: FOAM-FREE SURFACTANT COMPOSITIONS AND WATER-FREE FOAMS, BREAKING FOAMS AND GASES AND RESPECTIVE METHODS OF USE; United States Provisional Patent Application No. 61 / 331,126 filed on May 4, 2010, whose possible translation of the title would be: COMPOSITIONS, GELS AND FOAMS WITH REOLOGY MOULATORS AND THEIR METHODS OF USE, and; United States Provisional Patent Application No. 61 / 380,568 filed on September 7, 2010, whose possible translation of the title would be: FOAM COMPOSITIONS FREE OF SURFACTANT AND FREE OF WATER AND BREAKING FOAM AND THEIR METHODS OF USE; all of which are incorporated here in their entirety as a reference.
    Fundamentals of the Invention:
    Tetracyclines are broad-spectrum antibiotics that are routinely used orally to treat diseases
    2/96 dermatological conditions, such as acne and rosacea. However, despite their high therapeutic value, tetracyclines are very unstable and are known to be incompatible with formulation excipients, including water, various protic substances and oxidizing agents.
    Topical tetracycline was the first topical antibiotic approved for the treatment of acne, but its use was limited due to problems with the skin's penetration of the active ingredient (Adiçen E. et al., Topical tetracycline in the treatment of acne vulgaris, J Drugs Dermatol. 2008; 7: 953-5). The vehicle of this product is an ointment base, which comprises petrolatum (which is greasy and unusable in the case of facial treatment of acne and rosacea).
    Hydrophobic tetracycline compositions intended to be mixed with an external source of protic liquid are known. They comprise a non-hygroscopic hydrophobic silicone thickener, preferably a silicone elastomer, in concentrations greater than 5%. This mixture results in substantial tetracycline solubilization, thus making it “suitable for topical application”. Such a product, which requires mixing of two components before administration by the patient, is excessively laborious and has none or has little practical or viable value; and, in addition, it would degrade and form degradation products, if left for a while before treatment.
    Summary of the Invention:
    The present patent application relates to oil-based gel formulations, foaming formulations and foams containing tetracycline, which are stable, as well as their therapeutic uses.
    The present application also relates to foaming formulations and surfactant-free foam; and / or free of polymeric agents and surfactants. In one or more embodiments of the present invention, hydrophobic solvents are included as part of a drug carrier. For example, certain drugs require hydrophobic solvents to solubilize them.
    In one or more embodiments of the present invention, hydrophobic solvents are included to facilitate or increase penetration
    3/96 intradermal or the administration of a drug. In one or more additional cases, hydrophobic solvents are included to have an occlusive effect at the target site, for example, when the treatment site is damaged skin and the occlusive effect of hydrophobic solvents is desirable. The present application also relates to compositions comprising hydrophobic solvents and their receptive method of use. The present application also describes semi-solid gel compositions that liquefy upon the application of mild shear force, such as, for example, gentle friction.
    In one or more embodiments of the present invention, a brittle hydrophobic therapeutic composition for topical use is presented, comprising:
    The. a vehicle comprising:
    i. approximately 60% to approximately 99% by weight of at least one hydrophobic oil;
    ii. at least two viscosity modifying agents selected from the group consisting of a fatty alcohol, a fatty acid and a wax.
    B. a tetracycline antibiotic, characterized by the fact that:
    (i) at least a part of the tetracycline antibiotic is suspended in the composition;
    (ii) the viscosity of the composition is at least approximately 30% higher than the viscosity of the vehicle without the tetracycline antibiotic; and because it is higher than the viscosity of hydrophobic oil and tetracycline antibiotic without viscosity modifying agents;
    (iii) the amount of viscosity modifying agents can optionally be reduced by at least an amount by weight, which could increase the viscosity of the vehicle without the tetracycline antibiotic by at least 30%;
    - tetracycline being chemically stable in composition for at least six months;
    4/96
    - more than approximately 90% of tetracycline does not collapse;
    - being that, when packed in an aerosol container with the addition of liquefied or compressed propellant gas, the composition generates, upon the release of the container, a brittle foam of quality considered at least good, which breaks easily through the application of shear force.
    It is known in the art that foams can be easily formulated based on high amounts of water, in combination with surfactants, foam adjuvants and polymeric agents. As described in the literature, hydrophobic solvents can have an anti-foaming effect, which makes formulating foams based on hydrophobic solvents a challenge. To overcome this challenge, the prior art requires the use of substantial levels of surfactants that act as foaming agents. Surfactants are known to be irritating, especially ionic surfactants, and their repeated use can cause skin dryness and therefore it is desirable to reduce their use in pharmaceutical compositions intended for skin or mucous treatment. The prior art also teaches the incorporation of foam adjuvants, such as, for example, fatty alcohols and fatty acids, as foam-enhancing agents and also the incorporation of polymeric agents (for example, gelling agents) as foam stabilizers, which can prolong the foam collapse time. Waxes can also be introduced into these surfactant-based formulations, but as will be appreciated, waxes, which are solid at room temperature, can easily precipitate.
    The technical problems that must be overcome in the formulation of oleaginous vehicles and pharmaceutical compositions with hydrophobic solvent (a) free of surfactants, and / or (b) free of polymeric agents, and / or (c) free of water, and / or (e) free of short chain alcohols, and / or (f) free of polyols are diverse and include: finding an appropriate substitute for the surfactant that provides foaming properties; find an appropriate substitute that preferably does not need an adjuvant
    5/96 foam present with the surfactant (substitute), which, if present, among other things, would help to increase the foam and as an aid to the surfactant and preferably does not need to have a polymeric agent present with the agent surfactant (substitute), which, if present, among other things, would help to prolong foam stability.
    It has surprisingly been discovered in the present invention that surfactants can be advantageously eliminated and replaced with viscosity modifying agents consisting of a fatty alcohol, a fatty acid and a wax in the context of hydrophobic solvent based foams. Waxes have several advantages over other foaming agents such as, for example, excellent compatibility with the skin, almost no chemical reactivity, which ensures the stability of the active ingredients, and efficient skin occlusion, which helps to reduce water loss from the skin. skin and can improve the penetration of active agents into the skin. Although waxes introduce their own additional problems in the formulation of foaming compositions and foams, including their tendency to solidify and precipitate from a formulation and block the can valves, against which formulations must be designed in such a way that formulations cannot are adversely altered by adding an effective amount of the propellant and that the formulations can be agitated and homogeneous and can promptly reform, at least by light or reasonable agitation before use.
    Another challenge is how to adjust the rheology, as expressed primarily in the viscosity of the formulation before and after the addition of the propellant, in such a way that, before it can present properties similar to gel and that, after that, it can be agitated in the can. In addition, the composition must be capable of generating a foam that, when applied to a target, is neither liquid nor very viscous, but comfortable for convenient application. In addition, toxicology and testing costs can be substantially reduced when the gel and foam are capable of showing equivalence for pharmaceutical purposes.
    6/96
    Incorporated or additional to the challenge above, another aspect is how to provide formulations in which unstable active ingredients, such as tetracyclines, which break down easily can, however, remain sufficiently chemically stable for prolonged periods, in such a way as to allow a reasonable or acceptable amount of breakdown (for example, as may be accepted by a drug regulatory authority), being able to continue to provide a therapeutic effect or prevent or remit a disorder or disease (hereinafter referred to as chemically stable). Another challenge is to provide and administer a composition in which the active agent is homogeneous, especially when the active agent is not dissolved. In addition, formulations should avoid the use of substances that may be irritating, if applied to a sensitive target, or that may cause depletion or drying or pain when repeated use.
    Incorporated or additional to the challenge above, another aspect is how to provide physically stable formulations that are at least stable in the short term after release from the pressurized container and do not break due to exposure to skin temperature. Foams that are structurally stable on the skin for at least one minute are called stable in the short term. In another aspect of the physical stability of the foamable formulation including propellant it remains homogeneous and does not separate to any significant extent for at least one minute after being stirred (hereinafter called physically stable).
    In one aspect, a topical use brittle hydrophobic therapeutic composition includes a vehicle comprising from approximately 60% to approximately 99% by weight of at least one hydrophobic oil and at least one viscosity modifying agent selected from the group consisting of a fatty alcohol, a fatty acid and a wax; and a tetracycline antibiotic, characterized in that at least part of the tetracycline antibiotic is suspended in the composition and the viscosity of the composition is at least approximately 30% higher than the viscosity
    7/96 of the vehicle without the tetracycline antibiotic, and be greater than the viscosity of the hydrophobic oil and the tetracycline antibiotic without the viscosity modifying agents; and being that after storage at 25 ° C for at least two months, the composition retains at least 90% of the tetracycline initially present in the composition; and since, when packaged in an aerosol container to which a liquefied or compressed propellant gas is added, the composition provides, upon release of the container, a brittle foam of at least good quality, which breaks easily upon application of shear force.
    In one or more embodiments of the present invention, at least 95% or at least 97% of the tetracycline initially present is present after at least two months.
    In one or more embodiments of the present invention, at least 90% or at least 95% or at least 97% of the tetracycline initially present is present after at least three months.
    In one or more embodiments of the present invention, at least 90% or at least 95% or at least 97% of the tetracycline initially present is present after at least six months.
    In one or more embodiments of the present invention, the amount of tetracycline present is determined by High Performance Liquid Chromatography (HPLC or HPLC).
    In one or more embodiments of the present invention, the increase in viscosity is a synergistic increase, such that the combined viscosity of the vehicle and the viscosity of the hydrophobic oil and the tetracycline antibiotic is less than the viscosity of the composition.
    In one or more embodiments of the present invention, the hydrophobic brittle vehicle is in the form of a gel prior to the addition of propellant; said gel liquefying and spreading easily by applying the smooth shear force.
    8/96
    In one or more embodiments of the present invention, the hydrophobic brittle vehicle is in the form of a foam; said foam having a collapse time greater than approximately 3 minutes.
    In one or more embodiments of the present invention, the ratio between the different propellant composition and the propellant is from approximately 100: 1 to approximately 100: 25.
    In one or more embodiments of the present invention, the hydrophobic oil is selected from the group consisting of a mineral oil, a hydrocarbon oil, an ester oil, an ester of a dicarboxylic acid, a triglyceride oil, an oil of vegetable origin, an oil of animal origin, an unsaturated or polyunsaturated oil, a diglyceride, a PPG alkyl ether, an essential oil, a silicone oil, liquid paraffin, an isoparaffin, a polyalphaolefin, a polyolefin, a polyisobutylene, a synthetic isoalkane, isohexadecane, isododecane, alkylbenzoate, alkyloctanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate, arachidyl behenate, arachidyl propionate, benzyl laurate, benzyl myristate, benzyl dihydroethyl palmitate, dihydroleate butyl myristate, butyl stearate, cetearyl ethylhexanoate, cetearyl isononanoate, cetyl acetate, cetyl ethylhexanoate, cetyl lactate, myristate d and cetyl, cetyl octanoate, cetyl palmitate, cetyl ricinoleate, decyl oleate, diethylene glycol diethylhexanoate, diethylene glycol dioctanoate, diethylene glycol diisononate, diethylenexyl, diethylenexyl, diethylenexyl, diethylenexyl, diethylenexyl, diethylene diisopropyl adipate, diisopropyl dimerate, diisopropyl sebacate, diisostearyl dimer dilate, diisostearyl fumerate, dioctyl malate, dioctyl sebacate, dodecyl oleate, ethylhexyl palmitate, ethyl esters, coconut derivatives ethylhexyl ethyl hexanoate, ethylhexyl hydroxistarate, ethylhexyl isononanoate, ethylhexyl palmitate, ethylhexyl stearate, hexadecyl stearate, hexyl laurate, isoamyl laurate, isocetyl isate, isocetylate, lanol isocetyl stearate, isocetyl salicylate, isocetyl stearate, iso stearoyl stearate ocetyl, isocetearyl octanoate, ethylhexanoate
    9/96 isodecyl, isodecyl isononanoate, isodecyl oleate, isononyl isononanoate, isodecyl oleate, isohexyl decanoate, isononyl octanoate, isopropyl isostearate, isopropyl lanolate, isopropyl isopropyl laurate, isopropyl laurate, isopropyl laurate, isopropyl laurate, isopropyl laurate, isopropyl laurate, isopropyl isopropyl laurate of isopropyl, isostearyl beenate, isostearyl citrate, isostearyl erucate, isostearyl glycolate, isostearyl isononanoate, isostearyl isostearate, isostearyl lactate, isostearyl linolate, isostearyl linolenate, isostearostane malate, isostearostane malate , isostearyl salicylate, isostearyl tartrate, isotridecyl isononanoate, isotridecyl isononanoate, lauryl lactate, myristyl lactate, myristyl myristate, myristyl neopentanoate, octylodecanol, myristyl propionate, octyldentilate myristate, tipprotein octyl, octyl palmitate, octyldodecyl behenate a, octyldodecyl hydroxystearate, octyldodecyl myristate, stearoyl stearate octyldodecyl, oleyl erucicate, oleyl lactate, oleyl oleate, propyl myristate, propylene glycol propylene glycol, propylene glycol tipprate, propylene glycol tip, propylene glycol, propylene glycol tip, propylene glycol maleated soybean oil, stearyl caprate, stearyl heptanoate, stearyl propionate, tocopherol acetate, tocopherol linoleate, glyceryl oleate, tridecyl ethylhexanoate, tridecyl isononanoate, triisocetyl citrate, oil from the bay tree of Alexandria , avocado oil, apricot oil, barley oil, borage seed oil, calendula oil, cinnamon seed oil, canola oil, caprylic / capric triglyceride castor oil, coconut oil, corn oil, cotton oil, cottonseed oil, evening primrose oil, linseed oil, peanut oil, hazelnut oil, glycer triacetate eth, glycerol triheptanoate, glyceryl trioctanoate, glyceryl triundecanoate, hemp oil, jojoba oil, alfalfa oil, corn germ oil, oval pumpkin oil, millet oil, tipprilate / neopentyl glycol tip, olive oil , palm oil, passionflower oil, pentaerythrityl tetrastearate, poppy oil, propylene glycol ricinoleate, rapeseed oil, rye oil, safflower oil, sesame oil, shea butter, soybean oil, soybean oil , sweet almond oil, sunflower oil, rinchão oil, aromatic clove oil, tea tree oil, walnut oil,
    10/96 wheat germ glycerides, wheat germ oil, PPG-2 butyl ether, PPG4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butyl ether, PPG14 butyl ether, PPG-15 butyl ether, PPG-15 stearyl ether, PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-22 butyl ether, PPG-22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether , PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether, PPG-10 cetyl ether, PPG-28 cetyl ether, PPG-30 cetyl ether, PPG -50 cetyl ether, PPG-30 isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 methyl ether, PPG-3 myristyl ether, PPG-4 myristyl ether, PPG -10 oleyl ether, PPG-20 oleyl ether, PPG-23 oleyl ether, PPG30 oleyl ether, PPG-37 oleyl ether, PPG-40 butyl ether, PPG-50 oleyl ether, PPG-11 ester ether lico, herring oil, cod liver oil, salmon oil, cyclomethicone, dimethylpolysiloxane, dimethicone, epoxy modified silicone oil, fatty acid modified silicone oil, fluoro-modified silicone oil, methylphenylpolysiloxane, phenyltrimethicone and silicone oil modified by a polyether group.
    In one or more embodiments of the present invention, fatty alcohol has at least 12 carbon atoms in its carbon skeleton, said fatty acid having at least 12 carbon atoms in its carbon skeleton.
    In one or more embodiments of the present invention, the fatty alcohol and said fatty acid have a melting point greater than approximately 40 ° C.
    In one or more embodiments of the present invention, fatty alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, beetryl alcohol, tetracosanol, hexacosanol, octacosanol, triacontanol, tetratriacontanol, and; said fatty acid being selected from the group consisting of dodecanoic acid, tetradecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, eicosanoic acid, docosanoic acid, tetracosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid,
    11/96 dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid and pentatriacontanoic acid.
    In one or more embodiments of the present invention, the carbon chain of said fatty alcohol or said fatty acid is replaced by a hydroxyl group, and, for example, the carbon chain of said fatty acid is 12-hydroxy stearic acid.
    In one or more embodiments of the present invention, the wax is selected from the group consisting of a vegetable wax, such as, for example, carnauba wax, candelilla wax, uricuri wax, sugar cane wax, retamo wax, oil from jojoba; animal waxes, such as beeswax; petroleum derivative wax, such as paraffin waxes, polyethylene and their derivatives.
    In one or more embodiments of the present invention, the viscosity modifying agent is a combination comprising (i) at least one fatty alcohol and at least one fatty acid, or (ii) at least one fatty alcohol and at least one wax, or (iii) at least one fatty acid and at least one wax, or (iv) at least one fatty alcohol, at least one fatty acid and at least one wax.
    In one or more embodiments of the present invention, the hydrophobic brittle vehicle is substantially free of surfactants, protic solvents, polar aprotic solvents and silicone thickening agents.
    In one or more embodiments of the present invention, the hydrophobic brittle vehicle is substantially free of surfactants, polymeric gelling agents, polyols, short-chain alcohols and silicone thickening agents.
    In one or more embodiments of the present invention, the hydrophobic brittle vehicle contains less than approximately 0.4%; or less than approximately 0.2%; or less than approximately 0.1% of
    12/96 surfactants, protic solvents, polar aprotic solvents and silicone thickening agents.
    In one or more embodiments of the present invention, the tetracycline antibiotic is selected from the group consisting of tetracycline, oxytetracycline, demeclocycline, doxycycline, limecycline, meclocycline, metacycline, minocycline, rolitetracycline, chlorotetracycline and tigecycline, and, for example, the antibiotic it is hydrophobic.
    In one or more embodiments of the present invention, the tetracycline antibiotic is present in a free base form, a hydrate form, a salt form or in a complex form and, for example, the logarithm of the distribution constant of the antibiotic of tetracycline at pH 7.0 (buffer / chloroform) is equal to or less than approximately 0.2.
    In one or more embodiments of the present invention, the tetracycline antibiotic does not include any hydroxy group at carbons 5, 6, and 7, and, for example, the tetracycline antibiotic is selected from the group consisting of minocycline and doxycycline; or it's minocycline.
    In one or more embodiments of the present invention, the composition also comprises an additional active agent.
    In one or more embodiments of the present invention, the additional active agent is selected from the group consisting of an active herbal extract, an acaricide, a skin stain and keratosis removing agent, an allergen, an alpha hydroxyl acid, an agent analgesic, an androgen, an anti-acne agent, an anti-allergic agent, an anti-aging agent, an antibacterial agent, an antibiotic, an antique-burn agent, an anti-cancer agent, an anti-dandruff agent, an antidepressant agent, an anti-dermatitis agent, an anti-anemic agent, an antifungal agent, an antihistamine, an anthelmintic agent, an antihyperkeratosis agent, an anti-infective agent, an anti-inflammatory agent, an anti-irritant, an antilipemic agent, an antimicrobial agent, an antimycotic agent, an antioxidant, an antiparasitic agent, an agent
    13/96 antiproliferative agent, an antipruritic agent, an antipsoriatic agent, an anti-rosacea agent, an anti-seborrheic agent, an anti-swelling agent, an anti-swelling agent, an anti-viral agent, an anti-warming agent, an anti-wrinkle agent, an antileveduriform agent, an astringent, an beta-hydroxy acid, benzoyl peroxide, a topical cardiovascular agent, a chemotherapeutic agent, a corticosteroid, an immunogenic substance, a dicarboxylic acid, a disinfectant, an estrogen, a fungicidal agent, a hair growth regulating agent, a hapten , a hormone, a hydroxy acid, an immunosuppressive agent, an immunoregulatory agent, an immunomodulating agent, an immunostimulating agent, an insecticidal agent, an insect repellent agent, a keratolytic agent, a lactam, a local anesthetic agent, an lubricant, a masking agent, a metal, a metal oxide, a mutocide, a neuropeptide, an anti-infective agent non-steroidal mud, an oxidizing agent, a pediculicide, a peptide, a pesticide, a protein, a photodynamic therapy agent, a progesterone, a radical scavenger, an overfatting agent, a retinoid, a therapeutic agent, a scabicidal agent, a sedative agent, a self-tanning agent, a skin protection agent, a skin bleaching agent, a steroid, a steroid hormone, a vasoactive agent, a vasoconstricting agent, a vasodilating agent, a vitamin, a vitamin A, a derivative vitamin A, vitamin B, vitamin B derivative, vitamin C, vitamin C derivative, vitamin D, vitamin D derivative, vitamin D analogue, vitamin F, vitamin F derivative, a vitamin K, a derivative of vitamin K, a healing agent and a wart-removing agent.
    In one or more embodiments of the present invention, when tested in an in vitro model in Franz cell assays, using human skin or pig skin, it provides an amount of tetracycline in the skin that is higher than the respective amount transferred transdermally.
    In one or more embodiments of the present invention, when tested in an in vitro model in assays with Franz cells, by means of
    14/96 use of human skin or pig skin, the ratio between the amount of tetracycline in the skin and the respective amount transferred transdermally is greater than approximately 100: 1, or between approximately 100: 1 and approximately 10: 1, or between approximately 10: 1 and approximately 2: 1, or greater than 1: 1.
    In one or more embodiments of the present invention, the concentration of tetracycline in the hydrophobic brittle composition is greater than the lowest concentration that results in the intradermal administration of sufficient concentrations of tetracycline to have a therapeutic effect when tested in the in vitro model in cell test. Franz, through the use of human skin or pig skin.
    In one or more embodiments of the present invention, the composition prevents degradation of the tetracycline antibiotic by application to the target treatment site.
    In another aspect, a method of preventing, treating or alleviating the symptoms of a dermatological, ophthalmic, gynecological or mucosal disease includes topical application to the target area of a hydrophobic therapeutic composition such as, for example, that described herein.
    In one or more embodiments of the present invention, the disease includes bacterial infection, inflammation, oxidative stress and neurodegeneration and / or apoptosis as one of its etiological factors.
    In one or more embodiments of the present invention, the disease is selected from the group consisting of a dermatological condition, such as abscess, acne, acne conglobata, acne fulminans, acne vulgaris, acne scars, acute febrile neutrophilic dermatosis, acute lymphangitis, dermatitis of allergic contact, alopecia, athlete's foot, atopic dermatitis, bacterial skin infections, baldness, basal cell carcinoma, blisters, bromhidrosis, bullous pemphigoid, burn, calluses, candidiasis, carbuncles, cellulite, chemical burns, chickenpox, cholesteatoma, cholinergic urticaria, effects chronic sunlight, herpes, cold-induced urticaria, pustules, grains, cutaneous larva migrans, abscess
    15/96 cutaneous, cutaneous larva migrans, cutaneous myiasis, dark spots, delirium of parasitic infestation, Dercum's disease, dermatitis, herpetiform dermatitis, dermatological pain, dermatological inflammation, dermographism, dermatophytosis, rashes and drug reactions, dyshydrotic eczema, ectodermal dysplasia , eczema, ectima, epidermoid cyst, epidermal necrolysis, erysipelas, erythrasma, exfoliative dermatitis, erythema multiforme, erythema nodosum, folliculitis, fungal nasal infections, fungal skin infections, boils, gangrene, genital herpes, annular granuloma, supine granulosa, ringworm, ringworm hives, folliculitis, hirsutism, hyperhidrosis, hypohidrosis, ichthyosis, impetigo, inflammatory acne, ingrown nails, intertrigo, irritant contact dermatitis, ischemic necrosis, pruritus, fungal infection in the groin (Jock itch), Kaposi's sarcoma, keratosis pilaris, pilar keratosis simple chronic, lichen planus, lichen sclerosus, lymphadenitis, lymphangitis, melan malignant oma, mastocytosis, measles, melanoma, miliaria, signs, molluscum contagiosum, methicillin-resistant Staphylococcus aureus or SARM / MRSA, necrotizing subcutaneous infection, necrotizing fasciitis, necrotizing myositis, nodular papulopustular acne, noninflammatory acne, oral dermatitis panniculitis, paronychia, parapsoriasis, parasitic infections of the skin, pemphigus, photoallergy, photodamage, photoirritation, photosensitivity, papules, pediculosis, perioral dermatitis, pimples, pink pityriasis, lichenoid pityriasis, pink pityriasis, pityriasis rubenosa pilaris, herpiasis -operative or post-surgical, pressure ulcers, pressure urticaria, pruritus, beard pseudofolliculitis, psoriasis, itchy urticarial papules and plaques of pregnancy (PUPP), purple, pustules, pyogenic granuloma, skin rashes, mycosis, rosacea, rosacea, rosacea, rosacea, rosacea scabies, scalded skin syndrome, scars, scleroderma, sebá cyst ceo, seborrheic dermatitis, seborrheic keratosis, herpes zoster, skin aging, skin cancer, skin neoplasm, skin neoplasms, rash, skin ulcers, squamous cell carcinoma, scalded staphylococcal skin syndrome, stasis dermatitis, Stevens-Johnson, burns, sunspots, thermal burns, tinea corporis, tinea cruris, tinea pedis, tinea versicolor, toxic epidermal necrolysis, trauma or skin injury, chickenpox virus, vitamin D deficiency, viral skin infections, vitiligo , warts, aquagenic urticaria, wrinkles, xerosis,
    16/96 herpes zoster and yeast skin infections; a disease of a body cavity or mucous surface, a disease in the nose, mouth, ears, eyes, respiratory system, vagina, urethra or rectum, chlamydia infection, gonorrhea, hepatitis B, herpes, HIV / AIDS, human papilloma virus (HPV), genital warts, bacterial vaginosis, candidiasis, soft cancer, inguinal granuloma, venereal lymphogranuloma, mucopurulent cervicitis (MPC), contagious mollusk, non-gonococcal urethritis (UNG), trichomoniasis, vulvar diseases, vulvovirus, vulvovirus, vulvovirus, vulvovirus vulvar pain, yeast infection, vulvar dystrophy, intraepithelial vulvar neoplasia (VIN), contact dermatitis, pelvic inflammation, endometritis, salpingitis, oophoritis, genital cancer, cervical cancer, vulva cancer, vagina cancer, vaginal dryness, dyspareunia, anal and rectal disease, abscess / anal fistula, anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids, anal itching, anal itching, fecal incontinence, constipation, colon polyps and the rectum; an ophthalmic disease, such as eye redness, eye pain or sensitivity to light, blurred vision, loss of vision, visual disturbances - floaters, sparking, distortion, halos, etc., itching / burning, tearing / discharge, foreign body sensation in the eye, eyelid problems, double vision; ophthalmic allergy, blepharitis, cataracts, central serous chorioretinopathy, color vision problems, corneal abrasion, corneal edema, corneal ulcer, conjunctivitis, contact lens complications, dacryocystitis, blurred vision, dry eye, Eales disease , episcleritis, ectropion, eyelid entropion, eyelid cellulitis, tired sight, focal spasm, acute glaucoma, glaucoma, iritis, keratoconus, Lyme disease, macular degeneration, macular edema, macular hole, medication eye toxicity, severe myasthenia, cicatricial pemphigoid ocular, ophthalmic migraine, presbyopia, obstructed lacrimal duet, optic neuritis, optic nerve leak, orbital fracture, orbital cellulitis, phytotenulose, pterygium, recurrent corneal erosion, retinal artery occlusion, retinal detachment, retinal tear, vein occlusion retina, sarcoidosis, scleritis, sinus disease, strabismus (eye misalignment), subconjunctival hemorrhage, arteria temporal stroke, ocular thyroid disease, trichiasis, eyelid tumors, eyelid spasms (eyelid myokymia), uveitis, vitreous detachment and vitreous hemorrhage.
    17/96
    In one or more embodiments of the present invention, the disease is selected from the group consisting of a skin infection, acne, rosacea, an eye infection, eye rosacea, blepharitis, dry eye, trachoma and glaucoma.
    In one or more specific embodiments of the present invention, the drug carrier is formulated substantially free of elastomers. In one or more specific embodiments of the present invention, the drug carrier is formulated essentially free of elastomers. In one or more specific embodiments of the present invention, the drug carrier is formulated substantially free of silicones. In one or more specific embodiments of the present invention, the drug carrier is formulated essentially free of silicones. In one or more specific embodiments of the present invention, the drug carrier is formulated with less than approximately 30% silicone, or less than approximately 25% silicone, or less than approximately 20% silicone, or less than approximately 15% silicone. silicone, or less than approximately 10% silicone, or less than approximately 7.5% silicone, or less than approximately 5% silicone or less than approximately 2% silicone, or less than approximately 1% silicone, or less approximately 0.5% silicone.
    Detailed Description of the Invention:
    The present invention is a formulation of hydrophobic brittle tetracycline for topical administration, the formulation being (i) in the form of an oily gel that liquefies and spreads easily by applying the mild shear force, or; (ii) an oily foam, and said oily foam is stable upon the release of the aerosol container, breaks and spreads easily by applying a mild shear force.
    The formulation of the present invention is suitable for topical administration to the following areas: skin, mucous membranes, eyes, nasal cavity, ear canal and vaginal cavity.
    18/96
    A characteristic of a product for medical use is its prolonged stability. The compositions of the present invention are surprisingly stable. After studies of accelerated stability, they demonstrate desirable texture, do not break immediately after contact with a surface, spread easily over the treated area and absorb quickly.
    In one or more embodiments of the present invention, the composition has an acceptable validity of at least six months. In one or more embodiments of the present invention, the foam composition has an acceptable shelf life of at least one year. In one or more embodiments of the present invention, the foam composition has an acceptable validity of at least 15 months, or an acceptable validity of at least 18 months or an acceptable validity of at least 21 months or an acceptable validity of at least two years at room temperature.
    In one or more embodiments of the present invention, stability is, among other things, a product that includes: extensive effort and research; elimination of surfactants; elimination of water; choice of components; testing each individual component with the active agent (compatibility studies); combination of components, having an appropriate real weight (Aw) (eg <9), storage in an opaque and airtight container.
    In one or more embodiments of the present invention, the active agent is considered to be chemically stable when greater than approximately 90% of the active agent does not break after a period of two months in the formulation at room temperature. In one or more embodiments of the present invention, the period is six months. In one or more embodiments of the present invention, more than approximately 88% of the active agent does not break. In one or more embodiments of the present invention, the active agent is chemically stable in the composition at 40 ° C.
    19/96
    In one or more embodiments of the present invention, the drug carrier is formulated substantially free of short-chain alcohols, such as, for example, ethanol, propanol or butanol. In one or more embodiments of the present invention, the drug carrier is formulated essentially free of short-chain alcohols. In one or more specific embodiments of the present invention, the drug carrier is formulated essentially free of derivatives of fatty alcohols or fatty acids. In one or more specific embodiments of the present invention, the drug carrier is formulated essentially free of polyols. In one or more specific embodiments of the present invention, the drug carrier is formulated essentially free of surfactants and / or short-chain alcohols and / or polyols. In one or more specific embodiments of the present invention, the drug carrier is formulated essentially free of surfactants and / or short-chain alcohols and / or polyols. In one or more embodiments of the present invention, a composition is presented which is essentially free of water. In one or more embodiments of the present invention, a surfactant-free composition is presented, which is also free of short-chain alcohols and / or polyol. In one or more embodiments of the present invention, a substantially polymer-free composition is provided. In other embodiments of the present invention, an essentially polymer-free composition is provided. In other embodiments of the present invention, the composition is free of polymeric agent. In one or more embodiments of the present invention, a polymeric agent has a molecular weight of at least approximately 1000 Dalton.
    In one or more embodiments of the present invention, the composition is essentially free of two or more between: water, surfactant, polymeric agent, short-chain alcohol or polyol. In one or more embodiments of the present invention, the composition is essentially free of three or more of: water, polymeric agent, surfactant, short-chain alcohol or polyol. In one or more embodiments of the present invention, the composition is essentially free of four or more of: water, polymeric agent, surfactant, short-chain alcohol or polyol. In one or more embodiments of the present invention, the composition is
    20/96 essentially free of water, polymeric agent, surfactant, short-chain alcohol and polyol.
    In one or more specific embodiments of the present invention, the drug carrier is formulated substantially free of elastomers. In one or more specific embodiments of the present invention, the drug carrier is formulated essentially free of elastomers. In one or more specific embodiments of the present invention, the drug carrier is formulated substantially free of silicones. In one or more specific embodiments of the present invention, the drug carrier is formulated essentially free of silicones. In one or more specific embodiments of the present invention, the drug carrier is formulated with less than approximately 30% silicone, or less than approximately 25% silicone, or less than approximately 20% silicone, or less than approximately 15% silicone. silicone, or less than approximately 10% silicone, or less than approximately 7.5% silicone, or less than approximately 5% silicone or less than approximately 2% silicone, or less than approximately 1% silicone, or less approximately 0.5% silicone.
    Definitions:
    All percentage values are included on a weight by weight (w / w) basis.
    In one or more embodiments of the present invention, whenever an expression is used to refer to a concentration above X% or below X% it may also include X%, or above approximately X% or below approximately X% include approximately X%.
    In one or more embodiments of the present invention, the term approximately has its usual meaning in the context of pharmaceutical and cosmetic formulations, to allow reasonable variations in the amounts that can have the same effect. By the term approximately, as used in this patent, it is understood, as indicated above, that
    21/96 also a value or a variety of values can vary in modalities by up to plus or minus 30%. Therefore, in this embodiment of the present invention, if a value of approximately 1 is provided, then the amount can be up to 1.3 or 0.70. In other embodiments of the present invention, it may reflect a variation of plus or minus 20%. In still other embodiments of the present invention, it can describe a variation of plus or minus 10%. In still other embodiments of the present invention, it can describe a variation of plus or minus 5%. As will be appreciated by those skilled in the art, there is some reasonable flexibility in the formulation of the compositions, such that when one or more ingredients is / are varied, successful formulations can also be made even if an amount is slightly out of range . Therefore, to allow this possibility, the quantities are qualified by approximately. In one or more embodiments of the present invention, the numbers can be read without the prefix approximately.
    The term thixotropic, as used herein, means that the formulation shows a significant decrease in viscosity by applying shear force.
    The term free of water, as used herein, means that the composition does not contain or substantially does not, or is free from or does not incorporate or is not absorbed from water. Likewise, water-free or substantially water-free vehicles contain more incidental amounts and traces of water.
    The term single phase, as used herein, means that the liquid components of the composition or vehicle are fully miscible, and the solid components, if any, are either dissolved or suspended in the composition. By the expression "substantially a single phase" it means that the composition or the vehicle is primarily or essentially a single phase, as explained above, but it can also have a small amount of material that is capable of forming or can form a separate phase equivalent to less than approximately 5% of the composition or vehicle, preferably less than approximately 3%, and preferably less than
    22/96 approximately 1%. For the term "single phase" or "substantially a single phase", in the context of a foamable composition, the above meaning applies even after adding the propellant to the composition or vehicle.
    The term unstable active agent, as used herein, means an active agent that is oxidized and / or degraded in less than a day and, in some cases, in less than an hour after exposure to air, light, skin or water under environmental conditions.
    The term co-surfactant, as used herein, means a compound that alone is not capable of satisfactorily forming and stabilizing an oil-in-water emulsion, but when used in combination with a surfactant, such a co-surfactant can increase the power of emulsification of surfactants to create a stable emulsion. For example, fatty alcohols, such as cetyl alcohol, or a fatty acid such as, for example, stearic acid, can function as co-surfactants. Cetyl alcohol and stearyl alcohol are waxy hydrophobic substances that can be emulsified with water, using a surfactant. In certain circumstances, the co-surfactant itself can be converted into a surfactant or soap, for example, by adding a base, such as, for example, triethanolamine to a fatty acid, resulting in a fatty acid salt, which also it is called soap (a strong anionic surfactant).
    The identification of a polyol, as used herein, is an organic substance that contains at least two hydroxy groups in its molecular structure.
    Gel and foam presentations:
    The hydrophobic brittle topical therapeutic composition of the present invention can be presented as a gel or as a foam. The term “brittle”, as used herein, refers to a composition that is stable as a gel or as foam upon the release of a container, however, it breaks and spreads easily upon the application of mild shear force .
    23/96
    It has surprisingly been discovered in the present invention that certain compositions comprising a hydrophobic solvent, together with viscosity modifying agents, which can be at least one fatty alcohol and / or at least one fatty acid, and / or at least one wax and mixtures of two or more of these; and an active suspending agent; without any surface active agents, they offer, after packaging in an aerosol container and the addition of a propellant, a foam that is agitated and homogeneous, which releases a brittle foam with good to excellent quality (as defined here).
    The resulting foam is pharmaceutically equivalent to the respective gel (before the addition of the propellant), since immediately after the foam is released, the propellant evaporates and the composition after administration is similar to that of the gel. This is an important practical advantage, because many drug development activities, including costly and time-consuming toxicological studies with different animals and clinical trials with thousands of patients can be spared by conducting such studies once to present gel and foam , instead of twice (for each presentation).
    Gel:
    The essential primary components of the gel of the present invention comprise (a) at least one hydrophobic oil; (b) at least one viscosity modifying agent, and; (c) a tetracycline antibiotic. The concentration of the hydrophobic oil varies between approximately 60% and approximately 99% by weight. In one or more other embodiments of the present invention, the concentration varies between approximately 60% and approximately 95%, or between approximately 65% and approximately 99%, or between approximately 65% and approximately 95%, or between approximately 70% and approximately 95 %, or between approximately 75% and approximately 95%, or between approximately 80% and approximately 95%, or between approximately 85% and approximately 99%, or between approximately 85% and approximately 95%.
    24/96
    Surprisingly, it was found that, although the addition of viscosity modifying agents to the hydrophobic oil increased the viscosity of such an oil, even small amounts of a suspended tetracycline antibiotic synergistically increased the viscosity of the composition. The gel is stable and retains its viscosity by releasing a container, such as a tube, however, it liquefies and spreads easily through the application of the smooth shear force. In addition, although the gel is oily, it readily absorbs at the application site, such as, for example, on the skin, and after a few minutes the surface appears free of any oil or grease.
    The combination of a tetracycline with a mixture of one or more hydrophobic oils, fatty alcohols, fatty acids and waxes has a strong synergistic effect and increases the viscosity of the formulation. For example, the viscosity of a formulation containing 0.50% minocycline hydrochloride is approximately three times greater than the viscosity of the same formulation without tetracycline. The effect on the viscosity of the formulation is directly related to the concentration of tetracycline: the higher the concentration of tetracycline, the greater the viscosity of the formulation. In certain cases, the increasing viscosity effect of minocycline hydrochloride has been found to stabilize when the active ingredient is present at a concentration of approximately 0.50% or, in certain embodiments of the present invention, when the vehicle viscosity is in excess of approximately 25,000 cPs.
    Therefore, in one or more embodiments of the present invention, a gel containing at least one hydrophobic oil and one tetracycline is presented in a synergistic combination with a fatty alcohol, and / or a fatty acid and / or a wax, with the viscosity of the formulation is increased by adding the active ingredient by more than approximately 30%, or greater than approximately 50%, or greater than approximately 100%, or greater than approximately 200%, or greater than approximately 300%, or greater than approximately 500% .
    25/96
    In one or more embodiments of the present invention, the increase in the viscosity of the formulation is correlated with the concentration of the active agent.
    In one or more embodiments of the present invention, the viscosity of the formulation is directly proportional to the concentration of the active agent: the higher the concentration of the active ingredient, the greater the viscosity of the formulation.
    In one or more embodiments of the present invention, the increasing effect of the active ingredient viscosity stabilizes when the concentration of the active ingredient is increased.
    In one or more embodiments of the present invention, the viscosity of the formulation containing tetracycline is twice the viscosity of the sample formulation when the active ingredient is present at a concentration of less than approximately 10%, less than approximately 5%, less than approximately 1% , less than approximately 0.5%, less than approximately 0.1%, less than approximately 0.05%, less than approximately 0.01%.
    In one or more embodiments of the present invention, the viscosity of the gel is greater than approximately 10,000 cPs; or between approximately 1,000 cPs and approximately 100,000 cPs; or between approximately 5,000 cPs and approximately 50,000 cPs; or between approximately 10,000 cPs and approximately 30,000 cPs.
    In one or more embodiments of the present invention, the increase in viscosity of the composition is at least approximately 100% and the vehicle viscosity is less than approximately 12,000 cPs; or less than approximately 8,000 cPs; or less than approximately 2,000 cPs. In one or more embodiments of the present invention, the viscosity of the vehicle is greater than approximately 1,000 cPs; or more than approximately 1,300 cPs; or greater than approximately 1,500 cPs, or greater than approximately 1,800 cPs or greater than approximately 2,000 cPs. In one or more
    26/96 embodiments of the present invention, the vehicle viscosity is greater than approximately 150 cPs; or greater than approximately 300 cPs, or greater than approximately 500 cPs or greater than approximately 800 cPs.
    In one or more embodiments of the present invention, the change in viscosity varies between approximately 50% and approximately 100%. In one or more embodiments of the present invention, the change in viscosity varies between approximately 100% and approximately 500%. In one or more embodiments of the present invention, the change in viscosity varies between approximately 500% and approximately 1000%. In one or more embodiments of the present invention, the change in viscosity varies between approximately 1000% and approximately 1500%. In one or more embodiments of the present invention, the change in viscosity varies between approximately 1500% and approximately 2000%. In one or more embodiments of the present invention, the change in viscosity varies between approximately 2000% and approximately 2500%. In one or more embodiments of the present invention, the change in viscosity varies between approximately 50% and approximately 3000%. In one or more embodiments of the present invention, the change in viscosity varies between approximately 150% and approximately 1000%. In one or more embodiments of the present invention, the change in viscosity varies between approximately 1000% and approximately 2500% In one or more embodiments of the present invention, the change in viscosity varies between approximately 100% and approximately 2500%, between approximately 100% and approximately 2000%, between approximately 100% and approximately 1500%, or between approximately 100% and approximately 1000%.
    The gel composition has the unique property of stabilizing the tetracycline antibiotic and protecting it from degradation. For example, when a gel containing approximately 83% hydrophobic oils, approximately 4.5% waxes, approximately 6% fatty alcohols and 5% fatty acid and approximately 1% micronized minocycline hydrochloride
    27/96 was applied to the newly recovered and moist skin and stored in a Petri dish, with exposure to air and light for 6 hours, the product remained substantially stable. In addition, even when a sample of a hydrophobic gel with 1% minocycline was applied to the skin and exposed to direct sunlight for two days, there was no apparent degradation, as shown by the conservation of the skin color. As tetracycline and especially minocycline antibiotics are known to be susceptible to degradation by water, air and light, this protective effect is unique.
    In an additional observation, although minocycline has been protected against environmental factors (light, moisture and air), it is not tightly encapsulated or prevented, as demonstrated by its efficient release to the skin in an in vitro model in Franz cell assays, in an antibacterial test model and an anti-inflammation model, as exemplified hereinafter.
    Foam:
    One skilled in the art assumes that a surfactant is necessary to facilitate foam production. However, surprisingly, when the gel composition described above, comprising (a) at least one hydrophobic oil; (b) at least one viscosity modifying agent, and; (c) a tetracycline antibiotic is introduced into an aerosol can, closed with an aerosol valve and pressurized with a propellant, a brittle foam is created, that is, a foam that is stable upon the release of a container, despite to break and spread easily by applying mild shear force. As, for example, in the case of gel, the foam readily absorbs at the application site, such as, for example, on the skin, and after a few minutes the surface appears without any oil or grease.
    Sparkling propellant:
    28/96
    Examples of suitable propellants include compressed gases, volatile hydrocarbons, such as, for example, butane, isobutane propane and hydrocarbon gases, or mixtures thereof.
    In one embodiment of the present invention, the propellant is hydrophobic and miscible with oil in the composition.
    In certain embodiments of the present invention, fluorohydrocarbon propellants, with the exception of chlorofluorocarbons (CFCs) which are non-ozone-depleting propellants, are particularly useful in the production of a non-flammable foaming composition.
    Such propellants include, but are not limited to, hydrofluorocarbon (HFC) propellants, which do not contain chlorine atoms, and as such, concerns about the destruction of stratospheric ozone by chlorofluorocarbons or other dormant hydrocarbons are completely gone. Examples of non-flammable propellants in accordance with this aspect of the present invention include propellants made by DuPont under the trademark Dymel, such as, for example, 1,1,1,2 tetrafluoroethane (Dymel 134), and 1,1,1 , 2,3,3,3 heptafluoropropane (Dymel 227), 1,1, difluoro-ethane (Dymel 152) and 1,1,1,3,3,3-hexafluoropropane. Hydrofluorocarbons have an ozone depletion potential of 0.00 and therefore they are permitted for use as a propellant in aerosol products.
    In still other embodiments of the present invention, the propellant is a self-foaming propellant, that is, a volatile liquid with a boiling point below the temperature of the target treatment site (such as, for example, the skin). An example of a post-foaming propellant is isopentane (bp = 26 ° C).
    In one embodiment of the present invention, the proportion
    composition different from propellant to propellant varies in between about 100: 1 The about 100: 25, or varies in between about 100: 3 The about 100: 30, or varies in between about 100: 5 The about 100: 20 or varies in between
    29/96 approximately 100: 8 to approximately 100: 16, or varies between approximately 100: 20 and approximately 100: 50.
    In one or more embodiments of the present invention, a foam formulation can be expelled or helped to be expelled by means of a propellant, which is separated from the formulation using, for example, a valve in a bag (BOV) or can in aerosol canned system. A BOV system consists of an aerosol valve with a welded bag. With the BOV system, compressed air or other propellants are introduced into the aerosol can outside the bag and act as a propellant for the product in the bag. Through the use of such a system, it becomes possible to reduce the amount of propellant in the formulation, as well as allowing the foam to be expelled from the container with desirable qualities. Therefore, as an example, the concentration of the propellant in the bag varies between approximately 1% to 3%, or between approximately 2% to 4%; between approximately 3% to 5% (ratio of the formulation to the propellant from 100: 1 to 100: 3; from 100: 2 to 100: 4; from 100: 3 to 5; respectively).
    Foam properties:
    A foaming composition made according to one or more embodiments of the present invention is very easy to use. When applied on the surface of the afflicted body of mammals, that is, humans or animals, it is in a foamy state, which allows free application without spillage. By continuing to apply a mechanical force, such as, for example, rubbing the composition over the body surface, it spreads freely on the surface and is quickly absorbed.
    In one or more embodiments of the present invention, the foamable composition is a single phase solution. In one or more embodiments of the present invention, the foamable composition is substantially a single phase solution. In certain circumstances, where the active agent is insoluble and is presented as a homogeneous suspension, the formulation is cloudy or opaque.
    30/96
    In one or more embodiments of the present invention, the foam composition has an acceptable shelf life of at least one year, or at least two years at room temperature. A characteristic of a product for cosmetic or medical use is its prolonged stability. Propellants, which are a mixture of low molecular weight hydrocarbons, or HFCs, tend to impair stability. The foaming compositions of the present invention are surprisingly stable, even in the absence of surfactants. After accelerated stability studies, they demonstrate desirable texture, form fine bubble structures that do not break immediately after contact with a surface. They spread easily over the treated area and absorb quickly.
    The composition must also be free flowing so that it can flow through the opening of the container, such as an aerosol container, and create an acceptable foam. Compositions containing a substantial amount of semi-solid hydrophobic oils, such as, for example, white petrolatum, as the main ingredients in the oil phase of the emulsion, are likely to exhibit high viscosity and poor fluidity and may be inappropriate candidates for a foamy composition. Therefore, in one or more embodiments of the present invention, semi-solid hydrophobic oils are a secondary component in the composition, as, for example, they are present in less than approximately 25%, in less than approximately 20%, in less than approximately 15% , by less than approximately 10%, or less than approximately 5% by weight of the foaming composition. In other embodiments of the present invention, semi-solid hydrophobic oils may be present in higher amounts, due to the solvent effect of the propellant that dilutes the formulation and allows for fluidity or when the formulation is presented as a gel or ointment or when solvents are added that reduce viscosity, such as alkyl benzoates.
    Foam Quality:
    The quality of the foam can be classified as follows:
    31/96
    - Grade of Quality E (Excellent): very rich and creamy in appearance, has no bubble structure or has a very fine (small) bubble structure; it doesn't get cloudy quickly; when spread on the skin, the foam retains the creamy property and is not watery.
    - Quality Grade B (Good): rich and creamy in appearance, very small bubbles; becomes cloudy more quickly than Excellent Quality Grade foam; when spread on the skin, the foam retains the creamy property and is not watery.
    - Grade of Quality RB (Fairly Good): a moderate amount of visible creaminess; it has a visible bubble structure; when spread over the skin, it quickly becomes nebulous and becomes somewhat inferior to the apparent viscosity.
    - Grade of Quality R (Reasonable): very small visible creaminess; it has a bubble structure larger than the “Fairly Good” Quality Grade foam; when spread on the skin, its appearance becomes thin and watery.
    - Quality Grade P (Poor): no visible creaminess; has a structure of large bubbles; when spread on the skin, its appearance becomes thin and watery.
    - Quality Grade MP (Very Poor): dry foam; has a structure of large bubbles; difficult to spread on the skin.
    Foams that can be topically administered are generally excellent or good grade foams when released from an aerosol container. Smaller bubbles are indicative of a more stable foam, which does not spontaneously collapse, immediately after the container is released. The finer foam structure has a softer appearance, thus increasing its usability and attraction.
    32/96
    Foam Density:
    Another property of the foam is the specific gravity or density, as measured after the aerosol can is released. Typically, foams have a specific gravity of less than 0.5 g / ml; or less than 0.3 g / ml; or less than 0.2 g / ml; or less than 0.1 g / ml, depending on its composition and the concentration of the propellant. In one or more embodiments of the present invention, the foam density is less than approximately 0.3 g / ml.
    Ability to be subjected to agitation:
    The term "ability to be agitated" means that the composition contains sufficient or sufficient flux to allow the composition to be mixed or remixed under agitation. That is, it has fluid or semi-fluid properties. The ability to be subjected to agitation is described later in the item Tests. In one or more limited embodiments of the present invention, the formulation is poorly agitated, but it nevertheless flows well.
    Breaking capacity / collapse time:
    An additional aspect of the foam is its ability to break. The balance between the stability and the breaking capacity of the foam coming out of the container is very delicate: on the one hand, the foam should preferably not “break quickly”, that is, it should be stable after the pressurized container is released and not break due to exposure to skin temperature, and, on the other hand, it must be brittle, that is, it must spread easily, break and absorb on the skin or membrane by applying the gentle shear force. The brittle foam is thermally stable, but breaks under the shear force. The breaking capacity of the foam under the shear force is clearly advantageous over the thermally induced breaking capacity. Thermally sensitive foams can start to crumble immediately after exposure to skin temperature and therefore cannot be applied to the hand and then applied to the affected area.
    33/96
    The foam collapse time represents its tendency to be sensitive to temperature and its ability to be at least stable in the short term, so as to allow a user enough time to comfortably handle and apply the foam to a target area, without being rushed and / or concerned that the foam may quickly collapse, liquefy and / or disappear. The collapse time, as an indicator of thermal sensitivity, is examined during the distribution of a given amount of foam, sequentially photographing its appearance with time during the 36 ° C incubation. The simple collapse time can be measured by applying a foam sample to a body surface, such as fingers, at a normal body temperature of approximately 37 ° C.
    Oils can cause the foam to be thermolabile and break down quickly. However, in certain embodiments of the present invention, despite the presence of the high oil content, the foam is unexpectedly substantially thermally stable. The term substantially thermally stable means that the foam upon application to a warm skin or body surface at approximately 35-37 ° C does not collapse within 30 seconds. Therefore, in one or more embodiments of the present invention, the simple foam collapse time is greater than approximately 30 seconds or greater than approximately one minute or greater than approximately two minutes. In one or more limited embodiments of the present invention, the simple collapse time can be a little less than 30 seconds, but not less than approximately 20 seconds. In one or more additional or alternative embodiments of the present invention, the collapse time is measured by introducing a foam sample into an incubator at 36 ° C and the foam collapse time is greater than 30 seconds or greater than approximately one minute or more than approximately two minutes.
    Water activity:
    The term water activity, as used here, represents the hygroscopic nature of a substance, or the tendency of a
    34/96 substance that absorbs water from its surroundings. Microorganisms need water to grow and reproduce, and such water needs are best defined in terms of the substrate's water activity. The water activity of a solution is expressed as Aw = P / Po, where P is the vapor pressure of the water in the solution and Po is the vapor pressure of pure water at the same temperature. Each microorganism has a water activity limit (aw), below which it will not grow; for example, for Streptococci, Klebsiella spp, Escherichia coli, Clostridium perfringens and Pseudomonas spp, the value of water activity (aw) is 0.95. Staphylococcus aureus is more resistant and can proliferate with one of the water activity (aw) as low as 0.86, and fungi can survive one of the water activity (aw) of at least 0.7. In one or more embodiments of the present invention, the concentration of hydrophobic oil in the gel or foam composition is sufficient to provide a water activity value (aw) selected from the ranges of (1) approximately 0.8 and approximately 0, 9, (2) approximately 0.7 and approximately 0.8 and (3) less than approximately 0.7. When releasing the formulation from a pressurized package, moisture is not allowed to be absorbed by the preparation, and therefore, the composition's characteristic of being water-free cannot be damaged.
    Tetracycline:
    The primary active agent according to the present invention is a tetracycline compound (in this report, a tetracycline or tetracycline) or a hydrate or a pharmaceutically acceptable salt thereof substantially stabilized in a base. Tetracyclines are characterized by a carbonic skeleton composed of four linearly fused six-membered carbon rings (octahidrotetracene-2carboxamide skeleton). They are defined as a subclass of polyketides with an octahidrotetracene-2-carboxamide skeleton. They are known collectively as polycyclic derivatives of naphtacene carboxamide.
    Non-limiting examples of tetracyclines include naturally occurring tetracycline, chlortetracycline, oxytetracycline and
    35/96 demeclocycline, semi-synthetic doxycycline, limecycline, meclocycline, metacycline, minocycline, rolithetracycline, chlorotetracycline and tigecycline.
    Tetracyclines can be present in a free base form, a hydrate form, a salt form or a complex form. For example, minocycline can be present as the base form, as well as a hydrate or a hydrochloride salt.
    Notably, tetracyclines have several different hydrophilic / hydrophobic characteristics. For example, the Log Kp (logarithm of the pH 7.0 distribution constant; buffer solution / CHCh) is 1.91, which means that it is highly hydrophilic. The Log Kp for doxycycline is 0.2, and the Log Kp for minocycline is -1.6, which means the hydrophobic characteristic of this compound (see Leive L et al., “Tetracyclines of various hydrophobicities as a probe for permeability of Escherichia coli outer membrane ”, Antimicrobial Agents and Chemotherapy 1984: 25, 539-544). Although any tetracycline compound is suitable as an active agent, according to the present invention, there is a preference for tetracycline compounds that are more hydrophobic. Therefore, in an embodiment of the present invention, the active agent is selected as an agent having Log Kp equal to or less than approximately 0.2.
    In one embodiment of the present invention, the tetracycline antibiotic is hydrophobic in that it does not include any hydroxy group in Carbons 5, 6 and 7.
    In certain embodiments of the present invention, tetracycline is selected from the group consisting of doxycycline and minocycline, and in a particular embodiment of the present invention, tetracycline is minocycline.
    According to the present invention, tetracycline is employed in an amount ranging from approximately 0.001% to approximately 10%, or, in an amount ranging from approximately 0.025% to approximately 6%, or, in an amount ranging from approximately 0.1% and approximately 3%, by weight of the foaming composition.
    36/96
    Tetracycline according to the present invention is insoluble or partially soluble in the entire composition and all or part of it is suspended. It is known that each chemical compound has a different solubility in different solvents or compositions and, therefore, it is not possible to provide a general list of compounds that are not soluble or partially soluble or suspended in the composition. However, any tetracycline active agent, as exemplified herein, is suitable as insoluble or partially soluble or suspended, if a visual or microscopic observation demonstrates crystals or particles of such active agent in the oil composition.
    In other embodiments of the present invention, the concentration of tetracycline is determined by its ability to inhibit the occurrence of apoptosis in an ex vivo human skin model; or for its ability to inhibit the occurrence of pro-inflammatory cytokines in an ex-vivo human skin model. In alternative embodiments of the present invention, the concentration of tetracycline is greater than the lowest concentration that results in the intradermal administration of sufficient concentrations of tetracycline when tested in the in vitro model in Franz cell assays, using human or pig skin.
    Hydrophobic oil:
    The term hydrophobic oil refers to a material with solubility in distilled water at room temperature less than approximately 1 g per 100 ml, or less than approximately 0.5 g per 100 ml, or less than approximately 0.1 g per 100 ml . Hydrophobic oil is a liquid at room temperature, for example, at approximately 20-30 ° C.
    In an embodiment of the present invention, the topical therapeutic composition comprises at least one hydrophobic oil selected from the group consisting of a mineral oil, a hydrocarbon oil, an ester oil, a triglyceride oil, an oil of vegetable origin, an oil of animal origin, an unsaturated or polyunsaturated oil, a diglyceride, an alkyl ether of propylene glycol and a silicone oil.
    37/96
    As exemplified herein, members of each of the groups listed above of hydrophobic oils have been shown to be compatible with hydrophobic tetracyclines, such as, for example, minocycline and doxycycline.
    Non-limiting examples of hydrocarbon oils 5 include mineral oil, liquid paraffin, an isoparaffin, a polyalphaolefin, a polyolefin, polyisobutylene, a synthetic isoalkane, isohexadecane and isododecane.
    Non-limiting examples of ester oils include alkylbenzoate, alkyloctanoate, C12-C15 alkyl benzoate, C12C15 alkyl octanoate, arachidyl behenate, arachidyl propionate, benzyl laurate, benzyl myristate, benzyl palmitate, diodyl dihydrate (dihydroleate) stearoyl), butyl myristate, butyl stearate, cetearyl ethylhexanoate, cetearyl isononanoate, cetyl acetate, cetyl ethylhexanoate, cetyl lactate, cetyl myristate, cetyl octanoate, cetyl palmitate, ricinea diethylene glycol diethylhexanoate, diethylene glycol dioctanoate, diethylene glycol diisononanoate, diethylene glycol diisononanoate, diethylhexylate, diethylhexyl adipate, diethylhexyl malate, diethylhexyl succinate, diisopropyl diisopropylate, diisopropyl adipate -isoestearyl, diisostearyl fumerate, dioctyl malate, dioctyl sebacate, dod oleate ecyl, ethylhexyl palmitate, esters derived from lanolinic acid, ethylhexyl cocoate, ethylhexylate hexaneate, ethylhexyl hydroxistarate, ethylhexyl isylonylate, ethylhexyl palmitate, ethylhexyl stearate, hexadyl stearate, hexadyl stearate, hexadyl stearate , isoamyl laurate, isocetyl beenate, isocetyl lanolate, isocetyl palmitate, isocetyl stearate, isocetyl salicylate, isocetyl stearate, 25 isocetyl stearoyl stearate, isocetyl isocetyl olate, isodecane hexane isodecyl, isononyl isononanoate, isodecyl oleate, isohexyl decanoate, isononyl octanoate, isopropyl isostearate, isopropyl lanolate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, isearate stearate 30 isostearyl erucate, isostearyl glycolate, isostearyl isononanoate, isostearate isostearyl, isostearyl lactate, isostearyl linoleate, linolenate
    38/96 isostearyl, isostearyl malate, isostearyl neopentanoate, isostearyl palmitate, isostearyl salicylate, isostearyl tartrate, isotridecyl isononanoate, isotridecyl isononanoate, lauryl lactate, myristyl lactate, myristinate myristate, myristate lactate myristyl propionate, octyldodecyl myristate, neopentylglycol tipprate, octyl stearate, octyl dodecanol, octyl palmitate, octyldodecyl behenate, octyldodecyl hydroxystearate, octyldodyl hydrate, oleic stearate, oleic stearate, stearate oleyl, propyl myristate, propylene glycol myristyl ether acetate, propylene glycol tipprate, propylene glycol tipprilate, propylene glycol tipprilate, maleated soybean oil, stearyl caprate, stearyl heptanoate, stearyl propylate, tocopherol acetate, tocopherol acetate , glyceryl oleate, tridecyl ethylhexanoate, iso tridecyl nonanoate and triisocetyl citrate.
    Non-limiting examples of triglycerides and oils of plant origin include Alexandria bay oil, avocado oil, apricot oil, barley oil, borage seed oil, calendula oil, cinnamon seed oil, canola oil , caprylic / capric triglyceride castor oil, coconut oil, corn oil, cotton oil, cottonseed oil, evening primrose oil, flaxseed oil, peanut oil, hazelnut oil, glycereth triacetate, glycerol triheptanoate, glyceryl trioctanoate, glyceryl triundecanoate, hemp oil, jojoba oil, alfalfa oil, corn germ oil, oval pumpkin oil, millet oil, neopropylglycol tipprilate / olive oil, olive oil, olive oil palm oil, passionflower oil, pentaerythrityl tetrastearate, poppy oil, propylene glycol ricinoleate, rapeseed oil, rye oil, safflower oil, sesame oil, shea butter, oil soybeans, soybean oil, sweet almond oil, sunflower oil, rinchão oil, aromatic clove oil, tea tree oil, walnut oil, wheat germ glycerides and wheat germ oil.
    Non-limiting examples of alkyl ethers include PPG-2 butyl ether, PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butyl ether, PPG-14 butyl ether, PPG-15 butyl ether, PPG-15 ether
    39/96 stearyl, PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG20 butyl ether, PPG-22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether, PPG-30 butyl ether , PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether, PPG-10 cetyl ether, PPG-28 cetyl ether, PPG-30 cetyl ether, PPG-50 cetyl ether, PPG -30 isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 methyl ether, PPG-3 myristyl ether, PPG-4 myristyl ether, PPG-10 oleyl ether, PPG -20 oleyl ether, PPG-23 oleyl ether, PPG-30 oleyl ether, PPG-37 oleyl ether, PPG-40 butyl ether, PPG-50 oleyl ether and PPG-11 stearyl ether. The polypropylene glycol alkyl ethers according to the present invention include PPG-15 stearyl ether, PPG-2 butyl ether and PPG-9-13 butyl ether.
    Non-limiting examples of oils of animal origin include herring oil, cod liver oil and salmon oil.
    Non-limiting examples of silicone oils include cyclomethicone, dimethylpolysiloxane, dimethicone, epoxy-modified silicone oil, fatty acid-modified silicone oil, silicone oil modified by a fluoro group, methylphenylpolysiloxane, phenyltrimethicone and silicone oil modified by a polyether group .
    Viscosity modifying agent:
    A viscosity modifying agent, in the context of the present invention, is an agent that, when added to a hydrophobic oil, facilitates the creation of a hydrophobic brittle vehicle in the form of a brittle oily foam or a brittle oily gel. The term brittle refers to a unique property of oily gel or oily foam, and said oily gel and said oily foam are stable after the release of a container, however, they break and spread easily with the application of force smooth shear.
    The said viscosity modifying agent is selected from the group consisting of a fatty alcohol, a fatty acid and a wax,
    40/96 □ Said fatty alcohols and / or fatty acids have at least 12 carbon atoms in their carbon skeleton.
    Fatty alcohols and fatty acids:
    Preferably, the fatty alcohol and / or fatty acid and / or wax is / are solid at room temperature. In certain embodiments of the present invention, fatty alcohol and / or fatty acid and / or wax or mixture thereof have a melting point greater than approximately 40 ° C.
    In one embodiment of the present invention, fatty alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, beenyl alcohol, tetracosanol, hexacosanol, octacosanol, triacontanol, tetratriacontanol. In one embodiment of the present invention, fatty acid is selected from the group consisting of dodecanoic acid, tetradecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, eicosanoic acid, docosanoic acid, tetracosanoic acid, hexacosanoic acid, heptacosanoic acid triacontanoic, dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid and pentatriacontanoic acid.
    In certain embodiments of the present invention, the carbon chain of said fatty alcohol or said fatty acid is replaced by a hydroxyl group, and in another embodiment of the present invention, said fatty acid is 12-hydroxy stearic acid.
    Waxes:
    Waxes that can be used as part of the viscosity modifying agent include vegetable waxes, such as, for example, carnauba wax, candelilla wax, uricuri wax, sugar cane wax, rectum wax, jojoba oil; animal waxes, such as beeswax; petroleum derivative wax, such as paraffin waxes, which are mixtures of N- and saturated isoalkanes, naphthalenes and substituted aromatic alkyl- and naphthene compounds; polyethylene and related derivatives.
    41/96
    In one embodiment of the present invention, the wax is selected from the group consisting of vegetable wax, beeswax, Chinese wax, cotton wax, bayberry wax, candelilla wax, carnauba wax, castor wax, Cuban palm wax, esparto wax, fir wax, linen wax, flower wax, fat wax, japan wax, sandy wax, lanolin wax, ouricuri wax, palm waxes, rice bran wax, rice oil wax , shellac wax, soy wax, sugar cane wax, ucuuba wax, a hydrogenated oil, hydrogenated castor oil, hydrogenated cotton oil, or hydrogenated jojoba oil, mink wax, montana wax, paraffin wax natural, beeswax PEG-6, Rezo wax, barley pollen wax, stearyl dimethicone, a paraffin wax, paraffin wax at 58-62 ° C, paraffin wax at 51-53 ° C, paraffin wax at 42-44 ° C, synthetic mineral wax, Fischer-Tropsch wax, Duroxon wax, or Polymekon wax, synthetic waxes, Al wax bacer, Atlasene wax, BASF wax, Cardis wax, Ceramid wax, Glyco wax, Flex wax or oxazoline wax, as well as other waxes, as described in The Complete Technology Book on Wax and Polishes, Publisher: Asia Pacific Business Press Inc., 2006.
    Mixtures of qraxal alcohols, qraxic acids and waxes:
    It should be noted that at least one viscosity modifying agent is required, but combinations of more than one viscosity modifying agent are contemplated. In certain embodiments of the present invention, a combination of two viscosity modifying agents is preferred. In certain embodiments of the present invention, the combination of viscosity modifying agents contains at least one fatty alcohol and at least one fatty acid, or at least one fatty alcohol and at least one wax, or at least one fatty acid and at least one wax , or at least one fatty alcohol, at least one fatty acid and at least one wax.
    In one or more embodiments of the present invention, the range of fatty alcohol to fatty acid, or fatty alcohol to wax ratios is from approximately 100: 1 to approximately 1: 100, or from approximately 90: 1 to approximately 1:45, or approximately 80: 1 to
    42/96 approximately 1:40, or approximately 70: 1 to approximately 1:35, or approximately 60: 1 to approximately 1:30, or approximately 50: 1 to approximately 1:25, or approximately 40: 1 to approximately 1:20; or from approximately 30: 1 to approximately 1:15, or from approximately 20: 1 to approximately 1:10, or from approximately 15: 1 to approximately 1: 5, or from approximately 10: 1 to approximately 1: 1, or any variety of proportions between them, such as, for example, 1: 20-20: 01, or, preferably, 1:10 to 10: 1, or 1: 4 to 4: 1, or 2: 3 or 3: 2 .
    In certain embodiments of the present invention, the total concentration of viscosity modifying agents can be from approximately 0.1% to approximately 40% by weight, or approximately 0.4% to approximately 18% by weight, or approximately 1% at approximately 12% by weight.
    In certain embodiments of the present invention, the composition comprises two-class viscosity modifying agents (for example, at least one fatty alcohol and at least one fatty acid, or at least one fatty alcohol and at least one wax, or at least an acidic fat and at least one wax); and the concentration of each class, respectively, is within any of the following ranges (i) between approximately 0.1% and approximately 1%; (ii) between approximately 1% and approximately 5%; (iii) between approximately 5% and approximately 10%, or; (iv) between approximately 10% and approximately 20%.
    Other active agents:
    Since diseases that can be treated with a tetracycline are often associated with other diseases, such as inflammation and infection by other microorganisms (except bacteria), a combination of tetracycline and an additional active agent appropriate for treatment the main disease or the other disease that occurs substantially and concurrently in the same patient is useful for the simultaneous therapy of the patient's disease.
    43/96
    Suitable active agents include, but are not limited to, an active herbal extract, an acaricide, a skin stain and keratosis removing agent, an allergen, an alpha hydroxyl acid, an analgesic agent, an androgen, an anti-acne agent , an antiallergic agent, an anti-aging agent, an antibacterial agent, an antibiotic, an anti-aging agent, an anti-cancer agent, an anti-dandruff agent, an anti-depressant agent, an anti-dermatitis agent, an anti-fungal agent, an anti-fungal agent, an antihistamine , an anthelmintic agent, an anti-hyperkeratosis agent, an anti-infective agent, an anti-inflammatory agent, an anti-irritant, an antilipemic agent, an antimicrobial agent, an antimycotic agent, an antioxidant, an antiparasitic agent, an antiproliferative agent , an antipruritic agent, an antipsoriatic agent, an anti-rosacea agent, an antiseptic agent, an antiseptic agent, an anti-swelling agent, an antiviral agent, an anti-wart agent, an anti-wrinkle agent, an antileveduriform agent, an astringent agent, a beta-hydroxy acid, benzoyl peroxide, a topical cardiovascular agent, a chemotherapeutic agent, a corticosteroid, an immunogenic substance, an acid dicarboxylic, a disinfectant, an estrogen, a fungicidal agent, a hair growth regulating agent, a hapten, a hormone, a hydroxy acid, an immunosuppressive agent, an immunoregulatory agent, an immunomodulatory agent, an immunostimulating agent, an insecticidal agent, insect repellent agent, keratolytic agent, lactam, local anesthetic agent, lubricating agent, masking agent, metal, metal oxide, mutocide, neuropeptide, non-steroidal anti-inflammatory agent , an oxidizing agent, a pediculicide, a peptide, a pesticide, a protein, a photodynamic therapy agent, a progesterone, a rad pickup icals, an overfatting agent, a retinoid, a therapeutic agent, a scabicidal agent, a sedative agent, a self-tanning agent, a skin protection agent, a skin bleaching agent, a steroid, a steroid hormone, a vasoactive agent, a vasoconstrictive agent, a vasodilating agent, a vitamin, a vitamin A, a vitamin A derivative, a vitamin B, a vitamin B derivative, a vitamin C, a vitamin C derivative, a
    44/96 vitamin D, a vitamin D derivative, a vitamin D analogue, a vitamin F, a vitamin F derivative, a vitamin K, a vitamin K derivative, a healing agent and a wart-removing agent.
    Incompatible excipients and undesirable excipients:
    In certain embodiments of the present invention, the composition is free of petrolatum, surfactants, protic solvents, certain polar aprotic solvents and silicone thickening agents, and in certain embodiments of the present invention, the foaming composition is substantially free of such excipients. In the context of the present invention, the expression substantially free of refers to a composition containing a total of less than approximately 0.4% petrolatum, surfactants, protic solvents, certain polar aprotic solvents and silicone thickeners, cumulatively. Preferably, the composition comprises less than approximately 0.2% by weight of petrolatum, surfactants, protic solvents, certain polar aprotic solvents and silicone thickening agents, cumulatively, and preferably less than approximately 0.1%.
    Surfactants:
    Surfactants have been classified into different subclasses, depending on ionic characteristics, that is, nonionic, anionic, cationic, zwitterionic surfactants, amphoteric and amphiphilic surfactants. Surfactants of all types are undesirable in accordance with the present invention because (i) they have been found to cause degradation of the tetracycline antibiotic, and (ii) are generally known to have irritation potential.
    Non-limiting examples of classes of non-ionic surfactant agents considered to be undesirable according to the present invention include: (i) polyoxyethylene sorbitan esters (polysorbates), such as, for example, polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80; (ii) sorbitan esters, such as, for example, sorbitan monolaurate and sorbitan monooleate; (iii) polyoxyethylene fatty acid esters, such as, for example,
    45/96 example, PEG-8 stearate, PEG-20 stearate, PEG-40 stearate, PEG-100 stearate, PEG-150 distearate, PEG-8 laurate, PEG-10 laurate, PEG laurate -12, PEG-20 laurate, PEG-8 oleate, PEG9 oleate, PEG-10 oleate, PEG-12 oleate, PEG-15 oleate and PEG-20 oleate; (iv) fatty acid polyethylene glycol diesters; (v) polyethylene glycol (PEG) ethers of fatty alcohols; (vi) glycerol esters, such as, for example, glyceryl monostearate, glyceryl monolaurate, glyceryl monopalmitate and glyceryl monooleate; (vii) mixtures of mono- and di-esters of fatty acid-polyethylene glycol; (viii) fatty acid esters with polyethylene glycol and glycerol; (ix) fatty acid esters with propylene glycol; (x) mono- and di-glycerides; (xi) sugar esters (mono-, di- and tri-esters of sucrose with fatty acids) and; (XII) alkylphenols polyethylene glycol.
    In further embodiments of the present invention, the expression substantially free of surfactant refers to a composition in which the ratio of the viscosity modifying agent to the surfactant varies between 10: 1 or 5: 1, or between 20:01 and 10: 01 or between 100: 1 and 20: 1.
    In the context of the present invention, although fatty alcohols, fatty acids and waxes are determined to be amphipathic, these substances are not effective as stand-alone surfactants in foaming emulsion compositions, due to their very weak emulsifying capacity and also due to their own foaming capacity. weak. Therefore, fatty alcohols, fatty acids and certain waxes that constitute the viscosity modifying agent of the present invention are not undesirable.
    Protic solvents:
    Protic solvents, such as, for example, short-chain alcohols, glycols and glycerin, are incompatible with tetracyclines and are therefore undesirable.
    Polar aprotic solvents:
    46/96
    Certain aprotic polar solvents have been found to be incompatible with tetracycline antibiotics. Therefore, polar aprotic solvents, such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, acetone, methyl ethyl ketone, 1,4-dioxane and tetrahydrofuran (THF), N-methylpyrrolidone, pyridine, piperidine , dimethylformanide, Nmethyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone and azone (1-dodecylazacycloheptan-2one) are undesirable.
    Silicone thickeners:
    Silicone thickening agents comprise one or more components derived from polysiloxane. Such polysiloxanes are typically cross-linked and have rubber-like characteristics, which require their solubilization in an oil, usually in silicone oil. An example of such a silicone thickening agent is ST-Elastomer-10 (Dow Corning), which is a mixture of high molecular weight (12%) dimethicone cross polymer in cyclopentasiloxane (cyclomethicone, solvent silicone). With reference to the bioavailability of an active agent on the skin after topical application, it is conceivable that crossed polymers will create a non-permeable film that should block the penetration into the skin and, therefore, is undesirable. In addition, in the context of a brittle foam, cyclomethicone is known as a defoaming agent and therefore its presence in high concentrations in the hydrophobic brittle composition is undesirable.
    In one or more specific embodiments of the present invention, the drug carrier is formulated substantially free of elastomers. In one or more specific embodiments of the present invention, the drug carrier is formulated essentially free of elastomers. In one or more specific embodiments of the present invention, the drug carrier is formulated substantially free of silicones. In one or more specific embodiments of the present invention, the drug carrier is formulated essentially free of silicones. In one or more specific embodiments of the present invention, the drug carrier is formulated with less than approximately 30% silicone, or less than approximately 25% silicone, or less than approximately
    47/96
    20% silicone, or less than approximately 15% silicone, or less than approximately 10% silicone, or less than approximately 7.5% silicone, or less than approximately 5% silicone or less than approximately 2% silicone , or less than approximately 1% silicone, or less than approximately 0.5% silicone.
    Petrolato:
    Petrolate, also called petroleum jelly, can be disadvantageous due to its oily nature. Petrolate is known to leave a greasy and sticky feeling after application and occasionally to stain clothes. Therefore, white petrolatum and other semi-solid oils are not a preferred hydrophobic oil according to the present invention. In addition, compositions containing a substantial amount of semi-solid hydrophobic oils, such as, for example, white petrolatum, as the main ingredients in the oil phase of the emulsion, are likely to exhibit high viscosity and poor fluidity, and may be inappropriate candidates for a foamy composition. Therefore, in one or more embodiments of the present invention, semi-solid hydrophobic oils are a secondary component in the composition, for example, they are present in less than approximately 25%, less than approximately 20%, less than approximately 15%, less than approximately 10 %, or less than approximately 5% by weight of the brittle hydrophobic composition. In other embodiments of the present invention, formulations were made with more than 50% petrolatum, which produce foam of excellent quality, a collapse time of more than three minutes.
    Skin penetration:
    Surprisingly, despite the fact that said tetracyclines are hydrophobic at neutral pH (especially minocycline), they do not dissolve in hydrophobic oils, even at a concentration of 0.05%. Thus, it appears that, at any concentration greater than 0.1%, most of the tetracycline is suspended, rather than dissolved. However, although it is intuitively expected that the bioavailability of the drug on the skin after
    48/96 topical application is low, substantial amounts of tetracycline are found on the skin after application, as shown in in vitro skin penetration tests. The amounts found on the skin after an application of a brittle hydrophobic composition comprising 1% minocycline and 4% minocycline for 24 hours was 9.49 and 43.12 pg / cm 2 , respectively. The weight of the skin in the administration area is approximately 100 mg, which implies that the concentration of minocycline in the skin after 24 hours of exposure is approximately 90 pg / g of skin for the 1% formulation and approximately 430 pg / g for the 4% formulation. According to the literature, the minimum inhibitory concentration (MIC) for minocycline is less than 4 pg / ml and, therefore, it can be concluded that the concentrations found in the skin are sufficient or even higher than that needed to treat bacterial infections of the skin. skin.
    Even more surprisingly, although tetracycline penetrates the skin well, tetracycline does not permeate through the skin. This is a very important feature of the composition of the present invention, since it minimizes the likelihood of systemic side effects when topical application is carried out. In one or more embodiments of the present invention, there is no or negligible transdermal delivery. In one or more embodiments of the present invention, the ratio of intradermal to transdermal administration is approximately or more than 100: 1. This means that said hydrophobic minocycline vehicle is unique in guiding intradermal drug administration, rather than transdermal administration.
    In one embodiment of the present invention, the concentration of tetracycline in the hydrophobic brittle composition, when tested in the in vitro model in Franz cell assays, using human or pig skin, is greater than the lowest intradermal concentration of tetracycline that is required to kill bacteria on the skin, such as strains of staphylococci and streptococci.
    Therefore, in one embodiment of the present invention, the composition, when tested in the in vitro model in assays with Franz cells,
    49/96 using human or pig skin, provides an amount of tetracycline in the skin that is higher than the respective amount transferred transdermally. In certain embodiments of the present invention, when tested in the in vitro model in Franz cell assays using human or pig skin, the ratio between the amount of tetracycline in the skin and the amount transferred transdermally is greater than approximately 100, or between 100 and 10; or between 10 and 2, or greater than 1.
    Antimicrobial effect:
    In an in vitro study, it was revealed that the hydrophobic brittle composition comprising 1% minocycline and 4% minocycline inhibited the growth of streptococcus pyogenes, pseudomonas aeruginosa, staphylococcus aureus, as well as a methicillin resistant strain of staphylococcus aureus (SARM / MRSA ). The formulation was also effective against acnes propionbacterium, the microorganism that causes acne.
    This result was unexpected, since minocycline was basically suspended in the composition, thus minimizing its expected availability for the antibacterial effect.
    Anti-inflammatory and anti-apoptosis effect of the composition comprising a tetracycline:
    This effect of minocycline is surprising when treated after induction of inflammation, as the literature teaches that pre-treatment, but not post-treatment, with minocycline notably attenuated increased release of pro-inflammatory cytokines and oxidative and nitrosative stress in mononeuropathic rats (see , for example, Padi SS, Kulkarni SK, "Minocycline prevents the development of neuropathic pain, but not acute pain: possible antiinflammatory and antioxidant mechanisms", Eur J Pharmacol. 2008; 601: 79-87). In contrast, when minocycline was included in the hydrophobic brittle composition of the present invention and applied to skin samples after inducing injury by ultraviolet radiation, apoptosis significantly decreased,
    50/96 as measured by caspase 3 activity, and to increase the viability of skin cells.
    In one embodiment of the present invention, the concentration of tetracycline is determined by its ability to inhibit the occurrence of apoptosis or by its ability to decrease caspase 3 activity or by its ability to decrease the occurrence of pro-inflammatory cytokines in an ex-vivo model of human skin.
    Application Fields:
    The brittle hydrophobic tetracycline gel and foam compositions of the present invention are suitable for the treatment of any affected surface. In one or more embodiments of the present invention, the foaming vehicle is suitable for administration to the skin, a body surface, a body cavity or the mucosal surface, such as, for example, the nasal cavity and / or mucosa, mouth, eyes, respiratory system, vagina, urethra or rectum and ear canal (individually and indistinctly referred to here as the target location).
    Many diseases can be contemplated based on the antimicrobial properties of tetracyclines, in addition to the anti-inflammatory, antioxidant and neuroprotective effects of a certain tetracycline compound (such as, for example, minocycline and doxycycline).
    When selecting an appropriate tetracycline compound, or a combination of a tetracycline with at least one additional active agent, the composition of the present disclosure is useful in the treatment of an animal or a human patient suffering from any of a variety of dermatological diseases , including, but not limited to, the following list: abscess, acne, acne conglobata, acne fulminans, acne vulgaris, acne scars, acute febrile neutrophilic dermatosis, acute lymphangitis, allergic contact dermatitis, alopecia, athlete's foot, atopic dermatitis, bacterial skin infections, baldness, basal cell carcinoma, blisters, bromhidrosis, bullous pemphigoid, burns, calluses, candidiasis, carbuncles, cellulite, chemical burns, chicken pox, cholesteatoma,
    51/96 cholinergic urticaria, chronic effects of sunlight, herpes, cold-induced urticaria, pustules, grains, cutaneous larva migrans, cutaneous abscess, cutaneous larva migrans, cutaneous myiasis, dark spots, parasitic infestation delirium, Dercum disease, dermatitis , herpetiform dermatitis, dermatological pain, dermatological inflammation, dermographism, dermatophytosis, rashes and drug reactions, dyshidrotic eczema, ectodermal dysplasia, eczema, eczema, epidermoid cyst, epidermal necrolysis, erysipelas, erythrasma, exfoliative dermatitis, erythema erythema, multiforme , fungal nasal infections, fungal skin infections, boils, gangrene, genital herpes, annular granuloma, lice, suppurative hidradenitis, hives, folliculitis, hirsutism, hyperhidrosis, hypohidrosis, ichthyosis, impetigo, inflammatory acne, ingrown nails, intertrigo, dermatitis irritation, ischemic necrosis, itching, fungal infection in the groin a (Jock's itch), Kaposi's sarcoma, keratosis pilaris, chronic lichen simplex, lichen planus, lichen sclerosus, lymphadenitis, lymphangitis, malignant melanoma, mastocytosis, measles, melanoma, miliaria, signs, molluscum contagiosum, Staphylococcus aureus or methicilline resistant SARM / MRSA, necrotizing subcutaneous infection, necrotizing fasciitis, necrotizing myositis, nodular papulopustular acne, non-inflammatory acne, nummular dermatitis, oral herpes, panniculitis, paronychia, parapsoriasis, parasitic skin infections, pemphigus, photoalergy, photosynthesis, photoirritation, photosirritation, photosirritation, photoirritation , pediculosis, perioral dermatitis, pimples, pityriasis rosea, pityriasis rosea, pityriasis rosea, pityriasis rubra pilaris, poison ivy, post-operative or post-surgical skin diseases, pressure ulcers, pressure urticaria, pruritus, pseudofolliculitis of the beard, psoriasis of the beard, psoriasis and pruritic urticarial plaques of pregnancy (PUPP), purple, pustules, granulom pyogenic, skin rashes, ringworm, rosacea, roseola, rubella, scabies, scalded skin syndrome, scarring, scleroderma, sebaceous cyst, seborrheic dermatitis, seborrheic keratosis, herpes zoster, skin aging, skin cancer, skin cancer, neoplasms skin rash, skin ulcers, squamous cell carcinoma, staphylococcal scalded skin syndrome, stasis dermatitis, Stevens-Johnson syndrome, burns, sun spots, thermal burns, tinea corporis, tinea cruris, tinea pedis, tinea versicolor, toxic epidermal necrolysis,
    52/96 trauma or injury to the skin, varicella-zoster virus, vitamin D deficiency, viral skin infections, vitiligo, warts, aquagenic urticaria, wrinkles, xerosis, herpes zoster and yeast skin infections.
    Likewise, the gel or foam composition of the present invention is suitable for the treatment of a disease of a body cavity or mucosal surface, such as, for example, the surface and / or mucosa of the nose, mouth, eyes, ears, respiratory system, vagina, urethra or rectum. Non-limiting examples of such diseases include chlamydia infection, gonorrhea, hepatitis B, herpes, HIV / AIDS, human papilloma virus (HPV), genital warts, bacterial vaginosis, candidiasis, soft cancer, inguinal granuloma, venereal lymphogranuloma, mucopurulent cervicitis (MPC ), molluscum contagiosum, non-gonococcal urethritis (UNG), trichomoniasis, vulvar diseases, vulvodynia, vulvar pain, fungal infection, vulvar dystrophy, intraepithelial vulvar neoplasia (VIN), contact dermatitis, pelvic inflammation, endometritis, salpingitis, oophoritis , genital cancer, cervical cancer, vulvar cancer, vagina cancer, vaginal dryness, dyspareunia, anal and rectal disease, anal abscess / fistula, anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids, anal itching , anal itching, fecal incontinence, constipation, colon and rectal polyps.
    In one or more embodiments of the present invention, the brittle hydrophobic gel is specifically useful for ophthalmic administration. Unlike the usual ophthalmic ointments, which create a greasy film over the eye and blur the vision, the gel liquefies at the first blink of an eye and spreads over the surface of the eye.
    Ophthalmic diseases that can be contemplated based on the antimicrobial properties of tetracyclines, in addition to the anti-inflammatory, antioxidant and neuroprotective effects of a certain tetracycline compound (such as, for example, minocycline and doxycycline) can be categorized in a non-limiting way by symptoms, as follows: eye redness, eye pain or sensitivity to light, blurred vision, loss of vision, visual disturbances - floaters, sparking, distortion, halos, etc.,
    53/96 itching / burning, watering / discharge, foreign body sensation in the eye, eyelid problems, double vision.
    Examples of relevant diseases include macular degeneration, age-related macular degeneration, dry macular degeneration and wet macular degeneration, which are associated with photodamage and apoptosis, cataracts, which are associated with apoptosis, glaucoma, open-angle glaucoma, closed-angle glaucoma (associated with optic nerve death and apoptosis), retinopathy, proliferative diabetic retinopathy (apoptosis), macular edema (inflammation), uveitis, conjunctivitis and trachoma (infection).
    Non-limiting examples of ophthalmic diseases that can be treated by a tetracycline-brittle hydrophobic composition of the present invention or such diseases whose complications can be treated by said composition are included in the following list: ophthalmic allergy, blepharitis, cataract, serous central chorioretinopathy, problems color vision, corneal abrasion, corneal edema, corneal ulcer, conjunctivitis, contact lens complications, dacryocystitis, distant blurred vision, dry eye, Eales disease, episcleritis, ectropion, eyelid entropion, eyelid cellulitis, view tired, focal spasm, acute glaucoma, glaucoma, iritis, keratoconus, lyme disease, macular degeneration, macular edema, macular hole, medication eye toxicity, myasthenia gravis, ocular scar pemphigoid, ophthalmic migraine, presbyopia, obstructed tear duct, optic neuritis , effusion in the optic nerve, orbital fracture, cellulitis or bariatric, flictenulose, pterygium, recurrent corneal erosion, retinal artery occlusion, retinal detachment, retinal tear, retinal vein occlusion, sarcoidosis, scleritis, sinus disease, strabismus (ocular misalignment), subconjunctival hemorrhage, temporal arteritis, disease ocular thyroid, trichiasis, eyelid tumors, eyelid spasms (eyelid myokymia), uveitis, vitreous detachment and vitreous hemorrhage.
    Due to the hygroscopic nature of the composition, it is also suitable for the treatment and prevention of post-surgical adhesions. Adhesions are scars that form abnormal connections between the
    54/96 tissue surfaces. The formation of post-surgical adhesions is a natural consequence of the surgery, which results when the tissue itself recovers after incision, cauterization, suture or other means of trauma. When it comprises appropriate protective agents, the foam is suitable for the treatment or prevention of post-surgical adhesions. The use of foam is particularly advantageous because the foam can expand in the body cavity and penetrate hidden areas that cannot be reached by any other alternative means of administration.
    In one or more embodiments of the present invention, a composition is presented for use in preventing or improving or treating photodamage, radiation damage or photoaging or in reducing oxidative stress or inflammation in skin pathologies, which are known to be accompanied by by cell death from apoptosis or any two or more of these.
    In one or more embodiments of the present invention, a composition is presented for use in preventing or ameliorating or treating a disease, said tetracycline composition having at least one property or activity selected from a list, including: regenerative property, anti-apoptotic property, anti-inflammatory property, photodamage property, radiation anti-damage property and anti-photoaging property.
    In one or more embodiments of the present invention, a composition is presented that comprises a tetracycline for use in preventing or improving protection or treatment of skin lesions induced by ultraviolet radiation.
    In one or more embodiments of the present invention, a composition is presented that comprises a tetracycline for use in preventing, protecting, ameliorating or treating a disease with symptoms including increased apoptosis and / or decreased cell viability, the formulation being effective to decrease apoptosis and or increase viability
    55/96 cell. In one or more embodiments of the present invention, a composition is presented for use in reducing apoptosis and / or increasing cell viability.
    In one or more embodiments of the present invention, a composition is presented which comprises a tetracycline for use in preventing, protecting, ameliorating or treating diseases, by reducing oxidative stress and inflammation in skin pathologies that are known to accompanied by cell death from apoptosis, including rosacea and impetigo.
    In one or more embodiments of the present invention, a tetracycline composition with regenerative, or anti-apoptotic, or anti-inflammatory or anti-radiation damage, or anti-photo-aging, or protective and / or therapeutic properties in the case of induced skin lesions is provided. by ultraviolet radiation, or that decreases apoptosis and / or increases cell viability, or reduces oxidative stress and inflammation in skin conditions accompanied by cell death from apoptosis, including rosacea and impetigo, or antibacterial activity, or any two or more of these.
    Cosmetic use:
    In one or more embodiments of the present invention, the composition can be used for cosmetic use. For example, it can be used as part of a cosmetic formulation to prevent disease or to improve skin aesthetics.
    Administration:
    The compositions described herein can be applied to the target site as a gel or as a foam. The application can be hourly, every two hours, every three hours, every four hours, every six hours or every eight hours, every twelve hours, daily, on alternate days or intermittently, depending on required. For compliance reasons,
    56/96 less frequent applications, where possible, are preferable, such as twice daily applications or individual daily applications. In cases where prolonged or long-term treatment is required, a higher initial dose is provided followed by a gradual reduction to a lower maintenance dose, which can be increased if new outbreaks occur.
    EXAMPLES
    The present invention is described with reference to the examples below, in a non-limiting way. The following examples 10 exemplify the foaming compositions and methods described herein. The examples are included by way of illustration only and are not intended to limit the present invention. Many variations will be suggested and these will be within the intended scope.
    Materials
    Examples of possible ingredients suitable for the production of foaming compositions presented herein. Equivalent materials from other manufacturers can also be used satisfactorily.
    Chemical name Occupation Commercial name Provider White beeswax Foam additive Beeswax white Henry Lamotte Behenyl alcohol Foam additive Lanette 22 Cognis Cetostearyl alcohol Foam additive Speziol C16-C18 Cognis Cetyl alcohol Foam additive Speziol C16 Cognis Coconut oil Solvent Coconut oil Henry Lamotte Cyclomethicone-5 Solvent ST-cyclometh icon-5 Dow Heavy mineral oil Solvent Paraffin oil liquid heavy Gadot Hydrogenated castor oil Foam additive Cutina HR Cognis
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    Isostearic acid Foam additive Isostearic acid Stearinerie Dubois Lanolin Foam additive Lanolin Spectrum Light mineral oil Solvent Pioner 2076P Hansen & Rosenthal Medium chain triglyceride oil (MCT) Solvent Captex 355 Abitec Minocycline hydrochloride Active agent Minocycline HCI Hovione Myristyl alcohol Foam additive Speziol C14 Cognis Octyldodecanol Solvent Eutanol G Cognis Paraffin wax 51-53 Wax Paraffin 51-53 Merck PPG-15 stearyl ether Solvent Arlamol E Uniqema Propane / lsobutane / Butane(20: 78: 2) Propellant A-46 Aeropres Propane / lsobutane / Butane (55:18:27) Propellant AP-70 Aeropres Silicon dioxide Dispersant Aerosil R 972 PH Evonik-GoldschmidtGmbH Soy oil Solvent Soybean oil Spectrum Stearic acid Foam additive Edenol ST1M Cognis Stearyl alcohol Foam additive Speziol C18 Cognis
    PART A * Gel formulations Example 1 - general gel manufacturing processes
    The following procedures are used in the production of gel samples described in the examples below, in which only the relevant steps for each formulation are performed, depending on the type and nature of the ingredients used.
    Step 1: the hydrophobic oil is heated to 60-70 ° C.
    Step 2: fatty alcohols, if present, fatty acids, if present, wax, if present, are added to the hydrophobic oil and the formulation is mixed until complete melting.
    Step 3: the formulation is cooled to 30-4CTC, the tetracycline antibiotic is added and the formulation is mixed until homogeneity is obtained.
    Step 4: the formulation is cooled to room temperature with agitation and packed in appropriate containers.
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    As a non-limitative example, the tests are briefly defined below, as would be appreciated by a person skilled in the art.
    Viscosity is measured with Brookfield LVOV - II + PRO with SC4-25 rod at room temperature and 20, 10, 5 and 1 RPM. Viscosity is generally measured at 10RPM. However, at the apparent upper limit for the rod of approximately 50,000 CP, viscosity at 1RPM can be measured, although the numbers are of a greater magnitude.
    Chemical stability: the amount of the tetracycline antibiotic is analyzed chromatographically. The analysis is carried out after preparing the formulation at appropriate time intervals. Samples are usually stored in temperature-controlled incubators at one or more temperatures between 5 ° C, 25 ° C and 40 ° C for several weeks or months. At appropriate time intervals, samples are removed from the incubators and the concentration of the active agent is measured.
    Example 2 * Low viscosity gel formulations
    The different hydrophobic oils suitable for use in topical pharmaceutical compositions are generally liquid oils with a low viscosity. When these oils are used as they are for topical administration of active agents, they have, among other things, two undesirable properties: (1) due to their low viscosity, they tend to collapse and run and are therefore not easy to the patient apply on the skin; (2) they have poor suspension properties, which lead to rapid sedimentation of undissolved active ingredients (APIs), as described in Table 2.
    Table 2 - Low viscosity oil preparations
    Formulations 001P 001 002P 002 Ingredients %(weight / weight) %(weight / weight) %(weight / weight) %(weight / weight) Heavy mineral oil 75.00 75.00 - - Light mineral oil 25.00 25.00 - - Soy oil - - 100 100 Total 100.00 100.00 100.00 100.00 Hydrochloride - 0.1 - 0.1
    Minocycline Results
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    Viscosity 96 92 47 49 at 10rpm (cP)
    As shown in formulations 001P and 002P, mixtures of mineral oils and soy oil have a low viscosity. Formulations 001 and 002 show that, after the addition of minocycline hydrochloride, the viscosity of the formulation remains unchanged and the active ingredient settles.
    Example 3 - Mineral oil based formulations with improved viscosity
    The influence of the combination of a tetracycline with fatty alcohols, fatty acids and waxes on the viscosity of the formulation was evaluated, as described in Table 3a. Formulations containing a mixture of mineral oils with fatty alcohols, fatty acids or waxes were prepared and their viscosity was measured before and after the addition of a tetracycline, especially minocycline hydrochloride. Table 3a below shows the viscosity results of the formulation before and after the addition of a tetracycline, as well as the percentage increase in viscosity due to the addition of the active ingredient.
    Table 3a - Combination of a tetracycline with fatty alcohols, fatty acids and waxes
    Formulations 003 004 005 005B Ingredients %(weight / weight) %(weight / weight) % (weight / weight) %(weight / weight) Heavy mineral oil 65 65 65 65 Light mineral oil 25 25 25 25 Stearyl alcohol 10 - - - Stearic acid - 10 - - Beeswax - 10 - - Hydrogenated castor oil - - - 5 Total 100.00 100.00 100.00 100.00
    Results
    Viscosity results at 10 RPM (cP)
    Without minocycline hydrochloride 951 1858 942 848 With 0.1% minocycline hydrochloride 2652 8142 1695 6223 Viscosity Increase (%) + 179% + 338% + 80% + 634%
    Very surprisingly, it was discovered that the addition of minocycline hydrochloride to mineral oil-based formulations 003 to 005B led to a very substantial increase in viscosity, despite the amount
    60/96 very low minocycline hydrochloride used, basically at 0.1%. These totally unexpected results show that the combination of a tetracycline, even at very low concentrations, with fatty alcohols, fatty acids or waxes has a strong synergistic effect on the viscosity of the oil formulation.
    The influence of adding different concentrations of a tetracycline to a formulation based on mineral oils was then studied, when the active ingredient is combined with a mixture of mineral oils, fatty alcohols, fatty acids and waxes, as described in Tables 3b and 3c .
    10 Table 3b - Oilseed preparations Formulations 238PIngredients % (weight / weight)Heavy mineral oil 59.25 15 Light mineral oil 25.00Cyclomethicone 5.00Stearyl alcohol 1.50Beeswax 2.00Stearic acid 2.00 20 Hydrogenated castor oil 1.50Beenyl alcohol 1.00Cetostearyl alcohol 2.50Silicon dioxide 0.25Total 100.00 25 Minocycline hydrochloride -Results Viscosity results at 10 RPM (cP) 6639% Increase in viscosity -
    30 Formulations Table 3c - Oil preparations 238p 238A 238B 238C 238DIngredients % % % % % (weight / weight) (weight / weight) (weight / weight) (weight / weight) (weight / weight)Formulation 238p 100.00 99.90 99.80 99.50 99.00 35 Minocycline hydrochloride - 0.10 0.20 0.50 1.00Results Viscosity results at 10 RPM (cP)6639 15789 18476 20876 20748 40 Viscosity Increase (%) - + 138% + 178% + 214% + 213%
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    The combination of a tetracycline with a mixture of mineral oils, fatty alcohols, fatty acids and waxes has a strong synergistic effect and increases the viscosity of the formulation. The viscosity of a formulation containing 0.50% minocycline hydrochloride is approximately three times greater than the viscosity of the placebo formulation. The effect on the formulation viscosity is directly related to the concentration of tetracycline: the higher the concentration of tetracycline, the greater the viscosity of the formulation. In formulation 238, it appears that the increasing viscosity effect of minocycline hydrochloride stabilizes when the active ingredient is present at a concentration of approximately 0.50%.
    In one or more embodiments of the present invention, an oleaginous formulation containing mineral oils and a tetracycline is presented in synergistic combination with a fatty alcohol and / or a fatty acid and / or a wax, the viscosity of the formulation being increased by adding of the active ingredient by more than approximately 50%, by more than approximately 100%, by more than approximately 200%, by more than approximately 300%, by more than approximately 500%.
    In one or more embodiments of the present invention, an oleaginous formulation containing hydrophobic oils, an active ingredient in synergistic combination with a solidifying agent, is presented, with the formulation viscosity being increased by adding the active ingredient by more than approximately 50% , more than approximately 100%, more than approximately 200%, more than approximately 300%, more than approximately 500%.
    In one or more embodiments of the present invention, the increase in the viscosity of the formulation is related to the concentration of the active agent.
    In one or more embodiments of the present invention, the viscosity of the formulation is directly proportional to the concentration of the active agent: the higher the concentration of the active ingredient, the greater the viscosity of the formulation.
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    In one or more embodiments of the present invention, the effect of increasing viscosity of the active ingredient stabilizes when the concentration of the active ingredient is increased.
    In one or more embodiments of the present invention, the viscosity of the formulation containing the active ingredient is twice the viscosity of the sample formulation when the active ingredient is present at a concentration of less than approximately 10%, less than approximately 5%, less than approximately 1%, less than approximately 0.5%, less than approximately 0.1%, less than approximately 0.05%, less than approximately 0.01%.
    Example 4 - Formulations based on vegetable oils with improved viscosity
    The formulation with different vegetable oils, such as, for example, soybean oil and coconut oil, was prepared as described in Table 4a, to study the influence of the combination of a tetracycline with a fatty alcohol on the viscosity of the formulation.
    Table 4 · Formulation based on vegetable oils
    Formulations 006 007 Ingredients % %(weight / weight) (weight / weight) Soy oil 90 - Coconut oil - 90 Stearyl alcohol 10 10 Total 100.00 100.00 Minocycline hydrochloride - 1.15
    Results
    Viscosity results at 10 RPM (cP)
    Without minocycline hydrochloride 2771 24571 With 0.1% minocycline hydrochloride 1826 22459 Viscosity increase (%) -34% -9% In contrast with the phenomenon observed with the
    In mineral oil based formulations, no increase in viscosity was observed with the vegetable oil based formulation when a tetracycline is combined with a fatty alcohol.
    The influence of the addition of a tetracycline in formulations based on vegetable oils was then studied when the active ingredient is
    63/96 combined with a mixture of vegetable oils, fatty alcohols, fatty acids and waxes, as described in Table 4b.
    Table 4b - Formulation based on vegetable oils with improved viscosity
    5 Formulations 244p 244B 244AIngredients %(weight / weight) % (weight / weight) %(weight / weight)Soy oil 50.00 50.00 50.00 10 Coconut oil 23.60 23.60 23.60Light mineral oil 5.55 4.40 0.95Cyclomethicone 5.00 5.00 5.00Cetostearyl alcohol 3.50 3.50 3.50Stearic acid 3.00 3.00 3.00 15 Myristyl alcohol 2.50 2.50 2.50Hydrogenated castor oil 2.00 2.00 2.00Beeswax 2.00 2.00 2.00Stearyl alcohol 1.50 1.50 1.50Beenyl alcohol 1.10 1.10 1.10 20 Silicon dioxide 0.25 0.25 0.25Total 100.00 100.00 100.00Minocycline hydrochloride - 1.15 4.60Results 25 Viscosity results at 10 RPM (cP) 7214 14429 17084Viscosity Increase (%) - 100% 137%
    As shown in Table 4b, unexpectedly, the combination of a tetracycline with a mixture of hydrophobic oils, fatty alcohols, fatty acids and waxes has a strong thickened synergistic effect and increases the viscosity of the formulation. The viscosity of a formulation containing 1.15% minocycline hydrochloride was approximately twice as high as the viscosity of the placebo formulation. In addition, the effect on the viscosity of the formulation was directly related to the concentration of tetracycline: the higher the concentration of tetracycline, the greater the viscosity of the formulation.
    Therefore, in one or more embodiments of the present invention, an oleaginous formulation containing vegetable oils and a tetracycline is presented in synergistic combination with a fatty alcohol, a fatty acid and a wax, the viscosity of the formulation being increased through the
    64/96 addition of the active ingredient by more than approximately 50%, by more than approximately 100%, by more than approximately 200%, by more than approximately 300%, by more than approximately 500%.
    In another experiment, a gel sample of formulation 244B was stored for six months at 40 ° C and tested for uniformity of minocycline content. It was found that the minocycline was homogeneously dispersed in the formulation and remained so even after prolonged incubation at 40 ° C. In addition, the minocycline assay in the formulation did not change after six months of storage at 40 ° C. Therefore, in one or more embodiments of the present invention, a hydrophobic gel formulation is presented in which tetracycline is homogeneously dispersed in the gel and remains homogeneously dispersed and stable after six months of incubation at 40 ° C.
    PART B - Foam formulations Example 5 - General foam manufacturing procedures
    The following procedures are used to produce the foam samples described in the examples below, in which only the steps relevant to each formulation are performed, depending on the type and nature of the ingredients used.
    Step 1: hydrophobic oils, such as mineral oils, are mixed at room temperature. Other solvents, for example, silicones, if present, are added at room temperature with stirring until the homogeneity of the formulation is obtained.
    Step 2: The formulation is heated to 70-80 ° C and solid compounds, such as, for example, fatty alcohols, fatty acids and waxes, are added and mixed until complete dissolution.
    Step 3: The formulation is cooled to 30-40 ° C and the active agents are added under stirring until the homogeneity of the formulation is obtained.
    Step 4: The formulation is packed in aerosol cans that are closed with a valve, pressurized with the propellant and equipped with an appropriate actuator for foam distribution. Optionally, a
    65/96 metered metering unit can be used to deliver precise, desired and / or repeated doses of foam.
    Step 5: Pressurization is performed using a hydrocarbon gas or mixture of gases. The cans are filled and then heated for 30 seconds in a hot bath at 50 ° C and shaken well afterwards.
    Tests:
    As non-limiting examples, certain tests to characterize the foam and its stability are briefly described below.
    Collapse time:
    The collapse time, which is the measure of thermal stability, is examined by distributing a given amount of foam and sequentially photographing its appearance over time during the 36 ° C incubation. The result of the collapse time is defined as the moment when the foam height reaches 50% of its initial height or if the foam has not yet reached 50% of its initial height after 180 seconds, then the collapse time is recorded as being> 180. As an illustration, a foam can remain at 100% of its initial height for three minutes, a second foam can reach 90% of its initial height after three minutes, a third foam can reach 70% of its initial height after three minutes minutes and a fourth foam can reach 51% of its initial height after three minutes, however, in each of these four cases, the collapse time is recorded as> 180 seconds, since for practical purposes for easy application by a patient to a target, most of the foam remains intact for more than 180 seconds. If the foam, for example, reaches 50% of its original height after 100 seconds, it would be recorded as having a collapse time of 100 seconds. This is useful for evaluating foam products, which maintain structural stability at skin temperature for at least 1 minute. Foams that are structurally stable on the skin for at least one minute are called "stable in the short term" vehicles or foams.
    Density:
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    The foam product is distributed in pre-weighed tubes of known volume and weight. Duplicate measurements of the foam filling mass of the tube are made and the density is calculated.
    Viscosity:
    Viscosity is measured with a Brookfield LVDV-II + PRO viscometer with SC4-25 rod at room temperature and at 10, 5 and 1 RPM. Viscosity is generally measured at 10RPM. However, at approximately the upper apparent limit for the ~> 50,000 cP rod, viscosity at 1RPM can be measured, although the numbers are of a greater magnitude. Unless otherwise indicated, the viscosity of the pre-foam formulation (FPF) is provided. It is not practical to try and measure the viscosity of the foamable formulation with regular propellants, as these have to be stored in sealed pressurized containers or bottles. To simulate viscosity in foaming formulations with propellant, an equivalent weight of pentane (a low volatile hydrocarbon) is added and mixed with the pre-foam formulation (PFF) and left overnight. The viscosity is then measured as described above.
    Chemical stability:
    The amount of active agent present is analyzed chromatographically in foam released from several pressurized cylinders. The analysis is carried out at the beginning and then at appropriate time intervals. Cans are usually stored in temperature-controlled incubators at one or more of the following temperatures: 5 ° C, 25 ° C and 40 ° C. At the appropriate time intervals, the cans are removed and the amount of active agent in the foam sample is measured.
    Bubble size:
    Foams are made of bubbles of gas trapped in the liquid. The size of the bubble and the distribution reflect on the visual texture and softness of the foam. The size of the foam bubbles is determined by the distribution of a foam sample on a glass slide, a photograph of the foam surface is taken with a digital camera equipped with a macro lens. The diameter of approximately 30 bubbles is measured relative to the model of
    67/96 standard calibration. Statistical parameters, for example, mean bubble diameter, standard deviation and quartiles are then determined. The diameter measurement can also be performed with image analysis software. The camera used was a Nikon D40X Camera (10MP Resolution) equipped with Sigma Macro Lens (ref: APO MACRO 150 mm F2.8 EX DG HSM). The images obtained are cropped to maintain a square region of 400 pixels x 400 pixels.
    Microscopic observation:
    The light microscope allows you to observe and measure particles from a few millimeters to a micron. The light microscope is limited by the wavelength of visible light and is therefore useful for measuring particle sizes above 800 nanometers and from about 1 micron (1,000 nanometers).
    Ability to be subjected to agitation:
    The ability to be subjected to agitation represents the degree to which the user is able to feel / hear the presence of liquid contents when the pressurized filled can is stirred. Shaking is done with normal light force, without vigorous shaking or excessive force. When the user cannot feel the movement of the content during shaking, the product can be considered as non-shaking. This property can be of particular importance in cases where agitation is necessary to obtain the appropriate dispersion of the contents.
    Shaking capacity score table
    Good ability to be agitated (according to required quality specifications) 2 Moderate capacity to be subjected to agitation (according to the required quality specifications) 1 Non-agitable (does not meet the required quality specification), but it can still be drained and allows the formation of quality foam 0 It is substantially unable to pass through the valve Block
    Centrifugation:
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    The centrifugation used in this procedure serves as a stress condition that simulates the aging of the liquid formulation under investigation. Under these conditions, the applied centrifugal force facilitates the coalescence of the dispersed globules or the sedimentation of the dispersed solids, resulting in loss of the desired properties of the formulation.
    Centrifugation can also be performed at a higher rotation (RMP) for a shorter period or a lower rotation (RMP) for a longer period, considering that the G force experienced by the formulations is many times greater than a G to which a formulation would be exposed during its useful life. Centrifugation can also be performed at a higher rotation (RMP) during the same period, such as, for example, 3,000 or 10,000 RPM, to simulate an extremely high level of force.
    Example 6 - hydrophobic surfactant-free foam formulations
    Surfactants are known to be useful foaming agents, and therefore it is not right to produce good quality foams without surfactants. As shown in Table 6 below, formulations 001f and 002F containing a mixture of heavy mineral oil and light mineral oil, with or without cyclomethicone, cannot produce foams and release only liquids from the pressurized containers. Other compounds other than the usual surfactants have been identified below, which are suitable for foaming oleaginous vehicles.
    Table 6 - Oil compositions
    Formulations 001F 002F Ingredients % (weight / weight) % (weight / weight) Heavy mineral oil 75.00 70.00 Light mineral oil 25.00 25.00 Cyclomethicone - 5.00 Total 100.00 100.00 Propellant A46 12.00 12.00 Results Foam Quality Poor Poor
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    Silicone oils, such as cyclomethicone, are included in the formulations, mainly as a cosmetic agent, due to their contribution to the skin's sensation properties. Volatile cyclomethicone can help reduce the feeling of greasy skin that may be present in oil formulations.
    Example 7 - Surfactant-free foams containing fatty acid or fatty alcohol
    Two fatty acids were used in combination with heavy mineral oil, light mineral oil and cyclomethicone, and tested for their foaming properties. As described in Table 7a below, formulation 003F containing isostearic acid (a liquid fatty acid) did not give rise to the foam, but simply generated foaming liquids. Formulation 004F containing stearic acid (a solid fatty acid) initially produced a foam of reasonably good quality but was not stable and collapsed after 10 seconds. Likewise, compositions containing fatty alcohols produced foams of reasonably good quality that quickly collapsed (Table 7b). Therefore, only fatty acids or just fatty alcohols are not sufficient to stabilize a hydrophobic foam in the absence of a surfactant, even at reasonably high concentrations.
    Table 7a - Compositions containing a fatty acid
    Formulations 003F 004F Ingredients % (weight / weight) % (weight / weight) Heavy mineral oil 60.00 60.00 Light mineral oil 25.00 25.00 Cyclomethicone 5.00 5.00 Stearic acid (C18) - 10.00 Total 100.00 100.00 Propellant A46 12.00 12.00 Results Foam Quality Reasonable Fairly Good Collapse time (sec) 10 10 Foam density (/ ml) - 0.071
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    Viscosity of the pre-foam formulation (CP)
    1442
    Table 7b - Compositions containing fatty alcohols
    Formulations 005 006 007 009 Ingredients % (weight / weight) % (weight / weight) % (weight / weight) % (weight / weight) Heavy mineral oil 60.00 60.00 60.00 60.00 Light mineral oil 25.00 25.00 25.00 25.00 Cyclomethicone 5.00 5.00 5.00 5.00 Myristyl alcohol (C14) 10.00 - - - Cetyl alcohol (C16) - 10.00 - - Stearyl alcohol (C18) - - 10.00 - Beenyl alcohol (C22) - - - 10.00 Total 100.00 100.00 100.00 100.00 Propellant A46 12.00 12.00 12.00 12.00Results Foam Quality Reasonable Reasonable Reasonable Reasonable and Good Collapse time (sec) 10 10 10 10 Foam density (/ ml) - - - 0.160 Viscosity of the pre-foam formulation (cP) 206 938 585 3839
    Example 8 - Surfactant-free hydrophobic foam formulations 5 containing a combination of fatty acids and fatty alcohols
    Formulations containing a combination of fatty acids and fatty alcohols were prepared and checked for their foaming properties. As described in Table 8 below, formulation 010 (containing stearic acid and myristyl alcohol) and formulation 017 (containing isostearic acid and stearyl alcohol) did not produce quality foams, but simply generated foaming liquids.
    However, surprisingly, the combination of stearic acid with cetyl alcohol, stearyl alcohol, ceto-stearyl alcohol or beenyl alcohol (without any surfactants) produced good quality foams with a fine bubble structure, as shown in formulations 011, 012, 013 and 014. Such foams can be successfully produced, in the presence or absence of silicone oils, as shown in formulations 011 and 016, despite the silicone's defoaming effect. In addition, formulations 012 and 014 containing a combination of stearic acid
    71/96 with stearyl alcohol or beyl alcohol gave rise to stable foams that did not collapse after 180 seconds at 36 ° C. Therefore, it has been found that a combination of fatty alcohols and fatty acids has a synergistic effect and has effective foaming properties in the case of oilseed compositions, to obtain a stable thermally degradable foam. Interestingly, cetyl and stearyl alcohol had the lowest average bubble size, despite using a combination of the two, which led to a substantial reduction in the viscosity of the pre-foam formulation.
    Table 8 - Oil compositions containing various fatty acids and fatty alcohols
    Formulations 010 011 012 013 Ingredients % (weight / weight) % (weight / weight) % (weight / weight) % (weight / weight) Heavy mineral oil 60.00 60.00 60.00 60.00 light mineral oil 25.00 25.00 25.00 25.00 Cyclomethicone 5.00 5.00 5.00 5.00 Myristyl alcohol 5.00 - - - Cetyl alcohol5.00 - - Stearyl alcohol- 5.00 - Cetostearyl alcohol- - 5.00 Beenyl alcohol- - - Isostearic acid- - - Stearic acid 5.00 .5.00 5.00 5.00 Total 100.00 100.00 100.00 100.00 Propellant A46 12.00 12.00 12.00 12.00 Propellant AP-70 - - - - Results Foam Quality Reasonable Good Good Good Collapse time (sec) 10 30 > 180 30 Foam density (/ ml) - 0.142 0.157 0.210 Bubble size (micrometers) - 60 74 137 Viscosity of the pre-foam formulation (cP) 107 22763 23866 107
    Table 8 - Continuation
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    Formulations 014 015 016 017 Ingredients % (weight / weight) % (weight / weight) % (weight / weight) % (weight / weight) Heavy mineral oil 60.00 57.00 60.00 60.00 Light mineral oil 25.00 25.00 30.00 25.00 Cyclomethicone 5.00 5.00 - 5.00 Myristyl alcohol - 3.00 - - Cetyl alcohol - - - - Stearyl alcohol - 5.00 5.00 5.00 Cetostearyl alcohol - - - - Beenyl alcohol 5.00 - -Isostearic acid - - - 5.00 Stearic acid 5.00 5.00 5.00 - Total 100.00 100.00 100.00 100.00 Propellant A46 12.00 - 12.00 12.00 Propellant AP-70 - 8.00 - - Results Foam Quality Good Good Good Reasonable Collapse time (sec) > 180 > 180 > 180 10 Foam density (/ ml) 0.139 0.082 0.100 - Bubble size (micrometers) 139 - - - Viscosity of the pre-foam formulation (cP) 5023 18987 - -
    Example 9 - Hydrophobic foam formulations free of surfactant containing fatty alcohols, fatty acids and waxes
    Formulations containing a combination of 5 fatty acids, fatty alcohols and waxes were prepared and evaluated for their foaming properties. As noted in Table 9 below, formulations 018 containing fatty alcohols and low amounts of stearic acid did not produce quality foams, but generated a foam of reasonably good quality that quickly collapsed. Surprisingly, the addition 10 of hydrogenated castor oil and beeswax (in formulation 019), both of which are solid waxes at room temperature, improved the foam quality and a good quality foam that was stable at 36 ° C was obtained . In addition, formulations containing waxes were less greasy upon application to the skin. Therefore, it has been found that waxes, in combination with a fatty alcohol and a fatty acid, are useful in producing a high quality foam without surfactants.
    Table 9 - Hydrophobic foam compositions containing waxes
    Formulations 018 019
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    Ingredients % (weight / weight) %(weight / weight) Heavy mineral oil 63.00 59.50 Light mineral oil 25.00 25.00 Cyclomethicone 5.00 5.00 Hydrogenated castor oil - 1.50 Beeswax - 2.00 Cetostearyl alcohol 2.50 2.50 Stearyl alcohol 1.50 1.50 Beenyl alcohol 1.00 1.00 Stearic alcohol 2.00 2.00 Total 100.00 100.00 Propellant A46 12.00 12.00 Results Foam quality Fairly Good Good Collapse time (sec) 10 120 Foam density (g / ml) - 0.207 Bubble size (micrometers) 155 79
    Additional formulations containing only waxes were prepared and in combination with a fatty acid or a fatty alcohol and their foaming properties were verified. As described in Table 9b below, formulations 021, 021B and 022 containing only beeswax or in combination with hydrogenated castor oil did not produce quality foams, but simply generated foaming liquids. Formulations 020 containing only hydrogenated castor oil generated foam of reasonably good quality, which collapsed after 60 seconds. On the other hand, the combination of beeswax, hydrogenated castor oil and fatty alcohol improved the foam quality and produced a good quality foam, which was stable at 36 ° C for more than 180 seconds, as shown in formulation 023. However, formulations 024 and 024b composed of combinations of beeswax, hydrogenated castor oil and only fatty acids, without fatty alcohol, generated foam of reasonably good quality, which collapsed quickly. This shows the importance of the presence of fatty alcohols and waxes in foam oil compositions. In addition, wax, such as hydrogenated castor oil or beeswax, can not only be used in place of a fatty acid, but can also be used to
    74/96 facilitate at a lower level of presence of fatty acid, without compromising the foam properties.
    Table 9b - Hydrophobic foam compositions containing waxes
    Formulations 020 021 021b 022 023 024 024b Ingredients % (weight / feetO) % (weight / weight) % (weight / weight) % (weight / weight) % (weight / weight) % (weight / weight) % (weight / feetO) Heavy mineral oil 60.00 60.00 60.00 60.00 60.00 60.00 60.00 Light mineral oil 25.00 25.00 30.00 25.00 25.00 25.00 25.00 Cyclomethicone 5.00 5.00 - 5.00 5.00 5.00 5.00 Hydrogenated castor oil 10.00 - - 5.00 2.50 2.50 5.00 Beeswax - 10.00 10.00 5.00 2.50 2.50 2.50 Stearyl alcohol - - - - 5.00 - - Stearic alcohol - - - - - 5.00 5.00 Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Propellant A46 12.00 12.00 12.00 12.00 12.00 12.00 12.00 Results Foam quality Reasonably Good Reasonable Reasonable Reasonable Good Razoave Imente Boa Reasonably Good Collapse time (seconds) 10 10 10 10 > 180 10 10
    Example 10 - Tetracycline foam formulations containing different hydrophobic oils
    Minocycline foam formulations were prepared containing soybean oil, octyldodecanol, medium chain triglyceride oil (MCT) and coconut oil, which are other examples of hydrophobic oils. 10 parameters were evaluated, such as foam quality, collapse time and density. As described in Table 10, good quality foams that did not collapse at 36 ° C were obtained in different compositions containing these hydrophobic oils. Coconut oil, which in itself is a semi-solid paste as an oil, was used in combination with 15 liquid soy oil.
    Table 10 - Foam formulation containing different hydrophobic oils
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    Formulations 199 216 232A 235 238 245 248 251 252 Ingredients % (weight / weight) % (weight / weight) % (weight / weight) % (weight / weight) % (weight / weight) % (feet / feetO) % (feet / feetO) % (feet / feet) % (feet / feetO) Heavy mineral oil 55.89 58.82 - - 58.14 Light mineral oil 25.00 25.00 25, Õ0 - 25.00 4.44 3.04 4.44 5.54 Cyclomethicone 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Medium chain triglyceride oil (MCT) 48.89Octyldodecanol - - - 12.00 - - - - - Coconut oil - - 25.00 - - 23.60 25.00 21.60 25.00 PPG 15 stearyl ether-15.00Soy oil - - 28.39 - - 50.00 50.00 50.00 50.00 Lanolin - - - - - - - 2.0 2.00 Hydrogenated castor oil - 1.50 2.00 2.00 1.50 2.00 2.00 2.00 2.00 Beeswax1.87 2.50 2.50 2.00 2.00 2.00 2.00 2.00 Cholesterol - - - - - - 2.50 - - Myristyl alcohol 3.00 - - - - 2.50 - 2.50 - Cetostearyl alcohol - 2.50 - 2.50 2.50 1.50 1.50 3.50 2.50 Stearyl alcohol 5.00 1.50 5.00 5.00 1.50 3.50 3.50 1.50 1.50 Beenyl alcohol - 0.70 1.00 1.00 1.00 1.10 1.10 1.10 1.10 Aerosil (SiO2) - - - - 0.25 0.25 0.25 0.25 0.25 Stearic acid 5.00 2.00 5.00 5.00 2.00 3.00 3.00 3.00 2.00 Minocycline hydrochloride 1.11 1.11 1.11 1.11 1.11 1.11 1.11 1.11 1.11 Total 100 100 100 100 100 100 100 100 100 Propellant A46 - 12.00 - 12.00 - 12.00 12.00 12.00 12.00 Propellant A70 8.00 - 8.00 - 8.00 - - - - ResultsFoam Quality Good Great Great Good Great Great Great Good Good Collapse time at 36 ° C (seconds) > 180 160 > 180 150 > 180 140 > 180 > 180 > 180 Ís / mD foam density 0.082 0.225 0.149 0.293 0.237 0.295 0.211 0.223 0.167
    Comments: All foams were of high quality and had a collapse time at 36 ° C of over 100 seconds, a foam density of less than 0.3 g / ml and the formulations were able to withstand four 5 freeze-thaw cycles and still generate high quality foam with a collapse time at 36 ° C greater than 100 seconds. The above formulations, without the addition of propellant, are homogeneous compositions
    76/96 gel-like semi-solids, with no separation or sedimentation of the ingredients observed.
    Example 11 - Tetracycline foam formulations containing a wax
    The foaming properties of formulations containing mineral oil, a paraffin wax, a propellant and a tetracycline were studied. As shown in Table 11 below, formulations containing minocycline hydrochloride produced quality brittle foams with a collapse time greater than 1 minute at 36 ° C, despite the absence of fatty alcohols and fatty acids.
    Table 11 - tetracycline foam formulations that contain a wax
    Formulations 053D Ingredients %(weight / weight) Heavy mineral oil 79.0 Paraffin 51-53 20.0 Minocycline hydrochloride 1.0 Total 100.0 Propellant AP-70 8.0Results Foam quality Great Ability to be subjected to agitation 2 Collapse time at 36 ° C (seconds) > 180
    Example 12 - Foamy compositions based on petrolatum
    Foam formulations containing high amounts of petrolatum were prepared, in combination with liquid oils, fatty alcohols and waxes, according to the general manufacturing process described in Example 1. As described in Table 12a, quality brittle foams were obtained in different compositions containing petrolatum. Pre-foam formulations were viscous semi-solid. After the addition of propellant, the formulations were agitated, indicating that the formulation inside the aerosol container is liquid.
    Table 12a - Oil formulations containing petrolatum
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    Formulations TO 1 A2 A3 A8 White petroleum 70.00 50.00 50.00 91.00 Grape seed oil - 15.00 - - Jojoba Oil 15.00 15.00 15.00 - Mineral oil 5.00 9.00 10.00 - Wheat germ oil - - 15.00 - Paraffin Wax 51-53 - 2.00 5.00 - Beeswax 1.00 1.00 - 1.00 Cetostearyl alcohol 4.00 4.00 4.00 4.00 Hydrogenated castor oil 3.00 2.00 - 3.00 Cyclomethicone 5-NF 1.00 1.00 - - Beenyl alcohol 1.00 1.00 1.00 1.00 Total 100 100 100 100 Propellant A70 10.00 10.00 10.00 10.00Results Foam quality Great Great Great Great Collapse time (sec) 0.159 0.154 0.175 0.226 Foam density (g / ml) > 180 > 180 > 180 > 180 Bubble size (micrometers) - - 150 -
    In one or more embodiments of the present invention, a foaming formulation containing petrolatum, optionally a liquid oil, a fatty alcohol and a wax, is presented, the formulation generating quality brittle foam.
    Wax-free foam formulations were also prepared, containing high amounts of petrolatum, in combination with liquid oils and fatty alcohols, according to the general manufacturing process described in Example 1. As described in Table 12b, 10 quality brittle foams were obtained in different compositions containing petrolatum without wax. Pre-foam formulations were viscous semi-solid. After the addition of propellant, the formulations were stirred, indicating that the formulation inside the aerosol container is liquid.
    Table 12b - Oilaceous formulations containing petrolatum
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    Formulations A4 A5 A6 A7 White petroleum 50.00 70.00 70.00 75.00 Wheat germ oil - 10.00 - - Jojoba oil - 5.00 - - Avocado oil 15.00 - - - Coconut oil 15.00 - - - Mineral oil 10.00 3.00 20.00 20.00 Karite butter 5.00 5.00 5.00 - Cetostearyl alcohol 4.00 4.00 4.00 4.00 Cyclomethicone 5-NF - 2.00 - - Beenyl alcohol 1.00 1.00 1.00 1.00 Total 100 100 100 100 Propellant A70 10.00 10.00 10.00 10.00Results Foam quality Good Great Great Great Foam density (g / ml) 0.200 0.197 0.140 0.175 Collapse time at 36 ° C (sec.) 175 > 180 > 180 > 180
    In one or more embodiments of the present invention, a foaming formulation comprising petrolatum and a fatty alcohol with shea butter is optionally provided, the formulation generating a quality brittle foam. In one or more embodiments of the present invention, a foamable formulation is presented comprising petrolatum, optionally, a liquid oil, and a fatty alcohol with shea butter, optionally, the formulation generating a quality brittle foam.
    PART C - Additional properties of tetracycline compositions Example 13 - Stability of a tetracycline antibiotic in surfactant-free hydrophobic formulations
    Tetracycline antibiotics are known to be very unstable active agents, which are degraded by a wide variety of 15 commonly used pharmaceutical excipients. For example, it has been found that minocycline is degraded in a few days by different hydrophilic solvents
    79/96 (such as water, glycerin, sodium salt of pyrrolidone carboxylic acid, propylene glycol and polyethylene glycols), by polymers dispersed in water of (such as, for example, xanthan gum, poloxamers, carbomers, metocel, sodium carboxymethyl cellulose) and by surfactants (such as, for example, 5 polysorbates, sorbitan esters, polyoxyalkyl esters and also lanolin based surfactants). Therefore, the realization of a long-term stable foaming formulation of tetracycline antibiotics described here was a great challenge and it is necessary to do a lot of research and have a lot of creativity.
    The following example illustrates the physical stability of the 10 foams and the chemical stability of minocycline hydrochloride (MCH) in hydrophobic formulations, that is, formulations 238 and 244B, as described in Tables 13a, 13b (i) and 13b (ii) . In an accelerated stability study, samples were stored at 40 ° C, and minocycline hydrochloride concentrations were determined by High Performance Liquid Chromatography (HPLC or HPLC). The results of the stability test after two months, three months and six months of storage are shown in Tables 13b (i) and 13b (ii).
    Table 13 - Composition of the foam formulation incubated at 40 ° C
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    Formulations 238 244B Ingredients % (weight / weight) % (weight / weight) Heavy mineral oil 58.14 - Light mineral oil 25.00 4.44 Cyclomethicone 5.00 5.00 Coconut oil - 23.60 Soy oil - 50.00 Lanolin - - Hydrogenated castor oil 1.50 2.00 Beeswax 2.00 2.00 Cetostearyl alcohol 2.50 3.50 Stearyl alcohol 1.50 1.50 Beenyl alcohol 1.00 1.10 Myristyl alcohol2.50 Aerosil (SÍO2) 0.25 0.25 Stearic acid 2.00 3.00 Minocycline hydrochloride 1.11 1.11 Total 100 100 Propellant A46 - 12.00 Propellant A70 8.00 - Results Foam Quality Great Great Collapse time (seconds) > 180 > 160 Foam density (g / ml) 0.237 0.284
    Table 13b (i) - Chemical stability of foam compositions containing minocycline hydrochloride
    Minocycline content (% of data on the technical sheet) Formulation T0 2 months at 40 ° C 3 months at 40 ° C 6 months at 40 ° C 238 98.6 95.7 96.0 92.9 244B 98.7 97.1 93.8 90.3
    NM = not measured
    Table 13b (ii) - Physical stability of foam compositions containing minocycline hydrochloride
    Formulation test T0 2 months40 ° C 3 months40 ° C 6 months to40 ° C 238 Foam quality (g / ml) Great Good Good Good
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    Collapse time (seconds) > 180 > 180 160 NM Foam density 0.237 0.259 0.289 0.263 244B Foam quality Great Good Good Good Collapse time (seconds) > 180 > 180 180 NM Foam density(g / mi) 0.284 0.256 NM 0.232
    NM = not measured
    Surprisingly, and despite the known instability of tetracycline antibiotics, the results of the accelerated stability of both formulations after storage at 40 ° C showed minimal degradation of the active agent in the formulations. The formulations presented here, therefore, show prolonged accelerated stability for the tetracycline antibiotic and excellent physical stability.
    These results also illustrate the difficulty, the complexity, the unexpected and not obvious achievement of the discovery of surfactant-free and water-free formulations that are chemically stable and also physically stable for long, medium or short periods. Testing and identifying individual substances that are chemically compatible with the active agent is not enough. Combining multiple substances, which in themselves are compatible, can lead to collective incompatibility. Discovering and knowing the substances that are chemically compatible does not predict the physical stability of the composition or vice versa. Performing a compatibility study between the individual components of the formulation and the active agents does not guarantee achieving physical stability. Discovering combinations of ingredients that can lead to a physically stable formulation in the absence of surfactant is, in itself, unexpected.
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    Example 14 - Comparison of the stability of minocycline in a hydrophobic foam or gel formulation versus a reference gel, in contact with the skin.
    The aim of this study was to evaluate the degradation of minocycline after exposure to the skin. Two samples were tested:
    The. Hydrophobic formulation of minocycline # 244, containing 25% light mineral oil, 5% cyclomethicone, 25% coconut oil, 28.5% soy oil (hydrophobic oils); 2% hydrogenated castor oil, 2.5% beeswax (waxes); 5% stearyl alcohol, 1% beenyl alcohol (fatty alcohols), 5% stearic acid (fatty acid) and approximately 1% micronized minocycline hydrochloride.
    B. A reference minocycline gel, which comprised, among other components, silicone and ST 10 elastomer, which were mixed before application with an additional component that included water, ethanol and propylene glycol.
    The samples were applied to the skin of the newly recovered pig's ear and stored in a Petri dish, with exposure to air and light for 6 hours at 35 ° C, and the concentrations of minocycline hydrochloride and its degrading 4-epi were monitored by liquid chromatography.
    As shown in Table 14 below, the reference gel exhibited rapid degradation of minocycline. After 6 hours of exposure, the minocycline content decreased by 34% and its degrading 4-epi content reached 19.4%, showing that the reference gel product did not distribute the entire amount of the antibiotic to the skin, in its form. active.
    In complete contrast, formulation 244, surprisingly, and despite the known instability of minocycline, the results of skin stability after 6 hours showed minimal degradation of the active agent: with the content of the degrading 4-epi it only reached 3.3% and no detectable decrease was observed in the amount of minocycline. Therefore, the foam formulation has an active protective effect on the tetracycline antibiotic upon contact with the skin, and prevents its degradation at the target treatment site for several hours.
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    As a result of these observations, it is observed that the brittle hydrophobic composition protects the tetracycline antibiotic against degradation, and therefore is useful for the treatment of areas of the body and surfaces that are moist and exposed to air and / or light , without losing its potency after application.
    As is known in the medical art, the duration of a drug's effect is directly related to its permanence at the treatment site in its active form, and therefore it can be concluded that the present tetracycline brittle hydrophobic composition will provide treatment prolonged and will facilitate the administration of the drug less frequently compared to other forms of the same drug (if available).
    Table 14 - Skin stability results of compositions containing minocycline hydrochloride
    Reference Silicone Gel Formulation244 Initial minocycline concentration in the skin 96.90 92.20 Initial concentration of degrading 4-epi in the skin 2.60 0.80 Minocycline concentration in the skin after 6 hours at 35 ° C 64.00 93.70 Concentration of degrading 4-epi in the skin after 6 hours at 35 ° C 19.40 3.30
    Example 15: Safety of inactive ingredients
    All inactive ingredients used in tetracycline brittle hydrophobic formulations are intended for topical use and are listed in the current FDA database of inactive ingredients; and the concentrations used do not exceed the maximum concentrations given in the database. As an example, Table 15 sets out the effects of acute doses of inactive ingredients in the formulation of formulation 244, indicating that all of these ingredients can generally be considered safe (GRAS).
    Table 15: Effects of acute doses of inactive ingredients in the preparation of formulation 244
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    Ingredient Toxicity Cyclomethicone Oral LD50 (rats):> 24.134 mg / kg Coconut oil NA (edible) Soy oil LD50 IV (rats): 16.5 g / kg; IV DL50 Mouse: 22.1 g / kg Hydrogenated castor oil Oral LD50 (rats)> 10 g / kg Beeswax Oral LD50 (rats):> 5,000 mg / kg Myristyl alcohol Oral LD50 (rats):> 10,000 mg / kg; Dermal LD50 (rabbits):> 8,000 mg / kg Cetostearyl alcohol Oral LD50 (rats):> 10,000 mg / kg; Dermal LD50 (rabbits):> 8,000 mg / kg Stearyl alcohol Oral LD50 (rats):> 10,000 mg / kg; Dermal LD50 (rabbits):> 8,000 mg / kg Beenyl alcohol Oral LD50 (rats): 12,800 mg / kg Aerosil R 972 (modified silica) Oral LD50 (Brachydanio rerio):> 10,000 mg / kg Stearic acid Oral LD50 (rats): LD50 = 4640; Dermal LD50 (rabbits):> 5000 mg / kg
    Example 16: Eye irritation studies - HET CAM method
    The potential of compounds to cause irreversible or severe eye irritation or corrosion can be detected by observing 5 adverse changes that occur in the egg's chorioallantoic membrane (MCA) after exposure to test chemicals (Luepke, NP, Kemper, FH “ The HET-CAM Test: An Alternative to the Draize Eye Test. ”Fd Chem. Toxic. (1986) 24, 495-496). The fertilized chicken eggs are spun in an incubator for nine days, after which all defective eggs are discarded. The shell around the air cell is removed and the inner membranes are extracted to reveal the chorioallantoic membrane. Chemical substances are added to the membrane and left in contact for up to 5 minutes. The membrane is examined for vascular damage and the time required for the injury to occur is recorded. The irritation is scored according to the speed 15 that the damage occurs. To validate the HET-CAM data, positive and negative controls and vehicle control are tested in parallel with the test item.
    For each test item, the average score of replicated eggs is determined. The irritation score (IS) is interpreted as follows:
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    Irritation Score Irritation Classification 0-0.9 Non-irritating 1-4.9 Mild Irritant 5-8.9 Moderate irritant 9-21 Serious Irritant
    As can be seen in Table 16, using the HET-CAM method of in vitro irritation, FXFM244 without dilution showed no signs of irritation.
    Table 16: HET-CAM studies of formulation 244 with 1% and 4% minocycline
    Treatment Irritation Score Classification Negative Control 0 Non-irritating Positive Control 17.09 Serious Formulation 244B (1%) 0 Non-irritating Formulation 244A (4%) 0 Non-irritating FXFM244 - Placebo 0 Non-irritating
    As a result of these observations, the brittle hydrophobic composition of tetracycline is especially suitable for the treatment of eye diseases, as well as other diseases that afflict sensitive skin and mucous membrane areas. Notably, the composition does not include any surfactants, which are known to cause irritation to the eye and other sensitive areas.
    Ophthalmic diseases, which can be contemplated based on the antimicrobial properties of tetracycline, in addition to the anti-inflammatory, antioxidant, anti-apoptosis and neuroprotective effects of the tetracycline compound (such as, for example, minocycline and doxycycline), in a non-limiting way, can be categorized symptoms, as follows: eye redness, eye pain or sensitivity to light, blurred vision, vision loss, visual disturbances - floaters, sparking, distortion, halos, etc., itching / burning, watering / discharge, feeling of foreign body in the eye, eyelid problems, double vision.
    Examples of relevant diseases include macular degeneration, age-related macular degeneration, dry macular degeneration and wet macular degeneration, which are associated with
    86/96 photodamage and apoptosis, cataract, which is associated with apoptosis, glaucoma, open-angle glaucoma, closed-angle glaucoma (associated with optic nerve death and apoptosis), retinopathy, proliferative diabetic retinopathy (apoptosis), edema macular (inflammation), uveitis, conjunctivitis and trachoma (infection).
    Non-limiting examples of ophthalmic diseases that can be treated by a tetracycline-brittle hydrophobic composition of the present invention; or such diseases whose complications can be treated by said composition are included in the following list: ophthalmic allergy, blepharitis, cataract, central serous chorioretinopathy, color vision problems, corneal abrasion, corneal edema, corneal ulcer, conjunctivitis, complications with contact lenses, dacryocystitis, blurred distant vision, dry eye, Eales disease, episcleritis, ectropion, eyelid entropion, eyelid cellulitis, tired sight, focal spasm, acute glaucoma, glaucoma, iritis, keratoconus, Lyme disease, macular degeneration , macular edema, macular hole, medication eye toxicity, myasthenia gravis, ocular scar pemphigoid, ophthalmic migraine, presbyopia, obstructed lacrimal duct, optic neuritis, optic nerve effusion, orbital fracture, orbital cellulitis, phytenoid, pterygium, recurrent corneal erosion retinal artery occlusion, retinal detachment, retinal tear, ocular vein occlusion ethine, sarcoidosis, scleritis, sinus disease, strabismus (eye misalignment), subconjunctival hemorrhage, temporal arteritis, thyroid eye disease, trichiasis, eyelid tumors, eyelid spasms (eyelid myokymia), uveitis, vitreous detachment and vitreous and hemorrhage.
    Example 17: In vitro demonstration of the antibacterial effects of formulation 244
    In an in vitro study, formulation 244 with 1% and 4% minocycline was found to inhibit the growth of Streptococcus pyogenes, Pseudomonas aeruginosa, Staphylococcus aureus, as well as a methicillin resistant strain of Staphylococcus aureus (SARM / MRSA), as shown in Table 11. The formulation is also effective against Propionbacterium acnes, the acne-causing microorganism. A reference antibiotic product,
    87/96 that is, the Fucidine ointment (containing 2% fusidic acid) was effective only against strains of Streptococcus.
    Notably, this effect was observed even when the tetracycline antibiotic is suspended, and is not expected to be readily available for migration in the Petri dish, as needed, to excrete its antimicrobial activity.
    Table 17: In vitro antibacterial effect: comparison between formulation 244, Fucidine ointment and placebo - inhibition diameter (mm)
    2441% inhibition diameter * 2444% inhibition diameter * 244 Placebo Inhibition diameter * Fucidine Inhibition diameter * Staphylococcus aureus 6538 35.39.36 mm > 40,> 40,> 40 mm 13.21.20 mm > 40,> 40,> 40 mm Pseudomonas aeruginosa 9027 35.36.35 mm 40.40.40 mm 0.0.0 mm 11.12.16 mm Staphylococcus aureusMRSA 43300 32.30.21 mm > 40,> 40,> 40 mm 17.18.20 mm 40.40.38 mm Streptococcus pyogenes 19615 45.38.39 mm 38.43.40 mm 12.15 mm 10.12.22 mm Propionbacterium acnes 32.30.35 mm 32.30.35 mm AT AT * 0 = ineffective; > 30 = Very to Effective
    As a result of these observations, it is observed that the tetracycline brittle hydrophobic composition of the present invention is useful in the treatment of any condition or disease, which can be treated with a gel or foam, which includes a bacterial component as one of its etiological factors. .
    As a result of these observations, the tetracycline-brittle hydrophobic composition is especially suitable for the treatment of any condition involving, as a direct etiologic factor or as a secondary complication, an infection involving a microorganism that is susceptible to treatment with tetracycline.
    Skin diseases that can be contemplated, based on the antimicrobial properties of tetracycline, in addition to the anti-inflammatory, antioxidant and neuroprotective effects of certain tetracycline compounds (such as, for example, minocycline and doxycycline), include, for example, example: cellulite, skin abscess, erysipelas, erythrasma,
    88/96 folliculitis, boils and carbuncles, suppurative hidradenitis, impetigo, ectima, lymphadenitis, lymphangitis, methicillin-resistant staphylococcus aureus infections or SARM / MRSA, necrotizing subcutaneous infection and staphylococcal scalded skin syndrome.
    Likewise, the composition of the present invention is suitable for the treatment of any ophthalmic disease that involves bacterial infection, vaginal infections and any other infections of target sites that can be treated by a gel or foam.
    The same compositions can be applicable in any case of a disease involving a secondary infection, such as, for example, atopic dermatitis and other pruritus and xerotic diseases.
    Example 18: Administration to the skin and systemic bioavailability of minocycline
    The transdermal penetration of minocycline was tested using the in vitro diffusion system with Franz cells. This system is generally used to test drug delivery through the skin, using semi-solid topical dosage forms. Pig skin was used according to the new Proposal for Directive No. 428 of the Organization for Economic Cooperation and Development (OECD) due to its permeation characteristics similar to human skin. The following experimental parameters were used:
    - Two formulations were tested: 244 to 1% and 244 to 4% (comprising 1% and 4% minocycline, respectively).
    - Franz vertical diffusion cells were used (PermeGear, 1.77 cm 2 in area, 14 ml of receptor fluid).
    - Six cells were used to test the 4% formulation, five cells were used to test the 1% formulation and one cell was used as a negative control (without any sample applied). Approximately 500 mg of the product was placed in each cell.
    - Receptor compartments were sampled at the beginning and 3, 6, 9 and 24 hours after application. At the 24-hour time point, the skin was processed as follows:
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    - Material residues were removed from the skin using filter paper, followed by removing the skin with 3M Scotch Magic® Tape.
    -19 sequential tapes (9 and 10) were transferred to two separate containers with 3 ml of extraction solution (Stratum Corneum 1 and Stratum Corneum 2).
    - The circular area of the skin (1.77 cm 2 ) was cut and transferred to a 3 ml container of extraction solution (viable skin - VS samples).
    Table 18: In vitro skin administration *. Formulation 244 (1% and 4%)
    FMFX244 foam 1% (n = 5) FMFX244 foam 4% (n = 6)Minocycline pg / cm 2 STD Minocycline pg / cm 2 STD Stratum Corneum 1 7.77 4.32 33.63 20.41 Stratum Corneum 2 0.93 077 7.49 8.67 Total Stratum Corneum 8.70 4.97 41.12 16.89 Viable Skin 0.79 0.19 2.00 0.81 Total Intradermal Administration 9.4943.12 17.48 Receiving Compartment 0.000.00
    The following conclusions can be drawn from this experience
    1. Transdermal administration: after 24 hours of exposure, the amount that was found in the recipient cells was below the quantification limit (LOQ) of the analytical method (LOQ = 2 pg / ml). This result clearly demonstrates no systemic absorption of the drug from the FMFX244 foam formulation. Therefore, it can be concluded that the topical application of the FMFX244 foam should not involve any systemic adverse effects.
    2. Intradermal administration (administration to the skin): The average total amount of minocycline in the skin after 24 hours of exposure was 9.5 μ g / cm 2 for the 1% formulation and 43 pg / cm2 for the 4 formulation %. The weight of the skin in the administration area is approximately 100 mg, which implies that the concentration of minocycline in the skin after 24 hours of exposure is approximately 90 pg / g of skin for the 1% formulation and
    90/96 approximately 430 pg / g for the 4% formulation. According to the literature, the minimum inhibitory concentration (MIC) for minocycline is less than 4 pg / ml and, therefore, it can be concluded that the concentrations found in the skin are sufficient to treat bacterial infections of the skin.
    Notably, this skin penetration profile has been observed despite the tetracycline antibiotic being suspended, and is not expected to be readily available for migration to the skin.
    As a result of these observations, the tetracycline brittle hydrophobic composition is especially suitable for the treatment of any dermatological disease that occurs on the skin.
    Skin diseases that can be contemplated based on the antimicrobial properties of tetracycline, in addition to the anti-inflammatory, antioxidant, anti-apoptosis and neuroprotective effects of certain tetracycline compounds (such as, for example, minocycline and doxycycline), include, but are not limited to, for example: abscess, acne, acne scars, acute febrile neutrophilic dermatosis, acute lymphangitis, allergic contact dermatitis, alopecia, athlete's foot, atopic dermatitis, basal cell carcinoma, blisters, bromhidrosis, burn, corns, candidiasis, carbuncles, cellulite, chickenpox, cholinergic urticaria, chronic effects of sunlight, cold-induced urticaria, pustules, grains, cutaneous abscess, cutaneous larva migrans, cutaneous myiasis, dark spots, parasitic infestation delirium, dermatitis, herpetiform dermatitis, dermographism, dermatophytoses, rashes and reactions drugs, dyshidrotic eczema, ectime, epidermoid cyst, epidermal necrolysis ca, erysipelas, erythrasma, exfoliative dermatitis, erythema multiforme, erythema nodosum, folliculitis, fungal infections of the nail, boils, genital herpes, granuloma annulare, lice, hidradenitis suppurativa, urticaria, folliculitis, hirsutism, hyperhidrosis, nails, hypohidrosis, hypohydrosis, hypohydrosis, hypohidrosis, hypohidrosis, hypohidrosis, hypohidrosis, hypohidrosis, hypohidrosis, hypohidrosis, hypohidrosis, hypohidrosis, hypohidrosis, hypohidrosis, hypohidrosis, hypohidrosis. ingrown toenails, intertrigo, irritant contact dermatitis, itching, fungal infection in the groin (Jock itch), keratosis pilaris, chronic lichen simplex, lichen planus, lichen sclerosus, lymphadenitis, lymphangitis, mastocytosis, measles, melanoma, miliary, signs, molluscum contagiosum , Methicillin-resistant Staphylococcus aureus or SARM / MRSA, necrotizing subcutaneous infection, nummular dermatitis, oral herpes, panniculitis, paronychia, parapsoriasis, photoallergy,
    91/96 photodamage, photoirritation, photosensitivity, papules, perioral dermatitis, pimples, pityriasis rosea, pityriasis rosea, pityriasis rosea, pityriasis rubilar pilaris, poison ivy, pressure ulcers, pressure urticaria, pruritus, pseudofolliculitis of the beard, pseudoficulitis of barba, pruritic urticarial plaques of gestation (PUPP), pustules, pyogenic granuloma, skin rashes, ringworm, rosacea, roseola, rubella, scabies, sebaceous cyst, seborrheic dermatitis, seborrheic keratosis, herpes zoster, skin cancer, skin neoplasia, skin neoplasia, skin neoplasia, skin cancer, skin neoplasia staphylococcal scalded skin syndrome, stasis dermatitis, Stevens-Johnson syndrome, burns, tinea corporis, tinea cruris, tinea pedis, tinea versicolor, toxic epidermal necrolysis, varicella-zoster virus, vitamin D deficiency, aquagenic urticaria, xerosis, herpes -zoster.
    Example 19: Ex-vivo studies on the anti-apoptosis effects of formulation 244 with 1% and 4% minocycline
    Ultraviolet irradiation of the skin is known to decrease cell viability, total antioxidant capacity, while increasing levels of inflammation (secretion of pro-inflammatory cytokines) and apoptosis of epidermal cells.
    Pre-treatment with Formulation 244:
    Human skin samples in organ culture were treated topically with Formulation 244 (placebo, 1% and 4% minocycline) for 24 hours, then irradiated with ultraviolet radiation (400 mJ / cm 2 ) and incubated for an additional 72 hours . Activation of apoptosis was measured 24 hours after irradiation by measuring the extent of caspase3 activity in epidermal leaves.
    Table 19a and Table 19b demonstrate the effect of Formulation 244 (with or without minocycline) on epidermal cell apoptosis and viability after irradiating ultraviolet radiation from the skin organ culture. As shown in Table 19a, activation of apoptosis was significantly decreased by FXFM244 in a dose dependent manner.
    Cell viability as measured by the MTT assay 72 hours after irradiation was increased, as shown in Table 19b. A set of mediators involved in apoptosis belonging to caspases or
    92/96 aspartate-specific cysteine proteases. A member of this family, caspase3, has been identified as being a key mediator of mammalian cell apoptosis. In general terms, with increased caspase activation, a higher percentage of cell death occurs.
    Table 19a: Effect of Formulation 244 on activation of apoptosis in skin organ culture after ultraviolet irradiation
    Caspase 3 activity (slope / min) Non-irradiated Radiated Vehicle 24 177 244 - 1% minocycline hydrochloride (MCH) 4 100 244 - 4% minocycline hydrochloride (MCH) 3 69
    Table 19b: Effect of Formulation 244 on the viability of skin organ culture
    Viability (RFU 540/590 nm) Non-irradiated Radiated Vehicle 6971.25 6207.5 244 - 1% minocycline hydrochloride (MCH) 7615.25 8862.25 244 - 4% minocycline hydrochloride (MCH) 8155.5 9015.5
    Comments: It has been observed that, in the case of cells in contact with a placebo formulation, irradiation causes a decrease in cell viability. On the other hand, in cells in contact with a formulation containing minocycline, greater cell viability was observed both before and after irradiation, compared to placebo, which is a sign of cell regeneration. Therefore, the present formulation comprising minocycline is capable of preventing cell death in the event of irradiation and can even stimulate or cause cell regeneration.
    Treatment with Formulation 244 after inducing 20 damage caused by ultraviolet irradiation
    Samples of human skin in organ culture were irradiated with ultraviolet (400 mJ / cm 2 ) and incubated for an additional 72 hours. Formulation 244 at 4% was then applied to the skin and activation of apoptosis was
    93/96 measured 24 hours post-treatment by measuring the extent of caspase 3 activity in epidermal leaves.
    As shown in Table 19c, treatment with the 4% Formulation resulted in approximately 60% decrease in epidermal cell apoptosis.
    Table 19c: Therapeutic effect of Formulation 244 (post-irradiation application)
    Caspase 3 activity (slope / min.) Control 118 244 - 4% minocycline hydrochloride (MCH) 46
    Conclusion:
    These results demonstrate that Formulation 244 has protective properties in the case of sun damage and induced by ultraviolet irradiation or any other condition associated with exposure to sunlight or other light (such as, for example, laser). It may therefore be able to reduce photodamage and photoaging of the skin and, in general, reduce oxidative stress and inflammation in skin pathologies that are known to be accompanied by cell death due to apoptosis.
    Specifically, this skin penetration profile has been observed even when the tetracycline antibiotic is suspended and is not expected to be readily available for tissue migration and to provide the desirable anti-apoptotic effect.
    As a result of these observations, the brittle hydrophobic composition of tetracycline is especially suitable for the treatment of any condition that includes apoptosis as one of its etiological factors.
    Example 20 - Compatibility Study
    Procedure: Minocycline hydrochloride (MCH) was incubated as a suspension with various excipients at 25 ° C and 40 ° C for a maximum of sixty days or to the extent that degradation was suspected. The ratio between the excipient tested and the minocycline hydrochloride is detailed below. Visual inspection was the main criterion for indicating compatibility.
    94/96
    The color of the intact minocycline hydrochloride suspension is pale yellow; and any color change (for example, to dark orange, red, green, brown and black) indicates oxidation or degradation.
    Hydrophilic solvents were tested for compatibility with minocycline hydrochloride at a ratio of MCH: excipient of 1: 250. Dimethyl isosorbide, glycerin, ethanol, propylene glycol, butylene glycol, PEG 200, hexylene glycol, PEG 400, dimethyl sulfoxide and diethylene glycol monoethyl ether were considered incompatible with minocycline hydrochloride.
    Oily emollients and waxes were tested for compatibility with minocycline hydrochloride at a ratio of MCH: excipient of 1: 250 for oily emollients and 1:50 for waxes. Hydrogenated castor oil, castor oil, cocoglycerides, diisopropyl adipate, mineral oil, coconut oil, beeswax, medium chain triglycerides (MCT) oil, cyclomethicone, isododecane, cetearyl octanoate, gelled mineral oil, myristate, PPG ether 15 stearyl, heavy mineral oil, octyl dodecanol, white petrolatum, petrolatum, paraffin 51-53, paraffin 58-62, marigold oil, shea butter, grape seed oil, almond oil, jojoba oil, avocado, peanut oil, wheat germ oil and lard were considered compatible with minocycline hydrochloride. Pomegranate seed oil was considered incompatible with minocycline hydrochloride.
    The compatibility of minocycline hydrochloride with hydrophobic surfactant was tested after solubilization of the surfactant in mineral oil (mineral oil was previously considered compatible with minocycline hydrochloride). The surfactants were tested for compatibility with minocycline hydrochloride at a 1:50 MCH: excipient ratio. PEG150 distearate, laureth 4, hydrogenated castor oil PEG 40, lanolin PEG 75, GLUCAM P20 distearate, PEG100 stearate, glyceryl monostearate, PEG 40 stearate, montanov S (C-20 alcohol (E) C12-20 alkyl glucoside ), alkyl lactate, Benton gel, SPAN 60, sorbitan sesquistearate, SPAN 40, SPAN 80, Tween 20, Tween 60, ceteth 2, sucrose esters of stearic acid D1813, ceteareth 20, esteareth 2 / steareth 21, sesquistearate
    95/96 methylglucose, oleth 20 and PPG-20 methyl glucose ether were considered incompatible with minocycline hydrochloride. D1803 stearic acid sucrose esters, D1807 stearic acid sucrose esters and D1811 stearic acid sucrose esters were found to be compatible with minocycline hydrochloride, however, not all dissolved in oil (eg 1811, 1813).
    Foam adjuvants were tested for compatibility with minocycline hydrochloride at a ratio of MCH: 1:50 excipient. Isostearyl alcohol, beenyl alcohol, stearyl alcohol, cetyl alcohol, oleyl alcohol, myristyl alcohol, ceto-stearyl alcohol, palmitic acid, stearic acid and oleic acid were considered compatible with minocycline hydrochloride. Isostearic acid was not compatible with minocycline hydrochloride.
    The additives were tested for compatibility with minocycline hydrochloride at a ratio of MCH: excipient of 1:50. Aerosil and menthol were considered compatible with minocycline hydrochloride. Titanium dioxide and Ethocel were not compatible with minocycline hydrochloride.
    The additives were tested for compatibility with minocycline hydrochloride. Minimal amounts of water (100 pL) were added to the minocycline hydrochloride, suspended in excipients that demonstrated compatibility to examine whether water can increase oxidation / degradation in the absence or presence of antioxidant. In parallel, antioxidants were added to the minocycline hydrochloride suspensions comprising water. Antioxidants were also added to excipients that were considered not compatible with minocycline hydrochloride. The addition of water caused rapid degradation of minocycline hydrochloride. The addition of alpha-tocopherol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) and propylgalate antioxidants did not prevent minocycline hydrochloride degradation. Compatible excipients have become incompatible in the presence of water. The addition of antioxidants did not change this result.
    Example 21 - Color and Pigmentation Study
    Part A - Color change
    96/96
    Samples of formulations 238 and 216 with 1% minocycline were incubated for three months at 25 ° C, 30 ° C and 40 ° C. After this period, the foam product was activated and the color change was observed. Minimal or no change was observed after three months of storage 5 at all three temperatures.
    Part B - Pigmentation
    A large amount of 4% MCH 244 was activated on human skin to see if any skin pigmentation occurred. Minimal or no pigmentation of the skin was noticed after rubbing the foam over the skin, 10 when observed after approximately 30 seconds.
    权利要求:
    Claims (32)
    [1]
    1. TOPIC THERAPEUTIC COMPOSITION hydrophobic brittle comprising a vehicle comprising approximately 60% to approximately 99% by weight of at least one hydrophobic oil and at least one viscosity modifying agent selected from the group consisting of a fatty alcohol, a fatty acid and a wax, and a tetracycline antibiotic, characterized by the fact that
    - at least a part of the tetracycline antibiotic is suspended in the composition;
    - the viscosity of the composition is at least approximately 30% higher than the viscosity of the vehicle without the tetracycline antibiotic; and because it is higher than the viscosity of the hydrophobic oil and the tetracycline antibiotic without the viscosity modifying agents, and;
    - after storage at 25 ° C for at least six months, the composition retains at least 90% of the tetracycline initially present in the composition, and;
    - being that, when packaged in an aerosol container to which a liquefied or compressed propellant gas is added, the composition provides, upon release of the container, a brittle foam of at least good quality, which breaks easily upon application of shear force.
    [2]
    2. THERAPEUTIC TOPIC COMPOSITION, according to claim 1, characterized by the fact that the increase in viscosity is a synergistic increase, in such a way that the combined viscosity of the vehicle and the viscosity of the hydrophobic oil and the tetracycline antibiotic is less than the viscosity of the composition.
    [3]
    3. TOPIC THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that the hydrophobic brittle vehicle is in the form of a gel before the addition of propellant and said gel liquefies and spreads easily by applying the soft shear force .
    [4]
    4. THERAPEUTIC TOPIC COMPOSITION, according to claim 1, characterized by the fact that the hydrophobic brittle vehicle
    Petition 870170051409, of 7/21/2017, p. 8/20
    2/11 be in the form of a foam; said foam having a collapse time greater than approximately 3 minutes.
    [5]
    5. TOPIC THERAPEUTIC COMPOSITION, according to claim 3, characterized by the fact that the proportion of composition different from the propellant to the propellant is from approximately 100: 1 to approximately 100: 25.
    [6]
    6. TOPIC THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that at least one hydrophobic oil is selected from the group consisting of a mineral oil, a hydrocarbon oil, an ester oil, an ester of a dicarboxylic acid, a triglyceride oil, vegetable oil, animal oil, unsaturated or polyunsaturated oil, diglyceride, PPG alkyl ether, essential oil, silicone oil, liquid paraffin, isoparaffin, polyalphaolefin , a polyolefin, polyisobutylene, a synthetic isoalkane, isohexadecane, isododecane, alkylbenzoate, alkyloctanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate, arachidyl behenate, arachidyl propionate, benzyl laurate, benzyl laurate, benzyl laurate, benzyl laurate, benzyl myristate bis dimer (stearoyl octyldodecyl) dilinoleate, butyl myristate, butyl stearate, cetearyl ethylhexanoate, cetearyl isononanoate, c acetate ethyl, cetyl ethylhexanoate, cetyl lactate, cetyl myristate, cetyl octanoate, cetyl palmitate, cetyl ricinoleate, decyl oleate, diethylene glycol diethylene glycol, diethylene glycol diocyanate, diethylene glycol, diisonone hexanoate, diethylhexyl adipate, diethylhexil malate, diethylhexil succinate, diisopropyl adipate, diisopropyl dimerate, diisopropyl sebacate, dilinoleate diisostearyl dimer, diisostearyl fateate, dioctylate, dioctylate malate, deatylate malate, sebactyl , esters derived from lanolic acid, ethylhexyl cocoate, ethylhexyl ethylhexanoate, ethylhexyl hydroxistarate, ethylhexyl isononanoate, ethylhexyl palmitate, ethylhexyl stearate, hexadecyl stearate, hexyl laurate, hexyl laurate, la isocetyl, isocetyl lanolate, isocetyl palmitate, isocetyl stearate, iso salicylate cetyl, isocetyl stearate, isocetyl stearoyl stearate, isocetearyl octanoate, ethylhexanoate
    Petition 870170051409, of 7/21/2017, p. 9/20
    3/11 isodecyl, isodecyl isononanoate, isodecyl oleate, isononyl isononanoate, isodecyl oleate, isohexyl decanoate, isononyl octanoate, isopropyl isostearate, isopropyl lanolate, isopropyl isopropyl laurate, isopropyl laurate, miropropyl of isopropyl, isostearyl beenate, isostearyl citrate, isostearyl erucate, isostearyl glycolate, isostearyl isononanoate, isostearyl isostearate, isostearyl lactate, isostearyl linolate, isostearyl linolenate, isostearostane malate, isostearostane malate , isostearyl salicylate, isostearyl tartrate, isotridecyl isononanoate, isotridecyl isononanoate, lauryl lactate, myristyl lactate, myristyl myristate, myristyl neopentanoate, octylodecanol, myristyl propionate, octyldentilate myristate, tipprotein octyl, octyl palmitate, octyldodecyl behenate a, octyldodecyl hydroxystearate, octyldodecyl myristate, stearoyl stearate octyldodecyl, oleyl erucicate, oleyl lactate, oleyl oleate, propyl myristate, propylene glycol propylene glycol, propylene glycol tipprate, propylene glycol tip, propylene glycol, propylene glycol tip, propylene glycol maleated soybean oil, stearyl caprate, stearyl heptanoate, stearyl propionate, tocopherol acetate, tocopherol linoleate, glyceryl oleate, tridecyl ethylhexanoate, tridecyl isononanoate, triisocetyl citrate, oil from the bay tree of Alexandria , avocado oil, apricot oil, barley oil, borage seed oil, calendula oil, cinnamon seed oil, canola oil, caprylic / capric triglyceride castor oil, coconut oil, corn oil, cotton oil, cottonseed oil, evening primrose oil, linseed oil, peanut oil, hazelnut oil, glycer triacetate eth, glycerol triheptanoate, glyceryl trioctanoate, glyceryl triundecanoate, hemp oil, jojoba oil, alfalfa oil, corn germ oil, oval pumpkin oil, millet oil, tipprilate / neopentyl glycol tip, olive oil , palm oil, passionflower oil, pentaerythrityl tetrastearate, poppy oil, propylene glycol ricinoleate, rapeseed oil, rye oil, safflower oil, sesame oil, shea butter, soybean oil, soybean oil , sweet almond oil, sunflower oil, rinchão oil, aromatic clove oil, tea tree oil, walnut oil,
    Petition 870170051409, of 7/21/2017, p. 10/20
    4/11 wheat germ glycerides, wheat germ oil, PPG-2 butyl ether, PPG4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butyl ether, PPG14 butyl ether, PPG-15 butyl ether, PPG-15 stearyl ether, PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-22 butyl ether, PPG-22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether , PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether, PPG-10 cetyl ether, PPG-28 cetyl ether, PPG-30 cetyl ether, PPG -50 cetyl ether, PPG-30 isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 methyl ether, PPG-3 myristyl ether, PPG-4 myristyl ether, PPG -10 oleyl ether, PPG-20 oleyl ether, PPG-23 oleyl ether, PPG30 oleyl ether, PPG-37 oleyl ether, PPG-40 butyl ether, PPG-50 oleyl ether, PPG-11 stearyl ether co, herring oil, cod liver oil, salmon oil, cyclomethicone, dimethylpolysiloxane, dimethicone, epoxy modified silicone oil, fatty acid modified silicone oil, fluorinated silicone oil, methylphenylpolysiloxane, phenyltrimethicone and silicone oil modified by a polyether group.
    [7]
    7. TOPIC THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that said fatty alcohol has at least 12 carbon atoms in its carbon skeleton and said fatty acid has at least 12 carbon atoms in its carbon skeleton.
    [8]
    8. Composition topical therapy according to claim 1, characterized in that the said fatty alcohols and said fatty acid to have a melting point above about 40 C. Q
    [9]
    9. THERAPEUTIC TOPIC COMPOSITION, according to claim 9, characterized by the fact that said fatty alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, arachidyl alcohol, beyl alcohol, tetracosanol, hexacosanol, octacosanol , triacontanol, tetratriacontanol, and said fatty acid is selected from the group consisting of dodecanoic acid, tetradecanoic acid, hexadecanoic acid, heptacosanoic acid, octacosanoic acid, triacontanoic acid, dotriacontanoic acid, tritriacontanoic acid, and tritriacontanoic acid, tonic acid.
    Petition 870170051409, of 7/21/2017, p. 11/20
    5/11
    [10]
    10. THERAPEUTIC TOPIC COMPOSITION, according to claim 7, characterized by the fact that the carbon chain of said fatty alcohol or said fatty acid is replaced by a hydroxyl group.
    [11]
    11. TOPIC THERAPEUTIC COMPOSITION, according to claim 10, characterized by the fact that the carbon chain of said fatty acid is 12-hydroxy stearic acid.
    [12]
    12. TOPIC THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that said wax is selected from the group consisting of a vegetable wax, such as, for example, carnauba wax, candelilla wax, uricuri wax, cane wax sugar, rectum wax, jojoba oil; animal waxes, such as beeswax; petroleum derivative wax, such as paraffin waxes, polyethylene and their derivatives.
    [13]
    13. TOPIC THERAPEUTIC COMPOSITION, according to claim 1, characterized in that the viscosity modifying agent is a combination comprising (i) at least one fatty alcohol and at least one fatty acid, or (ii) at least one alcohol fatty and at least one wax, or (iii) at least one fatty acid and at least one wax, or (iv) at least one fatty alcohol, at least one fatty acid and at least one wax.
    [14]
    14. TOPICAL THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that the hydrophobic brittle vehicle is substantially free of surfactants, protic solvents, polar aprotic solvents and silicone thickening agents.
    [15]
    15. TOPIC THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that the hydrophobic brittle vehicle is substantially free of surfactants, polymeric gelling agents, polyols, short chain alcohols and silicone thickeners.
    [16]
    16. THERAPEUTIC TOPIC COMPOSITION, according to claim 15, characterized by the fact that the hydrophobic brittle vehicle contains less than approximately 0.4%; or less than approximately 0.2%; or less than approximately 0.1% of agents
    Petition 870170051409, of 7/21/2017, p. 12/20
    6/11 surfactants, protic solvents, polar aprotic solvents and silicone thickening agents.
    [17]
    17. TOPIC THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that the tetracycline antibiotic is selected from the group consisting of tetracycline, oxytetracycline, demeclocycline, doxycycline, limecycline, meclocycline, methaclicline, minocycline, rolithetracycline and tigecycline.
    [18]
    18. TOPIC THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that the tetracycline antibiotic is hydrophobic.
    [19]
    19. TOPIC THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that the tetracycline antibiotic is present in a free base form, a hydrate form, a salt form or in a complex form.
    [20]
    20. TOPIC THERAPEUTIC COMPOSITION, according to claim 19, characterized by the fact that the logarithm of the tetracycline antibiotic distribution constant at pH 7.0 (buffer / chloroform) is equal to or less than approximately 0.2.
    [21]
    21. THERAPEUTIC TOPIC COMPOSITION, according to claim 18, characterized by the fact that the tetracycline antibiotic does not include any hydroxy group in Carbons 5, 6, and 7.
    [22]
    22. THERAPEUTIC TOPIC COMPOSITION, according to claim 18, characterized by the fact that the tetracycline antibiotic is selected from the group consisting of minocycline and doxycycline; or be minocycline.
    [23]
    23. TOPICAL THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that it also comprises an additional active agent.
    [24]
    24. TOPICAL THERAPEUTIC COMPOSITION, according to claim 23, characterized by the fact that the additional active agent is selected from the group consisting of an active plant-based extract, an acaricide, a skin stain removing agent and keratosis, an allergen , an alpha hydroxyl acid, an analgesic agent, an androgen, an
    Petition 870170051409, of 7/21/2017, p. 13/20
    7/11 anti-acne, an anti-allergic agent, an anti-aging agent, an antibacterial agent, an antibiotic, an anti-aging agent, an anti-cancer agent, an anti-dandruff agent, an anti-depressant agent, an anti-dermatitis agent, an anti-fungal agent, an antifungal agent, an antihistamine, an anthelmintic agent, an anti-hyperkeratosis agent, an anti-infective agent, an anti-inflammatory agent, an anti-irritant, an antilipemic agent, an antimicrobial agent, an antimycotic agent, an antioxidant, an antiparasitic agent , an antiproliferative agent, an antipruritic agent, an antipsoriatic agent, an anti-rosacea agent, an anti-seborrheic agent, an anti-swelling agent, an anti-swelling agent, an anti-viral agent, an anti-warming agent, an anti-wrinkle agent, an antileveduriform agent, an astringent agent , a beta-hydroxy acid, benzoyl peroxide, a topical cardiovascular agent, a chemotherapeutic agent, a corticosteroid, an immunogenic substance, a dicarboxylic acid, a disinfectant, an estrogen, a fungicidal agent, a hair growth regulating agent, a hapten, a hormone, a hydroxy acid, an immunosuppressive agent, an immunoregulatory agent, an immunomodulatory agent, an immunostimulating agent, insecticidal agent, insect repellent agent, keratolytic agent, lactam, local anesthetic agent, lubricating agent, masking agent, metal, metal oxide, mutocide, neuropeptide, agent non-steroidal anti-inflammatory, an oxidizing agent, a pediculicide, a peptide, a pesticide, a protein, a photodynamic therapy agent, a progesterone, a radical scavenger, an overfatting agent, a retinoid, a therapeutic agent, an agent scabicide, a sedative, a self-tanning agent, a skin protection agent, a skin bleaching agent, a steroid, a steroid hormone, a vasoactive agent, vasoconstricting agent, vasodilating agent, vitamin, vitamin A, vitamin A derivative, vitamin B, vitamin B derivative, vitamin C, vitamin C derivative, vitamin D, derivative vitamin D, a vitamin D analogue, a vitamin F, a vitamin F derivative, a vitamin K, a vitamin K derivative, a healing agent and a wart-removing agent.
    Petition 870170051409, of 7/21/2017, p. 14/20
    11/11
    [25]
    25. TOPICAL THERAPEUTIC COMPOSITION, according to claim 1, characterized by the fact that, when tested in an in vitro model in tests with Franz cells, through the use of human skin or pig skin, provide an amount of tetracycline in the skin that is higher than the respective amount transferred transdermally.
    [26]
    26. TOPICAL THERAPEUTIC COMPOSITION, according to claim 25, characterized by the fact that, when tested in an in vitro model in tests with Franz cells, using human skin or pig skin, the ratio between the amount of tetracycline in the skin and the amount transdermally transferred is greater than approximately 100: 1, or between approximately 100: 1 and approximately 10: 1, or between approximately 10: 1 and approximately 2: 1, or greater than 1: 1.
    [27]
    27. THERAPEUTIC TOPIC COMPOSITION, according to claim 1, characterized by the fact that the concentration of tetracycline in the hydrophobic brittle composition is greater than the lowest concentration that results in the intradermal administration of sufficient concentrations of tetracycline to have a therapeutic effect when tested in in vitro model in tests with Franz cells, using human skin or pig skin.
    [28]
    28. THERAPEUTIC TOPIC COMPOSITION, according to claim 1, characterized by the fact that the composition prevents the degradation of the tetracycline antibiotic by application at the target treatment site.
    [29]
    29. METHOD OF PREVENTING, TREATING OR RELIEFING THE SYMPTOMS OF A DERMATOLOGICAL, OPHTHALMOLOGICAL, GYNECOLOGICAL OR MUCOUS DISEASE, characterized by the fact of understanding the topical application to the target area of a therapeutic hydrophobic composition of any of the claims below.
    [30]
    30. METHOD, according to claim 29, characterized by the fact that the disease includes bacterial infection, inflammation, oxidative stress and neurodegeneration and / or apoptosis as one of its etiological factors.
    Petition 870170051409, of 7/21/2017, p. 15/20
    9/11
    [31]
    31. METHOD, according to claim 29, characterized by the fact that the disease is selected from the group consisting of:
    - a dermatological condition, such as abscess, acne, acne conglobata, acne fulminans, acne vulgaris, acne scars, acute febrile neutrophilic dermatosis, acute lymphangitis, allergic contact dermatitis, alopecia, athlete's foot, atopic dermatitis, bacterial skin infections, baldness, basal cell carcinoma, blisters, bromhidrosis, bullous pemphigoid, burn, calluses, candidiasis, carbuncles, cellulite, chemical burns, chickenpox, cholesteatoma, cholinergic urticaria, chronic effects of sunlight, herpes, cold-induced urticaria, pustules, grains, larvae cutaneous migrans, cutaneous abscess, cutaneous larva migrans, cutaneous myiasis, dark spots, parasitic infestation delirium, Dercum disease, dermatitis, herpetiform dermatitis, dermatological pain, dermatological inflammation, dermographism, dermatophytoses, rashes and drug reactions, dyshydrotic eczema, dysplasia ectodermal, eczema, ectima, epidermoid cyst, epidermal necrolysis, eris ipela, erythrasma, exfoliative dermatitis, erythema multiforme, erythema nodosum, folliculitis, fungal nasal infections, fungal skin infections, boils, gangrene, genital herpes, granuloma annulare, lice, suppurative hydradenitis, urticaria, folliculitis, hirsutism, hyperhidrosis, hyperhidrosis, hyperhidrosis, hyperhidrosis, hyperhidrosis , impetigo, inflammatory acne, ingrown nails, intertrigo, irritant contact dermatitis, ischemic necrosis, itching, fungal infection in the groin (Jock's itch), Kaposi's sarcoma, keratosis pilaris, chronic simple lichen, lichen planus, lichen sclerosus, lymphadenitis, lymphangitis, malignant melanoma, mastocytosis, measles, melanoma, miliaria, signs, molluscum contagiosum, methicillin-resistant Staphylococcus aureus or SARM / MRSA, necrotizing subcutaneous infection, necrotizing fasciitis, necrotizing myositis, papulopustular acne, nodular acne, non-inflammatory acne, non-inflammatory acne oral, panniculitis, paronychia, parapsoriasis, parasitic skin infections, pênfi go, photoallergy, photodamage, photoirritation, photosensitivity, papules, pediculosis, perioral dermatitis, pimples, pityriasis rosea, pityriasis rosea, pityriasis rosea, pityriasis rubilar pilaris, poison ivy, post-operative or post-surgical skin diseases, pressure ulcers, pressure ulcers, pressure ulcers pressure, pruritus, beard pseudofolliculitis, psoriasis, pruritic urticarial papules and plaques of pregnancy
    Petition 870170051409, of 7/21/2017, p. 16/20
    10/11 (PUPP), purple, pustules, pyogenic granuloma, rashes, ringworm, rosacea, roseola, rubella, scabies, scalded skin syndrome, scars, scleroderma, sebaceous cyst, seborrheic dermatitis, seborrheic keratosis, herpes zoster skin, skin cancer, skin cancer, skin neoplasms, skin rash, skin ulcers, squamous cell carcinoma, staphylococcal scalded skin syndrome, stasis dermatitis, Stevens-Johnson syndrome, burns, sun spots, thermal burns, tinea corporis, tinea cruris, tinea pedis, tinea versicolor, toxic epidermal necrolysis, skin trauma or injury, varicella-zoster virus, vitamin D deficiency, viral skin infections, vitiligo, warts, aquagenic urticaria, wrinkles, xerosis, herpes zoster and yeast skin infections;
    - a disease of a body cavity or mucous surface, a disease in the nose, mouth, ears, eyes, respiratory system, vagina, urethra or rectum, chlamydia infection, gonorrhea, hepatitis B, herpes, HIV / AIDS, human papilloma virus (HPV), genital warts, bacterial vaginosis, candidiasis, soft cancer, inguinal granuloma, venereal lymphogranuloma, mucopurulent cervicitis (MPC), contagious molluscum, non-gonococcal urethritis (UNG), trichomoniasis, vulvovirus, vulvar diseases , vulvar pain, yeast infection, vulvar dystrophy, intraepithelial vulvar neoplasia (VIN), contact dermatitis, pelvic inflammation, endometritis, salpingitis, oophoritis, genital cancer, cervical cancer, vulva cancer, vagina cancer, vaginal dryness, dyspareunia, anal and rectal disease, abscess / anal fistula, anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids, anal itching, anal itching, fecal incontinence, constipation, colon polyps on and rectum;
    - an eye disease, such as eye redness, eye pain or sensitivity to light, blurred vision, vision loss, visual disturbances - floaters, sparking, distortion, halos, etc., itching / burning, watering / discharge, feeling of body strange in the eye, eyelid problems, double vision; ophthalmic allergy, blepharitis, cataracts, central serous chorioretinopathy, color vision problems, corneal abrasion, corneal edema, corneal ulcer, conjunctivitis, contact lens complications, dacryocystitis, blurred vision, dry eye, Eales disease episcleritis,
    Petition 870170051409, of 7/21/2017, p. 17/20
    11/11 ectropion, eyelid entropion, eyelid cellulitis, tired sight, focal spasm, acute glaucoma, glaucoma, iritis, keratoconus, Lyme disease, macular degeneration, macular edema, macular hole, medication eye toxicity, myasthenia gravis, cicatricial pemphigoid ocular, ophthalmic migraine, presbyopia, obstructed lacrimal duet, optic neuritis, optic nerve leak, orbital fracture, orbital cellulitis, phytotenulose, pterygium, recurrent corneal erosion, retinal artery occlusion, retinal detachment, retinal tear, vein occlusion retina, sarcoidosis, scleritis, sinus disease, strabismus (ocular misalignment), subconjunctival hemorrhage, temporal arteritis, ocular thyroid disease, trichiasis, eyelid tumors, eyelid spasms (eyelid myokymia), uveitis, vitreous detachment and vitreous hemorrhage.
    [32]
    32. METHOD, according to claim 30, characterized in that the disease is selected from the group consisting of a skin infection, acne, rosacea, an eye infection, ocular rosacea, blepharitis, dry eye, trachoma and glaucoma.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US1159250A|1914-05-01|1915-11-02|Frank Moulton|Vaginal irrigator.|
    US1666684A|1926-01-15|1928-04-17|Carstens Mfg Co H|Vaginal douche|
    US1924972A|1929-04-15|1933-08-29|Carl J Beckert|Stabilized egg product|
    US2085733A|1935-07-15|1937-07-06|John C Bird|Shaving cream|
    US2390921A|1943-03-23|1945-12-11|Ethel Hudson Clark|Applicator for facial creams|
    US2524590A|1946-04-22|1950-10-03|Carsten F Boe|Emulsion containing a liquefied propellant gas under pressure and method of spraying same|
    US2586287A|1948-12-11|1952-02-19|Colagte Palmolive Peet Company|Aluminum sulfamate antiperspirant preparation|
    US2617754A|1949-08-29|1952-11-11|Procter & Gamble|Cosmetic cream|
    US3062715A|1953-11-18|1962-11-06|George S Pfaus|Vaginal tablet|
    US2767712A|1954-03-01|1956-10-23|Neil S Waterman|Medicinal applicator|
    GB808104A|1955-01-04|1959-01-28|Udylite Res Corp|Electrodeposition of copper from aqueous alkaline cyanide solutions|
    GB808105A|1956-06-15|1959-01-28|Ici Ltd|New pharmaceutical compositions|
    US3092555A|1958-04-21|1963-06-04|Roy H Horn|Relatively collapsible aerosol foam compositions|
    US3144386A|1958-05-09|1964-08-11|Merck & Co Inc|Mastitis aerosol foam|
    US2968628A|1958-10-17|1961-01-17|Shulton Inc|Propellant composition|
    US3142420A|1959-11-09|1964-07-28|Neotechnic Eng Ltd|Metering dispenser for aerosol with fluid pressure operated piston|
    US3178352A|1959-02-27|1965-04-13|Erickson Roy|Shaving method and composition therefor|
    US3141821A|1959-03-17|1964-07-21|Lehn & Fink Products Corp|Synergistic combination of alkyl sulfonates, alkylaryl sulfonates and topical antibacterial agents for local antisepsis|
    US3004894A|1959-04-07|1961-10-17|Upjohn Co|Therapeutic composition comprising tetracycline and a dioxolane|
    GB922930A|1959-09-21|1963-04-03|Sunnen Joseph|Spermicidal composition and method of making same|
    US3092255A|1960-02-05|1963-06-04|Robert F Hohman|Sorting apparatus|
    US3067784A|1960-04-14|1962-12-11|Esta Medical Lab Inc|Adapter connecting aerosol container valve stem to dispenser for filling said dispenser|
    NL270627A|1960-10-26|
    US3154075A|1960-11-02|1964-10-27|Norwich Pharma Co|Vaginal applicator|
    GB998490A|1961-06-03|1965-07-14|Albert Fritz Albach|A foam projector|
    DE1926796U|1961-10-12|1965-11-11|Heidolph Elektro K G|FAN.|
    NL285082A|1962-02-28|
    US3330730A|1962-08-03|1967-07-11|Colgate Palmolive Co|Pressurized emulsion quick breaking foam compositions|
    US3252859A|1962-10-24|1966-05-24|Masti Kure Company Inc|Colloidal silica-oil composition and method of using same|
    US3244589A|1962-10-26|1966-04-05|Sunnen|Alkyl phenoxy polyethoxy ether spermicidal aerosol|
    US3261695A|1962-12-24|1966-07-19|Gen Foods Corp|Process for preparing dehydrated foods|
    US3298919A|1962-12-26|1967-01-17|Dow Corning|Shaving cream containing polysiloxanes|
    US3383280A|1963-01-09|1968-05-14|Miles Lab|Dermatological abradant stick-type applicator|
    FR1355607A|1963-01-22|1964-03-20|Improvements to cannula probes and their applications|
    US3149543A|1963-03-04|1964-09-22|Ingersoll Rand Co|Non-lubricated piston|
    FR3476M|1963-05-31|Mediline Ag|Bactericidal composition to spray.|
    US3824303A|1963-07-24|1974-07-16|Yardley Of London Inc|Collapsible foam pre-electric shave lotion containing diester lubricants|
    GB1081949A|1963-08-12|1967-09-06|Avon Prod Inc|Improvements in cosmetic mask|
    US3333333A|1963-08-14|1967-08-01|Rca Corp|Method of making magnetic material with pattern of embedded non-magnetic material|
    US3236457A|1963-08-21|1966-02-22|John R Kennedy|Composite spray container assembly|
    US3263867A|1963-12-26|1966-08-02|Valve Corp Of America|Metering button-type aerosol actuator|
    US3395214A|1964-01-09|1968-07-30|Scholl Mfg Co Inc|Antiperspirant composition providing a readily collapsible sprayable foam|
    US3278093A|1964-01-13|1966-10-11|Valve Corp Of America|Metering and non-metering aerosol actuator button|
    GB1052724A|1964-04-27|
    US3303970A|1964-07-14|1967-02-14|Jerome Marrow|Device for simultaneously dispensing from plural sources|
    US3395215A|1964-10-15|1968-07-30|Colgate Palmolive Co|Pressurized lotion composition|
    US3384541A|1964-10-28|1968-05-21|William G. Clark|Spermicidal vaginal pharmaceutical concentrate for producing nonaqueous foam with aerosol propellants|
    US3263869A|1964-11-03|1966-08-02|Calmar Inc|Liquid dispenser with overcap|
    US3342845A|1964-11-05|1967-09-19|Upjohn Co|Terphenyl triisocyanates|
    US3419658A|1965-01-25|1968-12-31|Du Pont|Nonaqueous aerosol foams containing mineral oil|
    US3346451A|1965-01-27|1967-10-10|S E Massengill Company|Concentrated liquid lactic acid douche preparation containing aromatics|
    US3301444A|1965-08-12|1967-01-31|Oel Inc|Aerosol metering valve|
    US3456052A|1965-09-28|1969-07-15|Garrett Lab Inc|Aerosol composition containing butoxymonoether of a polyoxyalkylene glycol|
    GB1121358A|1965-10-21|1968-07-24|Bristol Myers Co|Aerosol manufacture|
    US3849569A|1965-12-02|1974-11-19|Glaxo Lab Ltd|Composition containing procaine penicillin|
    BE692228A|1966-01-10|1967-07-05|
    US3401849A|1966-05-24|1968-09-17|Robert L. Weber|Low force metering valve|
    US3886084A|1966-09-29|1975-05-27|Champion Int Corp|Microencapsulation system|
    US3377004A|1966-10-03|1968-04-09|Gen Mills Inc|Metered dispensing container|
    GB1201918A|1966-12-21|1970-08-12|Bespak Industries Ltd|Improvements in or relating to valves for pressurised dispensers|
    US3527559A|1967-01-05|1970-09-08|Standard Pharmacal Corp|Dense aqueous aerosol foam depilatory compositions containing a mixture of alkaline metal and alkali metal thioglycolates and a fatty alcohol-alkylene oxide wax emulsifying agent|
    US3366494A|1967-02-15|1968-01-30|Du Pont|Pressurized aerosol food emulsions|
    US3561262A|1967-10-26|1971-02-09|Magnaflux Corp|Water soluble developer|
    US3540448A|1968-01-17|1970-11-17|Joseph Sunnen|Rechargeable applicator for dispensing substances in a foam condition|
    DE1926796A1|1968-05-27|1970-03-19|Dudiuyt Jean Paul|Aerosol compsn. and container|
    US3563098A|1968-06-28|1971-02-16|Rex Chainbelt Inc|Automatic quick release mechanism|
    US3559890A|1968-09-03|1971-02-02|William R Brooks|Foam dispenser|
    US3878118A|1968-09-06|1975-04-15|Wilkinson Sword Ltd|Self-heating chemical compositions|
    US3667461A|1968-11-05|1972-06-06|Paul A Zamarra|Disposable syringe|
    CA975500A|1969-02-06|1975-09-30|Joseph G. Spitzer|Structures such as applicator pads for cleaning and other purposes, propellant compositions for forming the same, and process|
    US3866800A|1969-02-12|1975-02-18|Alberto Culver Co|Non-pressurized package containing self-heating products|
    US3966090A|1969-02-17|1976-06-29|Dart Industries Inc.|Package for dispensing an antiseptic composition|
    US4001391A|1969-04-18|1977-01-04|Plough, Inc.|Means for depositing aerosol sprays in buttery form|
    US3819524A|1969-06-17|1974-06-25|Colgate Palmolive Co|Cosmetic composition for thermal dispensing|
    US3577518A|1969-07-18|1971-05-04|Nat Patent Dev Corp|Hydrophilic hairspray and hair setting preparations|
    US3787566A|1969-07-29|1974-01-22|Holliston Labor Inc|Disinfecting aerosol compositions|
    BE759520A|1969-11-28|1971-04-30|Aspro Nicholas Ltd|ASPIRIN COMPOSITIONS|
    GB1353381A|1971-02-04|1974-05-15|Wilkinson Sword Ltd|Substituted p-menthanes and compositions containing them|
    GB1351761A|1971-02-04|1974-05-01|Wilkinson Sword Ltd|Substituted p-menthane carboxamides and compositions containing them|
    GB1351762A|1971-02-14|1974-05-01|Wilkinson Sword Ltd|Tobacco and tobacco-containing manufactures|
    CA958338A|1971-03-08|1974-11-26|Bristol-Myers Canada Limited|Antiperspirant powder aerosol compositions containing aluminum chloride and water soluble aluminum compounds and methods of preparation|
    US3770648A|1971-07-12|1973-11-06|Bristol Myers Co|Anhydrous aerosol foam|
    US3912667A|1971-09-13|1975-10-14|Spitzer Joseph G|Structures such as applicator pads for cleaning and other purposes, propellant compositions for forming the same and process|
    BE788788A|1971-09-13|1973-03-13|Treuhandvereinigung Ag|PRODUCT FOR PRESERVING, PROMOTING AND RESTORING HAIR AND METHOD OF MANUFACTURING THIS PRODUCT|
    US3997467A|1971-11-26|1976-12-14|Pharmacia Aktiebolag|Foam forming composition|
    SE358308B|1971-11-26|1973-07-30|Pharmacia Ab|
    CH554911A|1971-12-30|1974-10-15|Ciba Geigy Ag|USE OUTSIDE THE TEXTILE INDUSTRY OF NEW 4,4'-DIVINYLDIPHENYL COMPOUNDS AS OPTICAL LIGHTENING AGENTS FOR ORGANIC MATERIALS.|
    JPS4892282U|1972-02-05|1973-11-06|
    US3963833A|1972-06-02|1976-06-15|Colgate-Palmolive Company|Antiperspirant composition and method containing a dihydro-benzofuran and an astringent metal salt|
    US3841525A|1972-06-14|1974-10-15|N Siegel|Aerosol spray device with cam activator|
    US3849580A|1972-09-05|1974-11-19|American Home Prod|Aerosol dispensing system for anhydrous edible fat compositions|
    US3751562A|1972-09-22|1973-08-07|Princeton Biomedix|Medicated gelled oils|
    US3970584A|1973-02-14|1976-07-20|S. C. Johnson & Son, Inc.|Aerosol package containing a foam-forming emulsion and propellent system|
    US4439416A|1973-03-23|1984-03-27|Colgate-Palmolive Company|Self-heating shaving composition|
    GB1423179A|1973-05-16|1976-01-28|Wilkinson Sword Ltd|Pressurised shaving foam dispensers|
    YU36328B|1973-07-18|1983-06-30|Elastin Werk Ag|Method of manufacturing red foils for packing sausages|
    US4110426A|1973-07-24|1978-08-29|Colgate-Palmolive Company|Method of treating skin and hair with a self-heated cosmetic|
    US3865275A|1973-07-30|1975-02-11|Raymond Lee Organization Inc|Apparatus for operating an aerosol can|
    US3929985A|1974-01-18|1975-12-30|Richardson Merrell Inc|Anhydrous candicidin foam compositions|
    DE2501548A1|1974-01-25|1975-07-31|Procter & Gamble|ORAL TREATMENT PRODUCTS|
    GB1457671A|1974-01-31|1976-12-08|Wilkinson Sword Ltd|Flavour|
    US3923970A|1974-03-29|1975-12-02|Carter Wallace|Stable aerosol shaving foams containing mineral oil|
    US3962150A|1974-04-10|1976-06-08|Richardson-Merrell Inc.|Foam producing cleansing compositions|
    US3953591A|1974-04-29|1976-04-27|The Procter & Gamble Company|Fatty acid, polysiloxane and water-soluble polymer containing skin conditioning emulsion|
    US3966632A|1974-06-06|1976-06-29|G. D. Searle & Co.|Vegetable oil emulsion|
    US4145411A|1974-09-05|1979-03-20|Colgate-Palmolive Company|Pressurized foaming shaving composition|
    JPS5729213B2|1974-11-12|1982-06-21|
    US4052513A|1974-12-13|1977-10-04|Plough, Inc.|Stable topical anesthetic compositions|
    US3952916A|1975-01-06|1976-04-27|Warner-Lambert Company|Automatic dispenser for periodically actuating an aerosol container|
    US3970219A|1975-03-03|1976-07-20|Spitzer Joseph G|Aerosol containers for foaming and delivering aerosols and process|
    US4019657A|1975-03-03|1977-04-26|Spitzer Joseph G|Aerosol containers for foaming and delivering aerosols|
    US4018396A|1975-05-05|1977-04-19|Bechtel International Corporation|Embedded housing for ore crusher|
    US3993224A|1975-09-08|1976-11-23|Aerosol Investments, Ltd.|Spout for two-component resin dispenser|
    DE2608226A1|1976-02-28|1977-09-08|Haarmann & Reimer Gmbh|AGENTS WITH PHYSIOLOGICAL COOLING EFFECT|
    US4100426A|1976-03-10|1978-07-11|Square D Company|Load controlling means|
    IL49491A|1976-04-29|1979-09-30|Rosenberg Peretz|Quickly-attachable connector for plastic pipes|
    US4102995A|1976-05-13|1978-07-25|Westwood Pharmaceuticals Inc.|Tar gel formulation|
    US4124149A|1976-07-19|1978-11-07|Spitzer Joseph G|Aerosol container with position-sensitive shut-off valve|
    CA1089368A|1976-08-02|1980-11-11|Daniel C. Geary|Polyethoxylated fatty alcohol in antiperspirant sticks|
    IL52045A|1976-08-25|1979-12-30|Mundipharma Ag|Sprayable germicidal foam compositions|
    US4310510A|1976-12-27|1982-01-12|Sherman Kenneth N|Self administrable anti-fertility composition|
    US4252787A|1976-12-27|1981-02-24|Cambridge Research And Development Group|Anti-fertility composition and method|
    US4083974A|1977-03-07|1978-04-11|The Upjohn Company|Topical steroidal anti-inflammatory preparations containing polyoxypropylene 15 stearyl ether|
    JPS5744429Y2|1977-04-14|1982-10-01|
    US4386104A|1977-04-19|1983-05-31|Nazzaro Porro Marcella|Process for the treatment of acne|
    GB2004746B|1977-10-03|1982-03-10|Scherico Ltd|Stable hopical anaesthetic compositions|
    JPS5639815Y2|1977-11-25|1981-09-17|
    SE7713618L|1977-12-01|1979-06-02|Astra Laekemedel Ab|LOCAL ANESTHETIC MIXTURE|
    IT1114950B|1977-12-30|1986-02-03|Porro Marcella|COMPOSITIONS FOR ACNE TREATMENT AND THERAPY|
    US4160827A|1978-02-06|1979-07-10|The Upjohn Company|Metronidazole phosphate and salts|
    US4229432A|1978-04-19|1980-10-21|Bristol-Myers Company|Antiperspirant stick composition|
    US4603812A|1978-06-27|1986-08-05|The Dow Chemical Company|Foam-generating pump sprayer|
    US4178373A|1978-08-21|1979-12-11|William H. Rorer, Inc.|Coal tar gel composition|
    US4214000A|1978-10-30|1980-07-22|Johnson & Johnson|Zinc salt of all-trans-retinoic acid for the treatment of acne|
    JPS5569682U|1978-11-08|1980-05-13|
    JPS5569682A|1978-11-20|1980-05-26|Toyo Aerosol Kogyo Kk|Foam shrinkable composition|
    US4213979A|1978-12-18|1980-07-22|Plough, Inc.|Stable sprayable hydrocortisone product|
    US4954487A|1979-01-08|1990-09-04|The Procter & Gamble Company|Penetrating topical pharmaceutical compositions|
    US4439441A|1979-01-11|1984-03-27|Syntex Inc.|Contraceptive compositions and methods employing 1-substituted imidazole derivatives|
    US4226344A|1979-02-06|1980-10-07|Booth, Inc.|Constant flow valve actuator|
    CH639913A5|1979-03-16|1983-12-15|Aerosol Service Ag|Container for receiving and delivering a liquid substance|
    US4335120A|1979-03-21|1982-06-15|Hoffmann-La Roche Inc.|Administration of biologically active vitamin D3 and vitamin D2 materials|
    US4230701A|1979-03-21|1980-10-28|Hoffmann-La Roche Inc.|Administration of biologically active vitamin D3 and vitamin D2 materials|
    US4278206A|1979-04-13|1981-07-14|Ae Development Corporation|Non-pressurized dispensing system|
    US4241048A|1979-05-01|1980-12-23|Bristol-Myers Company|Suspension composition of benzocaine|
    JPS5643443B2|1979-05-18|1981-10-13|
    US4268499A|1979-06-07|1981-05-19|Dow Corning Corporation|Antiperspirant emulsion compositions|
    US4241149A|1979-07-20|1980-12-23|Temple University|Canal clathrate complex solid electrolyte cell|
    DE2931469A1|1979-08-02|1981-02-26|Bayer Ag|SURFACE SEALED MOLDED BODIES MADE OF CELLED POLYURETHANE ELASTOMERS AND METHOD FOR THE PRODUCTION THEREOF|
    JPS5854931B2|1979-09-04|1983-12-07|Toyota Motor Co Ltd|
    US4323694A|1981-04-13|1982-04-06|Finetex, Inc.|Benzoic acid esters|
    US4271149B1|1979-09-21|1983-04-19|
    US4299826A|1979-10-12|1981-11-10|The Procter & Gamble Company|Anti-acne composition|
    EP0032309A3|1980-01-10|1981-08-05|Imperial Chemical Industries Plc|Production of catalyst component, catalyst and use thereof|
    US4309995A|1980-01-28|1982-01-12|Sacco Susan M|Vaginal irrigation apparatus|
    JPS6323971B2|1980-03-27|1988-05-18|Mitsubishi Chem Ind|
    SE8004580L|1980-06-19|1981-12-20|Draco Ab|PHARMACEUTICAL PREPARATION|
    US4338211A|1980-06-30|1982-07-06|The Procter & Gamble Company|Liquid surfactant skin cleanser with lather boosters|
    US4508705A|1980-07-02|1985-04-02|Lever Brothers Company|Skin treatment composition|
    US4323582A|1980-07-21|1982-04-06|Siegel Norman H|Method of treating animals and humans for internal and external parasites|
    JPS601113Y2|1980-07-22|1985-01-12|
    JPS5914282B2|1980-07-31|1984-04-04|Kobe Steel Ltd|
    US4329990A|1980-08-07|1982-05-18|Sneider Vincent R|Expanding swab applicator|
    US4325939A|1980-09-22|1982-04-20|Richardson-Vicks Inc.|Zinc derivatives and their use in dental compositions|
    US4305936A|1980-10-09|1981-12-15|Dermik Laboratories|Topical corticosteroid formulations|
    US4292250A|1980-11-17|1981-09-29|Wisconsin Alumni Research Foundation|Vitamin D derivatives|
    EP0052404B1|1980-11-19|1987-05-27|THE PROCTER &amp; GAMBLE COMPANY|Non-yellowing topical pharmaceutical composition|
    EP0065513B1|1980-11-27|1985-09-18|CHINOIN Gyogyszer és Vegyészeti Termékek Gyára RT.|Antimycotic synergistic pharmaceutical compositions and process for the preparation thereof|
    DE3147726A1|1980-12-03|1982-06-24|Leo Pharmaceutical Products Ltd. A/S , 2750 Ballerup|ANTIBIOTIC COMPLEXES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS THAT CONTAIN THESE COMPOUNDS|
    US4352808A|1980-12-12|1982-10-05|Schering Corporation|3-Aralkyloxy-2,3-dihydro-2-benzothiophenes and related derivatives, their use as antimicrobials and pharmaceutical formulations useful therefore|
    US4522948A|1981-04-24|1985-06-11|Syntex Inc.|Spermicidal substituted 1-alkylimidazoles|
    US4393066A|1981-06-05|1983-07-12|Garrett David M|Method for treatment of herpetic lesions|
    US4607101A|1981-08-27|1986-08-19|Jaye-Boern Laboratories, Inc.|Method of treating acne vulgaris with a composition containing carbamide peroxide|
    US4469674A|1981-09-03|1984-09-04|Richardson-Vicks Inc.|Stable oral compositions containing zinc and fluoride compounds|
    US4440320A|1981-11-30|1984-04-03|Wernicke Steven A|Foam dispensing apparatus|
    LU83876A1|1982-01-15|1983-09-02|Oreal|COSMETIC COMPOSITION FOR TREATMENT OF KERATINIC FIBERS AND METHOD FOR TREATING THE SAME|
    LU83949A1|1982-02-16|1983-09-02|Oreal|COMPOSITION FOR THE TREATMENT OF KERATINIC MATERIALS CONTAINING AT LEAST ONE CATIONIC POLYMER AND AT LEAST ONE ANIONIC LATEX|
    US5087618A|1982-05-18|1992-02-11|University Of Florida|Redox carriers for brain-specific drug delivery|
    US4529605A|1983-01-12|1985-07-16|Una E. Lynch|Bathing oil composition|
    US4661340A|1983-06-06|1987-04-28|Interkemia Vegyipari Gazdasagi Tarsasag|Quail egg based stabilized foam compositions for cosmetic purposes|
    GB8315787D0|1983-06-08|1983-07-13|Briggs J H|Coolant spray|
    JPS6347684B2|1983-06-20|1988-09-26|Kao Soap Co|
    US4552872A|1983-06-21|1985-11-12|The Procter & Gamble Company|Penetrating topical pharmaceutical compositions containing corticosteroids|
    NL8302559A|1983-07-18|1985-02-18|Philips Nv|ELECTROLYTIC CONDITIONER.|
    GB8330969D0|1983-11-21|1983-12-29|Wellcome Found|Promoting healing|
    US4612193A|1983-12-23|1986-09-16|Del Laboratories, Inc.|Sty ointment and method of using the same|
    GB8402748D0|1984-02-02|1984-03-07|Dunlop Ltd|Intravaginal device|
    US4985459A|1984-02-08|1991-01-15|Richardson-Vicks, Inc.|Analgesic and anti-inflammatory compositions comprising diphenhydramine and methods of using same|
    US4912124A|1984-02-23|1990-03-27|Ortho Pharmaceutical Corporation|Antifungal dermatological solution|
    NZ207341A|1984-03-01|1988-02-29|Harvey Alex Ind Ltd|Device containing chemical impregnants for insertion into a body cavity of an animal|
    US4628063A|1984-03-08|1986-12-09|Dana P. Brigham|Antiviral pharmaceutical preparations and methods for their use|
    US4877805A|1985-07-26|1989-10-31|Kligman Albert M|Methods for treatment of sundamaged human skin with retinoids|
    US4574052A|1984-05-31|1986-03-04|Richardson-Vicks Inc.|Crackling aerosol foam|
    GB8416638D0|1984-06-29|1984-08-01|Beecham Group Plc|Topical treatment and composition|
    DE3564973D1|1984-08-06|1988-10-20|Ciba Geigy Ag|Process for paper sizing with anionic hydrophobic sizing agents and cationic retention agents|
    US4595526A|1984-09-28|1986-06-17|Colgate-Palmolive Company|High foaming nonionic surfacant based liquid detergent|
    SE8404895L|1984-10-01|1986-03-17|Torkel Ingemar Fischer|MEANS OF A SENSITIVITY TEST|
    IE58110B1|1984-10-30|1993-07-14|Elan Corp Plc|Controlled release powder and process for its preparation|
    CA1261276A|1984-11-09|1989-09-26|Mark B. Grote|Shampoo compositions|
    US4701320A|1984-11-29|1987-10-20|Lederle , Ltd.|Composition stably containing minocycline for treating periodontal diseases|
    US4627973A|1984-12-14|1986-12-09|Charles Of The Ritz Group Ltd.|Skin mousse|
    AU5078885A|1984-12-20|1986-06-26|Warner-Lambert Company|Non-irritant detergent|
    US4673569A|1985-02-12|1987-06-16|Faberge Incorporated|Mousse hair composition|
    DE3670569D1|1985-03-01|1990-05-31|Procter & Gamble|Mild cleaning foam.|
    US5002680A|1985-03-01|1991-03-26|The Procter & Gamble Company|Mild skin cleansing aerosol mousse with skin feel and moisturization benefits|
    US4639367A|1985-03-18|1987-01-27|Product Resources International, Inc.|Aerosol foam|
    AU5549486A|1985-03-18|1986-10-13|Product Resources International, Inc.|Exothermic stable foam compositions|
    US4752465A|1985-09-20|1988-06-21|Product Resources International, Inc.|Aerosol foam|
    US5094853A|1985-04-26|1992-03-10|S. C. Johnson & Son, Inc.|Method of preparing a water-soluble stable arthropodicidally-active foam matrix|
    US4965063A|1985-05-24|1990-10-23|Irene Casey|Cleaner and disinfectant with dye|
    DE3521713A1|1985-06-18|1986-12-18|Henkel KGaA, 4000 Düsseldorf|OIL-IN-WATER EMULSIONS WITH IMPROVED VISCOSITY BEHAVIOR|
    US4672078A|1985-07-03|1987-06-09|Schering-Plough Corporation|Urea stabilized with a lactone in various pharmaceutical and cosmetic preparations|
    GB8519426D0|1985-08-01|1985-09-04|Ici Plc|Composition for personal care products|
    US4806262A|1985-08-14|1989-02-21|The Procter & Gamble Company|Nonlathering cleansing mousse with skin conditioning benefits|
    EP0213827A3|1985-08-14|1988-04-06|The Procter & Gamble Company|Nonfoaming cleansing mousse with skin conditioning benefits|
    AU6175586A|1985-09-11|1987-03-12|Chesebrough-Pond's Inc.|Petroleum jelly, mild detergent anhydrous base compositions|
    FR2591331A1|1985-12-10|1987-06-12|Drevet Jean Baptiste|Device for dispensing metered portions of a product contained in a pressurised receptacle|
    US4837378A|1986-01-15|1989-06-06|Curatek Pharmaceuticals, Inc.|Topical metronidazole formulations and therapeutic uses thereof|
    US5536743A|1988-01-15|1996-07-16|Curatek Pharmaceuticals Limited Partnership|Intravaginal treatment of vaginal infections with buffered metronidazole compositions|
    GB8607570D0|1986-03-26|1986-04-30|Euro Celtique Sa|Vaginal pharmaceutical preparation|
    JPS62241701A|1986-04-11|1987-10-22|Maeda Kogyo Kk|Quick releasing device for hub for bicycle|
    CA1291036C|1986-04-23|1991-10-22|Edwin I. Stoltz|Nasal administration of drugs|
    DE3614515A1|1986-04-29|1987-11-05|Pfeiffer Erich Gmbh & Co Kg|DISCHARGE DEVICE FOR MEDIA|
    FR2598392B1|1986-05-09|1988-08-26|Oreal|PACKAGING FOR TWO PRESSURIZED CONTAINERS|
    PH25150A|1986-06-05|1991-03-13|Ciba Geigy Ag|Novel pharmaceutical preparation for topical application|
    US4770634A|1986-06-11|1988-09-13|Pellico Michael A|Method for treating teeth with foamable fluoride compositions|
    JPH0380644B2|1986-06-18|1991-12-25|Matsuda Kk|
    US4837019A|1986-08-11|1989-06-06|Charles Of The Ritz Group Ltd.|Skin treatment composition and method for treating burned skin|
    US4906453A|1986-08-12|1990-03-06|Jumpeer Nails, Inc.|Mousse product|
    DE3628531C2|1986-08-22|1988-12-15|Merz + Co Gmbh & Co, 6000 Frankfurt, De|
    JPH01503784A|1986-09-05|1989-12-21|
    AU8025787A|1986-09-12|1988-04-07|Upjohn Company, The|Foams for delivery of minoxidil|
    LU86585A1|1986-09-15|1988-04-05|Oreal|COMPOSITION IN THE FORM OF AN AEROSOL FOAM BASED ON A POLYMER DERIVED FROM QUATERNIZED CELLULOSE AND ANIONIC POLYMER|
    JPH0778019B2|1986-11-08|1995-08-23|久光製薬株式会社|Foamed anti-inflammatory analgesic preparation|
    EP0270316A3|1986-12-04|1989-12-06|Pfizer Inc.|Topical compositions comprising 1-substituted imidazoles and nsaids for treatment of acne|
    US4822613A|1986-12-15|1989-04-18|S. C. Johnson & Son, Inc.|Water-soluble foamable insecticidally-active compositions|
    US4822614A|1986-12-19|1989-04-18|S. C. Johnson & Son, Inc.|Bioactive film-forming composition for control of crawling insects and the like|
    US5389677B1|1986-12-23|1997-07-15|Tristrata Inc|Method of treating wrinkles using glycalic acid|
    US4863900A|1987-01-15|1989-09-05|The Research Foundation Of State University Of New York|Method for reducing viral transmission with poly-L-histidine|
    JPS63119420U|1987-01-30|1988-08-02|
    DE3704907A1|1987-02-17|1988-08-25|Bayer Ag|TOPICALLY APPLICABLE PREPARATIONS OF GYRASE INHIBITORS IN COMBINATION WITH CORTICOSTEROIDS|
    US4828837A|1987-03-30|1989-05-09|Liposome Technology, Inc.|Non-crystalline minoxidil composition, its production and application|
    US4933330A|1987-04-01|1990-06-12|Dak-Laboratoriet|Benzoic acid derivatives and use thereof|
    LU86839A1|1987-04-10|1988-12-13|Oreal|DETERGENT AND FOAMING COSMETIC COMPOSITION, DELAYING RE-LUBRICATION OF HAIR|
    EP0311657A4|1987-04-21|1991-09-18|Chattan Nominees Pty. Ltd.|Vaginal douche|
    FR2615173B1|1987-05-13|1989-08-18|Valois|DOSING VALVE FOR LIQUID LOADED WITH A LIQUID OR LIQUEFIED GAS PROPELLER, FOR USE IN THE REVERSE POSITION|
    US4867967A|1987-06-04|1989-09-19|Crutcher Wilbert L|Method for the treatment of pseudofolliculitis barbae|
    US4780309A|1987-06-16|1988-10-25|Warner-Lambert Company|Edible aerosol foam compositions and method of preparing same|
    US4849117A|1987-06-17|1989-07-18|Sanitek Products, Inc.|Concentrated composition for forming an aqueous foam|
    US4885282A|1987-07-02|1989-12-05|Thornfeldt Carl R|Treatment of hyperhidrosis, ichthyosis and wrinkling|
    US4898246A|1987-07-06|1990-02-06|Total Walther Feuerschutz Gmbh|Quick release valve for sprinkler head|
    US5196405A|1987-07-08|1993-03-23|Norman H. Oskman|Compositions and methods of treating hemorrhoids and wounds|
    US4847068A|1987-08-06|1989-07-11|Johnson & Johnson Consumer Products, Inc.|Skin care compositions|
    US4913893A|1987-08-28|1990-04-03|Clairol Incorporated|Aerosol hair setting composition containing an alginate|
    CA1273576A|1987-09-16|1990-09-04|Patrick A. Beauchamp|Topical treatment for diseased skin disorders|
    CA1308664C|1987-09-23|1992-10-13|Paul Thau|Skin care aerosol foam composition containing vaseline|
    US4981677A|1987-09-23|1991-01-01|L'oreal|Petrolatum-containing aerosol foam concentrate|
    US4784842A|1987-09-25|1988-11-15|Jean London|Therapeutic composition for treatment of cuts, burns and abrasions|
    US4772427A|1987-12-01|1988-09-20|Colgate-Palmolive Co.|Post-foaming gel shower product|
    US5143717A|1987-12-30|1992-09-01|Code Blue Medical Corporation|Burn foam and delivery system|
    EP0326196B1|1988-01-14|1992-03-25|Akzo N.V.|Aqueous pharmaceutical preparation|
    JP2643217B2|1988-01-22|1997-08-20|エーザイ株式会社|Aqueous liquid of fat-soluble substance|
    US5719197A|1988-03-04|1998-02-17|Noven Pharmaceuticals, Inc.|Compositions and methods for topical administration of pharmaceutically active agents|
    US4849211A|1988-03-16|1989-07-18|Schrauzer Gerhard N|Product and method for the treatment of acne and other skin disorders|
    US4897262A|1988-03-22|1990-01-30|Playtex Jhirmack, Inc.|Non-aerosol hair spray composition|
    DE3811081A1|1988-03-30|1989-10-12|Schering Ag|USE OF TOPIC APPLICABLE PREPARATIONS FOR THE TREATMENT OF AGING SKIN|
    LU87187A1|1988-03-31|1989-10-26|Oreal|COMBINATION OF PYRIMIDINE DERIVATIVES AND SALICYLIC ACID DERIVATIVES FOR INDUCING AND STIMULATING HAIR GROWTH AND REDUCING HAIR LOSS|
    US4992478A|1988-04-04|1991-02-12|Warner-Lambert Company|Antiinflammatory skin moisturizing composition and method of preparing same|
    US4873078A|1988-04-22|1989-10-10|Plough, Inc.|High-gloss, high-shine lipstick|
    GB8811409D0|1988-05-13|1988-06-15|Unilever Plc|Cosmetic composition|
    US5378730A|1988-06-09|1995-01-03|Alza Corporation|Permeation enhancer comprising ethanol and monoglycerides|
    GB8813766D0|1988-06-10|1988-07-13|Efamol Holdings|Essential fatty acid compositions|
    US4827378A|1988-06-15|1989-05-02|Rockwell International Corporation|Jack coaxial connector EMI shielding apparatus|
    US5217707A|1988-06-16|1993-06-08|Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt.|Pharmaceutical composition and process for the preparation thereof|
    EP0349875A3|1988-07-07|1991-09-25|General Electric Company|Paintable elestomeric compositions|
    US4902281A|1988-08-16|1990-02-20|Corus Medical Corporation|Fibrinogen dispensing kit|
    US4950420A|1988-08-31|1990-08-21|Nalco Chemical Company|Antifoam/defoamer composition|
    US4855294A|1988-09-06|1989-08-08|Theratech, Inc.|Method for reducing skin irritation associated with drug/penetration enhancer compositions|
    GB8821129D0|1988-09-09|1988-10-12|Unilever Plc|Cosmetic composition|
    JPH0559090B2|1988-10-04|1993-08-30|Otsuka Pharma Co Ltd|
    US5135915A|1988-10-14|1992-08-04|Genentech, Inc.|Method for the treatment of grafts prior to transplantation using TGF-.beta.|
    US5186857A|1988-11-14|1993-02-16|Imaginative Research Associates, Inc.|Self-foaming oil compositions and process for making and using same|
    GB8828013D0|1988-12-01|1989-01-05|Unilever Plc|Topical composition|
    US5439670A|1989-11-28|1995-08-08|Riker Laboratories, Inc.|Medicinal aerosol formulations|
    US4970067A|1988-12-12|1990-11-13|Helene Curtis, Inc.|Method and composition to condition hair and impart semi-permanent hair set retention properties|
    US5262407A|1988-12-16|1993-11-16|L'oreal|Use of salicylic derivatives for the treatment of skin aging|
    FR2640942B1|1988-12-23|1991-04-26|Suchard Sa Jacobs|
    EP0376104B2|1988-12-27|2003-08-20|Osaka Shipbuilding Co., Ltd.|Aerosol composition|
    JP2960445B2|1988-12-28|1999-10-06|株式会社大阪造船所|Aerosol composition|
    FR2641185B1|1988-12-29|1991-04-05|Oreal|SHAVING COMPOSITION FOR THE SKIN BASED ON ACYLOXYALKYL FUNCTIONAL POLYORGANOSILOXANES AND METHOD FOR IMPLEMENTING SAME|
    JP2741230B2|1989-01-11|1998-04-15|株式会社コーセー|Foam anhydrous cosmetics|
    LU87449A1|1989-02-09|1990-09-19|Oreal|PROCESS FOR THE MANUFACTURE OF FOAMS FOR USE IN THE COSMETIC AND PHARMACEUTICAL AREAS AND FOAMS OBTAINED BY THIS PROCESS|
    US4919934A|1989-03-02|1990-04-24|Richardson-Vicks Inc.|Cosmetic sticks|
    US4996193A|1989-03-03|1991-02-26|The Regents Of The University Of California|Combined topical and systemic method of administration of cyclosporine|
    US5019375A|1989-03-14|1991-05-28|The Procter & Gamble Company|Low residue antiperspirant creams|
    ES2103737T3|1989-03-17|1997-10-01|Taisho Pharma Co Ltd|PREPARATION OF AEROSOL FOR EXTERNAL USE.|
    US5221696A|1989-03-29|1993-06-22|Alcon Laboratories, Inc.|Use of monoacyl phosphoglycerides to enhance the corneal penetration of ophthalmic drugs|
    DE69020211T2|1989-04-05|1995-11-02|Kao Corp|Cosmetic double emulsion composition.|
    US5071648A|1989-04-06|1991-12-10|Merocel Corporation|Polymeric broad-spectrum antimicrobial materials|
    US5204093A|1989-04-06|1993-04-20|Victor Steven A|Shaving cream composition for the treatment of acne vulgaris and pseudofolliculitis barbae and method of producing and using same|
    US5618798A|1989-04-20|1997-04-08|Bar-Shalom; Daniel|Use of sucralfate to treat baldness|
    US5221534A|1989-04-26|1993-06-22|Pennzoil Products Company|Health and beauty aid compositions|
    GB8909559D0|1989-04-26|1989-06-14|Smith Kline French Lab|Pharmaceutical compositions|
    US4874794A|1989-04-28|1989-10-17|Lidak Biopharmaceuticals|Inflammatory disease treatment|
    US5322683A|1989-05-01|1994-06-21|Leonard Mackles|Anhydrous aerosol foam|
    US5002540A|1989-05-22|1991-03-26|Warren Kirschbaum|Intravaginal device and method for delivering a medicament|
    GB8911853D0|1989-05-23|1989-07-12|Ici Plc|Co2 blown integral skin foams|
    CA1337279C|1989-06-06|1995-10-10|Robert J. Borgman|Intravaginal treatment of vaginal infections with buffered metronidazole compositions|
    US5208031A|1989-06-06|1993-05-04|Kelly Patrick D|Sexual lubricants containing zinc as an anti-viral agent|
    JPH0310636A|1989-06-09|1991-01-18|Matsushita Electric Works Ltd|Vegetable storage chamber under floor|
    US5122519A|1989-06-27|1992-06-16|American Cyanamid Company|Stable, cosmetically acceptable topical gel formulation and method of treatment for acne|
    MX21452A|1989-07-07|1994-01-31|Ciba Geigy Ag|PHARMACEUTICAL PREPARATIONS THAT ARE TOPICALLY ADMINISTERED.|
    JPH0350289A|1989-07-17|1991-03-04|Shiseido Co Ltd|Non-emulsion type foam aerosol composition|
    US5560859A|1989-07-26|1996-10-01|Pfizer Inc.|Post foaming gel shaving composition|
    WO1991001712A1|1989-07-28|1991-02-21|Hisamitsu Pharmaceutical Co., Inc.|Foamed aerosol preparation|
    US4981367A|1989-07-28|1991-01-01|Stranco, Inc.|Portable mixing apparatus|
    JPH0383914A|1989-08-18|1991-04-09|W R Grace & Co|Drug carrier|
    US5219877A|1989-09-25|1993-06-15|Bristol-Myers Squibb Company|Lauryl alcohol as skin penetration enhancer for topical imidazole agents|
    IL95952D0|1989-10-19|1991-07-18|Sterling Drug Inc|Aerosol composition for topical medicament|
    US5508033A|1989-12-06|1996-04-16|Societe D'engrais Composes Mineraux Et Amendments|Utilization of algae extract for the preparation of pharmaceutical, cosmetic, food or agricultural compositions|
    DE69034134T2|1989-12-07|2004-09-09|Instead, Inc., Missoula|METHOD FOR COLLECTING VAGINAL EMISSIONS|
    US5295984A|1989-12-07|1994-03-22|Ultrafem, Inc.|Vaginal discharge collection device and intravaginal drug delivery system|
    WO1991008733A1|1989-12-20|1991-06-27|Schering Corporation|Stable cream and lotion bases for lipophilic drug compositions|
    US4966779A|1989-12-21|1990-10-30|Basf Corporation|Stable, water miscible emulsion comprising a fat-soluble vitamin|
    US5733572A|1989-12-22|1998-03-31|Imarx Pharmaceutical Corp.|Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles|
    US4963351A|1989-12-26|1990-10-16|Bhn Associates|Shaving aid|
    US5100917A|1989-12-29|1992-03-31|Merrell Dow Pharmaceuticals Inc.|Novel a-nor-steroid-3-carboxylic acid derivatives|
    US5104645A|1990-02-02|1992-04-14|The Proctor & Gamble Company|Antidandruff shampoo compositions|
    SE9000485D0|1990-02-09|1990-02-09|Pharmacia Ab|FOAMABLE COMPOSITION FOR PHARMACEUTICAL USE, USE THEREOF AND METHOD OF TREATMENT|
    US5164367A|1990-03-26|1992-11-17|Procyte Corporation|Method of using copper containing compounds to accelerate wound healing|
    US5130121A|1990-04-17|1992-07-14|Isp Investments Inc.|Skin care compositions containing discrete microdroplets of an oil in water stabilized by in situ polymerization of water-soluble vinyl monomer|
    US5007556A|1990-04-18|1991-04-16|Block Drug Company, Inc.|Metering dispenser|
    US5156765A|1990-05-15|1992-10-20|Fox Valley Systems, Inc.|Aerosol foam marking compositions|
    US5112359A|1990-06-04|1992-05-12|Clairol, Inc.|Hair colorants|
    JP3649341B2|1990-06-15|2005-05-18|株式会社資生堂|COMPOSITE AND COMPOSITE COMPOSITION, EMULSION COMPOSITION, AND EMULSION COMPOSITION|
    JPH0451958A|1990-06-18|1992-02-20|Mitsubishi Materials Corp|Treating agent for circulation type toilet filth|
    US5034220A|1990-06-20|1991-07-23|Gaf Chemicals Corporation|Non-aerosol shaving gel|
    US5336692A|1990-06-28|1994-08-09|Medicis Pharmaceutical Corporation|Ointment base and method of use|
    IT1243379B|1990-07-27|1994-06-10|Giuliani Spa|PHARMACEUTICAL COMPOSITION SUITABLE FOR RECTAL ADMINISTRATION OF ACTIVE PRINCIPLES WHICH EXPLICATE A MEDICATION ACTION AT THE LEVEL OF THE COLON, PREVALENTLY TOPICAL|
    US5108556A|1990-09-14|1992-04-28|Minnesota Mining And Manufacturing Company|Process for preparing tertiary perfluoroamines|
    US5091111A|1990-09-19|1992-02-25|S. C. Johnson & Son, Inc.|Aqueous emulsion and aersol delivery system using same|
    US5114718A|1990-09-20|1992-05-19|The Procter & Gamble Company|Sustained release compositions for treating periodontol disease|
    GB9021546D0|1990-10-04|1990-11-21|Beecham Group Plc|Novel composition|
    FR2668927B1|1990-11-09|1993-01-08|Oreal|COSMETIC ANHYDROUS COMPOSITION IN AEROSOL FORM FOR THE FORMATION OF A FOAM.|
    US5073371A|1990-11-30|1991-12-17|Richardson-Vicks, Inc.|Leave-on facial emulsion compositions|
    DE9016291U1|1990-11-30|1991-03-28|Kali-Chemie Pharma Gmbh, 3000 Hannover, De|
    WO1992011839A1|1991-01-08|1992-07-23|Leonard Mackles|Anhydrous aerosol|
    AU1411992A|1991-01-15|1992-08-27|Robert A Bok|A composition containing a tetracycline and use for inhibiting angiogenesis|
    US5227163A|1991-01-18|1993-07-13|Clilco, Ltd.|Lice-repellant compositions|
    DE4102506C2|1991-01-29|1999-11-25|Pfeiffer Erich Gmbh & Co Kg|Discharge device for media|
    CA2101947A1|1991-02-05|1992-08-06|Jurgen Buil|Fire extinguishing and protection agent|
    US6753167B2|1991-02-22|2004-06-22|Sembiosys Genetics Inc.|Preparation of heterologous proteins on oil bodies|
    US5792922A|1992-04-02|1998-08-11|Sembiosys Genetics Inc.|Oil-body protein cis-elements as regulatory signals|
    US5948682A|1991-02-22|1999-09-07|Sembiosys Genetics Inc.|Preparation of heterologous proteins on oil bodies|
    US5650554A|1991-02-22|1997-07-22|Sembiosys Genetics Inc.|Oil-body proteins as carriers of high-value peptides in plants|
    US5658956A|1991-03-01|1997-08-19|Warner-Lambert Company|Bioadhesive-wound healing compositions and methods for preparing and using same|
    US5648380A|1991-03-01|1997-07-15|Warner-Lambert Company|Anti-inflammatory wound healing compositions and methods for preparing and using same|
    US5663208A|1991-03-01|1997-09-02|Warner-Lambert Company|Antifungal wound healing compositions and methods for preparing and using same|
    IT1247138B|1991-03-06|1994-12-12|Dompe Farmaceutici Spa|HYDROPHILE PHARMACEUTICAL COMPOSITION CONTAINING KETOPROFENE LYSINE SALT FOR TOPICAL USE.|
    JPH04282311A|1991-03-08|1992-10-07|Koike Kagaku Kk|Aerosol-type foamable wound-disinfectant|
    US5279819A|1991-03-18|1994-01-18|The Gillette Company|Shaving compositions|
    WO1992016236A1|1991-03-19|1992-10-01|Rajadhyaksha Vithal J|Compositions and method comprising aminoalcohol derivatives as membrane penetration enhancers|
    US5389676A|1991-03-22|1995-02-14|E. B. Michaels Research Associates, Inc.|Viscous surfactant emulsion compositions|
    AU658608B2|1991-03-25|1995-04-27|Astellas Pharma Europe B.V.|Topical preparation containing a suspension of solid lipid particles|
    US5167950A|1991-03-28|1992-12-01|S. C. Johnson & Son|High alcohol content aerosol antimicrobial mousse|
    DE4110973A1|1991-04-05|1992-10-08|Haarmann & Reimer Gmbh|MEDIUM WITH A PHYSIOLOGICAL COOLING EFFECT AND EFFECTIVE COMPOUNDS SUITABLE FOR THIS MEDIUM|
    JP3100416B2|1991-04-11|2000-10-16|オカモト株式会社|Moose-like lubricant|
    HU209605B|1991-04-15|1994-09-28|Chinoin Gyogyszer Es Vegyeszet|Process for production of wather-free transdermal preparation|
    IT1247529B|1991-04-24|1994-12-17|Poli Ind Chimica Spa|PHARMACEUTICAL COMPOSITIONS IN FOAM FORM FOR INTRAVAGINAL, SKIN AND ORAL ADMINISTRATION|
    US5204090A|1991-05-30|1993-04-20|Bristol Myers Squibb|Waterproof high-SPF sunscreen compositions|
    US5164357A|1991-06-05|1992-11-17|Appleton Papers Inc.|Thermally-responsive record material|
    FR2677544B1|1991-06-14|1993-09-24|Oreal|COSMETIC COMPOSITION CONTAINING A MIXTURE OF NANOPIGMENTS OF METAL OXIDES AND MELANIC PIGMENTS.|
    US5221530A|1991-06-24|1993-06-22|Helene Curtis, Inc.|Mild conditioning shampoo with a high foam level containing an anionic surfactant-cationic acrylate/acrylamide copolymer conditioning agent|
    DE4210165A1|1991-07-30|1993-02-04|Schering Ag|TRANSDERMAL THERAPEUTIC SYSTEMS|
    GB9118028D0|1991-08-21|1991-10-09|Secr Defence Brit|Improved transdrmal formulations|
    DE4127630A1|1991-08-21|1993-02-25|Bruno Jesswein|TWO-COMPONENT PRESSURE CAN, IN PARTICULAR FOR 2K FOAM|
    JP2969398B2|1991-09-12|1999-11-02|花王株式会社|Anhydrous foam cleaning agent|
    US5643600A|1991-09-17|1997-07-01|Micro-Pak, Inc.|Lipid vesicles containing avocado oil unsaponifiables|
    WO1993005755A1|1991-09-27|1993-04-01|Nof Corporation|Cosmetic composition and emulsion composition|
    GB2260079B|1991-10-01|1995-08-09|American Cyanamid Co|Pharmaceutical composition containing felbinac|
    US5230897A|1991-10-31|1993-07-27|G. D. Searle & Co.|Transdermal pentamidine|
    US5236707A|1991-11-08|1993-08-17|Dallas Biotherapeutics, Inc.|Stabilization of human interferon|
    EP0613369A1|1991-11-22|1994-09-07|Richardson-Vicks, Inc.|Combined personal cleansing and moisturizing compositions|
    DE4140474C2|1991-12-09|1995-07-13|Schuelke & Mayr Gmbh|Skincare additive|
    US5294365A|1991-12-12|1994-03-15|Basf Corporation|Hydroxypolyethers as low-foam surfactants|
    IT1253711B|1991-12-17|1995-08-23|Alfa Wassermann Spa|VAGINAL PHARMACEUTICAL FORMULATIONS CONTAINING RIFAXIMIN AND THEIR USE IN THE TREATMENT OF VAGINAL INFECTIONS|
    US5252246A|1992-01-10|1993-10-12|Allergan, Inc.|Nonirritating nonionic surfactant compositions|
    EP0552612A3|1992-01-22|1993-10-20|Hoffmann La Roche|Methods for determining and isolating compounds which bind directly to nucleosolic proteins|
    JP3146052B2|1992-01-31|2001-03-12|プレスコ株式会社|Aerosol massage agent|
    US5318774A|1992-02-28|1994-06-07|Richardson-Vicks Inc.|Composition and method for imparting an artificial tan to human skin|
    US5344051A|1992-04-27|1994-09-06|Insta-Foam Products, Inc.|Two-component foam dispensing apparatus|
    ZA932947B|1992-04-28|1993-10-27|Schering Plough Healthcare|Applicator for semisolid medications|
    US5254334A|1992-05-04|1993-10-19|Imaginative Research Associates, Inc.|Anhydrous foaming composition containing low concentrations of detergents and high levels of glycerin amd emollients such as oils and esters|
    US5409706A|1992-05-04|1995-04-25|Imaginative Research Associates, Inc.|Anhydrous foaming composition containing low concentrations of detergents and high levels of glycerin and emollients such as oils and esters|
    ZA933133B|1992-05-15|1994-10-05|Akzo Nv|Application for introducing a cream-type substance into a woman's vagina|
    AU4116993A|1992-05-18|1993-12-13|Procter & Gamble Company, The|Coolant compositions|
    US5389305A|1992-06-03|1995-02-14|Colgate Palmolive Co.|High foaming nonionic surfactant base liquid detergent|
    ES2137993T3|1992-06-11|2000-01-01|Theratech Inc|THE USE OF GLYCERINE TO MODERATE THE TRANSDERMAL CONTRIBUTION OF MEDICINES.|
    US5346135A|1992-06-16|1994-09-13|Vincent Edward C|Spraying apparatus for blending liquids in a gaseous spray system|
    US5300286A|1992-07-14|1994-04-05|Dow Corning Corporation|Silicone emulsion for personal care application|
    CA2141192C|1992-07-28|1999-02-02|Roberta C. Bloom|Pharmaceutical composition for topical use containing a crosslinked cationic polymer and an alkoxylated ether|
    FI933979A0|1992-09-10|1993-09-10|Mcneil Ppc Inc|BIOERODERBAR ANORDNING FOER DOSERING AV AKTIVA INGREDIENSER|
    JPH08501553A|1992-09-14|1996-02-20|スミス・ウォルター・ピー|Skin conditioning composition, its application and manufacture|
    JPH06100414A|1992-09-18|1994-04-12|Osaka Aerosol Ind Corp|Composition for aerosol|
    US6096756A|1992-09-21|2000-08-01|Albert Einstein College Of Medicine Of Yeshiva University|Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists|
    US5413775A|1992-09-29|1995-05-09|Amerchol Corporation|Hairsprays and acrylic polymer compositions for use therein|
    IT1255895B|1992-10-20|1995-11-17|Laura Chiodini|PHARMACEUTICAL COMPOSITIONS CONTAINING A CALCITONIN|
    US5527534A|1992-10-21|1996-06-18|Gynetech Laboratories, Ltd.|Vaginal sponge delivery system|
    ES2114993T3|1992-10-31|1998-06-16|Goldschmidt Ag Th|COSMETIC OR PHARMACEUTICAL PREPARATIONS.|
    DE4238860A1|1992-11-19|1994-05-26|Medicon Gmbh|Skin protection products for the protection of human skin|
    US5308643A|1992-11-30|1994-05-03|Osipow Lloyd I|Self-lather generating shaving compositions|
    JP3328344B2|1992-12-22|2002-09-24|タイホー工業株式会社|Method of controlling foaming state retention time of foaming type cleaning polishes|
    JPH06263630A|1993-03-10|1994-09-20|Lion Corp|Vitamin as-solubilizing eye drop|
    DE4309900C1|1993-03-26|1994-06-30|Goldschmidt Ag Th|Process for the preparation of amphoteric surfactants|
    JPH06279228A|1993-03-30|1994-10-04|Kao Corp|Foaming composition|
    US5326557A|1993-04-06|1994-07-05|Dow Corning Corporation|Moisturizing compositions containing organosilicon compounds|
    US5807571A|1993-05-06|1998-09-15|Lts Lohmann Therapie-Systeme Gmbh|Transdermal therapeutic systems for administering indole serotonin agonists|
    US5576016A|1993-05-18|1996-11-19|Pharmos Corporation|Solid fat nanoemulsions as drug delivery vehicles|
    AT219946T|1993-05-19|2002-07-15|Hisamitsu Pharmaceutical Co|3-L-MENTHOXY-PROPANE-1, 2-DIOL AS SOLUTION AND EXTERNAL PREPARATION THAT CONTAINS THEM|
    BR9406411A|1993-05-21|1995-12-19|Henkel Corp|Shampoo composition|
    JP3161869B2|1993-05-24|2001-04-25|株式会社ダイゾー|Water-in-oil aerosol composition and process for producing the same|
    US5635469A|1993-06-10|1997-06-03|The Procter & Gamble Company|Foaming cleansing products|
    US5447725A|1993-06-11|1995-09-05|The Procter & Gamble Company|Methods for aiding periodontal tissue regeneration|
    US5384308A|1993-06-14|1995-01-24|Henkin; R. I.|Composition and method for enhancing wound healing|
    US5744155A|1993-08-13|1998-04-28|Friedman; Doron|Bioadhesive emulsion preparations for enhanced drug delivery|
    US5398846A|1993-08-20|1995-03-21|S. C. Johnson & Son, Inc.|Assembly for simultaneous dispensing of multiple fluids|
    US6596260B1|1993-08-27|2003-07-22|Novartis Corporation|Aerosol container and a method for storage and administration of a predetermined amount of a pharmaceutically active aerosol|
    FR2709666B1|1993-09-07|1995-10-13|Oreal|Cosmetic or dermatological composition consisting of an oil-in-water emulsion based on oily globules provided with a lamellar liquid crystal coating.|
    JP2978043B2|1993-09-16|1999-11-15|高砂香料工業株式会社| -3-{-[5-methyl-2- cyclohexyl] oxy} -1,2-propanediol, its production method and use|
    US5766632A|1993-10-01|1998-06-16|Legere Pharmaceuticals, Ltd.|Method of using lectins for contraception|
    FR2710854B1|1993-10-08|1995-12-01|Oreal|Oil-in-water emulsion usable for obtaining a cream.|
    US5578315A|1993-12-01|1996-11-26|Rutgers, The State University Of New Jersey|Mucosal adhesive device for long-acting delivery of pharmaceutical combinations in oral cavity|
    FR2713486B1|1993-12-14|1996-02-09|Scophysa|New compositions for foams, in particular rectal foams, and foams thus obtained.|
    DE69426727D1|1993-12-23|2001-03-29|Procter & Gamble|ANTIMICROBIAL COMPOSITIONS FOR WIPES|
    US5527822A|1993-12-29|1996-06-18|Forest Laboratories, Inc.|Method of treatment of traumatic brain injury|
    DE9422052U1|1994-01-04|1997-10-30|Wuerth Adolf Gmbh & Co Kg|Filling device for filling a refillable dispensing container and refillable dispensing container|
    JP3530564B2|1994-02-03|2004-05-24|株式会社ノエビア|Aerosol foam cosmetics|
    DE4405127A1|1994-02-18|1995-08-31|Henkel Kgaa|Hair treatment products|
    US5514367A|1994-02-28|1996-05-07|Estee Lauder, Inc.|Skin tanning compositions and methods for their preparation and use|
    US5925669A|1994-03-22|1999-07-20|Molecular/Structural Bio Technologies, Inc.|Carrier compositions for anti-neoplastic drugs|
    IL109230A|1994-04-05|1998-08-16|Agis Ind 1983 Ltd|Anti-fungal composition containing bifonazole and fluocinonide|
    US5658749A|1994-04-05|1997-08-19|Corning Clinical Laboratories, Inc.|Method for processing mycobacteria|
    US5429815A|1994-04-11|1995-07-04|Chesebrough-Pond's Usa Co., Division Of Conopco, Inc.|Stable single-phase self-foaming cleanser|
    FR2719467B1|1994-05-05|1996-05-31|Oreal|Use of flavonoids to preserve and / or strengthen the mechanical properties of the hair and method of protecting hair using these compounds.|
    ES2079320B1|1994-05-17|1996-10-16|Cusi Lab|OPHTHALMIC DISSOLUTION BASED ON A DICLOFENACO AND TOBRAMYCIN AND ITS APPLICATIONS.|
    US5902574A|1994-05-23|1999-05-11|The Gillette Company|Shaving preparation for improved shaving comfort|
    US5545401A|1994-06-02|1996-08-13|Shanbrom; Edward|Antiviral, spermicidal vaginal gel and foam containing low molecular weight povidone-iodine|
    FR2720635B1|1994-06-03|1996-07-26|Oreal|Sunscreen cosmetic compositions and uses.|
    US6221381B1|1994-06-28|2001-04-24|The University Of British Columbia|Enhancing milk production by adding to feed a nonionic surfactant coated on a carrier|
    MA23592A1|1994-06-30|1995-12-31|Procter & Gamble|COMPOSITIONS FOR BODY CARE CONTAINING THERMOPLASTIC ELASTOMERIC GRAFT COPOLYMERS|
    US5679324A|1994-07-08|1997-10-21|The Procter & Gamble Co.|Aerosol foamable fragrance composition|
    US5976555A|1994-09-07|1999-11-02|Johnson & Johnson Consumer Products, Inc.|Topical oil-in-water emulsions containing retinoids|
    FR2722431B1|1994-07-12|1996-09-13|Lir France Sa|DOUBLE DISPENSER FOR FLUID PRODUCTS|
    US5444092A|1994-07-20|1995-08-22|Collins; Jerry|Method and composition for treating psoriasis|
    JP3173330B2|1994-07-20|2001-06-04|トヨタ自動車株式会社|Slip control device for vehicle lock-up clutch|
    US5869529A|1994-07-20|1999-02-09|Agis Industries Ltd.|Topical preparation for the prevention and treatment of lesions and sores associated with a herpes virus|
    GB9414699D0|1994-07-21|1994-09-07|Slagel David|Aqueous foamable composition|
    US5512555A|1994-07-21|1996-04-30|Merck & Co., Inc.|Method of treating sweat-related conditions using finasteride, epristeride and a cholestan-3-one|
    JP3241542B2|1994-07-29|2001-12-25|高砂香料工業株式会社|Method for purifying -n-isopulegol and citrus-based fragrance composition containing -n-isopulegol obtained by the method|
    JPH0840899A|1994-07-29|1996-02-13|Tokyo Tanabe Co Ltd|Aerosol of oxyconazone nitrate|
    DE4428096A1|1994-08-09|1996-02-15|Wella Ag|Two-chamber container|
    US5656586A|1994-08-19|1997-08-12|Rhone-Poulenc Inc.|Amphoteric surfactants having multiple hydrophobic and hydrophilic groups|
    US5547989A|1994-08-19|1996-08-20|Schering-Plough Healthcare Products, Inc.|Compositions for treating corns and calluses|
    CN1159159A|1994-08-26|1997-09-10|普罗克特和甘保尔公司|Personal cleansing compositions|
    JP3558393B2|1994-08-29|2004-08-25|株式会社ダイゾー|Foamable aerosol composition|
    TW460296B|1994-09-01|2001-10-21|Janssen Pharmaceutica Nv|Topical ketoconazole emulsion compositions without sodium sulfite|
    JP3604177B2|1994-09-14|2004-12-22|日東電工株式会社|Transdermal formulation|
    US5500211A|1994-09-22|1996-03-19|The Gillette Company|Soap-free self-foaming shave gel composition|
    US5905092A|1994-09-27|1999-05-18|Virotex Corporation Reel/Frame|Topical antibiotic composition providing optimal moisture environment for rapid wound healing that reduces skin contraction|
    US5955414A|1994-10-05|1999-09-21|S. C. Johnson & Son, Inc.|Cleaning foam having fluorinated stain repellent and low flammability|
    US5540853A|1994-10-20|1996-07-30|The Procter & Gamble Company|Personal treatment compositions and/or cosmetic compositions containing enduring perfume|
    EP0738516A4|1994-11-08|1997-01-15|Mochida Pharm Co Ltd|External preparation for skin protection|
    US5567420A|1994-11-16|1996-10-22|Mceleney; John|Lotion which is temporarily colored upon application|
    US5788664A|1994-11-30|1998-08-04|Scalise; Gaspare|Suppository applicator|
    GB9424562D0|1994-12-06|1995-01-25|Giltech Ltd|Product|
    US5641480A|1994-12-08|1997-06-24|Lever Brothers Company, Division Of Conopco, Inc.|Hair care compositions comprising heteroatom containing alkyl aldonamide compounds|
    US5529770A|1994-12-09|1996-06-25|West Agro, Inc.|Viscous liquid conditioning topical germicides|
    JP3355257B2|1994-12-09|2002-12-09|太陽化学株式会社|Cosmetics|
    DE4444238A1|1994-12-13|1996-06-20|Beiersdorf Ag|Cosmetic or dermatological drug combinations of cinnamic acid derivatives and flavone glycosides|
    FR2728166B1|1994-12-19|1997-02-07|
    CA2208078C|1994-12-21|2009-06-23|Cosmederm Technologies|Formulations and methods for reducing skin irritation|
    WO1996019921A1|1994-12-23|1996-07-04|Commonwealth Scientific And Industrial Research Organisation|Iodine biocidal material|
    DE4446891A1|1994-12-27|1996-07-04|Falk Pharma Gmbh|Stable aqueous budesonide solution|
    US5616136A|1995-01-09|1997-04-01|Med-Safe Systems, Inc.|Quick release needle removal apparatus|
    US5534261A|1995-01-17|1996-07-09|University Of Southern California|Retinoid-based compositions and method for preventing adhesion formation using the same|
    FR2729855B1|1995-01-26|1997-02-21|
    US5523078A|1995-02-03|1996-06-04|Michael E. Baylin|Method of preparing and composition for treatment of hair and scalp|
    US5587149A|1995-02-06|1996-12-24|R.P. Scherer Corporation|Topical application emulsions|
    FR2730930B1|1995-02-27|1997-04-04|Oreal|USE OF NO-SYNTHASE INHIBITORS TO REDUCE THE IRRITANT SKIN EFFECT OF PRODUCTS USED IN THE COSMETIC OR PHARMACEUTICAL FIELD|
    FR2730932B1|1995-02-27|1997-04-04|Oreal|TRANSPARENT NANOEMULSION BASED ON FLUID NON-IONIC AMPHIPHILIC LIPIDS AND USE IN COSMETICS OR DERMOPHARMACY|
    GB9504265D0|1995-03-03|1995-04-19|Medeva Plc|Corticosteroid-containing pharmaceutical composition|
    US5558872A|1995-03-07|1996-09-24|Healthpoint Medical Limited Partnership|Gelled mineral oil skin protectant|
    US5618850A|1995-03-09|1997-04-08|Focal, Inc.|Hydroxy-acid cosmetics|
    US5783202A|1995-03-14|1998-07-21|Soltec Research Pty. Ltd.|Pediculicidal mousse composition for killing head lice|
    AU5013996A|1995-03-29|1996-10-16|Shionogi & Co., Ltd.|Gelatin capsule with adjusted water activity|
    JPH08277209A|1995-04-07|1996-10-22|Taisho Pharmaceut Co Ltd|Revitalizing hair tonic|
    US5585104A|1995-04-12|1996-12-17|The Procter & Gamble Company|Cleansing emulsions|
    EP0738510A3|1995-04-20|2005-12-21|L'oreal|Use of a HMG-CoA reductase inhibitor as an anti-ageing agent and as an anti-acne agent. Composition comprising at least one HMG-CoA reductase inhibitor and at least one active substance with scaling properties.|
    FR2733417B1|1995-04-25|1997-06-06|Oreal|FOAMING OIL-IN-WATER EMULSION BASED ON NON-IONIC SURFACTANTS, A FATTY PHASE AND A CATIONIC OR ANIONIC POLYMER CROSS-LINKED AND USE IN TOPICAL APPLICATION|
    GB9510856D0|1995-05-27|1995-07-19|Cussons Int Ltd|Cleaning composition|
    UY24246A1|1995-06-06|1996-06-14|Neutrogena Corp|TROPIC VEHICLES CONTAINING SOLUBILIZED AND STABILIZED AZELAIC ACID|
    CA2224798A1|1995-06-22|1997-01-09|Matthew T. Scholz|Stable hydroalcoholic compositions|
    JP3542665B2|1995-07-07|2004-07-14|株式会社資生堂|Anti-aging skin external preparation, collagen cross-linking inhibition skin external preparation and anti-ultraviolet skin external preparation|
    US5705472A|1995-07-18|1998-01-06|Petroferm Inc.|Neutral aqueous cleaning composition|
    FR2736824B1|1995-07-18|1997-10-10|Fabre Pierre Dermo Cosmetique|MINOXIDIL HAIR COMPOSITION WITH LOW FAT SOLVENT CONTENT|
    DE29512760U1|1995-08-08|1995-11-16|Wella Ag|Pressurized gas container for dispensing foam|
    TW504387B|1995-09-06|2002-10-01|Kao Corp|Emulsified, water-in-oil type composition and skin cosmetic preparation|
    CN1062129C|1995-09-14|2001-02-21|徐荣祥|Medicine matrix and its use|
    US5881493A|1995-09-14|1999-03-16|D. B. Smith & Co. Inc.|Methods for applying foam|
    US7060253B1|1996-09-20|2006-06-13|Mundschenk David D|Topical formulations and delivery systems|
    JPH0984855A|1995-09-25|1997-03-31|Kyoto Yakuhin Kogyo Kk|Aerosol preparation for administer medicine to rectum or vagina|
    JPH0999553A|1995-10-09|1997-04-15|Fujitsu Ltd|Ink jet head|
    JP3425019B2|1995-10-16|2003-07-07|カネボウ株式会社|Oily foam cleansing cosmetic|
    US6221823B1|1995-10-25|2001-04-24|Reckitt Benckiser Inc.|Germicidal, acidic hard surface cleaning compositions|
    NZ330679A|1995-12-14|2000-03-27|Taisho Pharma Co Ltd|an aerosol preparation containing an alcohol having 1 to 3 carbons, alcohol having 12 or more carbons and a liquefied gas propellant; use as a pain relief spray|
    FR2742986B1|1995-12-29|1998-01-30|Rhone Poulenc Chimie|COSMETIC COMPOSITIONS FOR THE HAIR OR THE SKIN BASED ON SULPHONATED COPOLYESTERS WITH POLYORGANOSILOXANE MOTIFS|
    US5716611A|1996-01-02|1998-02-10|Euro-Celtique, S.A.|Emollient antimicrobial formulations containing povidone iodine|
    US5889028A|1996-02-09|1999-03-30|Mayo Foundation For Medical Education And Research|Colonic delivery of nicotine to treat inflammatory bowel disease|
    US5846983A|1996-02-09|1998-12-08|Mayo Foundation For Medical Education And Research|Colonic delivery of nicotine to treat inflammatory bowel disease|
    US5759524A|1996-02-09|1998-06-02|The Procter & Gamble Company|Photoprotective compositions|
    AUPN814496A0|1996-02-19|1996-03-14|Monash University|Dermal penetration enhancer|
    US5912007A|1996-02-29|1999-06-15|Warner-Lambert Company|Delivery system for the localized administration of medicaments to the upper respiratory tract and methods for preparing and using same|
    US6251369B1|1996-03-05|2001-06-26|Sultan Dental Products|Dental fluoride foam|
    FR2745716B1|1996-03-07|1998-04-17|Oreal|ULTRAFINE PRESSURIZABLE FOAMING OIL-IN-WATER EMULSIONS|
    US6251941B1|1996-04-19|2001-06-26|Sloan-Kettering Institute For Cancer Research|Use of inhaled retinoids in the prevention of cancer|
    US5910382A|1996-04-23|1999-06-08|Board Of Regents, University Of Texas Systems|Cathode materials for secondary lithium batteries|
    IT1283042B1|1996-05-21|1998-04-07|Condea Augusta Spa|COSMETIC COMPOUNDS DEODORANT AND / OR ANTI-BREATHING|
    US5797955A|1996-06-11|1998-08-25|Walters; David J.|Pressure application unit for positioning vertebra|
    US5833961A|1996-06-25|1998-11-10|Inolex Investment Corporation|Polyester-based suncreen formulations|
    WO1998000016A1|1996-07-01|1998-01-08|Sepracor, Inc.|Methods and compositions for treating urinary incontinence using enantiomerically enriched -glycopyrrolate|
    US5716621A|1996-07-03|1998-02-10|Pharmadyn, Inc.|Nonocclusive drug delivery device and process for its manufacture|
    AU726543B2|1996-07-10|2000-11-09|S.C. Johnson & Son, Inc.|Triclosan skin wash with enhanced efficacy|
    DE19631221C2|1996-08-02|1999-07-01|Beiersdorf Ag|Foam-form sunscreen preparations containing water-soluble sunscreen filter substances and surface-active substances|
    WO1998006419A1|1996-08-15|1998-02-19|Southern Illinois University|Enhancement of antimicrobial peptide activity by metal ions|
    US5833963A|1996-08-20|1998-11-10|Bristol-Myers Squibb Company|Non-tacky and quick-drying aqueous-based antiperspirant compositions|
    US5741509A|1996-08-26|1998-04-21|Alvin S. Berlat|Silicone wound dressing|
    US5837270A|1996-08-26|1998-11-17|Burgess; Nelson Leon|Topical anti-acne composition|
    EP0829259A1|1996-09-04|1998-03-18|Warner-Lambert Company|Foam/gel with microbeads and/or fine particles|
    US6271295B1|1996-09-05|2001-08-07|General Electric Company|Emulsions of silicones with non-aqueous hydroxylic solvents|
    US5952392A|1996-09-17|1999-09-14|Avanir Pharmaceuticals|Long-chain alcohols, alkanes, fatty acids and amides in the treatment of burns and viral inhibition|
    FR2754451B1|1996-10-14|1998-11-06|Oreal|SELF-FOAMING CREAM|
    WO1998017282A1|1996-10-23|1998-04-30|Vertex Pharmaceuticals Incorporated|Methods of using sucrose octasulfate to treat or prevent enveloped virus infection|
    US6093408A|1996-10-25|2000-07-25|The Procter & Gamble Company|Skin care compositions|
    IT1287114B1|1996-10-31|1998-08-04|Recordati Chem Pharm|ANTI-HERPETIC PHARMACEUTICAL COMPOSITIONS FOR TOPICAL APPLICATORS, CONTAINING ACICLOVIR|
    JP2986552B2|1996-11-04|1999-12-06|ザ、プロクター、エンド、ギャンブル、カンパニー|Hair mousse composition containing silicone emulsion|
    NZ335495A|1996-11-12|2002-03-28|Dov Tamarkin|alpha,omega-dicarboxylic acid esters and their use in treating dermatological disorders|
    FR2755854B1|1996-11-15|1998-12-24|Oreal|NANOEMULSION BASED ON NON-IONIC AND CATIONIC AMPHIPHILIC LIPIDS AND USES|
    WO1998022078A1|1996-11-16|1998-05-28|Wella Aktiengesellschaft|Agents for dying and decolorizing fibers|
    US5906992A|1996-11-21|1999-05-25|Colgate Palmolive Company|Foam cleaning compositions|
    AUPO379596A0|1996-11-22|1996-12-19|Soltec Research Pty Ltd|Percutaneous delivery system|
    US5951544A|1996-12-04|1999-09-14|Laser Industries Ltd.|Handpiece assembly for laser apparatus|
    US5759579A|1996-12-05|1998-06-02|American Home Products Corporation|Pharmaceutical suspension systems|
    US5695551A|1996-12-09|1997-12-09|Dow Corning Corporation|Water repellent composition|
    US5856452A|1996-12-16|1999-01-05|Sembiosys Genetics Inc.|Oil bodies and associated proteins as affinity matrices|
    US5672634A|1996-12-23|1997-09-30|Isp Investments Inc.|Crosslinked PVP-I2 foam product|
    US5879469A|1997-01-06|1999-03-09|Deeay Technologies Ltd.|Dishwashing method and detergent composition therefor|
    US6582711B1|1997-01-09|2003-06-24|3M Innovative Properties Company|Hydroalcoholic compositions thickened using polymers|
    SE520811C2|1997-01-17|2003-08-26|Ponsus Ab|Skin protection preparations containing lipophilic and hydrophilic components, method of preparation and use thereof|
    IN186803B|1997-02-05|2001-11-10|Panacea Biotec Ltd|
    US5843411A|1997-02-06|1998-12-01|Topix Pharmaceuticals Inc.|Stabilization of ascorbic acid, ascorbic acid derivatives and/or extracts containing ascorbic acid for topical use|
    EP0963198A4|1997-02-11|2001-08-29|Bernard Salafsky|ANTI-PARASITIC ACTION OF N,N-DIETHYL-m-TOLUAMIDE AND FORMULATIONS THAT PROLONG ITS ACTIVITY IN THE SKIN|
    ES2133090B1|1997-02-21|2000-04-01|Uriach & Cia Sa J|NEW APPLICATOR FOR THE ADMINISTRATION OF SEMI-SOLID MEDICATIONS.|
    CA2281755C|1997-02-24|2006-11-07|Michael Albert Kamm|Topical pharmaceutical composition comprising a cholinergic agent or a calcium channel blocker|
    JP3050289B2|1997-02-26|2000-06-12|日本電気株式会社|Output impedance adjustment circuit of output buffer circuit|
    US6433068B1|1997-03-07|2002-08-13|David S. Morrison|Hydrocarbon gels as suspending and dispersing agents and products|
    FR2760637B1|1997-03-11|1999-05-28|Fabre Pierre Dermo Cosmetique|COAL TAR EXTRACT WITH REDUCED AROMATIC HYDROCARBON CONTENT, PROCESS FOR OBTAINING AND DERMO-COSMETIC PREPARATIONS|
    US5922331A|1997-03-26|1999-07-13|Chanel, Inc.|Skin cream composition|
    US5951989A|1997-04-07|1999-09-14|Heymann; Warren R.|Method for the treatment of dry skin|
    USH2043H1|1997-05-23|2002-08-06|The Procter & Gamble Company|Skin care compositions|
    US6599513B2|1997-05-27|2003-07-29|Sembiosys Genetics Inc.|Products for topical applications comprising oil bodies|
    PT986309E|1997-05-27|2008-04-03|Sembiosys Genetics Inc|Uses of oil bodies|
    US6183762B1|1997-05-27|2001-02-06|Sembiosys Genetics Inc.|Oil body based personal care products|
    US6372234B1|1997-05-27|2002-04-16|Sembiosys Genetics Inc.|Products for topical applications comprising oil bodies|
    JP3113610B2|1997-06-04|2000-12-04|東洋ガスメーター株式会社|Mounting fixture for transmission equipment for gas meters|
    US6217887B1|1997-06-04|2001-04-17|The Procter & Gamble Company|Leave-on antimicrobial compositions which provide improved immediate germ reduction|
    EP0884045A1|1997-06-06|1998-12-16|Pfizer Products Inc.|Self-tanning dihydroxyacetone formulations having improved stability and providing enhanced delivery|
    US20050276836A1|1997-06-11|2005-12-15|Michelle Wilson|Coated vaginal devices for vaginal delivery of therapeutically effective and/or health-promoting agents|
    AU729680B2|1997-06-13|2001-02-08|Taisho Pharmaceutical Co., Ltd.|Aerosol preparation|
    JPH11111A|1997-06-13|1999-01-06|Kagoshima Pref Gov|Feed for fish breeding|
    FR2765799B1|1997-07-08|1999-08-27|Oreal|GLOSSY COMPOSITION CONTAINING AROMATIC OILS THICKENED BY A POLYSACCHARIDE ALKYLETHER|
    AU9162498A|1997-08-18|1999-03-08|Neubourg, Stephanie|Foaming skin cream, uses thereof and a method for producing the same|
    JP3553767B2|1997-08-22|2004-08-11|三洋電機株式会社|Transfer assistance device|
    SE9703226D0|1997-09-08|1997-09-08|Astra Ab|New pharmaceutical composition|
    US5885581A|1997-09-11|1999-03-23|Merz, Incorporated|Composition and method for improvement of the appearance of scars|
    US6241971B1|1997-09-25|2001-06-05|The Procter & Gamble Company|Hair styling compositions comprising mineral salt, lipophilic material, and low levels of surfactant|
    US5939376A|1997-09-25|1999-08-17|Colgate Palmolive Company|Liquid cleaning compositions containing an organic ester foam control agent|
    US6214318B1|1997-10-02|2001-04-10|Oms Holdings Llc|Aerosol ointment compositions for topical use|
    US6075056A|1997-10-03|2000-06-13|Penederm, Inc.|Antifungal/steroid topical compositions|
    FR2769299B1|1997-10-03|1999-12-31|Oreal|BI-PRODUCTS PACKAGING AND DISTRIBUTION SET|
    AUPO983897A0|1997-10-17|1997-11-06|Soltec Research Pty Ltd|Topical antifungal composition|
    US5961957A|1997-10-20|1999-10-05|Mcanalley; Bill H.|Foam compositions|
    US5911981A|1997-10-24|1999-06-15|R.I.T.A. Corporation|Surfactant blends for generating a stable wet foam|
    US5865347A|1997-10-27|1999-02-02|William T. Wilkinson|Multi-chamber dispenser for flowable materials|
    WO1999021562A1|1997-10-28|1999-05-06|Asivi, Llc|Treatment of female sexual dysfunction|
    US5877216A|1997-10-28|1999-03-02|Vivus, Incorporated|Treatment of female sexual dysfunction|
    JP3450680B2|1997-10-28|2003-09-29|高砂香料工業株式会社|Method for producing para-menthane-3,8-diol|
    JP4139860B2|1997-11-10|2008-08-27|ストラカンインターナショナルリミティッド|Penetration enhancement and stimulation reduction system|
    DE29720316U1|1997-11-17|1998-01-29|Andris Raimund Gmbh & Co Kg|Two-chamber dispenser|
    US5849042A|1997-11-19|1998-12-15|Bristol-Myers Squibb|Hair dye compositions containing 2,3 dialkyl-4-aminophenol and a 2-alkyl-1-naphthol|
    US5871720A|1997-11-20|1999-02-16|Colgate-Palmolive Company|Cosmetic compositions with DBS and functionalized silicones|
    JP2001525371A|1997-12-05|2001-12-11|イーライ・リリー・アンド・カンパニー|GLP-1 preparation|
    TWI225793B|1997-12-25|2005-01-01|Ajinomoto Kk|Cosmetic composition|
    JP3050289U|1997-12-29|1998-06-30|丸隆株式会社|Pet animal room excretion tools|
    DE19802206A1|1998-01-22|1999-07-29|Beiersdorf Ag|Stable cosmetic or dermatological composition with low viscosity|
    FR2774595A1|1998-02-06|1999-08-13|Rech D Innovation Et De Dev Ce|EMULSION FOR TRANSDERMAL STEROID ADMINISTRATION|
    DE19805918A1|1998-02-13|1999-08-19|Beiersdorf Ag|Lipidreduced preparations|
    US6110966A|1998-02-20|2000-08-29|Medi-Cell Laboratories, Inc.|Triple action complex|
    DE19807774A1|1998-02-24|1999-08-26|Beiersdorf Ag|Use of flavone, flavanone or flavonoid compound for protection of ascorbic acid or ascorbyl compound against oxidation, especially in cosmetic and dermatological preparations,|
    JP3514105B2|1998-02-27|2004-03-31|ティアック株式会社|Recording medium recording / reproducing device|
    US6017912A|1998-02-27|2000-01-25|Bussell; Letantia|Topical fluoroquinolone antibiotics in an alcohol and acetone vehicle|
    ES2245511T3|1998-03-04|2006-01-01|Teijin Limited|VITAMIN LOANS D3 ACTIVE IN THE FORM OF EMULSION.|
    US6121210A|1998-03-12|2000-09-19|Dap Products Inc.|Foamable silicone oil compositions and methods of use thereof|
    DE69937339T2|1998-03-12|2008-02-07|Oji Paper Co., Ltd.|BACTERICIDAL|
    US5990100A|1998-03-24|1999-11-23|Panda Pharmaceuticals, L.L.C.|Composition and method for treatment of psoriasis|
    AUPP310798A0|1998-04-22|1998-05-14|Soltec Research Pty Ltd|Vehicle system for a composition comprising a piperidinopyrimidine derivative|
    US5919830A|1998-04-30|1999-07-06|Gopalkrishnan; Sridhar|Stable non-aqueous blends for personal care compositions|
    US6649175B1|1998-05-04|2003-11-18|Schering-Plough Healthcare Products, Inc.|Skin barrier composition|
    GB9810949D0|1998-05-22|1998-07-22|Hewlett Healthcare Limited|Formulation|
    FR2779637B1|1998-06-15|2000-09-01|Oreal|PHOTOPROTECTIVE COSMETIC COMPOSITIONS CONTAINING A METAL OXIDE NANOPIGMENT AND AN ACRYLIC TERPOLYMER AND USE OF SUCH COMPOSITIONS FOR PROTECTING KERATINIC MATERIALS FROM ULTRAVIOLET RADIATION|
    US6706290B1|1998-07-06|2004-03-16|Olvai E. Kajander|Methods for eradication of nanobacteria|
    FR2780879B1|1998-07-09|2002-09-20|Oreal|PHOTOPROTECTOR COSMETIC COMPOSITION CONTAINING AN ANIONIC SURFACTANT, COMPOUND FILTERING ULTRAVIOLET RADIATION AND CATIONIC OR ZPHITTERIONIC AMPHIPHILIC COMPOUND AND USE THEREOF|
    US6146664A|1998-07-10|2000-11-14|Shaklee Corporation|Stable topical ascorbic acid compositions|
    US6124362A|1998-07-17|2000-09-26|The Procter & Gamble Company|Method for regulating hair growth|
    US6071541A|1998-07-31|2000-06-06|Murad; Howard|Pharmaceutical compositions and methods for managing skin conditions|
    JP4017758B2|1998-08-04|2007-12-05|高砂香料工業株式会社|Cooling agent composition|
    DE19835239A1|1998-08-04|2000-02-24|Johnson & Johnson Gmbh|Foaming oil preparation and its use|
    GB9817817D0|1998-08-14|1998-10-14|Unilever Plc|Cosmetic composition|
    DE69933775T2|1998-08-20|2007-10-04|3M Innovative Properties Co., St. Paul|SPRAYING AND ACTIVE SUBSTANCE SYSTEM|
    JP3712868B2|1998-09-02|2005-11-02|株式会社カネボウ化粧品|Aerosol composition|
    AUPP583198A0|1998-09-11|1998-10-01|Soltec Research Pty Ltd|Mousse composition|
    US8263580B2|1998-09-11|2012-09-11|Stiefel Research Australia Pty Ltd|Vitamin formulation|
    US6087310A|1998-09-23|2000-07-11|Castrol Limited|Skin cleaning compositions and uses comprising a polymer latex emulsion|
    CA2345641A1|1998-09-28|2000-04-06|Denise M. Visco|A method for treating inflammatory diseases by administering a thrombin inhibitor|
    US6914057B1|1998-09-28|2005-07-05|The Research Foundation Of State University Of New York|Inhibitor of cataract formation|
    US6607716B1|1998-09-29|2003-08-19|Tech Labs, Inc.|Pediculicidal compositions, a kit, and methods of use|
    RU2134052C1|1998-10-07|1999-08-10|Нерушай Сергей Алексеевич|Method and apparatus for aerosol application of perfumery liquids|
    US6287546B1|1998-10-09|2001-09-11|Colgate-Palmolive Company|Shampoos with stabilizers|
    JP3876081B2|1998-10-22|2007-01-31|東洋エアゾール工業株式会社|Aerosol composition for foam formation|
    US6551604B1|1999-06-28|2003-04-22|The Procter & Gamble Company|Skin care compositions|
    US6110477A|1998-10-30|2000-08-29|Topix Pharmaceuticals Inc.|Stabilization of ascorbic acid, ascorbic acid derivatives and/or extracts containing ascorbic acid for topical use|
    US7521068B2|1998-11-12|2009-04-21|Elan Pharma International Ltd.|Dry powder aerosols of nanoparticulate drugs|
    US5980904A|1998-11-18|1999-11-09|Amway Corporation|Skin whitening composition containing bearberry extract and a reducing agent|
    US6344218B1|1998-11-23|2002-02-05|The Procter & Gamble Company|Skin deodorizing and santizing compositions|
    DE19855097A1|1998-11-28|2000-05-31|Wella Ag|Pigment-containing, foamable gel|
    US20010006654A1|1998-12-09|2001-07-05|L'oreal|Compositions and methods for treating hair and skin using aqueous delivery systems|
    US6486207B2|1998-12-10|2002-11-26|Nexmed , Inc.|Compositions and methods for amelioration of human female sexual dysfunction|
    US6087317A|1998-12-10|2000-07-11|Dow Corning Corporation|Particle size stable silicone emulsions|
    US6262128B1|1998-12-16|2001-07-17|3M Innovative Properties Company|Aqueous foaming compositions, foam compositions, and preparation of foam compositions|
    FR2787325B1|1998-12-17|2001-01-26|Oreal|NANOEMULSION BASED ON OXYETHYLENE OR NON-OXYETHYLENE SORBITAN FATTY ESTERS, AND ITS USES IN THE COSMETIC, DERMATOLOGICAL AND / OR OPHTHALMOLOGICAL FIELDS|
    FR2787728B1|1998-12-23|2001-01-26|Oreal|NANOEMULSION BASED ON FATTY ESTERS OF PHOSPHORIC ACID, AND ITS USES IN THE COSMETIC, DERMATOLOGICAL, PHARMACEUTICAL AND / OR OPHTHALMOLOGICAL FIELDS|
    JP2000191429A|1998-12-28|2000-07-11|Kao Corp|Foamable cosmetic|
    EP1142588A4|1998-12-28|2007-01-10|Taisho Pharma Co Ltd|External preparation|
    FR2787703B1|1998-12-29|2001-01-26|Oreal|NANOEMULSION BASED ON ETHOXYL FATHER ETHERS OR ETHOXYL FATTY ESTERS, AND ITS USES IN THE COSMETIC, DERMATOLOGICAL AND / OR OPHTHALMOLOGICAL FIELDS|
    FR2788007B1|1999-01-05|2001-02-09|Oreal|NANOEMULSION BASED ON BLOCK COPOLYMERS OF ETHYLENE OXIDE AND PROPYLENE OXIDE, AND ITS USES IN THE COSMETIC, DERMATOLOGICAL AND / OR OPHTHALMOLOGICAL FIELDS|
    US6270781B1|1999-01-08|2001-08-07|Maxim Pharmaceuticals, Inc.|Method and compositions for topical treatment of damaged tissue using reactive oxygen metabolite production or release inhibitors|
    US6486168B1|1999-01-08|2002-11-26|3M Innovative Properties Company|Formulations and methods for treatment of mucosal associated conditions with an immune response modifier|
    FR2789371B1|1999-02-05|2001-04-27|Sofab|DISTRIBUTOR OF CHEMICALLY UNSTABLE PRODUCTS|
    EP1025836A1|1999-02-08|2000-08-09|F. Hoffmann-La Roche Ag|Cosmetic light screening composition|
    TWI262930B|1999-02-10|2006-10-01|Mitsui Chemicals Inc|High-durability flexible polyurethane cold molded foam and process for producing the same|
    US6423329B1|1999-02-12|2002-07-23|The Procter & Gamble Company|Skin sanitizing compositions|
    US6224888B1|1999-02-12|2001-05-01|The Procter & Gamble Company|Cosmetic compositions|
    JP3641152B2|1999-02-17|2005-04-20|株式会社ヤクルト本社|Topical skin preparation|
    US7374779B2|1999-02-26|2008-05-20|Lipocine, Inc.|Pharmaceutical formulations and systems for improved absorption and multistage release of active agents|
    DE50004303D1|1999-02-26|2003-12-11|Wella Ag|DEVICE FOR MIXING, FOAMING AND DISPENSING LIQUIDS FROM SEPARATE PRESSURE GAS TANKS|
    IL129102D0|1999-03-22|2000-02-17|J P M E D Ltd|An emulsion|
    DE60037689T2|1999-03-31|2009-01-02|Firmenich S.A.|Use of Cubebol as a flavoring agent|
    US6383471B1|1999-04-06|2002-05-07|Lipocine, Inc.|Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents|
    US6264964B1|1999-04-14|2001-07-24|Conopco, Inc.|Foaming cosmetic products|
    CN1355699A|1999-04-16|2002-06-26|藤泽药品工业株式会社|Antifungal compositions|
    US6284802B1|1999-04-19|2001-09-04|The Procter & Gamble Company|Methods for regulating the condition of mammalian keratinous tissue|
    US6433003B1|1999-04-23|2002-08-13|Arthur M. Bobrove|Method for treating hyperhidrosis in mammals|
    LT2915534T|1999-04-23|2018-06-25|Leo Pharma A/S|Pharmaceutical composition for dermal use to treat psoriasis comprising a vitamin D and a corticosteroid|
    GB9909711D0|1999-04-27|1999-06-23|Unilever Plc|Mousse forming hair treatment composition|
    FR2793479B1|1999-05-10|2001-06-29|Lir France Sa|DOUBLE DISPENSER FOR FLUID OR PASTY PRODUCTS|
    AU4841700A|1999-05-12|2000-11-21|Nitromed, Inc.|Nitrosated and nitrosylated potassium channel activators, compositions and methods of use|
    US6168576B1|1999-05-24|2001-01-02|Irene N. Reynolds|Device for dispensing vaginal medication|
    US6518228B1|1999-05-27|2003-02-11|Clairol Incorporated|Ultra-mild, clear, aqueous, foamable skin cleanser|
    US6395300B1|1999-05-27|2002-05-28|Acusphere, Inc.|Porous drug matrices and methods of manufacture thereof|
    WO2000072805A1|1999-05-28|2000-12-07|Unilever Plc|Foamable shower oil composition|
    JP2000351726A|1999-06-08|2000-12-19|Lion Corp|Aerosol preparation|
    JP2000354623A|1999-06-14|2000-12-26|Shiigeru Kk|Deodorant and deodorizing spray|
    US6113888A|1999-06-15|2000-09-05|Neutrogena Corporation|Self-tanning mousse|
    GB9913951D0|1999-06-15|1999-08-18|Unilever Plc|Mousse-forming shampoo compositions|
    US6190365B1|1999-06-21|2001-02-20|Chun Lim Abbott|Vaginal douche applicator and method of vaginal deodorization using the same|
    KR100352088B1|1999-06-21|2002-09-12|한미약품공업 주식회사|Dermal emulsion composition comprising minoxidil|
    US6524594B1|1999-06-23|2003-02-25|Johnson & Johnson Consumer Companies, Inc.|Foaming oil gel compositions|
    NL1012419C2|1999-06-23|2000-12-28|Airspray Nv|Aerosol for dispensing a liquid.|
    JP2001002526A|1999-06-23|2001-01-09|Koike Kagaku Kk|Foam aerosol composition|
    US6761903B2|1999-06-30|2004-07-13|Lipocine, Inc.|Clear oil-containing pharmaceutical compositions containing a therapeutic agent|
    WO2001001949A1|1999-07-01|2001-01-11|Johnson And Johnson Consumer Companies, Inc.|Cleansing compositions|
    US20060254597A1|2000-12-14|2006-11-16|40J's Llc|Method of treatment of atrophic vaginitis by topical clitoral menthol or a related cooling compound|
    US6762158B2|1999-07-01|2004-07-13|Johnson & Johnson Consumer Companies, Inc.|Personal care compositions comprising liquid ester mixtures|
    FR2795643B1|1999-07-02|2004-06-11|Oreal|FIRMING COSMETIC COMPOSITION INCLUDING AT LEAST ONE HYDROXYSTILBENE IN ASSOCIATION WITH ASCORBIC ACID|
    JP4058199B2|1999-07-06|2008-03-05|ポーラ化成工業株式会社|Warm feeling pack|
    WO2001005366A1|1999-07-15|2001-01-25|Playtex Products, Inc.|Sunscreen aerosol composition|
    US6548074B1|1999-07-22|2003-04-15|Elizabeth Arden Co., Division Of Conopco, Inc.|Silicone elastomer emulsions stabilized with pentylene glycol|
    FR2796925B1|1999-07-29|2001-10-05|Valois Sa|DISPENSER WITH ARTICULATED DISPENSING HEAD|
    AU7389300A|1999-08-02|2001-02-19|First Horizon Pharmaceutical Corporation|Methods of administration of glycopyrrolate compositions|
    US6303552B1|1999-08-04|2001-10-16|Napier International Technologies, Inc.|Aerosol paint stripper compositions|
    DE19938757A1|1999-08-16|2001-02-22|Beiersdorf Ag|Cosmetic or dermatological preparations of the oil-in-water type|
    ES2221624T3|1999-08-26|2005-01-01|Ganeden Biotech, Inc.|USE OF EMU OIL AS A VEHICLE FOR ANTIFUNGIC, ANTIBACTERIAL AND ANTIVIRIC MEDIATIONS.|
    US6777591B1|1999-08-27|2004-08-17|Sembiosys Genetics Inc.|Legume-like storage protein promoter isolated from flax and methods of expressing proteins in plant seeds using the promoter|
    US6308863B1|1999-09-02|2001-10-30|Owens-Brockway Plastic Products Inc.|Dual chamber package for pressurized products|
    US6479058B1|1999-09-02|2002-11-12|Mccadden Michael E.|Composition for the topical treatment of poison ivy and other forms of contact dermatitis|
    JP4394775B2|1999-09-03|2010-01-06|株式会社ダイゾー|Water-in-oil foam aerosol composition and method for producing the same|
    JP4045475B2|1999-09-06|2008-02-13|東洋紡績株式会社|Nucleic acid / protein purification equipment|
    US6986883B2|1999-09-09|2006-01-17|Discus Dental, Inc.|Increased peroxide content tooth bleaching gel|
    US6283336B1|1999-09-20|2001-09-04|The Procter & Gamble Company|Article for the delivery of foam products|
    US6437006B1|1999-09-27|2002-08-20|American Cyanamid Company|Pharmaceutical carrier formulation|
    US6528086B2|1999-09-28|2003-03-04|Zars, Inc.|Methods and apparatus for drug delivery involving phase changing formulations|
    FR2798849B1|1999-09-29|2001-11-23|Oreal|COMPOSITION FOR WASHING KERATIN MATERIALS, BASED ON A DETERGENT SURFACE-ACTIVE AGENT, A DIALKYL DIALLYL AMMONIUM HOMOPOLYMER AND AN ACRYLIC TERPOLYMER|
    US6667045B2|1999-10-01|2003-12-23|Joseph Scott Dahle|Topical applications for skin treatment|
    US6790435B1|1999-10-01|2004-09-14|Unilever Home & Personal Care Usa Division Of Conopco, Inc.|Antiperspirant compositions comprising microemulsions|
    FR2799369B1|1999-10-08|2001-12-21|Oreal|COMBINATION OF ESCINE AND DEXTRAN SULFATE AND THE USE THEREOF|
    US6186367B1|1999-10-19|2001-02-13|Valley Design Inc.|Metered liquid squeeze dispenser|
    FR2799963B1|1999-10-22|2002-07-19|Oreal|EMULSIONS CONTAINING AT LEAST ONE INSOLUBLE ORGANIC UV FILTER AND A NON-FILTERING ORGANOMODIFIED SILICONE|
    US6080394A|1999-11-08|2000-06-27|Dow Corning Corporation|Polar solvent-in-oil emulsions and multiple emulsions|
    US20030077301A1|1999-12-16|2003-04-24|Maibach Howard I.|Topical pharmaceutical composition for the treatment of inflammatory dermatoses|
    UA66796C2|1999-12-27|2004-06-15|Univ Nat Pharmaceutical|Composition "profesol foamy" for treating radiation lesions of skin|
    US8512718B2|2000-07-03|2013-08-20|Foamix Ltd.|Pharmaceutical composition for topical application|
    US6967023B1|2000-01-10|2005-11-22|Foamix, Ltd.|Pharmaceutical and cosmetic carrier or composition for topical application|
    IL133969D0|2000-01-10|2001-04-30|Thixo Ltd|Thixotropic compositions containing unsaturated oils and food products containing the same|
    US7001690B2|2000-01-18|2006-02-21|Valence Technology, Inc.|Lithium-based active materials and preparation thereof|
    US6528033B1|2000-01-18|2003-03-04|Valence Technology, Inc.|Method of making lithium-containing materials|
    FR2804016B1|2000-01-21|2006-07-28|Oreal|NANEMULSION CONTAINING AMPHIPHILIC LIPIDS AND PEG ESTER AND USES THEREOF|
    FR2804015B1|2000-01-21|2005-12-23|Oreal|NANEMULSION CONTAINING AMPHIPHILIC LIPIDS AND NONIONIC POLYMER AND USES THEREOF|
    WO2001054679A2|2000-01-27|2001-08-02|Children's Hospital Research Foundation|Transdermal composition containing an anesthetic and a vasodilator agent|
    US6780443B1|2000-02-04|2004-08-24|Takasago International Corporation|Sensate composition imparting initial sensation upon contact|
    FR2804666B1|2000-02-04|2002-06-14|Oreal|DISPENSER FOR STORING AT LEAST TWO COMPONENTS AND SELECTIVE DISPENSING EITHER OF A SINGLE CONSTITUENT, EITHER OF THEIR MIXTURE, AND METHOD FOR THE IMPLEMENTATION THEREOF|
    NL1014389C2|2000-02-15|2001-08-16|Dija Zeist Bv|Tanning preparation for the skin.|
    US20040161447A1|2000-02-17|2004-08-19|Leonard Paul|Liquid foam producing compositions and dispensing system therefor|
    US7117199B2|2000-02-22|2006-10-03|Metacarta, Inc.|Spatially coding and displaying information|
    EP1189579B1|2000-02-22|2004-09-08|Color Access, Inc.|Gelled aqueous cosmetic compositions|
    DE10008896A1|2000-02-25|2001-08-30|Beiersdorf Ag|Improving the solubility and compatibility of benzotriazole UV filters in oils, e.g. in cosmetics or dermatological compositions, by addition of dialkylnaphthalates|
    DE10008837A1|2000-02-25|2001-08-30|Henkel Kgaa|Dental cleaner containing propellant gas|
    US6664287B2|2000-03-15|2003-12-16|Bethesda Pharmaceuticals, Inc.|Antioxidants|
    IL135222A|2000-03-22|2005-06-19|Univ Ben Gurion|Compositions containing molecular iodine|
    DE20006099U1|2000-04-01|2000-07-06|Megaplast Gmbh & Co Kg|Dosing pump dispenser with at least two dosing pumps|
    US6649571B1|2000-04-04|2003-11-18|Masi Technologies, L.L.C.|Method of generating gas bubbles in oleaginous liquids|
    AU5890100A|2000-04-06|2001-10-23|Nicholas V Perricone|Treatment of skin damage using olive oil polyphenols|
    FR2807322B1|2000-04-10|2004-02-20|Oreal|COMPOSITION, ESPECIALLY COSMETIC, COMPRISING ASCORBIC ACID IN ASSOCIATION WITH AN ASCORBIC ACID DERIVATIVE|
    US7758888B2|2000-04-21|2010-07-20|Sol-Gel Technologies Ltd.|Composition exhibiting enhanced formulation stability and delivery of topical active ingredients|
    JP2002012513A|2000-04-24|2002-01-15|Kanebo Ltd|Urea-containing whipped cosmetic|
    US6358541B1|2000-05-03|2002-03-19|David S. Goodman|Topical preparation for the treatment of hair loss|
    US6410036B1|2000-05-04|2002-06-25|E-L Management Corp.|Eutectic mixtures in cosmetic compositions|
    EP1278504A2|2000-05-05|2003-01-29|R.P. Scherer Technologies, Inc.|Oil-in-water emulsion formulation containing hydroquinone and retinol|
    EP1286652B1|2000-05-08|2006-09-06|Pfizer Products Inc.|Skin protectant spray compositions|
    US6433024B1|2000-05-08|2002-08-13|Karl F. Popp|Topical anti-acne composition|
    FR2808685B1|2000-05-12|2004-10-08|Sanofi Synthelabo|PHARMACEUTICAL COMPOSITIONS FOR TRANSDERMAL DELIVERY OF ANTI-INFLAMMATORY AGENTS|
    JP2001326952A|2000-05-15|2001-11-22|Nec Corp|Broadcast confirmation system, method and device for broadcast confirmation, and recording medium with broadcast confirmation program recorded thereon|
    FR2809010B1|2000-05-22|2002-07-12|Oreal|NANOEMULSION BASED ON ANIONIC POLYMERS, AND ITS USES IN PARTICULAR IN THE COSMETIC, DERMATOLOGICAL, PHARMACEUTICAL AND / OR OPHTHALMOLOGICAL FIELDS|
    JP4653282B2|2000-05-23|2011-03-16|昭和薬品化工株式会社|Minocycline-containing composition|
    DE10028638A1|2000-06-09|2001-12-20|Schuelke & Mayr Gmbh|Storage-stable composition useful in cosmetic and pharmaceutical compositions comprises combination of glycerol monoalkyl ether with antioxidant|
    WO2001095728A1|2000-06-13|2001-12-20|Fd Management, Inc.|Cosmetic composition for stressed skin under extreme conditions|
    AU7201501A|2000-06-23|2002-01-08|Combe Internat Ltd|Stable foam for use in disposable wipe|
    US20020164381A1|2000-06-30|2002-11-07|Medicis Pharmaceutical Corporation|Mitocidal compositions and methods|
    CA2313659A1|2000-07-06|2002-01-06|Barry J. Barclay|B complex vitamin compositions that protect against cellular damage caused by ultraviolet light|
    DE10033414B4|2000-07-08|2004-02-19|Wella Aktiengesellschaft|Clear, two-phase, foam-forming aerosol hair care product|
    US6468989B1|2000-07-13|2002-10-22|Dow Pharmaceutical Sciences|Gel compositions containing metronidazole|
    FR2811564B1|2000-07-13|2002-12-27|Oreal|NANOEMULSION CONTAINING NON-IONIC POLYMERS, AND ITS USES IN PARTICULAR IN THE COSMETIC, DERMATOLOGICAL, PHARMACEUTICAL AND / OR OPHTHALMOLOGICAL FIELDS|
    DE10035930A1|2000-07-21|2002-01-31|Clariant Gmbh|fine emulsions|
    US20020035070A1|2000-07-26|2002-03-21|The Procter & Gamble Company|Method of regulating hair growth using metal complexes of oxidized carbohydrates|
    FR2812191B1|2000-07-28|2003-10-17|Oreal|USE OF PROSTAGLANDIN E2 RECEPTOR AGONISTS TO ATTENUATE, DECREASE OR STOP HAIR AND HAIR GROWTH IN COSMETIC PREPARATIONS|
    JP4166931B2|2000-08-02|2008-10-15|ポーラ化成工業株式会社|Fever foam cosmetic|
    US6514487B1|2000-08-08|2003-02-04|Teresa Leigh Barr|Foam and gel oat protein complex and method of use|
    AU8520101A|2000-08-22|2002-03-04|Procter & Gamble|Personal care compositions containing adhesive elastomeric polymer and inorganiccolloid|
    US6299023B1|2000-08-24|2001-10-09|Miles Arnone|Device for dispensing two substances in a user selectable ratio with replaceable cartridges|
    WO2002015860A1|2000-08-24|2002-02-28|Tim Ioannides|Topical antioxidant having vitamin c and method of combination with topical agent by user|
    FR2813189B1|2000-08-31|2003-02-28|Oreal|COSMETIC FOAMING CREAM FOR THE TREATMENT OF OILY SKIN|
    WO2002022086A2|2000-09-14|2002-03-21|Quantum Energy Technologies|Application of water nanoclusters to skin|
    AU8803901A|2000-09-21|2002-04-02|Taisho Pharma Co Ltd|Suppositories sustained in the lower rectum|
    AUPR048600A0|2000-10-02|2000-10-26|Soltec Research Pty Ltd|Pharmaceutical vehicle|
    DE10049147A1|2000-10-04|2002-04-25|Wella Ag|Hair wax product with waxes, non-volatile oils and volatile, hydrophobic substances|
    FR2814959A1|2000-10-09|2002-04-12|Menarini France|Atomiser for pharmaceutical products based on antiinflammatory agents comprises pressurized container, dosing pouch and metering valve|
    US6547063B1|2000-10-10|2003-04-15|The Procter & Gamble Company|Article for the delivery of foam products|
    GB2367809A|2000-10-12|2002-04-17|Bespak Plc|Metering valve with collapsible chamber|
    US6403069B1|2000-10-20|2002-06-11|Colgate-Palmolive Company|High oil clear emulsion with elastomer|
    FR2815616B1|2000-10-20|2003-01-24|Oreal|DISTRIBUTION ASSEMBLY FOR THE EXTEMPORARY DISTRIBUTION OF TWO PRODUCTS|
    US20040018228A1|2000-11-06|2004-01-29|Afmedica, Inc.|Compositions and methods for reducing scar tissue formation|
    DE10058384B4|2000-11-24|2004-12-16|Wella Aktiengesellschaft|Cosmetic or dermatological agent in the form of a creamy permanent foam or a stably foamed cream, its use and method for producing the agent|
    US6299032B1|2000-11-27|2001-10-09|George W. Hamilton|Disposable actuator with cap opener for aerosol cans|
    US6969521B1|2000-11-28|2005-11-29|Avon Products, Inc.|Aerosol insect repellent composition having low VOC content and method of applying same to the skin|
    AU1789602A|2000-11-28|2002-06-11|Avon Prod Inc|Foaming insect repellent compositions|
    US20050013853A1|2000-11-29|2005-01-20|Irit Gil-Ad|Anti-proliferative drugs|
    US6774100B2|2000-12-06|2004-08-10|Imaginative Research Associates, Inc.|Anhydrous creams, lotions and gels|
    GB0030068D0|2000-12-11|2001-01-24|Lawrence Malcolm|Highway vehicular traffic flow control|
    JP3497466B2|2000-12-12|2004-02-16|高砂香料工業株式会社|Warming composition|
    DE10063342A1|2000-12-19|2002-06-20|Beiersdorf Ag|Cosmetic or dermatological composition contains three-part emulsifier system and gas|
    US6749860B2|2000-12-22|2004-06-15|Kimberly-Clark Worldwide, Inc.|Absorbent articles with non-aqueous compositions containing botanicals|
    US20040079361A1|2001-01-17|2004-04-29|Clayton Colin D.|Medicinal aerosols|
    FR2819427B1|2001-01-18|2003-04-11|Oreal|TRANSLUCENT NANOEMULSION, MANUFACTURING METHOD THEREOF AND USES THEREOF IN THE COSMETIC, DERMATOLOGICAL AND / OR OPHTHALMOLOGICAL FIELDS|
    US20030013692A1|2001-01-19|2003-01-16|Gullans Steven R.|Methods of treating neurological disorders|
    WO2002062324A2|2001-02-05|2002-08-15|Michael Albert Kamm|A treatment of oesophageal motility disorders and gastro-oesophageal reflux disease|
    DE10110336A1|2001-03-03|2002-09-12|Clariant Gmbh|Surfactant-free cosmetic, dermatological and pharmaceutical agents|
    CA2440141A1|2001-03-06|2002-09-12|Cellegy Pharmaceuticals, Inc.|Compounds and methods for the treatment of urogenital disorders|
    CA2448231A1|2001-03-07|2002-10-03|The Procter & Gamble Company|Cosmetic topical composition comprising a functional aromatic derivative bonding agent|
    AU2002254396A1|2001-03-26|2002-10-08|Dana-Farber Cancer Institute, Inc.|Method of attenuating reactions to skin irritants|
    AT273206T|2001-03-26|2004-08-15|3M Innovative Properties Co|DOOR VALVE FOR A DOSING INHALATOR WITH IMPROVED FLOW|
    CA2442281C|2001-03-27|2010-06-08|Galen Limited|Intravaginal drug delivery devices for the administration of an antimicrobial agent|
    CA2441730C|2001-03-29|2008-11-18|The Dial Corporation|Antibacterial compositions for skin care|
    JP2002302419A|2001-03-30|2002-10-18|Aldeep Cosmetics Japan Inc|Cosmetic composition|
    US20040115261A1|2001-04-05|2004-06-17|Ashley Robert A.|Controlled delivery of tetracycline compounds and tetracycline derivatives|
    US6848597B2|2001-04-18|2005-02-01|James A. Vlodek|Methods and apparatus for extruding foam through orifices|
    US20030053980A1|2001-04-30|2003-03-20|The Gillette Company|Shaving compositions containing highly lubricious water soluble polymers|
    US6682726B2|2001-04-30|2004-01-27|The Gillette Company|Self-foaming shaving lotion|
    US7078048B2|2001-05-09|2006-07-18|The Regents Of The University Of Michigan|Method and compositions for treating rosacea|
    US20020187181A1|2001-05-14|2002-12-12|3M Innovative Properties Company|System for delivering cosmetics and pharmaceuticals|
    ITMI20011019A1|2001-05-17|2002-11-18|Carlo Ghisalberti|FURILIC SUBSTANCES FOR TOPICAL USE|
    WO2002096374A2|2001-05-31|2002-12-05|Upsher-Smith Laboratories, Inc.|Dermatological compositions and methods comprising alpha-hydroxy acids or derivatives|
    MXPA03011927A|2001-06-20|2004-03-26|Procter & Gamble|Personal care composition comprising polyol-in-silicone emulsion.|
    US7270828B2|2001-06-20|2007-09-18|The Procter & Gamble Company|Personal care composition comprising hydrophobic gel|
    FR2826292B1|2001-06-22|2004-01-23|Rhodia Chimie Sa|OIL-IN-OIL EMULSIONS COMPRISING A SILICONE, DISPERSIONS OF SUCH EMULSIONS AND USE THEREOF|
    US6544562B2|2001-06-25|2003-04-08|Blistex Inc.|Acne treatment including dual-package system|
    US6428772B1|2001-06-25|2002-08-06|Blistex Inc.|Acne treatment composition with cooling effect|
    WO2003002082A1|2001-06-26|2003-01-09|The Procter & Gamble Company|Pressurized anhydrous antiperspirant emulsions|
    WO2003002426A1|2001-06-27|2003-01-09|Kanebo,Limited|Mixer/extractor|
    JP2003012511A|2001-06-27|2003-01-15|Rohto Pharmaceut Co Ltd|Aerosol composition|
    US20030053961A1|2001-07-13|2003-03-20|Eccard Wayne Ellis|Mousse forming compositions comprising quaternary ammonium agents|
    US20060194773A1|2001-07-13|2006-08-31|Paratek Pharmaceuticals, Inc.|Tetracyline compounds having target therapeutic activities|
    DE10134786A1|2001-07-17|2003-02-06|Beiersdorf Ag|Foamable preparations|
    EP1420783A4|2001-08-03|2009-09-30|Takeda Pharmaceutical|Stable emulsion composition|
    DE10138495B4|2001-08-04|2004-11-11|Beiersdorf Ag|Foaming preparations and their use|
    AT469639T|2001-08-08|2010-06-15|Dominguez Maria Antonia Garcia-Olmedo|INJECTABLE FOAM AND NEW PHARMACEUTICAL APPLICATIONS THEREFOR|
    JP2005511493A|2001-08-09|2005-04-28|クローダ，インコーポレイテッド|Anti-irritant|
    JP4707279B2|2001-08-09|2011-06-22|ポーラ化成工業株式会社|Cosmetics for massage with cool-down effect|
    US6971556B2|2001-08-11|2005-12-06|Aventis Pharma Limited|Pressurized aerosol dispenser|
    US6638981B2|2001-08-17|2003-10-28|Epicept Corporation|Topical compositions and methods for treating pain|
    US20030049218A1|2001-08-28|2003-03-13|Amit Patel|Antiperspirant deodorant emulsion|
    EP1455888B1|2001-08-29|2009-04-29|PharmaKodex Limited|Topical administration device|
    US6709663B2|2001-08-31|2004-03-23|Healthpoint, Ltd.|Multivesicular emulsion drug delivery systems|
    US6479060B1|2001-09-04|2002-11-12|Healthpoint, Ltd.|Elegant hydrogenated castor oil ointments|
    FR2829693B1|2001-09-20|2004-02-27|Oreal|FOAMING COSMETIC CREAM|
    DE10147820A1|2001-09-27|2003-04-10|Beiersdorf Ag|Self-foaming, foam-like, post-foaming or foamable cosmetic or dermatological preparations containing waxes or lipids which are solid and / or semi-solid at room temperature|
    US7931533B2|2001-09-28|2011-04-26|Igt|Game development architecture that decouples the game logic from the graphics logics|
    JP2005508937A|2001-10-05|2005-04-07|ザジェネラルホスピタルコーポレーション|Methods and compositions for treating skin lesions|
    US20030185839A1|2001-10-05|2003-10-02|Podolsky Daniel K.|Methods and compositions for treating dermal lesions|
    CA2463308C|2001-10-10|2010-12-14|Exxonmobil Research And Engineering Company|Biodegradable non-toxic gear oil|
    US20030082120A1|2001-10-26|2003-05-01|Milstein Harold J.|Method for reducing systemic effects of aging, effects of aging on the skin, and incidence of skin damage from sun exposure using antibiotics of the tetracycline family|
    EP1438946B1|2001-10-26|2009-01-14|Taiyo Kagaku Co., Ltd.|Composition for oily foamable aerosol|
    US7255869B2|2001-10-30|2007-08-14|The Procter & Gamble Company|Anhydrous cosmetic compositions containing polyols|
    DE10154324A1|2001-11-06|2003-08-07|Merz Pharma Gmbh & Co Kgaa|Topically applicable compositions with external active substance depot formation, their production and their use|
    DE10155956A1|2001-11-09|2003-05-22|Beiersdorf Ag|Self-foaming, foam-like, post-foaming or foamable cosmetic or dermatological preparations|
    WO2003041667A2|2001-11-13|2003-05-22|The Procter & Gamble Company|Compositions containing enzymes stabilized with certain osmo-protectants and methods for using such compositions in personal care|
    DE10155792A1|2001-11-14|2003-05-22|Beiersdorf Ag|Self-foaming, foam-like, post-foaming or foamable cosmetic or dermatological preparations containing siloxane elastomers|
    EP1565189A4|2001-11-16|2006-11-02|Beatrice M Klysz|Anti-aging skin care composition and uses thereof|
    DE10159002A1|2001-11-30|2003-06-18|Clariant Gmbh|Use of multi-phase foaming agents from foam dispensers|
    FR2833246B1|2001-12-06|2005-06-24|Beatrice France Touteau|DEVICE FOR SIMULTANEOUSLY ACTING TWO AEROSOLS CONTAINING TWO PRODUCTS TO BE MIXED AT THE TIME OF USE|
    US6531118B1|2001-12-11|2003-03-11|Avon Products, Inc.|Topical compositions with a reversible photochromic ingredient|
    US8226972B2|2001-12-20|2012-07-24|Femmepharma Holding Company, Inc.|Vaginal delivery of drugs|
    SE0104421D0|2001-12-21|2001-12-21|Ponsus Pharma Ab|New composition|
    US6765001B2|2001-12-21|2004-07-20|Medicis Pharmaceutical Corporation|Compositions and methods for enhancing corticosteroid delivery|
    US20030118515A1|2001-12-21|2003-06-26|Robert Jew|Cosmetic composition containing carbon dioxide|
    US20030129259A1|2001-12-28|2003-07-10|Avon Products, Inc.|Topical lightening compostitions and methods of use|
    JP4549625B2|2002-01-05|2010-09-22|株式會社アモーレパシフィック|Finely emulsified particles containing ginseng saponin metabolites as active ingredients, a method for producing the same, and a cosmetic composition for preventing skin aging containing the same|
    US7192601B2|2002-01-18|2007-03-20|Walker Edward B|Antimicrobial and sporicidal composition|
    US6992049B2|2002-01-31|2006-01-31|Exxonmobil Research And Engineering Company|Lubricating oil compositions|
    NZ517094A|2002-02-08|2005-03-24|Advanced Animal Technology Ltd|Improvements in and relating to substance delivery device|
    AU2002234653A1|2002-02-14|2003-09-04|Quimversion, S.L.|Aluminium and hexamethylenetetramine complex and the applications thereof|
    US6589216B1|2002-02-20|2003-07-08|Abbott Research Group, Inc.|Vaginal douches, vaginal douche applicators and methods of vaginal douching|
    US6682511B2|2002-02-21|2004-01-27|Robert Wallace Besoyan|Brief protector|
    US7635463B2|2002-02-27|2009-12-22|Pharmain Corporation|Compositions for delivery of therapeutics and other materials|
    US6691898B2|2002-02-27|2004-02-17|Fomo Products, Inc.|Push button foam dispensing device|
    WO2003075851A2|2002-03-06|2003-09-18|Cellegy Pharmaceuticals, Inc.|Compositions and methods for the treatment of anorectal disorders|
    US20050281766A1|2002-03-11|2005-12-22|Avon Products, Inc.|Method of improving the aesthetic appearance of epithelia|
    US6736860B2|2002-03-12|2004-05-18|Unilever Home & Personal Care Usa Division Of Conopco, Inc.|Gradual permanent coloring of hair using dye intermediates dissolved in alkaline water with fatty alcohol|
    CA2422244A1|2002-03-14|2003-09-14|Homax Products, Inc.|Aerosol systems and methods for mixing and dispensing two-part materials|
    JP2005520675A|2002-03-19|2005-07-14|エアースプレーインターナショナルビーブイ|Dispenser device|
    US20030180347A1|2002-03-19|2003-09-25|W.F. Young, Incorporated|Patch for the delivery of topical agents|
    JP4322124B2|2002-03-28|2009-08-26|伯東株式会社|Method for stabilizing bubbles in foam-containing cosmetics|
    AU2003230927A1|2002-04-12|2003-10-27|Dreamwell, Ltd.|Cassette bedding system|
    US8192749B2|2003-04-16|2012-06-05|Galderma Laboratories Inc.|Methods of simultaneously treating ocular rosacea and acne rosacea|
    US8846039B2|2002-04-26|2014-09-30|Asan Laboratories Company , Limited|Method for ameliorating pruritus|
    US6875438B2|2002-04-27|2005-04-05|Aventis Pharma Deutschland Gmbh|Preparations for topical administration of substances having antiandrogenic activity|
    CA2384922C|2002-05-03|2008-09-02|Purepharm Inc.|Topical glycopyrrolate product for the reduction of sweating|
    CA2500134A1|2002-05-06|2003-11-13|Collagenex Pharmaceuticals, Inc.|Methods of simultaneously treating mucositis and fungal infection|
    CN100531822C|2002-05-10|2009-08-26|荷兰联合利华有限公司|Hair conditioning compositions|
    US6783027B2|2002-05-15|2004-08-31|The Procter & Gamble Company|Metered-dose underarm product and package|
    US20030215472A1|2002-05-16|2003-11-20|Bonda Craig A|Methods and compositions employing a dialkyl amide|
    JP2005533766A|2002-05-20|2005-11-10|コッラジェネックスファーマシューチカルスインコーポレイテッド|How to treat allergic reactions|
    JP4050094B2|2002-05-28|2008-02-20|株式会社三谷バルブ|Metering valve mechanism and aerosol products|
    US6723309B1|2002-06-10|2004-04-20|Jeffrey Alan Deane|Hair cleansing conditioner|
    FR2840903B1|2002-06-13|2005-01-28|Oreal|GLUCOSE AND VITAMIN F DERIVATIVE, COMPOSITIONS COMPRISING THE SAME, AND USES FOR IMPROVING THE CONDITION OF HAIR AND HAIR|
    US7763587B2|2002-06-13|2010-07-27|L'oreal S.A.|Derivative of glucose and of vitamin F, compositions comprising it, uses and preparation process|
    US7163669B2|2002-06-19|2007-01-16|J.M. Huber Corporation|Cosmetic compositions comprising calcium silicates|
    AT490932T|2002-06-26|2010-12-15|Daizo Co Ltd|PACKAGING CONTAINERS FOR DISTRIBUTING MULTIPLE CONTENTS, PACKAGING PRODUCT WITH THE PACKAGING CONTAINER AND METHOD FOR PRODUCING THE PACKAGING PRODUCT|
    JP2004026605A|2002-06-27|2004-01-29|Asahi Fiber Glass Co Ltd|Greige goods for glass fiber yarn and glass fiber yarn made using this|
    US20040002550A1|2002-06-28|2004-01-01|Mercurio Anthony Fred|Post foaming compositions|
    US6785629B2|2002-07-02|2004-08-31|Agilent Technologies, Inc.|Accuracy determination in bit line voltage measurements|
    JP3833972B2|2002-07-08|2006-10-18|古河電気工業株式会社|Wire harness assembly system|
    US7137536B2|2002-07-22|2006-11-21|Seaquist Perfect Dispensing Foreign, Inc.|Inverted aerosol dispenser|
    DE10233330B4|2002-07-22|2007-04-26|Sasol Germany Gmbh|Microemulsion containing UV photoprotective filter and / or anti-dandruff agent|
    US6897195B2|2002-07-24|2005-05-24|Nanjing Zhongshi Chemical Co.|Composition of menthol and menthyl lactate, its preparation method and its applications as a cooling agent|
    US20020182162A1|2002-08-07|2002-12-05|Mohsen Shahinpoor|Nitric oxide donor+cGMP-PDE5 inhibitor as a topical drug for enhanced hair growth|
    FR2843373B1|2002-08-12|2005-03-04|Jean Augustin|DEVICE FOR PACKAGING AND APPLYING A PRODUCT IN FLUID FORM|
    US7939170B2|2002-08-15|2011-05-10|The Rockefeller University|Water soluble metal and semiconductor nanoparticle complexes|
    US20060240123A1|2002-08-26|2006-10-26|S.L.A. Pharma Ag|Pharmaceutical composition|
    US6770607B2|2002-09-12|2004-08-03|Unilever Home & Personal Care Usa, Division Of Conopco, Inc.|Viscoelastic cleansing gel with micellar surfactant solutions|
    US7906473B2|2002-09-13|2011-03-15|Bissell Homecare, Inc.|Manual spray cleaner|
    US6968982B1|2002-09-18|2005-11-29|Burns Caleb E S|Multiple-mist dispenser|
    GB0221697D0|2002-09-18|2002-10-30|Unilever Plc|Novel compouds and their uses|
    US7179481B2|2002-09-19|2007-02-20|Kimberly-Clark Worldwide, Inc.|Vaginal health products|
    US6949037B2|2002-09-27|2005-09-27|Richard A. Enos|Quick-release fastener for releasably attaching lacrosse stick head to shaft|
    DE60324641D1|2002-09-30|2008-12-24|Kao Corp|Foamable emulsion of the oil-in-water type|
    FR2845672B1|2002-10-09|2006-02-10|Airlessystems|FLUID PRODUCT DISPENSER|
    CA2528776A1|2002-10-24|2004-05-06|G & R Pharmaceuticals, Llc|Antifungal formulations|
    US20050205086A1|2002-10-25|2005-09-22|Foamix Ltd.|Retinoid immunomodulating kit and composition and uses thereof|
    US20070292359A1|2002-10-25|2007-12-20|Foamix Ltd.|Polypropylene glycol foamable vehicle and pharmaceutical compositions thereof|
    US20120156144A1|2002-10-25|2012-06-21|Foamix|Foamable Compositions, Kits and Methods for Hyperhidrosis|
    NZ540166A|2002-10-25|2007-06-29|Foamix Ltd|Cosmetic and pharmaceutical foam|
    US20070292355A1|2002-10-25|2007-12-20|Foamix Ltd.|Anti-infection augmentation foamable compositions and kit and uses thereof|
    US8119150B2|2002-10-25|2012-02-21|Foamix Ltd.|Non-flammable insecticide composition and uses thereof|
    US20060018937A1|2002-10-25|2006-01-26|Foamix Ltd.|Steroid kit and foamable composition and uses thereof|
    US9668972B2|2002-10-25|2017-06-06|Foamix Pharmaceuticals Ltd.|Nonsteroidal immunomodulating kit and composition and uses thereof|
    US20060193789A1|2002-10-25|2006-08-31|Foamix Ltd.|Film forming foamable composition|
    IL152486D0|2002-10-25|2003-05-29|Meir Eini|Alcohol-free cosmetic and pharmaceutical foam carrier|
    US20080031907A1|2002-10-25|2008-02-07|Foamix Ltd.|Cosmetic and pharmaceutical foam|
    US20080152596A1|2005-07-19|2008-06-26|Foamix Ltd.|Polypropylene glycol foamable vehicle and pharmaceutical compositions thereof|
    US10117812B2|2002-10-25|2018-11-06|Foamix Pharmaceuticals Ltd.|Foamable composition combining a polar solvent and a hydrophobic carrier|
    US20080138296A1|2002-10-25|2008-06-12|Foamix Ltd.|Foam prepared fromnanoemulsions and uses|
    US20160158261A1|2002-10-25|2016-06-09|Foamix Pharmaceuticals Ltd.|Antibiotic Kit and Composition and Uses Thereof|
    US20050186142A1|2002-10-25|2005-08-25|Foamix Ltd.|Kit and composition of imidazole with enhanced bioavailability|
    US20080206161A1|2002-10-25|2008-08-28|Dov Tamarkin|Quiescent foamable compositions, steroids, kits and uses thereof|
    US9211259B2|2002-11-29|2015-12-15|Foamix Pharmaceuticals Ltd.|Antibiotic kit and composition and uses thereof|
    US8119109B2|2002-10-25|2012-02-21|Foamix Ltd.|Foamable compositions, kits and methods for hyperhidrosis|
    US20080317679A1|2002-10-25|2008-12-25|Foamix Ltd.|Foamable compositions and kits comprising one or more of a channel agent, a cholinergic agent, a nitric oxide donor, and related agents and their uses|
    US8900554B2|2002-10-25|2014-12-02|Foamix Pharmaceuticals Ltd.|Foamable composition and uses thereof|
    US8486376B2|2002-10-25|2013-07-16|Foamix Ltd.|Moisturizing foam containing lanolin|
    US9265725B2|2002-10-25|2016-02-23|Foamix Pharmaceuticals Ltd.|Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof|
    US7700076B2|2002-10-25|2010-04-20|Foamix, Ltd.|Penetrating pharmaceutical foam|
    CA2711703A1|2008-01-08|2009-07-16|Foamix Ltd.|Sensation modifying topical composition foam|
    US20060233721A1|2002-10-25|2006-10-19|Foamix Ltd.|Foam containing unique oil globules|
    US20050271596A1|2002-10-25|2005-12-08|Foamix Ltd.|Vasoactive kit and composition and uses thereof|
    AU2003271498A1|2002-10-28|2004-05-13|Givaudan Sa|Coolant solutions and compositions comprising the sameitle|
    JP2004250435A|2002-11-21|2004-09-09|Dai Ichi Seiyaku Co Ltd|Composition for hair growth|
    JP4282311B2|2002-11-26|2009-06-17|三洋電機株式会社|Ice making equipment|
    WO2008075207A2|2006-04-04|2008-06-26|Foamix Ltd.|Anti-infection augmentation foamable compositions and kit and uses thereof|
    US20070134167A2|2002-12-12|2007-06-14|Neubourg Skin Care Gmbh & Co. Kg|Stable foam cream|
    GB0229071D0|2002-12-13|2003-01-15|Unilever Plc|Cosmetic method and composition for enhancing attractiveness|
    US20040191196A1|2002-12-16|2004-09-30|Dov Tamarkin|Novel conjugate compounds and dermatological compositions thereof|
    FR2848847B1|2002-12-18|2005-10-14|Coletica|COSMETIC OR DERMOPHARMACEUTICAL COMPOSITION COMPRISING AN AQUEOUS INSOLUBLE ENZYME AND USES THEREOF|
    US7842791B2|2002-12-19|2010-11-30|Nancy Jean Britten|Dispersible pharmaceutical compositions|
    FR2848998B1|2002-12-20|2006-04-07|Oreal|DISPENSING DEVICE HAVING MEANS FOR DISTRIBUTING TWO PRODUCTS IN VARIABLE PROPORTIONS|
    JP2006515026A|2003-01-02|2006-05-18|フェムファーマホールディングカンパニー，インコーポレイテッド|Pharmaceutical preparations for the treatment of breast diseases and disorders|
    WO2004064769A2|2003-01-21|2004-08-05|Hector Herrera|Methods for making and using topical delivery agents|
    JP4828404B2|2003-01-24|2011-11-30|ステフェルリサーチオーストラリアプロプライエタリーリミティッド|Clindamycin phosphate foam|
    US20040151756A1|2003-02-04|2004-08-05|Richards Anthony P.|Edible low density high surface area drug vehicle, method of manufacturing low density high surface area drug vehicle|
    AU2004210201B2|2003-02-06|2009-10-08|Cipla Limited|Topical immunotherapy and compositions for use therein|
    JP2006514700A|2003-02-12|2006-05-11|コネティックスオーストラリアピーティーワイリミテッド|Film-forming hydroalcoholic foam|
    US6841547B2|2003-02-28|2005-01-11|Albert Einstein College Of Medicine Of Yeshevia University|Method for decreasing low density lipoprotein|
    US20040175347A1|2003-03-04|2004-09-09|The Procter & Gamble Company|Regulation of mammalian keratinous tissue using hexamidine compositions|
    GB0305010D0|2003-03-05|2003-04-09|Unilever Plc|Changing colours|
    US20040198706A1|2003-03-11|2004-10-07|Carrara Dario Norberto R.|Methods and formulations for transdermal or transmucosal application of active agents|
    US6843390B1|2003-03-17|2005-01-18|Joe G. Bristor|Multiple fluid closed system dispensing device|
    US7357950B2|2003-03-21|2008-04-15|Elizabeth Anne Mazzio|Topical treatment for dyshidrosis and dry skin disorders|
    WO2004084905A2|2003-03-24|2004-10-07|University Of Florida|Use of 5-ht2c receptor activity affecting compounds for treating idiopathic hyperhidrosis and associated conditions|
    US7488757B2|2003-03-24|2009-02-10|Becton, Dickinson And Company|Invisible antimicrobial glove and hand antiseptic|
    US7648711B2|2003-05-25|2010-01-19|Yuwan Wang|Dimethicone-containing sustained release injection formulation|
    DE10315936A1|2003-04-03|2004-10-28|Ing. Erich Pfeiffer Gmbh|Discharge device for at least one medium|
    GB0308585D0|2003-04-14|2003-05-21|Pz Cussons Int Ltd|Cleaning composition|
    US20040220187A1|2003-04-22|2004-11-04|Pharmacia Corporation|Compositions of a cyclooxygenase-2 selective inhibitor and a sodium ion channel blocker for the treatment of pain, inflammation or inflammation mediated disorders|
    WO2004093895A1|2003-04-22|2004-11-04|Pharmacia Corporation|Compositions of a cyclooxygenase-2 selective inhibitor and a potassium ion channel modulator for the treatment of pain, inflammation or inflammation mediated disorders|
    US7575739B2|2003-04-28|2009-08-18|Foamix Ltd.|Foamable iodine composition|
    DE10319771B4|2003-05-02|2005-03-17|Koenig & Bauer Ag|System for inspecting a printed image|
    JP2004353084A|2003-05-08|2004-12-16|Sanyo Electric Co Ltd|Evaporator fixation member|
    FR2854821B1|2003-05-16|2006-12-08|Oreal|ASSEMBLY FOR PACKAGING AND DISPENSING A PRODUCT, IN PARTICULAR IN THE FORM OF A SAMPLE|
    JP4232535B2|2003-05-20|2009-03-04|セイコーエプソン株式会社|Printer maintenance system, print control server, client, method related thereto and program related thereto|
    US7222802B2|2003-05-23|2007-05-29|Meadwestvaco Corporation|Dual sprayer with external mixing chamber|
    US7186416B2|2003-05-28|2007-03-06|Stiefel Laboratories, Inc.|Foamable pharmaceutical compositions and methods for treating a disorder|
    US20050079228A1|2003-05-30|2005-04-14|Ashish Jaiswal|Clear, stable topical compositions of clarithromycin and processes for their preparation|
    US20070010580A1|2003-05-30|2007-01-11|Gianfranco De Paoli Ambrosi|Formulation for chemical peeling|
    US20050208083A1|2003-06-04|2005-09-22|Nanobio Corporation|Compositions for inactivating pathogenic microorganisms, methods of making the compositons, and methods of use thereof|
    JP4018032B2|2003-06-17|2007-12-05|高砂香料工業株式会社|Hair and body cleaning composition|
    EP1643990B8|2003-06-18|2007-05-09|Galderma S.A.|Metronidazole-based green tinted topical pharmaceutical composition|
    EP1643964A1|2003-06-19|2006-04-12|The Procter & Gamble Company|Polyol-in-silicone emulsions|
    JPWO2005002623A1|2003-07-03|2006-08-10|独立行政法人科学技術振興機構|Sarcoidosis therapeutics and methods|
    US20070140999A1|2003-07-18|2007-06-21|Hill Dermaceuticals, Inc.|Topical skin care composition containing refined peanut oil|
    WO2005009416A1|2003-07-24|2005-02-03|Ranbaxy Laboratories Limited|Modified release compositions for minocycline|
    US7226230B2|2003-07-28|2007-06-05|Raymond Liberatore|Spreader|
    US20070292461A1|2003-08-04|2007-12-20|Foamix Ltd.|Oleaginous pharmaceutical and cosmetic foam|
    US20080292560A1|2007-01-12|2008-11-27|Dov Tamarkin|Silicone in glycol pharmaceutical and cosmetic compositions with accommodating agent|
    US8795693B2|2003-08-04|2014-08-05|Foamix Ltd.|Compositions with modulating agents|
    US20080069779A1|2003-08-04|2008-03-20|Foamix Ltd.|Foamable vehicle and vitamin and flavonoid pharmaceutical compositions thereof|
    US7820145B2|2003-08-04|2010-10-26|Foamix Ltd.|Oleaginous pharmaceutical and cosmetic foam|
    US7704518B2|2003-08-04|2010-04-27|Foamix, Ltd.|Foamable vehicle and pharmaceutical compositions thereof|
    US8486374B2|2003-08-04|2013-07-16|Foamix Ltd.|Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses|
    EP1670435A2|2003-08-04|2006-06-21|Foamix Ltd.|Foam carrier containing amphiphilic copolymeric gelling agent|
    US20050042182A1|2003-08-13|2005-02-24|Moshe Arkin|Topical compositions of urea|
    ES2541488T3|2003-08-25|2015-07-21|Foamix Pharmaceuticals Ltd.|Penetrating Pharmaceutical Foam|
    US20060140990A1|2003-09-19|2006-06-29|Drugtech Corporation|Composition for topical treatment of mixed vaginal infections|
    WO2005030083A2|2003-09-25|2005-04-07|Dmi Biosciences Inc.|Methods and products which utilize n-acyl-l-aspartic acid|
    FR2860143B1|2003-09-26|2008-06-27|Oreal|COSMETIC COMPOSITION COMPRISING A SEQUENCE POLYMER AND A NON-VOLATILE SILICONE OIL|
    US20050084551A1|2003-09-26|2005-04-21|Jensen Claude J.|Morinda citrifolia-based oral care compositions and methods|
    GB2406330B|2003-09-29|2005-12-07|Bespak Plc|A dispensing apparatus|
    KR20060113907A|2003-09-29|2006-11-03|에테나 헬스케어 인코포레이티드|- high alcohol content gel-like and foaming compositions|
    CA2528818C|2003-10-03|2010-08-10|Collegium Pharmaceutical, Inc.|Topical aerosol foams|
    FR2860502B1|2003-10-07|2007-09-14|Valois Sas|DOSING VALVE AND DEVICE FOR DISPENSING FLUID PRODUCT COMPRISING SUCH A VALVE|
    GB0323908D0|2003-10-11|2003-11-12|Nupharm Lab Ltd|Pharmaceutical foam formulation|
    AT416012T|2003-10-14|2008-12-15|Showa Denko Kk|FOR EXTERNAL APPLICATION TO THE SKIN OF MEANS OF A SALT OF AN ASCORBINIC ACID DERIVATIVE, METHOD FOR THE STABILIZATION OF THE AGENT FOR EXTERNAL APPLICATION TO THE SKIN|
    FR2860976B1|2003-10-20|2006-02-10|Ravi Shrivastava|NOVEL SYNERGISTIC COMPOSITIONS FOR IMPROVING THE BIODAVAILABILITY AND EFFICIENCY OF POLYUNSATURATED FATTY ACIDS FOR THE TREATMENT OF BRAIN FUNCTIONING DISORDERS.|
    US7419498B2|2003-10-21|2008-09-02|Nmt Medical, Inc.|Quick release knot attachment system|
    WO2005044219A1|2003-10-31|2005-05-19|The Procter & Gamble Company|Skin care composition containing dehydroacetic acid and skin care actives|
    DE602004005073T2|2003-11-06|2007-06-21|Unilever N.V.|IMPROVED COSMETIC COMPOSITION WITH VITAMIN B3, VITAMIN B6 AND AN ORGANIC ACID|
    US8157788B2|2003-11-06|2012-04-17|Paolo L. Manfredi|Multi-site drug delivery platform|
    EP1684768A4|2003-11-06|2007-06-06|Univ New York State Res Found|Methods of treating eczema|
    CA2544215A1|2003-11-17|2005-06-02|The Procter & Gamble Company|Antiperspirant composition and applicator therefor|
    DE10354051A1|2003-11-17|2005-06-16|Beiersdorf Ag|Dispensers containing cosmetic preparations containing aids for keeping the donor in motion|
    JP2007512312A|2003-11-21|2007-05-17|ファイザー・プロダクツ・インク|Use of antibiotics as vaccine adjuvants|
    US20050115988A1|2003-12-01|2005-06-02|Brian Law|Multiple liquid foamer|
    US20050123496A1|2003-12-08|2005-06-09|Unilever Home & Personal Care Usa, Division Of Conopco, Inc.|Self foaming non-aqueous personal wash cleansers with little or no surfactant|
    DE10361022A1|2003-12-23|2005-07-28|Merckle Gmbh Chem.-Pharm. Fabrik|Topical preparations containing dimethyl sulfoxide and dexpanthenol|
    DK1716162T3|2003-12-30|2011-01-10|Gilead Sciences Inc|Phosphonates, amidomonophosphonates, amidobis phosphonates for the treatment of viral diseases|
    IL159729D0|2004-01-06|2004-06-20|Doron I Friedman|Non-aqueous composition for oral delivery of insoluble bioactive agents|
    AU2005201455A1|2004-02-04|2005-08-25|Foamix Ltd.|Cosmetic and pharmaceutical foam with solid matter|
    US7225518B2|2004-02-23|2007-06-05|Boston Scientific Scimed, Inc.|Apparatus for crimping a stent assembly|
    JP4381169B2|2004-02-27|2009-12-09|花王株式会社|Hair cosmetics|
    US8404249B2|2004-03-03|2013-03-26|Revance Therapeutics, Inc.|Compositions and methods for topical application and transdermal delivery of botulinum toxins|
    EP1725132A2|2004-03-18|2006-11-29|Bodypoint Designs, Inc.|Pivoting side mount and quick release assembly for a pelvic stabilization device|
    DE102004016710B4|2004-04-05|2020-11-19|Greppmayr GmbH|Foot care formulation|
    SI1734927T1|2004-04-08|2012-09-28|Meda Pharma S A R L|Pimecrolimus foam composition containing hexylene glycol, optionally oleyl alcohol, dimethylisosorbide and/or medium chain triglycerides|
    EP1737429B1|2004-04-19|2013-07-17|Strategic Science & Technologies, LLC|Transdermal delivery of beneficial substances effected by a high ionic strength environment|
    NL1026031C2|2004-04-23|2005-10-25|Airspray Nv|Delivery assembly.|
    ZA200507019B|2004-04-28|2008-02-27|Foamix Ltd|Body cavity foams|
    JP2005314323A|2004-04-30|2005-11-10|Sato Pharmaceutical Co Ltd|Hair growth formulation|
    US20050244354A1|2004-04-30|2005-11-03|Sam Speron|Oxygenated personal care products|
    WO2005115336A2|2004-05-15|2005-12-08|Collegium Pharmaceutical, Inc.|Sprayable formulations for the treatment of acute inflammatory skin conditions|
    US7083125B2|2004-05-17|2006-08-01|S.C. Johnson & Son, Inc.|Detachable tube assembly|
    US7143909B2|2004-05-21|2006-12-05|Sonoco Development, Inc.|Reconfigurable metered material dispenser|
    US8394394B2|2004-05-26|2013-03-12|L'oréal|Mousse formulations|
    ITBO20040338A1|2004-05-28|2004-08-28|Progine Farmaceutici Srl|VAGINAL NEBULIZATION DISPENSER|
    US20050268416A1|2004-06-03|2005-12-08|Sommers J E|Foldable lotion applicator|
    JP4368250B2|2004-06-09|2009-11-18|ポーラ化成工業株式会社|Post-form dosage form of warm cosmetic|
    FR2871696B1|2004-06-17|2006-11-10|Galderma Sa|TOPICAL COMPOSITION FOR THE TREATMENT OF PSORIASIS|
    FR2871698B1|2004-06-17|2008-07-04|Galderma Sa|SPRAY COMPOSITION COMPRISING AN ASSOCIATION OF PHARMACEUTICAL ASSETS AND AN OILY PHASE|
    US8211449B2|2004-06-24|2012-07-03|Dpt Laboratories, Ltd.|Pharmaceutically elegant, topical anhydrous aerosol foam|
    JP4355264B2|2004-06-25|2009-10-28|ポーラ化成工業株式会社|Warm feeling non-water foam cosmetic|
    US7207655B2|2004-06-28|2007-04-24|Eastman Kodak Company|Latency stirring in fluid ejection mechanisms|
    US6991789B2|2004-06-29|2006-01-31|Allergas, Inc.|Methods of modulating intracellular degradation rates of toxins|
    US20060008432A1|2004-07-07|2006-01-12|Sebastiano Scarampi|Gilsonite derived pharmaceutical delivery compositions and methods: nail applications|
    US20080035155A1|2004-07-09|2008-02-14|Gilead Sciences, Inc.|Topical Antiviral Formulations|
    WO2006017232A1|2004-07-12|2006-02-16|Taro Pharmaceuticals Industries Ltd.|Topical gel formulation comprising insecticide and its preparation thereof|
    US20070225357A1|2004-07-19|2007-09-27|Pfizer Inc.|Formulation for Stimulating Hair Growth|
    WO2006010589A2|2004-07-29|2006-02-02|Mipharm S.P.A.|Post foaming gel mousse|
    JP4557624B2|2004-07-29|2010-10-06|株式会社吉野工業所|Quantitative dispenser|
    US20060029565A1|2004-08-09|2006-02-09|The Gillette Company|Self-heating shave foam product|
    US20060034620A1|2004-08-12|2006-02-16|Triaccess Technologies, Inc.|Low noise optical receiver|
    AU2005279704B2|2004-08-31|2010-05-13|Stiefel Research Australia Pty Ltd|Microemulsion and sub-micron emulsion process and compositions|
    KR100623013B1|2004-09-04|2006-09-19|김영대|Nano-emulsion, the use thereof, and preparing method thereof|
    CA2989941A1|2004-09-23|2006-03-30|Arc Pharmaceuticals, Inc.|Pharmaceutical compostions and methods relating to inhibiting fibrous adhesions or inflammatory disease using low sulphate fucans|
    SI1791791T1|2004-09-27|2019-10-30|Special Water Patents B V|Methods and compositions for treatment of water|
    FR2875797B1|2004-09-30|2006-11-24|Oreal|DISTRIBUTION ASSEMBLY FOR THE EXTENDED DISTRIBUTION OF TWO PRODUCTS|
    BRPI0404595A|2004-10-26|2006-06-13|Natura Cosmeticos Sa|oil-in-water nanoemulsion, cosmetic composition and cosmetic product comprising same, process for preparing said nanoemulsion|
    DE102004052986A1|2004-11-02|2006-05-04|Lindal Ventil Gmbh|Device for mixing two different components|
    US7350673B2|2004-11-19|2008-04-01|Glynntech, Inc.|Metered dose squeeze dispenser|
    US20060110415A1|2004-11-22|2006-05-25|Bioderm Research|Topical Delivery System for Cosmetic and Pharmaceutical Agents|
    US8080560B2|2004-12-17|2011-12-20|3M Innovative Properties Company|Immune response modifier formulations containing oleic acid and methods|
    FR2880802B1|2005-01-14|2008-12-19|Sederma Soc Par Actions Simpli|COSMETIC OR DERMOPHARMACEUTICAL COMPOSITION CONTAINING EUGLENE EXTRACT|
    WO2006081327A2|2005-01-25|2006-08-03|University Of Vermont And State Agricultural College|Small molecules that reduce fungal growth|
    BRPI0607038A2|2005-01-28|2009-12-01|Basf Ag|use of polymers cosmetic compositions for hair and skin and dermatological composition|
    US20060177392A1|2005-02-10|2006-08-10|William Walden|Oil-based composition for acne|
    US20060193813A1|2005-02-11|2006-08-31|L'oreal|Nanoemulsion containing a hydroxylated urea compound|
    WO2006099687A1|2005-03-24|2006-09-28|Ensign Laboratories Pty Ltd|Sunscreen aerosol spray|
    GB0506141D0|2005-03-24|2005-05-04|Transphase Ltd|A topical compostion and its uses|
    US20060222675A1|2005-03-29|2006-10-05|Sabnis Ram W|Personal care compositions with color changing indicator|
    EP1976774A2|2005-04-19|2008-10-08|Foamix Ltd.|Apparatus and method for releasing a measured amount of content from a container|
    US20070069046A1|2005-04-19|2007-03-29|Foamix Ltd.|Apparatus and method for releasing a measure of content from a plurality of containers|
    US9084734B2|2005-05-05|2015-07-21|Danisco Us Inc.|Peptide personal care compositions and methods for their use|
    AU2006313443A1|2005-05-09|2007-05-18|Foamix Ltd.|Foamable vehicle and pharmaceutical compositions thereof|
    WO2006122158A2|2005-05-10|2006-11-16|Xanthone Plus International, Llc|Skin care compositions containing xanthones|
    ES2525410T3|2005-05-10|2014-12-22|Dermipsor Ltd|Compositions and methods for the treatment of dermal hyperproliferative diseases|
    US20060260655A1|2005-05-23|2006-11-23|Martin William R|Asbestos removal process|
    AU2006253913B2|2005-06-01|2010-09-16|Mayne Pharma Llc|Vitamin formulation|
    US20060272199A1|2005-06-02|2006-12-07|Bmc Manufacturing, Llc|Aqueous gel candle for use with a warming device|
    US8211874B2|2005-06-03|2012-07-03|Galderma Laboratories Inc.|Inhibition of thrombin generation|
    WO2007099396A2|2005-06-07|2007-09-07|Foamix Ltd.|Antibiotic kit and composition and uses thereof|
    WO2007085899A2|2005-07-06|2007-08-02|Foamix Ltd.|Foamable arthropocidal composition for tropical application|
    US20070009607A1|2005-07-11|2007-01-11|George Jones|Antibacterial/anti-infalmmatory composition and method|
    US20070015738A1|2005-07-15|2007-01-18|Walker Stephen G|Use of non-antibacterial tetracycline formulations for inhibiting bacterial spores from becoming infectious vegetative cells|
    ES2765897T3|2005-07-18|2020-06-11|Procter & Gamble|Method for conditioning hair with a cream spray foam|
    WO2007085902A2|2005-07-19|2007-08-02|Foamix Ltd.|Foamable composition combining a polar solvent and a hydrophobic carrier|
    AT410997T|2005-07-22|2008-10-15|Wella Ag|HAIR TREATMENT METHOD WITH A DRY FOAM USED AS A MECHANICAL CARRIER|
    CN100531515C|2005-07-22|2009-08-19|鸿富锦精密工业（深圳）有限公司|Printing circuit board with modified power zone block|
    DE102005037844A1|2005-08-04|2007-04-05|Intendis Gmbh|Anhydrous multi-phase gel system|
    CA2618974C|2005-08-09|2014-01-28|Nanobio Corporation|Nanoemulsion compositions having anti-inflammatory activity|
    CA2632183A1|2005-08-25|2007-03-01|Philip R. Houle|Treatment systems for delivery of sensitizer solutions|
    FR2890559B1|2005-09-13|2011-06-24|Galderma Sa|DERMATOLOGICAL FOAMS BASED ON METRONIDAZOLE AND EMULSIONS FOR PREPARATION|
    DE202006004676U1|2005-09-28|2007-02-08|Neubourg Skin Care Gmbh & Co. Kg|Formulation, useful as foam skin cream and to treat e.g. dermatitis and psoriasis, comprises an aqueous emulsion, propellant gas, urea emulsion, hyaluronic acid, free fatty acid and at least two emulsions|
    EP2100601B1|2005-10-24|2012-06-27|Precision Dermatology, Inc.|Topical pharmaceutical foam composition|
    US20070134174A1|2005-11-03|2007-06-14|Christopher Irwin|Personal care composition|
    JP2007131539A|2005-11-08|2007-05-31|Koike Kagaku Kk|Chilling foam cosmetic|
    US20070148194A1|2005-11-29|2007-06-28|Amiji Mansoor M|Novel nanoemulsion formulations|
    JP4885529B2|2005-12-08|2012-02-29|住友重機械工業株式会社|Radiation detection unit and radiation inspection apparatus|
    US20070160548A1|2005-12-13|2007-07-12|Playtex Products, Inc.|Moisturizing sunless tanning composition|
    US20070142263A1|2005-12-15|2007-06-21|Stahl Katherine D|Color changing cleansing composition|
    US20070148112A1|2005-12-28|2007-06-28|Avon Products, Inc.|Foaming, color-changing topical composition and method of imparting a cosmetic effect|
    US20070166273A1|2006-01-19|2007-07-19|Krivulka Joseph J|Skin treatment educational kit|
    CA2637408C|2006-01-19|2013-12-03|Disphar International B.V.|Foam-forming composition|
    WO2007103555A2|2006-03-08|2007-09-13|Nuviance, Inc.|Transdermal drug delivery compositions and topical compositions for application on the skin|
    US20070224143A1|2006-03-21|2007-09-27|Kamedis Ltd.|Cosmetic and pharmaceutical foam carrier|
    CN101404972B|2006-03-22|2012-11-14|宝洁公司|Aerosol product comprising a foaming concentrate composition comprising particulate materials|
    US7252816B1|2006-03-29|2007-08-07|Dow Pharmaceutical Sciences|Topical acne vulgairs medication with a sunscreen|
    PL2010133T3|2006-03-31|2017-08-31|Stiefel Research Australia Pty Ltd|Foamable suspension gel|
    US20070264317A1|2006-05-15|2007-11-15|Perrigo Israel Pharmaceuticals Ltd.|Imiquimod cream formulation|
    WO2007142967A2|2006-05-31|2007-12-13|The Dial Corporation|Alcohol-containing antimicrobial compositions having improved efficacy|
    JP4892282B2|2006-06-09|2012-03-07|アルプス電気株式会社|Lubricating composition for electrical contacts|
    WO2008110872A2|2006-06-23|2008-09-18|Foamix Ltd.|Foamable compositions and kits comprising one or more of a channel agent, a cholinergic agent, a nitric oxide donor, and related agents and their uses|
    US7826675B2|2006-07-04|2010-11-02|Hewlett-Packard Development Company, L.P.|Feature-aware image defect removal|
    WO2008038147A2|2006-07-05|2008-04-03|Foamix Ltd.|Foamable vehicle comprising dicarboxylic acid or dicarboxylic acid ester and pharmaceutical compositions thereof|
    MX2009000507A|2006-07-14|2009-06-12|Stiefel Res Australia Pty Ltd|Fatty acid pharmaceutical foam.|
    NO343857B1|2006-07-18|2019-06-24|Meda Ab|Immune Response Modifying Foam Formulations|
    US20080031908A1|2006-07-25|2008-02-07|L'oreal|Oily cosmetic composition in aerosol form|
    JP2008040899A|2006-08-08|2008-02-21|Fuji Xerox Co Ltd|Printing controller, program, and method|
    US20080166303A1|2006-09-08|2008-07-10|Dov Tamarkin|Colored or colorable foamable composition and foam|
    ES2315123B1|2006-09-25|2009-12-30|Divasa-Farmavic, S.A.|STABLE PHARMACEUTICAL COMPOSITIONS OF TETRACICLINES IN SOLUTION, PROCEDURE FOR OBTAINING AND USES.|
    HU0600765A2|2006-10-06|2008-10-28|Istvan Piller|Container for stable carbondioxide foam, process for producing stable carbondioxide foam and method for using of foam|
    US20080206155A1|2006-11-14|2008-08-28|Foamix Ltd.|Stable non-alcoholic foamable pharmaceutical emulsion compositions with an unctuous emollient and their uses|
    US20080260655A1|2006-11-14|2008-10-23|Dov Tamarkin|Substantially non-aqueous foamable petrolatum basedpharmaceutical and cosmetic compositions and their uses|
    EP2097065A2|2006-11-29|2009-09-09|Foamix Ltd.|Foamable waterless compositions with modulating agents|
    KR101249227B1|2006-12-15|2013-04-03|더 프록터 앤드 갬블 캄파니|Skin care composition|
    US20080153789A1|2006-12-26|2008-06-26|Femmepharma Holding Company, Inc.|Topical administration of danazol|
    BE1017901A3|2007-01-16|2009-10-06|Bart Rossel|FOAMING COMPOSITION FOR KILLING ARTHROPODS AND ITS USE.|
    US20080188446A1|2007-02-02|2008-08-07|Warner Chilcott Company Inc.|Tetracycline compositions for topical administration|
    WO2008097850A1|2007-02-02|2008-08-14|Warner Chilcott Company, Inc.|Tretracycline compositions for topical administration|
    PT103661B|2007-02-23|2010-09-07|Hovione Farmaciencia S A|MINOCYCINE PREPARATION PROCESS CRYSTALLINE|
    GB0703909D0|2007-02-28|2007-04-11|Neuropharm Ltd|Treatment of anxiety disorders|
    FR2915891B1|2007-05-10|2012-05-11|Oreal|FOAM COMPOSITION COMPRISING A SILICONE POLYMER|
    US9511016B2|2007-06-12|2016-12-06|Epicentrx, Inc.|Topical composition for treating pain|
    US8636982B2|2007-08-07|2014-01-28|Foamix Ltd.|Wax foamable vehicle and pharmaceutical compositions thereof|
    US8617100B2|2007-09-04|2013-12-31|Foamix Ltd.|Device for delivery of a foamable composition|
    MX2010003503A|2007-09-30|2010-04-21|Valeant Pharmaceuticals Int|Silicone gel-based compositions for wound healing and scar reduction.|
    US20090130029A1|2007-11-21|2009-05-21|Foamix Ltd.|Glycerol ethers vehicle and pharmaceutical compositions thereof|
    US9439857B2|2007-11-30|2016-09-13|Foamix Pharmaceuticals Ltd.|Foam containing benzoyl peroxide|
    US8518376B2|2007-12-07|2013-08-27|Foamix Ltd.|Oil-based foamable carriers and formulations|
    WO2009090495A2|2007-12-07|2009-07-23|Foamix Ltd.|Oil and liquid silicone foamable carriers and formulations|
    EP2242476A2|2008-01-14|2010-10-27|Foamix Ltd.|Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses|
    US8652443B2|2008-02-14|2014-02-18|Precision Dermatology, Inc.|Foamable microemulsion compositions for topical administration|
    ES2330291B1|2008-02-29|2010-10-18|Lipotec Sa|USEFUL PEPTIDES IN THE TREATMENT OF SKIN, MUCOSAS AND / OR LEATHER HAIR AND ITS USE IN COSMETIC OR PHARMACEUTICAL COMPOSITIONS.|
    JP2011513404A|2008-03-05|2011-04-28|パラテックファーマシューティカルズインコーポレイテッド|Minocycline compounds and methods of use thereof|
    AU2009221793B2|2008-03-06|2015-02-19|Anacor Pharmaceuticals, Inc|Boron-containing small molecules as anti-inflammatory agents|
    US20120141384A1|2008-05-06|2012-06-07|Dov Tamarkin|Antibacterial conjugated boronic acids and pharmaceutical compositions thereof|
    KR102080429B1|2008-06-26|2020-02-21|안테리오스, 인코퍼레이티드|Dermal delivery|
    RU2459277C1|2008-08-07|2012-08-20|Шарп Кабусики Кайся|Display device|
    MX2011001464A|2008-08-08|2011-03-29|Interdigital Patent Holdings|Method and apparatus for reporting a buffer status.|
    WO2010050889A1|2008-10-31|2010-05-06|Moberg Derma Ab|Topical composition comprising a combination of at least two penetration enhancing agents|
    WO2010068465A2|2008-11-25|2010-06-17|Citrix Systems. Inc.|Systems and methods for maintaining persistence by a backup virtual server|
    AT500817T|2008-12-23|2011-03-15|Intendis Gmbh|FOAMABLE COMPOSITION WHICH IS ESSENTIALLY FREE OF PHARMACEUTICALLY ACTIVE INGREDIENTS FOR THE TREATMENT OF HUMAN SKIN|
    JP5213734B2|2009-01-22|2013-06-19|サンウエーブ工業株式会社|Cabinet with flap door|
    US20100202978A1|2009-02-12|2010-08-12|Gurge Ronald M|Foamable benzoyl peroxide compositions for topical administration|
    PL2400951T3|2009-02-25|2019-02-28|Mayne Pharma Llc|Topical foam composition|
    WO2010124280A2|2009-04-24|2010-10-28|New Century Pharmaceuticals, Inc.|Human serum albumin-based topical ointment for treatment of acne, psoriasis, egfr-induced toxicity, premature skin aging and other skin conditions|
    US20120087872A1|2009-04-28|2012-04-12|Foamix Ltd.|Foamable Vehicles and Pharmaceutical Compositions Comprising Aprotic Polar Solvents and Uses Thereof|
    PT104644B|2009-06-26|2012-11-06|Hovione Farmaciencia S A|Topical formulation containing a tetracycline and a method of treating skin infections using the same|
    US8255186B2|2009-07-09|2012-08-28|Air Liquide Large Industries U.S. Lp|Presenting dynamic SCADA data|
    CA2769625C|2009-07-29|2017-04-11|Foamix Ltd.|Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses|
    CA2769677A1|2009-07-29|2011-02-03|Foamix Ltd.|Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses|
    US20110052506A1|2009-08-31|2011-03-03|Collegium Pharmaceutical, Inc.|Stable Aerosol Topical Foams Comprising a Hypochlorite Salt|
    GB2474930B|2009-10-02|2012-07-04|Foamix Ltd|Topical tetracycline compositions|
    US20140121188A1|2009-10-02|2014-05-01|Foamix Ltd.|Compositions for the improved treatment of acne and related disorders|
    WO2011138678A2|2010-05-04|2011-11-10|Foamix Ltd.|Compositions, gels and foams with rheology modulators and uses thereof|
    US9849142B2|2009-10-02|2017-12-26|Foamix Pharmaceuticals Ltd.|Methods for accelerated return of skin integrity and for the treatment of impetigo|
    CA2776366C|2009-10-02|2017-07-18|Foamix Ltd.|Surfactant-free water-free foamable compositions, breakable foams and gels and their uses|
    US20140186269A1|2013-01-03|2014-07-03|Foamix Ltd.|Vehicle compositions essentially free of pharmaceutically active agents for the improved treatment of acne and related disorders|
    US8735377B1|2010-02-04|2014-05-27|Susan Anna Sipos|Methods of treating herpes zoster|
    US20110212035A1|2010-02-26|2011-09-01|Collegium Pharmaceutical, Inc.|Emollient foams for treatment of dermatoses|
    WO2011115700A2|2010-03-18|2011-09-22|Precision Dermatology, Inc.|Emollient foams for treatment of seborrheic dermatitis|
    US8592380B2|2010-03-26|2013-11-26|Precision Dermatology, Inc.|Aerosol foams comprising clindamycin phosphate|
    US20120076766A1|2010-04-21|2012-03-29|Phillips D Howard|Topical drug delivery system with dual carriers|
    EP2579851A4|2010-06-11|2014-08-13|Prec Dermatology Inc|High oil-content emollient aerosol foam compositions|
    WO2012007843A2|2010-07-12|2012-01-19|Foamix Ltd.|Apparatus and method for releasing a unit dose of content from a container|
    JP6245983B2|2010-08-11|2017-12-13|ドレクセル ユニバーシティ|Novel D3 dopamine receptor agonists for treating dyskinesia in Parkinson's disease|
    US20120064136A1|2010-09-10|2012-03-15|Nanobio Corporation|Anti-aging and wrinkle treatment methods using nanoemulsion compositions|
    US20120093876A1|2010-10-13|2012-04-19|Aciex, Inc.|Ophthalmic Formulations, Methods Of Manufacture And Methods of Normalizing Meibomian Gland Secretions|
    US8895537B2|2010-10-29|2014-11-25|Infirst Healthcare Ltd.|Compositions and methods for treating cardiovascular diseases|
    FR2969492B1|2010-12-23|2013-07-05|Galderma Res & Dev|DERMATOLOGICAL FOAMS OBTAINED FROM GEL OR SUSPENSION CONTAINING ADAPALENE|
    EP2665483B1|2011-01-19|2020-08-26|Laboratory Skin Care, Inc.|Topical minocycline compositions and methods of using the same|
    WO2013009586A1|2011-07-08|2013-01-17|The Research Foundation Of State University Of New York|Topical minocycline ointment for suppression of allergic skin responses|
    JP2014532717A|2011-11-03|2014-12-08|プレシジョン ダーマトロジー インコーポレイテッドＰｒｅｃｉｓｉｏｎ Ｄｅｒｍａｔｏｌｏｇｙ， Ｉｎｃ．|Stable skin aerosol foam with reactive propellant|
    US8801680B2|2012-03-14|2014-08-12|Becton, Dickinson And Company|Angled retracting sheath for safety needle|
    IL225239D0|2012-03-15|2013-06-27|Meir Eini|Compositions for the treatment of acne and related disorders|
    WO2013142251A1|2012-03-22|2013-09-26|Precision Dermatology, Inc.|Cyclodextrin-based microemulsions, and dermatological uses thereof|
    CA2775393C|2012-05-02|2014-04-29|Samy Saad|Topical non-aqueous pharmaceutical formulations|
    WO2013170908A1|2012-05-15|2013-11-21|Telefonaktiebolaget L M Ericsson |Interference management for network assisted device-to-device communication|
    CA2878462A1|2012-07-13|2014-01-16|Paratek Pharmaceuticals, Inc.|Tetracycline compounds for treating neurodegenerative disorders|
    PT106679B|2012-11-27|2015-03-25|Hovione Farmaciencia Sa|TOPICAL FORMULATIONS OF TETRACYCLINES, THEIR PREPARATION AND USES|
    US8778365B1|2013-01-31|2014-07-15|Merz Pharmaceuticals, Llc|Topical compositions and methods for making and using same|
    US20140242016A1|2013-02-22|2014-08-28|Stiefel Laboratories, Inc.|Non-aqueous solid stabilized emulsions|
    WO2014134427A1|2013-02-28|2014-09-04|Precision Dermatology, Inc.|Controlling the bioavailability of active ingredients in topical formulations|
    US20140243299A1|2013-02-28|2014-08-28|Precision Dermatology, Inc.|Topical Formulations of Corticosteroids with Enhanced Bioavailability|
    WO2014151347A1|2013-03-15|2014-09-25|Revance Therapeutics, Inc.|Minocycline derivatives|
    EA201592236A1|2013-06-04|2016-06-30|Вайом Байосайнсиз Пвт. Лтд.|PARTICULATED COATINGS AND COMPOSITIONS INCLUDING SUCH PARTICLES|
    US20160120803A1|2013-06-17|2016-05-05|Contract Pharmaceuticals Limited|Non-aerosol foams for topical administration|
    EP3065717A1|2013-11-04|2016-09-14|Biopharmx, Inc.|Dosage form comprising an active ingredient and a plurality of solid porous microcarriers|
    IN2013MU03646A|2013-11-20|2015-07-31|Lupin Ltd|
    PT107433B|2014-01-28|2018-12-04|Hovione Farm S A|PARTICLE SIZE REDUCTION AND CONTROL PROCESS|
    WO2015153864A2|2014-04-02|2015-10-08|Hopkins Patricia T|Methods for treating inflammatory conditions|
    US9841142B2|2014-12-22|2017-12-12|Rockwell Automation Technologies, Inc.|Single-wire industrial safety system with safety device diagnostic communication|
    CA2980527A1|2015-03-23|2016-09-29|BioPharmX, Inc.|Pharmaceutical tetracycline composition for dermatological use|
    US20160287615A1|2015-04-03|2016-10-06|BioPharmX, Inc.|Novel encapsulation of fluorescent, photo-sensitive, or oxygen-sensitive active ingredient for topical application|
    US9877971B2|2015-06-15|2018-01-30|Banner Life Sciences Llc|Soft lozenges comprising corticosteroids|
    WO2017011600A1|2015-07-13|2017-01-19|Dr. Reddy's Laboratories, Ltd.|Topical retinoid compositions|
    EP3346998A4|2015-08-17|2019-08-28|Sidmak Laboratories PVT. Ltd.|Topical film delivery system|
    WO2017029647A1|2015-08-20|2017-02-23|Meir Eini|Tetracycline management of egfr inhibitor associated dermatoses|
    PT108978B|2015-11-24|2020-03-09|Hovione Farm S A|TETRACYCLINE SALTS|
    US10398641B2|2016-09-08|2019-09-03|Foamix Pharmaceuticals Ltd.|Compositions and methods for treating rosacea and acne|
    CA3078783A1|2017-10-24|2019-05-02|Glenmark Pharmaceuticals Limited|Topical pharmaceutical composition of adapalene and minocycline|US20080138296A1|2002-10-25|2008-06-12|Foamix Ltd.|Foam prepared fromnanoemulsions and uses|
    US9668972B2|2002-10-25|2017-06-06|Foamix Pharmaceuticals Ltd.|Nonsteroidal immunomodulating kit and composition and uses thereof|
    US9265725B2|2002-10-25|2016-02-23|Foamix Pharmaceuticals Ltd.|Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof|
    US7700076B2|2002-10-25|2010-04-20|Foamix, Ltd.|Penetrating pharmaceutical foam|
    NZ540166A|2002-10-25|2007-06-29|Foamix Ltd|Cosmetic and pharmaceutical foam|
    US9211259B2|2002-11-29|2015-12-15|Foamix Pharmaceuticals Ltd.|Antibiotic kit and composition and uses thereof|
    US20080152596A1|2005-07-19|2008-06-26|Foamix Ltd.|Polypropylene glycol foamable vehicle and pharmaceutical compositions thereof|
    US20050271596A1|2002-10-25|2005-12-08|Foamix Ltd.|Vasoactive kit and composition and uses thereof|
    US20050205086A1|2002-10-25|2005-09-22|Foamix Ltd.|Retinoid immunomodulating kit and composition and uses thereof|
    US20080206161A1|2002-10-25|2008-08-28|Dov Tamarkin|Quiescent foamable compositions, steroids, kits and uses thereof|
    US10117812B2|2002-10-25|2018-11-06|Foamix Pharmaceuticals Ltd.|Foamable composition combining a polar solvent and a hydrophobic carrier|
    IL152486D0|2002-10-25|2003-05-29|Meir Eini|Alcohol-free cosmetic and pharmaceutical foam carrier|
    US20060233721A1|2002-10-25|2006-10-19|Foamix Ltd.|Foam containing unique oil globules|
    US20070292359A1|2002-10-25|2007-12-20|Foamix Ltd.|Polypropylene glycol foamable vehicle and pharmaceutical compositions thereof|
    US20060018937A1|2002-10-25|2006-01-26|Foamix Ltd.|Steroid kit and foamable composition and uses thereof|
    US8900554B2|2002-10-25|2014-12-02|Foamix Pharmaceuticals Ltd.|Foamable composition and uses thereof|
    US20080031907A1|2002-10-25|2008-02-07|Foamix Ltd.|Cosmetic and pharmaceutical foam|
    US7575739B2|2003-04-28|2009-08-18|Foamix Ltd.|Foamable iodine composition|
    US7820145B2|2003-08-04|2010-10-26|Foamix Ltd.|Oleaginous pharmaceutical and cosmetic foam|
    US8795693B2|2003-08-04|2014-08-05|Foamix Ltd.|Compositions with modulating agents|
    US7704518B2|2003-08-04|2010-04-27|Foamix, Ltd.|Foamable vehicle and pharmaceutical compositions thereof|
    EP1670435A2|2003-08-04|2006-06-21|Foamix Ltd.|Foam carrier containing amphiphilic copolymeric gelling agent|
    US8486374B2|2003-08-04|2013-07-16|Foamix Ltd.|Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses|
    JP2005310310A|2004-04-23|2005-11-04|Sanyo Electric Co Ltd|Tracking balance adjustment device|
    US20080166303A1|2006-09-08|2008-07-10|Dov Tamarkin|Colored or colorable foamable composition and foam|
    US20080260655A1|2006-11-14|2008-10-23|Dov Tamarkin|Substantially non-aqueous foamable petrolatum basedpharmaceutical and cosmetic compositions and their uses|
    US8636982B2|2007-08-07|2014-01-28|Foamix Ltd.|Wax foamable vehicle and pharmaceutical compositions thereof|
    US9439857B2|2007-11-30|2016-09-13|Foamix Pharmaceuticals Ltd.|Foam containing benzoyl peroxide|
    WO2009090495A2|2007-12-07|2009-07-23|Foamix Ltd.|Oil and liquid silicone foamable carriers and formulations|
    EP2242476A2|2008-01-14|2010-10-27|Foamix Ltd.|Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses|
    US20120087872A1|2009-04-28|2012-04-12|Foamix Ltd.|Foamable Vehicles and Pharmaceutical Compositions Comprising Aprotic Polar Solvents and Uses Thereof|
    CA2769677A1|2009-07-29|2011-02-03|Foamix Ltd.|Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses|
    CA2769625C|2009-07-29|2017-04-11|Foamix Ltd.|Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses|
    JP5833007B2|2009-08-31|2015-12-16|ドクター・レディーズ・ラボラトリーズ・リミテッド|Topical preparations containing steroids|
    WO2011138678A2|2010-05-04|2011-11-10|Foamix Ltd.|Compositions, gels and foams with rheology modulators and uses thereof|
    CA2776366C|2009-10-02|2017-07-18|Foamix Ltd.|Surfactant-free water-free foamable compositions, breakable foams and gels and their uses|
    US9849142B2|2009-10-02|2017-12-26|Foamix Pharmaceuticals Ltd.|Methods for accelerated return of skin integrity and for the treatment of impetigo|
    US20120076766A1|2010-04-21|2012-03-29|Phillips D Howard|Topical drug delivery system with dual carriers|
    WO2013009586A1|2011-07-08|2013-01-17|The Research Foundation Of State University Of New York|Topical minocycline ointment for suppression of allergic skin responses|
    EP2731590B1|2011-07-13|2018-05-23|The Foundry, LLC|Methods and apparatus for delivering a therapeutic agent to nasopharyngeal mucosa targets|
    US10537581B2|2012-12-21|2020-01-21|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|
    US10806740B2|2012-06-18|2020-10-20|Therapeuticsmd, Inc.|Natural combination hormone replacement formulations and therapies|
    MX365818B|2011-11-23|2019-05-30|Therapeuticsmd Inc|Natural combination hormone replacement formulations and therapies.|
    US20130338122A1|2012-06-18|2013-12-19|Therapeuticsmd, Inc.|Transdermal hormone replacement therapies|
    US9301920B2|2012-06-18|2016-04-05|Therapeuticsmd, Inc.|Natural combination hormone replacement formulations and therapies|
    US20150196640A1|2012-06-18|2015-07-16|Therapeuticsmd, Inc.|Progesterone formulations having a desirable pk profile|
    EA027534B1|2012-02-05|2017-08-31|ТиЮСиСи ТЕКНОЛОДЖИ, ЭлЭлСи|Earth metal peroxide fluidized compositions|
    IL225239D0|2012-03-15|2013-06-27|Meir Eini|Compositions for the treatment of acne and related disorders|
    RU2019142698A|2012-05-18|2020-05-27|Дженентек, Инк.|HIGHLY CONCENTRATED COMPOSITIONS OF MONOCLONAL ANTIBODIES|
    US11246875B2|2012-12-21|2022-02-15|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|
    US11266661B2|2012-12-21|2022-03-08|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|
    US10806697B2|2012-12-21|2020-10-20|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|
    US10471072B2|2012-12-21|2019-11-12|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|
    US10568891B2|2012-12-21|2020-02-25|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|
    RU2504383C1|2012-07-10|2014-01-20|Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Омский государственный аграрный университет имени П.А. Столыпина"|Method of treating acute postpartum endometritis in cows|
    US10507245B2|2012-07-19|2019-12-17|Luis Felipe Vejarano Restrepo|Ophthalmic formulation and method for ameliorating presbyopia|
    CA2880027C|2012-07-27|2021-12-07|Rhodes Technologies|Progesterone compositions and treatment for eye diseases and disorders|
    PT106679B|2012-11-27|2015-03-25|Hovione Farmaciencia Sa|TOPICAL FORMULATIONS OF TETRACYCLINES, THEIR PREPARATION AND USES|
    US9180091B2|2012-12-21|2015-11-10|Therapeuticsmd, Inc.|Soluble estradiol capsule for vaginal insertion|
    AU2014235779B2|2013-03-15|2015-11-26|NanoRx, Inc.|Metadichol liquid and gel nanoparticle formulations|
    US20140322428A1|2013-03-15|2014-10-30|Leading Edge Innovations, LLC|Compositions having an oil-in-water dispersion of submicron particles to enhance foods and beverages|
    AU2014239192B2|2013-03-15|2018-11-29|Leading Edge Innovations, LLC|Substantially surfactant-free, submicron dispersions of hydrophobic agents containing high levels of water miscible solvent|
    DE102013217242A1|2013-08-29|2015-03-05|Beiersdorf Ag|Emulsifier-free, skin-conditioning, cosmetic or dermatological preparation with peeling active ingredients|
    EP3065717A1|2013-11-04|2016-09-14|Biopharmx, Inc.|Dosage form comprising an active ingredient and a plurality of solid porous microcarriers|
    US9226890B1|2013-12-10|2016-01-05|Englewood Lab, Llc|Polysilicone base for scar treatment|
    EP3102182A1|2014-02-07|2016-12-14|Coty Inc.|Free standing color cosmetic stick|
    EP3699168A1|2014-02-18|2020-08-26|Elevance Renewable Sciences, Inc.|Branched-chain esters and methods of making and using the same|
    BR112016021023A2|2014-03-11|2021-09-14|Promius Pharma, LLC|TOPICAL CORTICOSTEROID COMPOSITIONS|
    US20160184431A1|2014-03-11|2016-06-30|Promius Pharma Llc|Topical compositions comprising a corticosteroid|
    JP2017516768A|2014-05-22|2017-06-22|セラピューティックスエムディー インコーポレーテッドＴｈｅｒａｐｅｕｔｉｃｓｍｄ， Ｉｎｃ．|Natural combination hormone replacement therapy and therapy|
    BR112016029338A2|2014-07-29|2017-08-22|Therapeuticsmd Inc|transdermal cream|
    AU2014407159B2|2014-09-23|2018-05-10|Colgate-Palmolive Company|Non-greasy personal care compositions|
    US9895311B2|2014-09-25|2018-02-20|Pharmiva Ab|Foam-forming compositions and methods for delivering an active to a body cavity|
    FR3026641B1|2014-10-02|2018-01-26|Pierre Fabre Dermo-Cosmetique|COSMETIC AND / OR PHARMACEUTICAL COMPOSITION IN THE FORM OF DISPERSION, PREPARATION METHOD AND USE FOR THE TREATMENT OF SKIN|
    CN104352527A|2014-10-20|2015-02-18|中山百鸥医药科技有限公司|Application of cod liver oil to the treatment of gynaecopathia|
    CA2966325A1|2014-10-31|2016-05-06|Pomega, Inc.|Formulations containing pomegranate seed oil, rosa canina fruit oil and inula viscosa oleoresin or extract|
    KR102332621B1|2014-11-21|2021-12-01|삼성전자주식회사|Signal Receiving and Transmitting circuit and electronic device including the same|
    ES2691372T5|2014-12-23|2021-11-22|Kalle Gmbh|Pre-humidified sponge cloth, biocide-free|
    US10751271B2|2015-02-19|2020-08-25|Conopco, Inc.|Fast rinsing cleansing composition|
    JP2018506554A|2015-02-25|2018-03-08|サン、ファーマ、アドバンスト、リサーチ、カンパニー、リミテッドＳｕｎ Ｐｈａｒｍａ Ａｄｖａｎｃｅｄ Ｒｅｓｅａｒｃｈ Ｃｏｍｐａｎｙ Ｌｉｍｉｔｅｄ|Nanoparticle composition|
    CA2980527A1|2015-03-23|2016-09-29|BioPharmX, Inc.|Pharmaceutical tetracycline composition for dermatological use|
    WO2016172481A1|2015-04-23|2016-10-27|The Procter & Gamble Company|Concentrated personal cleansing compositions and methods|
    KR101875997B1|2015-05-04|2018-07-06|엔 앤드 엔 파마세우티칼스 인크.|Method for treating shingles with n-methanocarbathymidine|
    JP6760275B2|2015-05-12|2020-09-23|ライオン株式会社|Ophthalmic composition|
    CN107666902B|2015-05-21|2021-09-21|德玛万科学有限责任公司|Topical pharmaceutical composition|
    DE102015209752A1|2015-05-28|2016-12-01|Beiersdorf Ag|Sprayable highly viscous cosmetic preparation|
    RU2018102133A3|2015-06-19|2019-10-17|
    US10328087B2|2015-07-23|2019-06-25|Therapeuticsmd, Inc.|Formulations for solubilizing hormones|
    US20190307778A1|2015-08-20|2019-10-10|Foamix Pharmaceuticals Ltd.|Tetracycline management of egfr inhibitor associated dermatoses|
    AU2016323770A1|2015-09-16|2018-03-29|Dfb Soria, Llc|Delivery of drug nanoparticles and methods of use thereof|
    US9617504B2|2015-09-22|2017-04-11|Scott Robert Sorenson|Non-medicated personal care cleansing solution and a method of synthesizing the same|
    US20170121098A1|2015-11-02|2017-05-04|American Sterilizer Company|Non-aspirating transport gel dispenser|
    US20170173075A1|2015-12-22|2017-06-22|Johnson & Johnson Consumer Inc.|Stable foaming composition and method of use|
    EP3435977A4|2016-04-01|2019-10-16|Therapeuticsmd, Inc.|Steroid hormone pharmaceutical composition|
    US10286077B2|2016-04-01|2019-05-14|Therapeuticsmd, Inc.|Steroid hormone compositions in medium chain oils|
    KR102354954B1|2016-04-04|2022-01-24|오메자 엘엘씨|Fish Oil Topical Composition|
    EP3443025A4|2016-04-15|2019-10-23|Nusil Technology LLC|Surfactant free silicone emulsion|
    CN113413375A|2016-05-30|2021-09-21|傅远桥|External-use medicine composition for treating various wound surfaces of skin and preparation method thereof|
    US10398641B2|2016-09-08|2019-09-03|Foamix Pharmaceuticals Ltd.|Compositions and methods for treating rosacea and acne|
    GB201615693D0|2016-09-15|2016-11-02|Combinatorx Infection Ltd|Combinations|
    EP3528777B1|2016-10-21|2021-09-01|The Procter & Gamble Company|Skin cleansing compositions and methods|
    US11185486B2|2016-10-21|2021-11-30|The Procter And Gamble Company|Personal cleansing compositions and methods|
    US10675231B2|2017-02-17|2020-06-09|The Procter & Gamble Company|Packaged personal cleansing product|
    KR20200014270A|2017-03-15|2020-02-10|디에프비 소리아, 엘엘씨|Topical therapies for the treatment of skin malignancies with taxane nanoparticles|
    JP2020521001A|2017-05-23|2020-07-16|ファーミバ アーベーＰｈａｒｍｉｖａ Ａｂ|Foam-forming composition for delivering an active substance to a body cavity|
    CA3067308A1|2017-06-20|2018-12-27|Foamix Pharmaceuticals Ltd.|Stable topical tetracycline compositions|
    FR3075532A1|2017-12-14|2019-06-21|Orange|METHOD FOR GENERATING A MULTI-CARRIER SIGNAL, DEMODULATION METHOD, COMPUTER PROGRAM PRODUCT, AND CORRESPONDING DEVICES|
    RU2020125984A3|2018-01-07|2022-02-07|
    EP3743047A1|2018-01-26|2020-12-02|The Procter & Gamble Company|Methods and compositions for reducing the feeling of vaginal dryness|
    US10285998B1|2018-04-04|2019-05-14|The Menopause Method, Inc.|Composition and method to aid in hormone replacement therapy|
    GB201813876D0|2018-08-24|2018-10-10|Antibiotx As|Treatment|
    WO2020089467A1|2018-11-02|2020-05-07|UNION therapeutics A/S|Dosage regimen|
    BR112021008417A2|2018-11-02|2021-09-14|UNION therapeutics A/S|HALOGENATED SALICYLANYLIDES TO TREAT DERMATITIS SYMPTOMS|
    CA3144250A1|2019-06-28|2020-12-30|Nexzol Pharma, Inc.|Transdermal formulations|
    WO2021022056A1|2019-07-31|2021-02-04|Foamix Pharmaceuticals Ltd.|Compositions and methods and uses thereof|
    BE1027141B1|2019-08-30|2020-10-15|Oystershell Nv|POLYISOBUTENE FOR USE IN THE TREATMENT OR PREVENTION OF INFECTION BY Arthropods|
    US20210401794A1|2020-06-30|2021-12-30|Np Pharma Holdings, Llc|Methods of Using Cannabinoid Compositions for Inducing and Promoting Sleep|
    法律状态:
    2017-08-01| B12F| Other appeals [chapter 12.6 patent gazette]|
    2019-05-21| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-07-09| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 9A ANUIDADE. |
    2020-05-26| B08K| Patent lapsed as no evidence of payment of the annual fee has been furnished to inpi [chapter 8.11 patent gazette]|Free format text: REFERENTE AO DESPACHO 8.6 PUBLICADO NA RPI 2531 DE 09/07/2019. |
    2021-09-21| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    US24814409P| true| 2009-10-02|2009-10-02|
    US32214810P| true| 2010-04-08|2010-04-08|
    US33112610P| true| 2010-05-04|2010-05-04|
    US34991110P| true| 2010-05-31|2010-05-31|
    US38056810P| true| 2010-09-07|2010-09-07|
    US38538510P| true| 2010-09-22|2010-09-22|
    US38888410P| true| 2010-10-01|2010-10-01|
    PCT/IB2010/002617|WO2011039638A2|2009-10-02|2010-10-01|Topical tetracycline compositions|
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