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    • 专利摘要:
    The present invention relates to an ivermectin-containing composition for topical application which is not rinsed and is in the form of a foam intended to be applied to the skin, comprising: at least one intermediate composition, at least one agent gas generator, - at least one activating agent of the gas-generating agent, and - ivermectin. The present invention also relates to a single multi-compartment kit or container containing such a composition.
    公开号:FR3041540A1
    申请号:FR1559205
    申请日:2015-09-29
    公开日:2017-03-31
    发明作者:Jean-Christophe Buge；Karine Nadau-Fourcade
    申请人:Galderma Research and Development SNC；
    IPC主号:
    专利说明:

    Self-foaming cleaning composition to be rinsed, containing ivermectin
    The present invention relates to a cleaning topical pharmaceutical or cosmetic cleaning composition in the form of a rinsing foam comprising a compound of the avermectin family, preferably ivermectin.
    The present invention also relates to a cleaning topical pharmaceutical composition in the form of a rinsing foam comprising a compound of the avermectin family, preferably ivermectin, for use in patients with inflammatory skin diseases.
    The class of avermectins is a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds JEF (Ed) (1993) Martindale, The Extra Pharmacopoeia, 29th Edition, Pharmaceutical Press, London). Among these macrocyclic lactones belonging to the avermectin class, mention may be made of ivermectin, avermectin, abamectin, doramectin, eprinomectin, selamectin, aversectin B, AB or C, emamectin B1b and their derivatives, or latidectin.
    According to the invention, the compound of the avermectin family is preferably ivermectin. Ivermectin is a mixture of 22,23-dihydroavermectin B1a and 22,23-dihydroavermectin B1b. Ivermectin contains mainly 22,23-dihydroavermectin B1a. Ivermectin is known in the prior art for its antiparasitic and anthelmintic properties. In the mid-1980s, the molecule was presented as a broad-spectrum pest control drug for veterinary use (CAMPBELL, WC, et al., (1983).) Ivermectin: a patented new antiparasitic agent, Science, 221, 823-828.) . It is effective against most common intestinal worms (except tapeworms), most mites, and some lice. It has a significant affinity for glutamate-dependent chloride channels, in particular those dependent on the neuromediator GABA (gamma-amino-butyric acid), present in the nerve and muscle cells of invertebrates, conferring on it an antiparasitic activity. More particularly, its binding on these channels promotes an increase in membrane permeability to chloride ions resulting in hyperpolarization of the nerve or muscle cell. This results in neuromuscular paralysis that can lead to the death of certain parasites. Ivermectin also interacts with other chlorine channels. Ivermectin is conventionally used in the dermatological treatment of endoparasitic manifestations such as onchocerciasis and myasthenia.
    US 6,133,310 and US 5,952,372 also disclose the use of ivermectin in the treatment of rosacea to reduce and eliminate the parasite Demodex folliculorum. Ivermectin is also known for its use in the treatment and / or prevention of many inflammatory skin diseases such as acne, eczema, atopic dermatitis or psoriasis and in particular rosacea.
    The mechanism of action of ivermectin in inflammatory lesions of rosacea is based on its anti-inflammatory and antiparasitic properties. Ivermectin eliminates Demodex mites that are involved in inflammatory skin rashes. These mites can be present both on the skin and the scalp, cleansing compositions containing ivermectin suitable for cleaning the scalp, or that of the skin or both at the same time are of particular interest in this pathology and its treatment.
    Dermatological conditions are often linked to an increased sensitivity of the skin, particularly in the case of rosacea, which is an inflammatory dermatosis that mainly affects the central part of the face and is characterized by the redness of the face, flushing, facial erythema Patients with rosacea have very sensitive skin and cleansing products must have a very high tolerance. However, most cleaning products and in particular shampoos have a high content of cleaning and foaming surfactants so as to generate a large amount of foam to aid cleaning. However foaming surfactants are generally irritating. There is therefore a need for new galenic forms of foaming cleanser in which the ivermectin is stable, solubilized, effective, pleasant to apply and allowing a generation of foam and gentle cleaning ensuring good tolerance of the product through a content decreased or no foaming surfactant.
    Surprisingly, the Applicant has developed cleaning foaming pharmaceutical compositions intended to be rinsed, comprising a compound of the family of avermectins, including ivermectin, very well tolerated by sensitive skin thanks to better dose control, their spreading properties and their low density.
    The composition according to the present invention can be used in an interesting way in patients with inflammatory skin diseases such as rosacea but also acne, eczema, or atopic dermatitis.
    The composition according to the present invention has the advantage of being a cleaning foaming composition generated extemporaneously and very well tolerated.
    After its application, the composition according to the invention is removed by rinsing.
    There are various methods for evaluating the tolerance of a pharmaceutical or cosmetic product for cutaneous use among which may be mentioned the in vivo test "in used" or "human patch test" but also the in vitro test such as the test of Measurement of irritation on Reconstructed Human Epidermis (RHE) described in the TG439 OECD protocol. This last method is detailed in example 3.
    There are currently foams or foaming cleansing compositions on the market. However, they all have a number of disadvantages:
    Indeed, there are 3 types of foams or foaming compositions: aerosols in which the foam is generated by a propellant gas but with the disadvantage of being aerosols with risks well known to them (pollution, respiratory risks) especially). - Loose creams in which air bubbles are introduced into the product through a particular manufacturing process. This process has the disadvantage of being binding at the industrial level and requires a heavy investment in packaging equipment. Foaming formulas that are not very rich in foaming surfactants but packaged in a package provided with a mechanical foam generating system (pump with pulvorex type grid). This type of formulation has the disadvantage of being compatible only with very fluid dosage forms. The product must indeed be liquid to allow the passage in the grid and the generation of foam.
    There remains the need to develop a pharmaceutical or cosmetic composition whose dosage form is different from the known dosage forms in order, inter alia, to allow the use of Tivermectin in solubilized form in well-tolerated compositions intended for topical application rinsed in humans, especially for cleaning the skin and scalp (that is, the composition is removed by rinsing after application).
    The object of the present invention is therefore to provide a composition that meets these needs.
    The applicant has thus developed a novel cosmetic and / or pharmaceutical composition, intended for topical rinsed application, which is in the form of a foam which preferably does not contain foaming surfactant or in a very small amount (lower content or equal to 2.5% by weight of active ingredient relative to the weight of the total composition).
    Foaming surfactants are defined as surfactants which produce a voluminous, stable and unctuous foam when they are mixed with water according to the tests well known to those skilled in the art.
    Foaming surfactants include anionic surfactants, cationic surfactants, amphoteric surfactants and nonionic surfactants of the alkylpolyglucoside and glucamide family.
    The dosage form according to the invention has the advantage of ensuring good solubility and stability of ivermectin. In addition, this formulation advantageously leads to the production of a soft, perfectly tolerated and non-irritating foam, which allows the treatment and cleaning of the skin and the scalp while overcoming the problems of tolerance and satisfying the patient in quality matter and quantity of foam.
    Finally, advantageously, this dosage form does not require for its implementation the use of propellants or aerosols. Thus the so-called aerosol or spray foams are excluded from the scope of the invention. Similarly, foams of the prior art of expanded cream type and / or foaming formulas requiring a mechanical foam generating system (pulvorex type) are also excluded from the invention.
    Finally, the subject of the present invention is the cosmetic use of the composition according to the invention, by topical application thereof to the skin or the scalp, as well as a medicinal product intended for topical application to skin and leather. hairy, including such a composition. According to the invention, after its application, the composition is removed by rinsing.
    The present invention also relates to the composition according to the invention for its use in the treatment of inflammatory skin diseases and in particular rosacea, acne, eczema, atopic dermatitis.
    The present invention will be described in more detail in the description and examples hereinafter. In the following description, unless expressly stated otherwise the contents of the ingredients are expressed in terms of amounts of active ingredient.
    The composition according to the invention is capable of taking the form of a foam by the mere fact of its composition and can also be defined as a foaming composition for topical application.
    The present invention therefore, as a first object, a composition containing ivermectin intended for rinsed topical application in the form of a foam, advantageously of semi-solid consistency, advantageously containing no or little foaming surfactant, and comprising a pharmaceutically compatible medium with a topical application rinsed especially on the skin and the scalp.
    By composition in the form of a foam, (also hereinafter referred to as self-foaming composition), is meant a composition of semi-solid consistency having an aerated form comparable to a foam.
    The composition according to the invention is a self-foaming composition which comprises at least the following ingredients: at least one composition or intermediate formula, at least one gas-generating agent, at least one activating agent for the gas-generating agent , and ivermectin.
    In a preferred aspect, the self-foaming composition comprises at least two compositions or intermediate formulas in variable proportions and in particular the following ingredients: at least one composition or intermediate formula A, at least one composition or intermediate formula B, at least a gas generating agent, at least one agent for activating the gas generating agent, ivermectin contained in at least one intermediate composition.
    Preferably, the gas generating agent is present in one of the intermediate formulas mentioned above.
    In a still more preferred aspect, the self-foaming composition comprises at least two compositions or intermediate formulas in variable proportions and in particular the following ingredients: at least one composition or intermediate formula A comprising an agent for activating the generating agent gas ; at least one intermediate composition or formula B comprising the gas-generating agent; ivermectin contained in at least one of said intermediate formulas A and B.
    According to the invention, the composition is self-foaming, that is to say that it foam by simple mixing of the intermediate compositions A and B. The subject of the present invention is also the composition resulting from the mixing of said intermediate compositions A and B.
    According to the invention, each intermediate composition (or formula) can have a viscosity (measured at 25 ° C. and at atmospheric pressure) of between 1 cP and 500,000 cP, advantageously between 500 cP and 350000 cP, measured with a conventional method of the type brookfield RV dv II: Needle 6 lives 2.
    According to the invention, the gas generated by the gas-generating agent may be any physiologically compatible gas which makes it possible to obtain a foam, such as for example carbon dioxide (CO 2) or oxygen (O 2). Preferably, the gas generated from the gas generating agent is carbon dioxide (CO 2).
    According to the invention, the gas concentration can vary, the amount of bubbles in the composition can vary and thus give a composition that can go from unventilated to very highly aerated.
    According to the invention, the term "activating agent of the gas generating agent" means an ingredient which, by chemical reaction with the gas generating agent, releases a gas. Preferably it is an acid / base reaction.
    Thus according to the invention, the self-foaming composition may be preferably in all forms ranging from aerated to a very expanded foam.
    The composition according to the invention is suitable for topical application and may further comprise a physiologically acceptable medium, that is to say a medium compatible with the skin and superficial body growths. It is preferably a pharmaceutically acceptable medium.
    In addition, the composition may comprise any active agent capable of exhibiting an activity, which may be therapeutic. These active agents can be, among others, chosen from emollient agents, cleaning agents, humectants, anti-radical agents, anti-inflammatory agents, vitamins, depigmenting agents, anti-acne agents, agents and the like. anti-seborrhics, anti-fungal agents, keratolytic agents, sunscreens, slimming agents, skin coloring agents.
    According to the invention, the self-foaming composition (that is to say, ready to be applied) may have a pH of between 2 and 8, preferably between 4 and 7.
    Insofar as the intermediate composition (s) (or formula (s)) need (s) storage in at least 2 compartments for reasons of stability of the ingredients, the present invention relates either to a single compartmentalized container (each compartment hosting an intermediate formula) and preferably comprising 2 or 3 compartments, or a kit comprising each intermediate formula stored independently of one another and physically separated.
    The extemporaneous intimate mixture (directly on the skin or on any other support) of the intermediate formulas makes it possible to obtain the self-foaming composition according to the invention.
    More specifically, the intermediate composition (or formula) A may be in the form of a solution, an emulsion (lotion, cream, cream without emulsifier, milk, fluid cream) or a gel. This composition advantageously contains the activating agent for the gas generating agent, preferably an acid in sufficient quantity (which may be in the form of an acid / base buffer at acidic pH) which may be by way of non-limiting example the citric acid / sodium citrate couple.
    Formula B can be in the form of a solution, a gel, an emulsion (lotion, cream, cream without emulsifier, milk, fluid cream). This composition advantageously contains in sufficient quantity a gas generating agent, which may in particular be sodium bicarbonate.
    Thus, the subject of the invention is also a kit or a single multi-compartment container as defined above, enabling the extemporaneous preparation of a self-foaming composition according to the invention, comprising separately at least two intermediate formulas (or intermediate compositions): an intermediate formula A comprising at least one activating agent for the gas generating agent; and an intermediate formula B comprising at least one gas generating agent; - Ivermectin being contained in at least one of said intermediate formulas A and B. The ivermectin is indifferently contained in the intermediate composition A and / or in the intermediate composition B. GAS ACTIVATION AGENT: The activating agent of the gas-generating agent (also referred to as "gas-activating agent") is a compound which reacts with the gas-generating agent by a chemical reaction (preferably an acid-base reaction) releasing a gas.
    It is advantageously an acid, a partially salified polyacid salt or a weak acid buffer solution and its conjugate base, or a mixture of such compounds.
    According to the invention, the acid / base buffer of said acid may be any acidic buffer / base of the weak acid such as, for example, a citric acid / sodium citrate buffer or a tartaric acid / sodium tartrate buffer. Preferably, we will mention the alpha-hydroxy acids which are weak acids preferably having a pKa of between 2 and 6 such as citric acid, tartaric acid, malic acid, lactic acid but also acid phosphoric acid and pyrophosphoric acid and their optionally partially salified salts such as disodium pyrophosphate or sodium dihydrogen phosphate also called monosodium phosphate.
    Preferably, according to the invention, the gas-activating agent is chosen from a tartaric acid / tartrate salt buffer (for example sodium tartrate); citric acid / sodium citrate buffer alone; phosphoric acid, monosodium phosphate, disodium pyrophosphate alone or as a mixture with a citric acid / sodium citrate buffer.
    According to a very preferred embodiment, the gas-activating agent is a citric acid / sodium citrate buffer alone or in admixture with monosodium phosphate and / or disodium pyrophosphate.
    In compositions for sensitive skin or for damaged skin, such as acne skin, the content of citric acid / sodium citrate is preferably less than or equal to 2.4% relative to the total weight of the intermediate composition A, so as to limit any risk. tingling. In order to improve tolerance and to avoid the tingling sensation, preferably the citric acid / sodium citrate buffer is used in admixture with disodium pyrophosphate or sodium dihydrogenphosphate.
    According to the invention, said gas-activating agent may be present in the intermediate formula A in an amount ranging from 0.001% to 95% by weight relative to the total weight of the intermediate formula A. GAS GENERATING AGENT:
    By gas generating agent is meant any agent that has the property of generating a gas by chemical reaction. In this respect, any compound which, when mixed with a weak acid, can form a gas by a chemical reaction equivalent to the following:
    NaHC03 + RCOOH RCOONa + H20 + C02
    According to the invention, the gas generated from the gas generating agent present in the intermediate composition B is preferably carbon dioxide or carbon dioxide (CO 2).
    According to the invention, the gas generating agent is preferably selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and mixtures thereof.
    Preferably according to the invention, the intermediate formula B comprises a carbon dioxide generating agent which is particularly preferably sodium bicarbonate.
    Said gas generating agent may be present in the intermediate formula B in an amount ranging from 1% to 10%, preferably from 2% to 8% by weight relative to the weight of the intermediate composition B.
    According to the invention, the intermediate formula A may have an acidic pH, advantageously between 1.0 and 6.0, and the intermediate formula B may have a basic pH, advantageously between 7 and 12.
    According to the invention, one (or more) intermediate formula (s) comprises ivermectin la in an amount ranging from 0.01% to 6% by weight relative to the total weight of the total composition.
    Preferably, the total formula (mixture of the intermediate of formulation A with the intermediate of formulation B) contains ivermectin at concentrations ranging from 0.5% to 5% by weight, more preferably from 0.8% to 4% by weight. weight, relative to the total weight of the total formula.
    In the present description, the term "total composition" or "total formula" means the composition of the product in the form of foam after the mixing of said intermediate compositions. The ivermectin is contained in the intermediate composition A or in the intermediate composition B or simultaneously in the two compositions.
    Intermediate formula A may be in any galenic form compatible with the desired dosage form for the final composition obtained by mixing formula A with formula B. Advantageously formula A may be a gel, a solution, a suspension, an emulsion (cream, cream without surfactant, lotion, milk, fluid cream).
    Intermediate formula B can be in any galenic form compatible with the desired dosage form for the final composition obtained by mixing formula B with formula A. Advantageously formula B can be a gel, a solution, a suspension, a emulsion (cream, cream without surfactant, milk lotion, fluid cream).
    Each intermediate formula of the multi-compartment kit or container as defined above, according to the invention comprises a physiologically acceptable medium, carrying the compound (s), and chosen in such a way that the compounds are capable of reacting with each other. other for forming a self-foaming composition upon mixing of at least intermediate formulas A and B.
    Thus, extemporaneous mixing of at least two formulas, for example formula A and formula B, creates the self-foaming composition according to the invention.
    When the two formulas A and B are mixed, the gas-generating agent, such as sodium bicarbonate, reacts with the gas-activating agent such as the acid, and thus gives in particular the salt corresponding to the acid, of water and gas C02. It is this gas, trapped in the bubbles of the composition, which creates the foam which characterizes the self-foaming composition of the invention.
    Thus, by mixing at least the intermediate formula A and the intermediate formula B, the so-called total composition foam composition according to the invention is obtained.
    In the composition obtained after mixing at least the formulas A and B, it may of course remain gas-activating agent and / or unreacted gas generating agent.
    Advantageously, the kit or the single multi-compartment container according to the invention can be designed such that during the preparation of the composition according to the invention, the intermediate formulas A and B can be mixed in a ratio by weight A / B ranging from 0.5 to 2, preferably from 0.5 to 1.5, more preferably close to 1 (that is to say from 0.9 to 1.1), and even more preferably from 1. means that the kit may be designed to simultaneously release doses (by weight) of intermediate compositions A and B which may be in a weight ratio ranging from 2 doses of B for 1 dose of A at 2 doses of A for 1 dose of B preferably 2 doses of B for 1 dose of A at 3 doses of A for 2 doses of B. According to a preferred embodiment of the invention, the kit is designed to simultaneously release 1 dose by weight of A and 1 dose in weight of B.
    According to the invention, the kit may be in any form compatible with, on the one hand, a separate preservation of the intermediate formulas A and B and, on the other hand, the ability to make the mixture of A and B extemporaneously.
    For example intermediate formulas A and B may be packaged in a housing with at least two separate compartments, each containing formulas A or B.
    In another aspect, the kit may be in the form of a syringe to at least two separate bodies, each provided with a piston, said two bodies containing the respective formulas A and B, and being designed to release simultaneously by exercise. The invention also relates to a process for the preparation of a composition according to the invention, characterized in that, in order to obtain the self-foaming composition, the mixture is mixed in such a way that extemporaneous intermediate formula A and an intermediate formula B of the kit as defined above, in relative proportions by weight A / B may range from 0.5 to 2, preferably from 0.5 to 1.5 and more preferably from 1 to .
    In order to obtain an optimum foam (final composition), the inventors have experimentally sought the optimal contents of gas-generating agent (preferably sodium bicarbonate) and of gas-activating agent (preferably citric acid and / or disodium pyrophosphate and / or sodium dihydrogen phosphate or monosodium phosphate.
    Thus, it has been determined experimentally that when the gas-activating agent is citric acid, the weight ratio citric acid / sodium bicarbonate is advantageously between 0.1 and 2, preferably between 0.5 and 1, and very preferably preferred equal to 0.7.
    Similarly, it has been determined that when the gas-activating agent is disodium pyrophosphate, the weight ratio of disodium pyrophosphate / sodium bicarbonate is between 0.5 and 5, preferably between 1 and 3, and very preferably is equal to 2.4.
    Similarly, it has been determined that when the gas-activating agent is sodium dihydrogenphosphate, the sodium dihydrogenphosphate monohydrate / sodium bicarbonate weight ratio is between 0.5 and 5, preferably between 1 and 3, and very preferably The exemplification of ratios sodium bicarbonate / citric acid, sodium bicarbonate / sodium pyrophosphate, sodium bicarbonate / sodium hydrogen phosphate is described in Example 4.
    Surprisingly, the citric acid / sodium citrate, disodium pyrophosphate or sodium dihydrogenphosphate combination and a gelling system compatible with the galenic form made it possible to obtain a formula with very stable physicochemical properties. A composition is considered physically stable when its organoleptic characteristics, pH, viscosity and homogeneity of ivermectin do not change with time under different temperature conditions: ambient temperature (RT, or TA), 30 ° C and 40 ° C.
    According to the invention, the ambient temperature corresponds to a temperature ranging from 15 ° C. to 25 ° C.
    A composition is considered chemically stable when the content of active ingredient that it contains does not change with time under the various temperature conditions (RT and 40 ° C.)
    According to the invention, the composition is considered stable when its ivermectin content (expressed by weight relative to the weight of the intermediate formula) is included in the specifications ranging from 90% to 110%.
    The composition according to the invention may furthermore comprise one or more agents chosen from dispersing agents, solubilizing agents, stabilizing agents, preserving agents, fatty substances, thickening agents, dyes, perfumes, surfactants, gelling agents, complexing agents, neutralizing agents, non-foaming emulsifiers, fillers, sequestering agents, reducing agents, odor masks, plasticizing agents, softening agents, moisturizing agents, pigments, clays, mineral fillers, mineral colloids, polymers, proteins, pearlescent agents, waxes, oils such as paraffins, silicones, fatty acids, solid esters of fatty alcohol or of acids fatty, gums, wetting agents.
    Water-soluble dyes such as FD & C Blue 1 (of the formula Csrh + NaNaaOgSs) and fat-soluble dyes such as Sudan Red III or Red Nil have the advantage of coloring one of the formulation intermediates. This coloration makes it possible to control the good mixture of the two formulation intermediates and to enhance the formation of the foam.
    GELIFYING AGENTS OF THE INTERMEDIATE FORMULA CONTAINING THE GAS ACTIVATOR
    The intermediate composition A advantageously containing at least one gas-activating agent preferably contains at least one gelling agent and / or suspending agent.
    Formulation A can contain high amounts of acid and electrolytes, these gels are known to be very complicated to stabilize. The viscosity and the suspensive power of these formulas are often hard to guarantee over time. By way of nonlimiting example of gelling agents and / or suspending agents that are resistant to both electrolytes and acidic pHs that can be used in compositions A according to the invention, mention may be made of ready-to-use mixtures such as polysaccharides with, by way of nonlimiting examples, xanthan gum such as Xantural180® sold by Kelco, gellan gum sold under the name Kelcogel® by Kelco, Sclerotium Gum sold under the name Amigel® by Alban Muller industry, guar gum and its derivatives such as Hydroxypropyl Guar sold under the name Jaguar HP-105® resold by Rodhia, cellulose and its derivatives such as microcrystalline cellulose and sodium carboxymethyl cellulose sold under the name Blanose CMC 7H4XF® by Hercules, hydroxypropylmethylcellulose, in particular the product sold under the name Methocel E4M® premium by Dow Chemical or hydroxyethylcellulose, in particular the product sold under the name Natrosol HHX 250® by the company Aqualon, the family of aluminum magnesium silicates such as Veegum K®, Veegum Plus® or Veegum Ultra® sold by Vanderbilt, the family of modified starches such as modified potato starch sold under the name Structure Solanace®, the carrageenan family in particular divided into four major families: κ, λ, β, ω such as Viscarin® and Gelcarin® marketed by the company IMCD . Or else Polyvinyl Alcohol also known by the abbreviation PVA sold by Merck under the name POLYVINYL ALCOHOL 40-88®. Preferably, Veegum K® and Xantural 180® will be used in combination. The gelling agent as described above may be used at preferential concentrations ranging from 0.001% to 15% and, more preferably, ranging from 0.15% to 5% by weight relative to the weight of the intermediate formula A.
    GELIFYING AGENTS OF THE INTERMEDIATE FORMULA CONTAINING THE GAS GENERATOR By way of nonlimiting example of gelling agents and / or suspending agents and / or gelling agents that are resistant to both electrolytes and basic pHs that can enter the intermediate compositions B according to US Pat. acrylic acid polymers such as Acrylates / C 10-30 Alkyl Acrylate Crosspolymer such as so-called non-electrolyte sensitive carbomers sold under the name Ultrez 20®, Ultrez 10®, Carbopol 1382® or Carbopol ETD2020NF®, AQUA SF1® sold by the Lubrizol Company, the Ammonium Acrylate / Acrylamide Copolymer & Polyisobutene & Polysorbate 20 sold by Seppic under the name Sepiplus 265®, polysaccharides with, by way of nonlimiting examples, xanthan gum such as Xantural180® sold by Kelco, gellan gum sold under the name Kelcogel® by the company Kelco, the Sclerotium Gum sold under the name Amigel® by Alban Muller industry, guar gum and its derivatives such as Hydroxypropyl Guar sold under the name Jaguar HP-105® resold by Rodhia, cellulose and its derivatives such as microcrystalline cellulose and sodium carboxymethyl cellulose sold under the name Blanose CMC 7H4XF® by the company Hercules, hydroxypropylmethylcellulose, in particular the product sold under the name Methocel E4M® premium by Dow Chemical or hydroxyethylcellulose, in particular, the product sold under the name of Natrosol HHX 250® by Aqualon, the family of aluminum magnesium silicates such as Veegum K®, Veegum Plus® or Veegum Ultra® sold by the company Vanderbilt, the family of modified starches such as modified potato starch sold under the name Solanace® Structure or Tapioca Flour known as Naviance Tapioca P® sold by Akzo Novel or the family of carrageenans in particular divided into four major families: κ, λ, β, ω such as Viscarin® and Gelcarin® marketed by IMCD. Preferably, Vegum K® and Xantural 180® will be used in combination. The gelling agent as described above may be used at preferential concentrations ranging from 0.001% to 15% and, more preferably, ranging from 0.15% to 5% by weight relative to the weight of the intermediate formula B.
    HUMICANTS
    Among the humectant and / or emollient agents whose role is to moisturize the skin and to facilitate the application of the formulation, optional compounds are optionally used, without this list being limiting, such as a water-miscible polyol. at ambient temperature (25 ° C.), in particular chosen from polyols having in particular from 2 to 20 carbon atoms, preferably having from 2 to 10 carbon atoms, and preferably having from 2 to 6 carbon atoms, such as glycerol glycol derivatives such as propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, dipropylene glycol, diethylene glycol, propylene 1.3 glycol sold under the name Zemea by the company DuPont Tate & Lyle Bio Products Company, LLC and their mixtures but also sugars (for example glucose, lactose), polyethylene glycol (PEG) (for example Lutrol E400®), urea, acids amines (for example serine, citrulline, arginine, asparagine, alanine). As preferred humectant and / or emollient, mention may be made of glycerol and propylene glycol.
    The humectants may be used, alone or in combination, at preferential concentrations ranging from 0.001% to 30% and, more preferably, ranging from 0.01% to 10% by weight relative to the weight of the total formula.
    CHELATING AGENTS
    Among the chelating agents that may be mentioned as non-limiting examples are ethylene diamine tetraacetic acid (EDTA), diethylene triamine penta-acetic acid (DTPA) and ethylene diamine di (O-hydroxyphenyl) acid. acetic acid) (EDDHA), 2-hydroxyethylenediamine triacetic acid (HEDTA), ethyldiamine-di (O-hydroxy-p-methylphenyl) acetic acid (EDDHMA) and ethylene diamine di (5 -carboxy-2-hydroxyphenyl) acetic acid (EDDCHA). As preferred chelating agent, mention may be made of ethylene diamine tetraacetic acid (EDTA) sold in particular under the name Titriplex III® it may be used at preferential concentrations ranging from 0.001% to 1% and, more preferably 0.05% % to 0.1% by weight relative to the weight of the total formula;
    EXCIPIENTS WITH ADDITIONAL PROPERTIES
    The composition according to the invention may contain one or more excipients with specific properties, such as, for example, allantoin with antiirritant properties, dipotassium glycyrrhizate for these anti-inflammatory properties or the alpha bisabolol cicatrisant, lithium digluconate for its anti-redness properties.
    LOADS AND PARTICLES
    Fillers and / or particles can be used to stabilize and boost the foam. Some of them have the particular property of being placed at the interface water / air and thus stabilize this interface. As fillers, mention may be made of talc, metal oxides such as zinc oxide, TiO 2 T2000 titanium dioxide sold by Merck under the name Eusolex® T-2000, clays such as laponites, bentones or bentonites but also cellulose ethers such as Methocel® K100 LV marketed by DOW, silicas such as Aerosil® R972 sold by EVONIK or SILICE HDK® H13L sold by WACKER they can be used in concentrations ranging from 0.01% to 10% by weight relative to the weight of the total formula.
    OILS OF THE FAT PHASE
    The composition according to the invention may also comprise a fatty phase. This fatty phase may be present in one and / or the other of the intermediate compositions A and B. The fatty phase may according to the dosage form of the intermediate formulas represent from 0% to 95% by weight relative to the weight of each formula intermediate.
    The fatty phase of the composition according to the invention may comprise, for example, vegetable, mineral, animal or synthetic oils, silicone oils, and mixtures thereof.
    As an example of mineral oil, there may be mentioned, for example, paraffin oils of different viscosities such as Primol 352®, Marcol 82®, Marcol 152® sold by the company Esso.
    As a vegetable oil, mention may be made of sweet almond oil, palm oil, soybean oil, sesame oil, sunflower oil, olive oil, sesame
    As animal oil or their substitute of vegetable origin, mention may be made of lanolin, squalene, fish oil, with as derivative perhydrosqualene sold under the name Sophiderm® by Sophim.
    As synthetic oil, mention may be made of an ester such as cetearyl isononanoate such as the product sold under the name Cetiol SN PH® by Cognis France, isononyl isononanoate such as DUB ININ® sold by Stéarine Dubois, isopropyl myristate sold under the name Crodamol IPM by the company CRODA, diisopropyl adipate as the product sold under the name Crodamol DA® by Croda, isopropyl palmitate as the product sold under the name Crodamol IPP® by the company Croda company, caprylic caprylic triglyceride such as Miglyol 812® sold by the company Univar. As hydrogenated polyisobutene, mention may be made of Parleam® sold by Rossow, C12-15 alkyl benzoate sold under the name CRODAMOL AB by the company CRODA, octyldodecanol or Eutanol G sold by BASF, oleic alcohol sold under the name KOLLICREAM OA by the company BASF, the PPG-11 STEARYL ETHER arlamol PS11E sold by the company CRODA
    As silicone oil, there may be mentioned a dimethicone such as the product sold under the name Q7-9120 Silicone Fluid® with a viscosity of 20 to 12500 is by the company Dow Corning, a cyclomethicone such as the product sold under the name ST- Cyclomethicone 5NF® also by Dow Corning.
    NON-LIQUID BODIES
    The composition according to the invention, and in particular the intermediate formula B, can also comprise solid fatty substances such as natural or synthetic waxes, fatty acids such as stearic acid, fatty alcohols such as Speziol C18® pharma or Speziol C16® sold by the company Cognis, and texture agents of the tribehenate type, such as Compritol 888® sold by the company Gattefossé or hydrogenated castor oils such as Cutina HR® sold by the company Cognis or the glyceryl stearate such as GELEOL® sold by Gattefosse or De 9045 Elastomer Blend® sold by Dow Corning.
    These non-liquid fatty substances may be used alone or as a mixture of 0 to 30% by weight relative to the weight of the total formula. However, an exceptional foam quality has been observed when fatty alcohols of formula CH 3 (CH 2) n OH (n is between 11 and 23) are present at contents greater than 1% by weight relative to the weight of the total formula.
    NON IONIC EMULSIFIERS
    The composition according to the invention and especially the intermediate formula B can also comprise one or more nonionic emulsifiers. As preferred emulsifiers, mention may be made of hydrophilic emulsifiers of the Glyceryl Stearate (and) PEG-100 Stearate type sold under the name Arlacel 165FL® by the company Uniquema, lipophilic emulsifiers of the Glucate SS® and Glucamate SSE®, Polyoxyethylene ( 21) Stearyl Ether sold under the name Brij721® by Uniquema or in the same family Brij S2®, Brij S20®. The self emulsifying Wax sold by Croda under the name Polawax N F®. There may also be mentioned nonionic surfactants having a high HLB, sorbitan esters such as POE (20) sorbitan monooleate, sold under the name "Tween 80®" (HLB = 15); POE (20) sorbitan monostearate sold under the name "Tween 60®" (HLB = 14.9); fatty alcohol ethers such as POE (21) stearyl ether (HLB = 15.5), or ceteareth 20 sold under the name Eumulgin B2 PH® by Cognis (HLB 15.5, or nonionic surfactants of low HLB, sorbitan esters, such as sorbitan monostearate (sold under the name Span 60® by Uniquema), glycerol esters such as glycerol monostearate (Cutina GMS® from Cognis), sucrose esters of In another embodiment according to the invention, the surfactants that can be used are the polyglycerol esters, which are esters of polyglycerinated fatty acids obtained by condensation of glycerin, glycolipidic emulsifiers such as Montanov. 202® sold by the company SEPPIC Certain emulsifiers may be sold in the form of a mixture such as Emulium Kappa® and Emulium Delta® sold by Gattefosse These active Tensio may be used alone or in combination so that the HLB of the system is greater than 12 and preferably greater than 15.
    Such emulsifiers can be used between 0.01% and 30% by weight relative to the weight of the total composition, preferably between 0.1% and 15%, and more preferably between 0.5% and 7%.
    In a particular embodiment, the composition B containing the gas generating agent is a cream without foaming surfactant and contains non-foaming cleaning agents which alone are not capable of generating foam such as Disodium PEG-12 Dimethicone Sulfosuccinate sold by Rodhia under the name Mackanate® ultra Si, Sodium Cocoamphoacetate or Disodium Cocoamphodiacetate sold by Evonik under the name Rewoteric AMC® and Rewoteric AM2CNM®, sugar esters such as those sold by Sisterna under the name PS750-C® or SP70 -C®. The amounts of these cleaning agents are advantageously between 0 and 1% by weight relative to the total weight of formula B. CLEANING AGENTS OF COMPOSITION A or B:
    In a particular embodiment of the non-foaming cleaning product, composition A or composition B contain non-foaming cleaning agents, that is to say agents which alone are not capable of generating foam such as Disodium. PEG-12 Dimethicone Sulfosuccinate sold by Rodhia under the name Mackanate® ultra Si, Sodium Cocoamphoacetate or Disodium Cocoamphodiacetate sold by Evonik under the name Rewoteric AMC® and Rewoteric AM2CNM®, sugar esters such as those sold by Sisterna under the name PS750 -C® or SP70-C®. The amounts of these cleaning agents are advantageously between 0 and 1% by weight relative to the total weight of the total composition.
    FOAMING SURFACTANTS
    In another embodiment, the intermediate composition A and / or the intermediate composition B may contain a small amount of foaming surfactants compatible with ivermectin.
    As examples of surfactants which may be used, mention may be made of: anionic surfactants of the sulphonate family such as Sodium C14-C16 Olefin Sulfonate, of the glycinate family such as Sodium Cocoyl Glycinate sold by Clariant under the name Hostapon SG, the family of isethionates such as Sodium Cocoyl Isethionate sold by Clariant under the name Hostapon SCI85 G, Sodium Lauroyl Methyl Isethionate sold by Innospec under the name Iselux LG, of the sulphate family such as Zinc Coceth Sulfate sold by Zschimmer & Schwarz under the name Zetesol Zn or Sodium Laureth sulfate sold under the name Texapon N70, from the family of sulfosuccinates such as Disodium PEG-5 Laurylcitrate Sulfosuccinate sold by Evonik under the name Rewopol SB C55, Disodium PEG-12 Dimethicone Sulfosuccinate sold by Rodhia under the name Mackanate Ultra Si, Sodium Cocoamphoacetate or Disodium Cocoamphodiacetate sold by Evonik under the name Rewoteric AMC and Rewoteric AM2CNM, the sodium cocoyl glutamate made under the name Protelan AGL95 by Zschimmer & Schwarz, the sodium capryolyl glutamate sold under the name Protelan AG8 by Zschimmer & Schwarz or even sodium lauroyl saccosinate sold by Zschimmer & Schwarz under the name Protelan LS911.
    It is also possible to use nonionic surfactants, such as Decyl Glucoside sold by Cognis under the name Plantacare 2000 Up, Glyceryl Monolaurate sold by Rossow under the name POEM DL 100, and Sucrose Laurate sold by Sisterna under the name Sisterna L70. vs.
    It is also possible to use amphoteric surfactants such as those of the betaine family, such as cocobetaine sold under the name Dehyton AB30 or cocamidopropyl betaine sold under the name Tego betaine F50.
    These surfactants can be used alone or in combination.
    The total content of these surfactants is preferably less than or equal to 2.5% by weight, and more preferably less than or equal to 1% by weight, relative to the weight of the total composition.
    According to one embodiment, the composition according to the invention does not contain foaming surfactant.
    EMULSIFIING POLYMERS
    By way of example of emulsifying polymer that may be used in the compositio according to the invention, there may be mentioned polyacrylate-13 & Polyisobutene & Polysorbate 20 sold by Seppic under the name Sepiplus 400®, Ammonium Acrylate / Acrylamide Copolymer & Polyisobutene & Polysorbate 20 sold by Seppic under the name Sepiplus 265®, Acrylates / C 10-30 Alkyl Acrylate Crosspolymer sold by Lubrizol under the names Pemulen ™ TR-1 Polymeric Emulsifier and Pemulen ™ TR-2 Polymeric Emulsifier. CONSERVATIVE AGENTS:
    Examples of preservatives that may be mentioned include benzalkonium chloride, bronopol, chlorhexidine, chlorocresol and its derivatives, ethyl alcohol, phenoxyethanol, potassium sorbate, diazolidinyl urea, benzyl alcohol, parabens, sodium benzoate or mixtures thereof.
    As the preferred preservative system, mention may be made of phenoxyethanol and pentylene glycol.
    The following examples illustrate the invention without restricting its scope EXAMPLES: EXAMPLE 1: Examples of formulas
    Example of Formulas A: Intermediate compositions containing the gas-activating agent, formulated at acidic pH
    Intermediate formulas A were prepared according to the following method:
    Step 1: At a temperature above 60 ° C, add with stirring the main gelling agent (Veegum K) to the main water phase.
    Step 2: Add the acidic buffering agents and then cool to 40 ° C
    Step 3: remaining annex. Transfer this annex phase into the main phase
    Step 4: Add the other gelling agent (s) with stirring
    Step 5: Add the other excipients of the formula with stirring
    In the formula examples below, the amounts are expressed in relation to the weight of the intermediate formula and not to the weight of the total formula.
    Example A1
    Example A2
    Example A3 (example of placebo gel)
    Examples of Formulas B: Intermediate compositions containing the gas-generating agent, formulated at basic pH
    The intermediate formulas were prepared according to the following method:
    Step 1 ': At a temperature above 60 ° C, add stirring the gelling agents to the main water phase.
    Step 2 'Optional: At the same time heat the fatty phase (containing oils, waxes, and surfactants) to a temperature above 60 ° C.
    Step 3: At a temperature above 60 ° C, emulsify by adding the fat phase to the main phase.
    Step 4: Add additives such as preservatives or ethanol at a temperature suitable for the additive.
    Step 5 ': Neutralize the mixture.
    Step 6 ': At a temperature below 40 ° C add sodium bicarbonate
    Example B1:
    Example B2:
    Example B3 (example of placebo gel)
    The table below represents the mixtures in a 1: 1 weight ratio of the intermediate compositions A and B described above. A cross at the intersection of two formulation intermediates indicates that mixing is possible and generates a foam with the desired properties.
    EXAMPLE 2 Foam Density From the examples of formulas described in Example 1, foam density measurements were made at the time of contacting intermediate formulas A and B (TO) and then when the chemical reaction generated by bringing the two
    compositions is complete. These studies have shown that the final composition is in the form of a foam having a suitable density. EXAMPLE 3 Comparative Study for Measuring Irritation Study Protocol. The study was carried out according to the current TG439 OECD protocol for the short application time (contact time RHE / product 15min). This protocol is suitable for a long application time (contact time RHE / product 18h). The objective of this study is to evaluate the tolerance of the supports of the complete and intermediate formulas on reconstructed human epidermis (RHE, Episkin model) through: the evaluation of the reduction of MTT (cell viability) the measurement of the release IL-1 alpha (irritation marker)
    The formulas tested are: an intermediate composition of acid formulation placebo (that is to say, not containing ivermectin), an intermediate composition of basic formulation: The complete formula composed of the mixture of the acid formulation placebo and the basic formulation (in a 50/50 ratio by weight), - A commercial reference in the form of a hygiene product.
    This study has shown that all formulas tested are non-irritating. EXAMPLE 4
    The ideal content of citric acid, sodium pyrophosphate and sodium dihydrogen phosphate monohydrate has been established empirically to react with 5% sodium bicarbonate. The values are expressed in percent weight / weight with respect to the weight of each of the two intermediate formulas.
    In order for the pH of the formula containing the gas activator to be optimally compatible with the skin, we added sodium citrate to create a citric acid / sodium citrate buffer.
    A portion of the citric acid / sodium citrate buffer can advantageously be substituted with disodium pyrophosphate and vice versa, as the contents cited by way of example in Table I below:
    Table III: the values are expressed in weight / weight percentage with respect to the weight of each of the two intermediate formulas
    A portion of the citric acid / sodium citrate buffer may advantageously be substituted with sodium dihydrogen phosphate monohydrate and vice versa, as the contents cited by way of example in Table IV below:
    Table IV: The values are expressed as a weight / weight percentage relative to the weight of each of the two intermediate formulas
    In a particular embodiment, it has been determined that when the amount of citric acid is greater than or equal to 1.4, the amount of foam is optimal when the disodium pyrophosphate is present in the composition according to the following equation: [C] = 2.4 [B] -2.4 [A] /0.7 When:
    [C] = content by weight of disodium pyrophosphate in intermediate composition A
    [A] = weight content of citric acid monohydrate in the intermediate composition A
    [B] = weight content of sodium bicarbonate in the intermediate composition B The equation above thus makes it possible to calculate the optimum levels between sodium bicarbonate, citric acid and sodium pyrophosphate.
    权利要求:
    Claims (26)
    [1" id="c-fr-0001]
    1. A composition containing ivermectin for rinsed topical application and in the form of a foam, comprising: - at least one intermediate composition, - at least one gas-generating agent, - at least one activating agent, the gas generating agent, and - ivermectin.
    [2" id="c-fr-0002]
    2. Composition according to claim 1, characterized in that it comprises: at least one intermediate composition A comprising said agent for activating the gas generating agent, at least one intermediate composition B comprising said gas generating agent, and ivermectin contained in at least one of said intermediate compositions A and B.
    [3" id="c-fr-0003]
    3. Composition according to the preceding claim, characterized in that the ivermectin is contained in the intermediate composition A and / or in the intermediate composition B.
    [4" id="c-fr-0004]
    4. Composition according to any one of the preceding claims, characterized in that it is self-foaming.
    [5" id="c-fr-0005]
    5. Composition according to any one of the preceding claims, characterized in that it does not comprise foaming surfactants, or that it contains such surfactants in a content of less than or equal to 2.5% by weight, preferably less than or equal to 1% by weight, relative to the weight of the total composition.
    [6" id="c-fr-0006]
    6. Composition according to any one of the preceding claims, characterized in that the gas generated from the gas generating agent is carbon dioxide (CO2).
    [7" id="c-fr-0007]
    7. Composition according to any one of the preceding claims, characterized in that the gas generating agent is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and mixtures thereof, and preferably the gas generating agent is sodium bicarbonate.
    [8" id="c-fr-0008]
    8. Composition according to any one of claims 2 to 7, characterized in that the gas generating agent is present in the intermediate composition B in an amount ranging from 1% to 10%, preferably from 2% to 8% by weight. weight, relative to the weight of the intermediate composition B.
    [9" id="c-fr-0009]
    9. Composition according to any one of claims 2 to 7, characterized in that the intermediate composition B has a basic pH, advantageously between 7 and 12.
    [10" id="c-fr-0010]
    10. Composition according to any one of the preceding claims, characterized in that the activating agent of the gas generating agent is chosen from an acid, an acid salt, a weak acid buffer solution and its base. conjugates, and mixtures of these compounds.
    [11" id="c-fr-0011]
    11. Composition according to the preceding claim, characterized in that the activating agent of the gas generating agent is selected from citric acid, tartaric acid, malic acid, lactic acid, phosphoric acid. and the pyrophosphoric acid, and the salts of these acids, and more preferably said activating agent is chosen from: a tartaric acid / tartrate salt buffer; - a citric acid / sodium citrate buffer alone; phosphoric acid, sodium phosphate, disodium pyrophosphate alone or as a mixture with a citric acid / sodium citrate buffer.
    [12" id="c-fr-0012]
    12. Composition according to the preceding claim, characterized in that the activating agent of the gas generating agent is a citric acid / sodium citrate buffer alone or in admixture with sodium phosphate and / or disodium pyrophosphate.
    [13" id="c-fr-0013]
    13. Composition according to any one of claims 2 to 12, characterized in that the gas generating agent is present in the intermediate composition A in an amount ranging from 0.001% to 95% by weight, relative to the total weight of the intermediate composition A.
    [14" id="c-fr-0014]
    14. Composition according to any one of claims 2 to 13, characterized in that the intermediate composition has an acidic pH, advantageously between 1.0 and 6.0.
    [15" id="c-fr-0015]
    15. Composition according to any one of claims 2 to 14, characterized in that the intermediate composition A is in the form of a solution, a gel, or an emulsion.
    [16" id="c-fr-0016]
    16. Composition according to any one of claims 2 to 15, characterized in that the intermediate composition B is in the form of a solution, a gel, or an emulsion.
    [17" id="c-fr-0017]
    17. Composition, characterized in that it results from the mixture of said intermediate compositions A and B according to any one of claims 2 to 16.
    [18" id="c-fr-0018]
    18. Composition according to any one of the preceding claims, characterized in that it further contains one or more active agents chosen from emollients, humectants, anti-radical agents, anti-inflammatory agents, vitamins, depigmenting agents, anti-acne agents, anti-seborrhics agents, anti-fungal agents, keratolytic agents, sunscreens, slimming agents, skin coloring agents.
    [19" id="c-fr-0019]
    19. Composition according to any one of the preceding claims, characterized in that it additionally contains one or more agents chosen from dispersing agents, solubilizing agents, stabilizing agents, preserving agents, fatty substances, thickening agents. , dyes, perfumes, surfactants, gelling agents, complexing agents, neutralizing agents, foaming emulsifiers, non-foaming emulsifiers, fillers, sequestering agents, reducing agents, odor masks, plasticizers, softening agents, moisturizing agents, pigments, clays, mineral fillers, mineral colloids, polymers, proteins, pearlescent agents, propellants, waxes, oils such as paraffins, fatty acids, solid esters of fatty alcohol or fatty acids, gums, wetting agents.
    [20" id="c-fr-0020]
    20. Cosmetic use of a composition according to any one of the preceding claims, by topical application of this composition to the skin, followed by removal of the composition by rinsing.
    [21" id="c-fr-0021]
    21. A medicament for topical application to the skin, comprising a composition as defined in any one of claims 1 to 19.
    [22" id="c-fr-0022]
    22. Composition according to any one of claims 1 to 19, for its use in the treatment of inflammatory skin diseases and in particular rosacea, acne, eczema, atopic dermatitis.
    [23" id="c-fr-0023]
    23. A single multi-compartment kit or container separately comprising at least two intermediate compositions: an intermediate composition A comprising at least one activating agent for the gas generating agent, as defined in any one of claims 2 to 19; and an intermediate composition B comprising at least one gas generating agent as defined in any one of claims 2 to 19; - Ivermectin being contained in at least one of said intermediate compositions A and B.
    [24" id="c-fr-0024]
    24. Kit or single container with multiple compartments according to claim 23, characterized in that it is designed to simultaneously release doses of the intermediate compositions A and B in a ratio by weight ranging from 2 doses of B to 1 dose of A to 2 doses of A for 1 dose of B, preferably 2 doses of B for 1 dose of A at 3 doses of A for 2 doses of B and more preferably 1 dose of A for 1 dose of B.
    [25" id="c-fr-0025]
    25. Kit or single container with multiple compartments according to one of claims 23 and 24, characterized in that it is designed to mix the intermediate compositions A and B in a ratio by weight A / B ranging from 0.5 to 2 preferably from 0.5 to 1.5, more preferably from 0.9 to 1.1, and even more preferably from 1.
    [26" id="c-fr-0026]
    26. Process for the preparation of a self-foaming composition intended for rinsed topical application containing ivermectin, in which an intermediate composition A as defined in any one of Claims 2 to 19 is mixed with an intermediate composition. B as defined in any one of claims 2 to 19, in relative proportions by weight A / B ranging from 0.5 to 2, preferably from 0.5 to 1.5 and more preferably from 1.
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    同族专利:
    公开号 | 公开日
    MX2018003551A|2018-06-18|
    EP3355869B1|2020-03-18|
    US20190046441A1|2019-02-14|
    KR20180063204A|2018-06-11|
    AU2016330788A1|2018-05-10|
    CN108289853A|2018-07-17|
    FR3041540B1|2018-10-26|
    WO2017055295A1|2017-04-06|
    JP2018530548A|2018-10-18|
    EP3355869A1|2018-08-08|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US20020061855A1|2000-06-29|2002-05-23|Parks L. Dean|Method of treating acne vulgaris using avermectin compound|
    FR2924944A1|2007-12-18|2009-06-19|Galderma Sa|Pharmaceutical composition, useful for preparing a medicament to treat and/or prevent skin disease, preferably rosacea, comprises a compound of family of avermectins or milbemycin and sulfur and its derivative and/or one of its salts|
    US20130244976A1|2010-09-24|2013-09-19|Daido Chemical Corporation|Foam-type external skin preparation|
    CN104382863A|2014-11-29|2015-03-04|郑州后羿制药有限公司|Ivermectin effervescent granules for poultries|
    US6177092B1|1998-11-10|2001-01-23|Color Access, Inc.|Self-foaming cleansing systems|
    FR2830415B1|2001-10-09|2004-07-09|Rhodia Chimie Sa|USE OF A XANTHANE GUM COMPOSITION AS A STABILIZER OF SOFT FOAMS, AND FOAMS BASED ON THIS COMPOSITION|
    FR2854074B1|2003-04-24|2007-11-23|Galderma Res & Dev|USE OF IVERMECTIN FOR THE TREATMENT OF DERMATOLOGICAL DISORDERS|EP3863716A1|2018-10-12|2021-08-18|Hovione Scientia|Macrocyclic lactone formulations, methods of their preparation and use of the formulations in treating pathologies secondary to ophthalmic parasites|
    CN109464300B|2018-12-28|2021-07-09|中山市天图精细化工有限公司|Post-foaming facial cleanser and preparation method thereof|
    US11253111B2|2019-08-22|2022-02-22|Gpcp Ip Holdings Llc|Skin care product dispensers and associated self-foaming compositions|
    KR102150494B1|2020-04-20|2020-09-02|김해성|Cosmetics composition aimed at preventing, improving, and treating demodex acne, seborrheic dermatitis and inflammation of fugitive prickle cell|
    KR102235754B1|2020-08-25|2021-04-02|김해성|Cosmetics for the prevention and improvement of skin inflammation using anthelmintic|
    法律状态:
    2016-08-16| PLFP| Fee payment|Year of fee payment: 2 |
    2017-03-31| PLSC| Search report ready|Effective date: 20170331 |
    2017-08-10| PLFP| Fee payment|Year of fee payment: 3 |
    2018-08-13| PLFP| Fee payment|Year of fee payment: 4 |
    2019-08-15| PLFP| Fee payment|Year of fee payment: 5 |
    2021-06-11| ST| Notification of lapse|Effective date: 20210506 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1559205A|FR3041540B1|2015-09-29|2015-09-29|SELF-MOUSING CLEANING COMPOSITION FOR RINSING, CONTAINING IVERMECTIN.|
    FR1559205|2015-09-29|FR1559205A| FR3041540B1|2015-09-29|2015-09-29|SELF-MOUSING CLEANING COMPOSITION FOR RINSING, CONTAINING IVERMECTIN.|
    KR1020187012155A| KR20180063204A|2015-09-29|2016-09-27|Ivermectin-containing rinse-off self-foamable cleansing composition|
    AU2016330788A| AU2016330788A1|2015-09-29|2016-09-27|Rinse-off self-foaming cleansing composition containing ivermectin|
    US15/763,631| US20190046441A1|2015-09-29|2016-09-27|Rinse-off self-foaming cleansing composition containing ivermectin|
    EP16778271.3A| EP3355869B1|2015-09-29|2016-09-27|Rinse-off self-foaming cleansing composition containing ivermectin|
    CN201680069661.7A| CN108289853A|2015-09-29|2016-09-27|Including the wash type of ivermectin is from frothing cleaning composition|
    PCT/EP2016/073012| WO2017055295A1|2015-09-29|2016-09-27|Rinse-off self-foaming cleansing composition containing ivermectin|
    JP2018516516A| JP2018530548A|2015-09-29|2016-09-27|Rinse-off self-foaming cleaning composition containing ivermectin|
    MX2018003551A| MX2018003551A|2015-09-29|2016-09-27|Rinse-off self-foaming cleansing composition containing ivermectin.|
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