pharmaceutical composition for topical administration of a moisture-activated active pharmaceutical

专利摘要:
PHARMACEUTICAL COMPOSITIONS OF NITRIC OXIDE RELEASE. The present invention generally relates to nitric oxide release pharmaceutical compositions and methods of using them.
公开号:BR112014021501B1
申请号:R112014021501-4
申请日:2013-02-28
公开日:2020-12-08
发明作者:Ryan Doxey
申请人:Novan, Inc；
IPC主号:

专利说明:

Related Order Data
[001] This application claims the benefit of Provisional Patent Application Serial No. US 61 / 610,563, filed on March 14, 2012, the description of which is incorporated herein by reference in its entirety. Field of the Invention
[002] The present invention relates in general to pharmaceutical compositions of nitric oxide release and methods of using them. Background of the Invention
[003] Various diseases or skin disorders result from inflammation with the associated release of mediators from a variety of inflammatory and resident cells. Neutrophils, mast cells and lymphocytes orchestrate an inflammatory response that results in significant release of inflammatory mediators and the creation of several free radicals. Skin diseases where inflammation is a significant component include, but are not limited to, acne and rosacea, atopic dermatitis, contact dermatitis, drug rashes, psoriasis, seborrheic dermatitis, connective tissue diseases (such as lupus and scleroderma), others autoimmune disorders such as bullous pemphigoid bullous disease or pemphigus, pigmentary diseases (such as post-inflammatory hyperpigmentation, melasma and vitiligo), hives or skin rashes, inflammation associated with skin infections such as body tingling or fungal infection of the fingernails or feet, among others. Inflammation is an important stage for most of these diseases. New compositions for treating inflammatory skin conditions and methods of making and / or using such compositions may be desirable.
[004] Similarly, many wounds, chronic or acute, can have inflammatory aspects. In inflammatory conditions and wounds, administration of a therapeutic agent should be provided without irritation or substantial exacerbation of the inflammatory condition. Also, if the active ingredient is activated by moisture, aqueous vehicles may be inappropriate. Mineral oil ointments alone can protect the moisture-activated agent from moisture before application, but they can also reduce the effectiveness of the active agent at the time of application. In this way, new compositions for the administration of active agents activated by moisture and, in some cases, suitable for use in the treatment of indications with an inflammatory aspect to the disease.
[005] The present invention relates to prior drawbacks in the art through the provision of nitric oxide release pharmaceutical compositions and methods of using them. Summary of the Invention
[006] A first aspect of the present invention comprises a pharmaceutical composition for topical administration of a moisture-activated active pharmaceutical ingredient, the composition comprising: a hydrophobic base and an amphiphilic compound.
[007] A second aspect of the present invention comprises a pharmaceutical composition for topical administration of a moisture-activated active pharmaceutical ingredient, the composition comprising: a moisture-activated active pharmaceutical ingredient present in the composition at a concentration of from about 0.1 % to about 35%; a hydrophobic polymer present in the composition at a concentration of from about 30% to about 60%; a mineral oil present in the composition in a concentration of from about 1% to about 30%; an amphiphilic compound present in the composition at a concentration of from about 1% to about 20%; a cosolvent present in the composition at a concentration of from about 1% to about 25%; and a humectant present in the composition at a concentration of from about 1% to about 25%.
[008] A further aspect of the present invention comprises a method of treating an individual's skin, the method comprising topically administering a pharmaceutical composition of the present invention in an amount effective to treat an individual's skin.
[009] The above and other aspects of the present invention will be described in more detail with respect to other modalities described here. It should be understood that the invention can be realized in different ways and should not be considered as limited to the modalities shown here. On the contrary, these modalities are provided in such a way that the present invention will be integral and complete and will fully transmit the scope of the invention to those skilled in the art. Brief Description of Drawings
[0010] The drawings that follow are provided to illustrate various aspects of the concept of the present invention and are not intended to limit the scope of the present invention unless specified here.
[0011] Figure 1 shows a flow chart of operations for preparing a pharmaceutical composition according to some embodiments of the present invention.
[0012] Figure 2 shows a graph of time of death of Pseudomonas aeruginosa for ointments with Nitricil® 2% and a topical gel with Nitricil® 2% according to some modalities of the concept of the present invention.
[0013] Figure 3 shows a graph of time of death of Pseudomonas aeruginosa for an ointment with and without Nitricil® 2% according to some modalities of the concept of the present invention.
[0014] Figure 4 shows a graph of time of death of Pseudomonas aeruginosa for an ointment with and without Nitricil® 2% according to some modalities of the concept of the present invention.
[0015] Figure 5 shows a graph of the release profiles of two types of Nitricil® ointments, NVN1 and NVN4, according to some modalities of the present invention under physiological conditions.
[0016] Figure 6 shows a process flow chart for the manufacture on a 5.5 kg scale of an ointment according to some modalities of the present invention.
[0017] Figure 7 shows a graph of the effect of nitric oxide release from Nitricil® NVN1 ointment on skin reepithelization.
[0018] Figure 8 shows a graph of IL-8 expression levels in wound tissue measured using qPCT in wounds treated with Nitricil® NVN1 0.1% and 0.5%, vehicle and Tegaderm.
[0019] Figure 9 shows a graph of the white cell infiltrate assayed by the presence and quantity of mixed subepithelial leukocytic infiltrates. Detailed Description of the Invention
[0020] The present invention will now be described more fully hereinafter. The present invention can, however, be embodied in different forms and should not be considered as limited to the modalities shown here. Instead, these modalities are provided in such a way that the present description will be integral and complete and will fully convey the scope of the invention to those skilled in the art.
[0021] The terminology used in the specification of the present invention is for the purpose of describing particular modalities only and is not intended to limit the invention. As used in the specification and the appended claims, the singular forms "one", "one" and "o", "a" are intended to include plural forms as well, unless the context clearly indicates otherwise.
[0022] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as is generally understood by a person skilled in the art to which the present invention belongs. It will also be understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the present application and relevant technique and should not be interpreted in an idealized or overly formal sense unless that expressly defined here then. The terminology used in the report described in the present invention is for the purpose of describing particular modalities only and is not intended to limit the invention. All publications, patent applications, patents and other references mentioned here are incorporated by reference in their entirety. . In the event of conflicting terminology, this application will prevail.
[0023] Also as used herein, "and / or" refers to and comprises any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").
[0024] Unless the context indicates otherwise, it is specifically intended that the various features of the invention described here can be used in any combination. In addition, the present invention also understands that in some embodiments of the invention any feature or combination of features shown here can be excluded or omitted. To illustrate, if the report states that a complex consists of components A, B and C, it is specifically intended that any of A, B or C, or a combination thereof, can be omitted and rejected.
[0025] As used herein, the transitional expression "consisting essentially of" (and grammatical variants) is also interpreted as comprising the materials or steps mentioned "and those that do not materially affect the basic characteristic (s) and new (s) "of the claimed invention. See, In re Herz, 537 F.2d 549, 55152, 190 U.S.P.Q. 461, 463 (CCPA 1976) (emphasis on the original); see also MPEP § 2111.03. Accordingly, the term "consisting essentially of" as used here should not be interpreted as equivalent to "comprising".
[0026] The term "about", as used herein when referring to a measurable value such as an amount or concentration of a compound, dose, time, temperature and the like, is intended to comprise variations of ± 20%, ± 10%, ± 5%, ± 1%, ± 0.5% or even ± 0.1% of the specified quantity. A range provided here for a measurable value can include any other range and / or individual value in it.
[0027] The present invention provides pharmaceutical compositions that can be administered topically. A pharmaceutical composition of the present invention can comprise, essentially consist of or consist of a hydrophobic base and an amphiphilic compound. In particular embodiments of the present invention, a pharmaceutical composition further comprises a moisture-activated active pharmaceutical ingredient. A pharmaceutical composition of the present invention may comprise an ointment, ointment, cream and / or the like.
[0028] "Hydrophobic base" as used herein refers to a natural and / or synthetic fat, wax, oil and / or similar. Any suitable hydrophobic base can be used in a pharmaceutical composition of the present invention. In certain embodiments of the present invention, a pharmaceutical composition comprises two or more hydrophobic bases, such as, but not limited to, 2, 3, 4, 5 or more hydrophobic bases. Exemplary hydrophobic bases include, but are not limited to, branched and unbranched hydrocarbons, branched or unbranched hydrocarbon waxes, petroleum jelly, hydrocarbon gel, liquid paraffin, white petrolatum, petrolatum, microcrystalline wax, andelila wax, carnauba wax, lanolin (wool wax), wool wax alcohol, esparto grass wax, cork wax, guaruma wax, rice bran wax, sugar cane wax, berry wax, ouricuri wax, wax soybean, jojoba oil, uropigial fat, ceresin, paraffin waxes, micro waxes, plant oils, animal oils, carnauba wax, beeswax, cocoa butter, hard fat, mineral oil, vegetable oil, avocado oil , borage oil, canola oil, castor oil, chamomile oil, coconut oil, corn oil, cottonseed oil, rapeseed oil, evening primrose oil, safflower oil, sunflower oil , soybean oil, sweet almond, palm oil, seed oil palm, Arctic limpet seed oil, sesame oil, borago officinalis seed oil, rapeseed oil, brassica campestris oleifera, brevoortia oil, marrow oil, cistus ladaniferus rockrose oil, Guinean palm oil, almond oil, pine oil, olive oil, peanut oil, wheat germ oil, grape seed oil, thistle oil, lard, tallow, palm olein, ilipê butter, shea butter, butter cocoa, kokum butter, salt butter, lecithin, Japanese wax lanolin, partially hydrogenated vegetable oils, hydrophobic polymers and any combination thereof.
[0029] In some embodiments of the present invention, a hydrophobic base can comprise a hydrophobic polymer. Any suitable hydrophobic polymer can be used in a pharmaceutical composition of the present invention. Exemplary hydrophobic polymers include, but are not limited to, hydrocarbon polymers and / or copolymers, aromatic polyurethanes, silicone rubber, polysiloxanes, polycaprolactone, polycarbonate, polyvinyl chloride, polyethylene, poly-L-lactide, poly-DL-glycolide, polyetheretherketone (PEEK), polyamide, polyimide and polyvinyl acetate. In particular embodiments of the present invention, a pharmaceutical composition of the present invention comprises one or more hydrocarbon polymers and / or copolymers. In certain embodiments, a pharmaceutical composition of the present invention comprises one or more hydrocarbon polymers and / or copolymers such as, but not limited to, those commercially available from Calumet Specialty Products Partners of Indianapolis, IN under the trademark Versagel® and / or those commercially available from Croda International Plc of East Yorkshire, United Kingdom under the trademark Crodabase SQ.
[0030] In some embodiments of the present invention, a hydrophobic polymer can act as a thickening and / or gelling agent in a pharmaceutical composition. Specifically, a hydrophobic polymer can act as a viscoelastic substance and can retain the composition at the application site, along with any compounds dispersed therein (for example, an active pharmaceutical ingredient, etc.). A hydrophobic polymer can be present in a pharmaceutical composition of the present invention in a concentration of from about 30% to about 60% by weight or any range therein, such as, but not limited to, from about from 35% to about 55% by weight or about 40% to about 50% by weight.
[0031] In particular embodiments of the present invention, a hydrophobic base comprises one or more plant and / or mineral oils. Any suitable oil can be used in the pharmaceutical compositions of the present invention. Exemplary mineral oils include, but are not limited to, light mineral oil, white mineral oil, paraffinic oils, naphthenic oils, aromatic oils and any combination thereof. An oil (for example, plant and / or mineral oil) can be present in a pharmaceutical composition of the present invention in a concentration of from about 1% to about 30% by weight or any range therein, such as , but not limited to, from about 5% to about 20% by weight or about 5% to about 15% by weight.
[0032] In some embodiments of the present invention, a hydrophobic base such as, but not limited to, an oil (e.g., a plant and / or mineral oil), can be used to adjust the viscosity and / or spreadability pharmaceutical composition. For example, a low viscosity hydrophobic base, such as a light mineral, can be used to fine tune (i.e., reduce viscosity) a pharmaceutical composition, such as a pharmaceutical composition comprising a high viscosity hydrophobic base. This can allow the application of a pharmaceutical composition of the present invention over a wide area, and can serve to maintain any compounds dispersed therein (for example, an active pharmaceutical ingredient, etc.) at the application site. In certain embodiments of the present invention, a hydrophobic base comprises a mineral oil and a hydrophobic polymer.
[0033] A hydrophobic base can be present in a pharmaceutical composition of the present invention in a concentration of from about 35% to about 90% by weight or any range in the same as, but not limited to, from from about 40% to about 80% by weight or about 50% to about 70% by weight. In certain embodiments of the present invention, a hydrophobic base is present in a pharmaceutical composition of the present invention in a concentration of from about 45% to about 55% by weight.
[0034] "Amphiphilic compound" as used herein refers to a compound comprising hydrophilic and hydrophobic properties. An amphiphilic compound may comprise two or more compounds, each of which may provide the hydrophilic and / or hydrophobic property. In some embodiments, the amphiphilic compound comprises a compound having hydrophilic and hydrophobic properties. In particular embodiments of the present invention, an amphiphilic compound can absorb moisture without substantially absorbing vaporous moisture. Moisture absorption may allow the activation of a moisture-activated active pharmaceutical ingredient in a pharmaceutical composition of the present invention upon contact with moisture, but not upon contact with vaporous moisture. "Absorbing substantially" (and its grammatical variations) as used herein means that the amount of vaporous moisture absorbed is more than 2% by weight of an amphiphile compound. In this way, an amphiphilic compound of the present invention absorbs vaporous moisture in less than about 2%, 1.5%, 1%, 0.5%, 0.25% by weight of an amphiphilic compound or any range thereof. In some embodiments of the present invention, an amphiphilic compound can prevent and / or minimize a pharmaceutical composition of the present invention from substantially absorbing vaporous moisture, thus moisture can be present in a pharmaceutical composition of the present invention in less than about 2% .
[0035] "Humidity" as used herein refers to a liquid, such as, but not limited to, a body fluid such as, but not limited to, blood, sweat, mucus, saliva, sebum, tears, exudate and / or vaginal secretions; Water; deoxygenated water; saline solutions; acidic or alkaline buffer solutions; and / or any combination thereof. "Vapor moisture" as used herein refers to moisture in the gas phase. For example, vaporous moisture includes, but is not limited to, water vapor. Thus, in some embodiments of the present invention, an amphiphilic compound can prevent and / or minimize the absorption of water vapor, in this way, when the active pharmaceutical ingredient (API) (Active Pharmaceutical Ingredient) comprises a moisture activated pharmaceutical ingredient, the API in a pharmaceutical composition of the present invention is not activated by vaporous moisture (for example, water vapor). In contrast, an amphiphilic compound can absorb and / or allow moisture (e.g., water, a body fluid, etc.) to be absorbed when a pharmaceutical composition of the present invention is contacted with moisture, thereby activating the API when the API comprises an active pharmaceutical ingredient activated by moisture.
[0036] In particular embodiments of the present invention, an amphiphilic compound absorbs water vapor by less than about 2% by weight or about 1% by weight. This can minimize and / or prevent a pharmaceutical composition of the present invention from absorbing water vapor and then water can be present in a pharmaceutical composition of the present invention in less than about 2% by weight or about 1% by weight of water. . In certain embodiments of the present invention, an amphiphilic compound absorbs less than about 0.5% by weight of water vapor and then a pharmaceutical composition of the present invention can comprise less than about 0.5% by weight of water.
[0037] An amphiphilic compound can have a hydrophilic-lipophilic (HLB) balance value (Hydrophilic-Lipophilic Balance) of 12 to 20 or any range between them, such as, but not limited to, 15 to 20 or 18 to 20. In certain embodiments of the present invention, an amphiphilic compound comprises an HLB value of 19.
[0038] Exemplary amphiphilic compounds include, but are not limited to, fatty acid esters. One or more fatty acid esters can be present in the pharmaceutical compositions of the present invention, such as 2, 3, 4 or more fatty acid esters. Exemplary fatty acid esters include, but are not limited to, C6-C22 alkyl and / or alkenyl fatty acid esters such as methyl laurate, ethyl laurate, ethyl myristate, ethyl palmitate, ethyl linoleate, ethyl isobutylate , isopropyl laurate, isopropyl myristate, isopropyl palmitate, oleyl myristate, oleyl stearate and oleyl oleate; ether-esters such as fatty acid esters of ethoxylated fatty alcohols; polyhydric alcohol esters such as ethylene glycol mono- and di-fatty esters, diethylene glycol mono- and di-fatty esters; polyethylene glycol (6-2000) fatty acid mono- and / or diesters such as PEG-6-laurate, PEG-6-stearate, PEG-8-dilaurate, PEG-8-distearate, etc; polyethylene glycol glycerol fatty acid esters such as glyceryl PEG-20-laurate, glyceryl PEG-20-stearate and glyceryl PEG-20-oleate; propylene glycol mono- and di-fatty acid esters; 2000 polypropylene glycol monooleate; 2000 polypropylene glycol monostearate; ethoxylated propylene glycol monostearate; esters of glyceryl mono- and di-fatty acid; polyglycerol fatty acid esters such as polyglyceryl laurate-10, etc .; ethoxylated glyceryl monostearate; 1,3-butylene glycol monostearate; 1,3-butylene glycol distearate; polyoxyethylene glycol fatty acid ester; sorbitan fatty acid esters including sorbitan trioleate and sorbitan monolaurate; polyethylene glycol sorbitan fatty acid esters such as PEG-6 sorbitan monooleate; polyoxyethylene sorbitan fatty acid esters including polyoxyethylene (20) sorbitan monolaurate; sucrose fatty acid esters such as sucrose monopalmitate and sucrose monostearate; wax esters such as beeswax, spermaceti, myristyl myristate; stearyl stearate and arachidyl beenate; polyethylene glycol alkyl ethers such as PEG-10 oleyl ether or PEG-9 cetyl ether; polyethylene glycol alkyl phenols such as nonyl phenol PEG-10-100; polyoxyethylene-polyoxypropylene block copolymers such as poloxamer 188; sterol esters such as cholesterol fatty acid esters and any combination thereof.
[0039] A fatty acid ester can comprise a polyethylene glycol glyceride (PEG). The polyethylene glycol portion of a PEG glyceride may provide the hydrophilic property of an amphiphilic compound and may include, but is not limited to, PEG 5-1000 or any band therein and any combination thereof. The glyceride portion of a PEG glyceride may provide the hydrophilic property of an amphiphilic compound and may include, but is not limited to, a natural and / or hydrogenated oil such as, but not limited to, castor oil, hydrogenated castor oil , vitamin A, vitamin D, vitamin E, vitamin K, a plant oil (e.g., corn oil, olive oil, peanut oil, palm seed oil, apricot seed oil, almond oil, etc. ) and any combination thereof. Exemplary polyethylene glycol (PEG) glycerides include, but are not limited to, PEG-20 castor oil, PEG-20 hydrogenated castor oil, PEG-20 corn glycerides, PEG-20 almond glycerides; PEG-23 trioleate, PEG-40 palm seed oil, PEG-8 caprylic / capric glycerides, PEG-6 caprylic / capric glycerides, macrogol-32 lauroyl glyceride, macrogol stearoyl glyceride, PEG-1000 tocopheryl succinate and any combination thereof. In some embodiments of the present invention, a fatty acid ester comprises a PEG 5-30 (i.e., PEG 5, 6, 7, 8, 9, 10, etc.) and a caprylic / capric glyceride. In particular embodiments of the present invention, a pharmaceutical composition comprises a capric / capric PEG-5-glyceride, a capric / capric PEG-6-glyceride, a capric / capric PEG-7-glyceride and / or caprylic / PEG-8-glyceride / capric. In certain embodiments of the present invention, a pharmaceutical composition comprises one or more fatty acid esters such as, but not limited to, those commercially available from Sasol of Hamburg, Germany under the trademark SOFTIGEN®.
[0040] An amphiphilic compound can be present in a pharmaceutical composition of the present invention in a concentration of from about 1% to about 30% by weight or any range thereof such as, but not limited to, from about from 2% to about 20% by weight or about 5% to about 15% by weight. In certain embodiments of the present invention, an amphiphilic compound is present in a pharmaceutical composition of the present invention in a concentration of about 10% by weight.
[0041] A pharmaceutical composition of the present invention can further comprise one or more excipients. Excipients for use in pharmaceutical compositions are well known in the art and examples can be found in the Handbook of Pharmaceutical Excipients (Rowe, R.C. et al., APhA Publications; 5th ed., 2005). Excipient classes can include, but are not limited to, an emollient, a humectant, a co-solvent, a pH modifier, a water repellant, a defoamer, a surfactant, a solubilizer, a wetting agent, a penetration enhancer, an antioxidant and / or solvent. Excipients can be present in a pharmaceutical composition of the present invention in any suitable concentration.
[0042] In particular embodiments of the present invention, a pharmaceutical composition can further comprise a co-solvent. A co-solvent can be present in a pharmaceutical composition of the present invention in a concentration of from about 1% to about 30% by weight or any range therein such as, but not limited to, from about 2% to about 20% by weight or about 5% to about 15% by weight. In certain embodiments of the present invention, a co-solvent is present in a pharmaceutical composition of the present invention in a concentration of from about 10% to about 15% by weight.
[0043] Exemplary co-solvents include, but are not limited to, a fatty acid ester, propylene glycol, glycerol, polyethylene glycol. In some embodiments of the present invention, a co-solvent may comprise a neutral oil. In certain embodiments of the present invention, a co-solvent comprises a caprylic and / or capric triglyceride such as, but not limited to, those commercially available from Sasol of Hamburg, Germany under the trademark MIGLYOL®.
[0044] The pharmaceutical compositions of the present invention can comprise a humectant. Any suitable humectant or combination of humectants can be used. A humectant can be present in a pharmaceutical composition of the present invention in a concentration of from about 1% to about 25% by weight or any range therein such as, but not limited to, from about 2% about 20% by weight or about 5% to about 15% by weight. In certain embodiments of the present invention, a humectant is present in a pharmaceutical composition of the present invention in a concentration of from about 10% to about 15% by weight.
Exemplary humectants include, but are not limited to, glycols, such as polyhydric alcohol, diethylene glycol monoethyl ether and methoxypolyethylene glycol; glycerols such as propylene glycol, glycerol, isopropanol, ethanol, ethylene glycol, polyethylene glycol, ethoxydiglycol or mixtures thereof; sugar polyols, such as sorbitol, xylitol and maltitol; polyols such as polydextroses; dimethyl isosorbide; quilaia; urea; and any combination thereof. In particular embodiments of the present invention, a humectant comprises an alkylene glycol, such as hexylene glycol, butylene glycol, pentylene glycol and any combination thereof.
[0046] A pharmaceutical composition of the present invention can comprise an active pharmaceutical ingredient (API). The API can be present in a pharmaceutical composition of the present invention in any suitable concentration. In particular embodiments of the present invention, the API comprises a moisture-activated active pharmaceutical ingredient, such as, but not limited to, a nitric oxide releasing compound and / or a water-soluble API. In some embodiments of the present invention, a pharmaceutical composition of the present invention can provide a controlled and / or sustained release of the API by controlling the amount of moisture absorbed by the pharmaceutical composition. In particular embodiments of the present invention, a moisture-activated API is present in the composition at a concentration of from about 0.1% to about 70% and weight or any range therein such as, but not limited to, from to from about 1% to about 50% by weight or from about 2% to about 30% by weight.
[0047] In order to avoid a sandy feeling in a pharmaceutical composition of the present invention, the maximum particle size for the API can be less than about 100 pm and, in some embodiments, less than about 20 pm, and in additional modalities, less than about 10 pm.
[0048] Any suitable active pharmaceutical ingredient (API) or combinations of APIs can be included in the compositions according to modalities of the invention. Examples of APIs include, but are not limited to, antimicrobial agents, anti-acne agents, anti-inflammatory agents, analgesic agents, anesthetic agents, antihistamine agents, antiseptic agents, immunosuppressants, anti-hemorrhagic agents, vasodilators, wound healing agents , anti-film agents and mixtures thereof.
[0049] Examples of antimicrobial agents include, but are not limited to, penicillins and related drugs, carbapenemas, cephalosporins and related drugs, erythromycin, aminoglycosides, bacitracin, gramicidin, mupirocin, chloramphenicol, thiamphenicol, clindinicide, macridide, sodium novobiocin, polymyxins, rifamycins, spectinomycosine, tetracyclines, vanomycin, teicoplanin, streptogramins, antifolate agents including sulfonamides, trimethoprim and their combinations and pyrimethamines, synthetic antibacterials including nitrofurans, methenamine mandolin and fluoride, methenamine, quinolone, quinolone, quinolone , pyrazinamide, para-aminosalicylic acid (PAS), cycloserine, capreomycin, ethionamide, protionamide, thiacetazone, viomycin, eveminomycin, glycopeptide, glyclyclicline, ketolides, oxazolidinone; imipenen, amikacin, netylmycin, fosfomycin, gentamicin, ceftriaxone, ziracin, linezolid, sinercide, aztreonam and metronidazole, epiroprim, sanfetrinem sodium, biapenem, dinemicin, cefluprenam, cefoselem, cefluprenem, cefoselem, cefoselem, cefoselem, cefoselem, cefoselem, cefoselem Sulopenem, ritipenam acoxil, Ciclothialidina, micacocidina A, carumonam, Cefozopram and Cefetamete pivoxil.
[0050] Examples of topical anti-acne agents include, but are not limited to, adapalene, azelaic acid, benzoyl peroxide, clindamycin and clindamycin phosphate, doxycycline, erythromycin, keratolytics such as salicylic acid and retinoic acid (Retin-A "), norgestimate, organic peroxides, retinoids such as isotretinoin and tretinoin, sodium sulfacetamide and tazarotene Particular anti-acne agents include adapalene, azelaic acid, benzoyl peroxide, clindamycin (for example, clindamycin phosphate), doxycycline (for example, dexicyclohydrate) erythromycin, isotretinoin, norgestimate, sodium sulfacetamide, tazarotene, etretinate and acetretine.
Examples of antihistamine agents include, but are not limited to, diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate, isotypendyl hydrochloride, triphenamine hydrochloride, promethazine hydrochloride, hydrochloride and hydrochloride similar. Examples of local anesthetic agents include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, 2- (di-ethylamino) hydrochloride ethyl p-butylaminobenzoic acid ester, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride , oxyprocaine hydrochloride, mepivacaine, cocaine hydrochloride, piperococaine hydrochloride, diclonin and diclonine hydrochloride.
[0052] Examples of antiseptic agents include, but are not limited to, alcohols, quaternary ammonium compounds, boric acid, chlorhexidine and chlorhexidine derivatives, iodine, phenols, terpenes, bactericides, disinfectants including timerossal, phenol, thymol, benzalkonium chloride , benzethonium chloride, chlorhexidine, povidone iodine, cetylpyridinium chloride, eugenol and trimethylammonium bromide.
[0053] Examples of anti-inflammatory agents include, but are not limited to, non-steroidal anti-inflammatory agents (NSAIDs); propionic acid derivatives such as ibuprofen and naproxen; acetic acid derivatives such as indomethacin; enolic acid derivatives such as meloxicam, acetaminophen; methyl salicylate; monoglycol salicylate; aspirin; mefenamic acid; flufenamic acid; indomethacin; diclofenac; alclofenac; diclofenac sodium; ibuprofen; ketoprofen; naproxen; pranoprofen; fenenoprofen; sulindac; fenclofenac; clidanac; flurbiprofen; fentiazac; bufexamaco; piroxicam; phenylbutazone; oxyphenbutazone; clofezone; pentazocine; mepirizole; thiaramide hydrochloride; steroids such as clobetasol propionate, betamethasone dipropionate, halbetasol propionate, diflorasone diacetate, fluocinonide, halcinonide, amcinonide, dexosimethasone, triamcinolone acetonide, mometasone furoate, fluticasone propionate, fluticasone propionate, acetonate dihydrate , fluocinolone acetonia, hydrocortisone valerate, prednicarbate, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone and others known in the art, prednisolone, dexamethasone, fluocinolone acetonide, hydrocortisone acetate, prednisolone acetate, betamethasone acetate, betamethasone, betamethasone acetate flumetasone, fluorometolone, beclomethasone dipropionate, fluocinonide, topical corticosteroids and may be one of the less potent corticosteroids such as hydrocortisone, hydrocortisone-21-monoesters (eg hydrocortisone-21-acetate, hydrocortisone-21-butyrate, hydrocortisone own rionate, hydrocortisone-21-valerate, etc.), hydrocortisone-17-21-diesters (e.g. hydrocortisone-17-21-diacetate, hydrocortosine-17-acetate-21-butyrate, hydrocortisone-17-21-dibutyrate, etc.) , alclomethasone, dexamethasone, flumetasone, prednisolone or methylprednisolone, or may be a higher potency corticosteroid such as clobetasol propionate, betamethasone benzoate, betamethasone dipropionate, diphlorasone diacetate, fluocinonide, mometasone furoate, acetone and acetone.
[0054] Examples of analgesic agents include, but are not limited to, alfentanil, benzocaine, buprenorphine, butorfanol, butambem, capsaicin, clonidine, codeine, dibucaine, enkephalin, fentanyl, hydrocodone, hydromorphone, indomethacin, lidocaine, levorphanol, meperidine, meperidine, meperidine, meperidine, meperidine , morphine, nicomorphine, opium, oxybutocaine, oxycodone, oxymorphone, pentazocine, pramoxin, proparacaine, propoxyphene, proximetacaine, sufentalin, tetracaine and tramadol.
[0055] Examples of anesthetic agents include, but are not limited to, alcohols such as phenol; benzyl benzoate; calamine; chloroxylenol; diclonin; ketamine; menthol; pramoxin; resorcinol; troclosan; procaine drugs such as benzocaine, bupivacaine, chloroprocaine; cinchocaine; cocaine; dexivacaine; diamocaine; dibucaine; ethidocaine; hexylcaine; levobupivacaine; lidocaine; mepivacaine; oxetazaine; prilocaine; procaine; proparacaine; propoxicaine; pyrrocaine; risocaine; rhodocaine; ropivacaine; tetracaine; and derivatives, such as pharmaceutically acceptable salts and esters including bupivacaine HCl, chloroprocaine HCl, diamocaine cyclamate, dibucaine HCl, diclonin HCl, ethidocaine HCl, levobupivacaine HCl, lidocaine HCl, mepivacaine HCl, prokacaine HCl , Prilocaine HCl, procaine HCl, proparacaine HCl, propoxicaine HCl, ropivacaine HCl and tetracaine HCl.
[0056] Examples of anti-hemorrhagic agents include, but are not limited to, thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, sodium carbaxochrome chrome, rutin and hesperidin.
[0057] In some embodiments of the present invention, an active pharmaceutical ingredient (API) comprises, consists essentially of, or consists of a compound that releases nitric oxide (NO). Any suitable NO release compound can be used in a pharmaceutical composition of the present invention. In some embodiments of the present invention, the NO release compound comprises a small molecule compound that includes a NO donor group. "Small molecule compound" as used herein refers to a compound having a molecular weight of less than 500 daltons and includes small organic and / or inorganic molecules. In some embodiments of the present invention, the NO release compound comprises a macromolecule that includes a NO donor group. A "macromolecule" as used herein refers to a compound that has a molecular weight of 500 daltons or more. Any macromolecule can be used, including cross-linked or non-cross-linked polymers, dendrimers, metallic compounds, organometallic compounds, inorganic-based compounds and other molecule bases. In some embodiments, the macromolecule has a nominal diameter ranging from about 0.1 nm to about 100 pm and can comprise the aggregation of two or more macromolecules, where the structure of the macromolecule is modified further with a donor group. AT THE.
[0058] In certain embodiments of the present invention, the NO donor of a NO release compound releases nitric oxide upon exposure to an external condition, such as light, heat, water, acid, base and / or the like. For example, in some embodiments of the present invention, the NO-releasing compound comprises a diazeniodiolate functional group as a NO donor. The diazeniodiolate functional group can produce nitric oxide under certain conditions, such as exposure to water. As another example, in some embodiments of the present invention, a NO-releasing compound may comprise, but are not limited to, a nitrosothiol functional group such as the NO donor. The NO donor can produce nitric oxide under certain conditions, such as when exposed to light. Examples of other NO donor groups include, but are not limited to, nitrosamine, hydroxyl nitrosamine, hydroxyl amine and hydroxyurea. Any suitable combination of NO donors and / or NO release compounds can be used in a pharmaceutical composition of the present invention. . In addition, the NO donor can be incorporated into and / or over a small molecule and / or macromolecule through covalent and / or non-covalent interactions.
[0059] In some embodiments of the present invention, NO release compounds may be in the form of NO release particles, such as those described in US Publication No. 2009/0214618, the description of which is incorporated herein by reference in its entirety. Such particles can be prepared using methods described therein.
[0060] The NO release compound can release nitric oxide through any suitable mechanism, including via reaction with water and / or thermal degradation. Examples of functional NO-releasing groups that can be included in the NO-releasing compound include, but are not limited to, diazeniodiolate, nitrosamine, hydroxyl nitrosamine, nitrosothiol, hydroxyl amine, hydroxyurea and nitrosyl metal complexes. Other functional NO-releasing groups that are capable of releasing nitric oxide in a therapeutic manner, such as acidified nitrite, can also be used.
[0061] The NO-releasing compound may be a small molecule compound, an oligomer and / or a polymer and may be in any suitable physical form such as, but not limited to, a particle, coating, film, liquid, solution and the like. In some embodiments, the nitric oxide releasing compound comprises polysiloxane macromolecules functionalized with diazeniodiolate as described above. Other non-limiting examples of NO release compounds include NO release zeolite as described in United States Patent Publication No. 2006/0269620 or 2010/0331968; organic metal structures (MOFs) (Metal Organic Frameworks) for NO release as described in United States Patent Application Publication No. 2010/0239512 or 2011/0052650; multi-donor NO release compounds as described in U.S. Provisional Patent Application Serial No. 61 / 526,918 entitled "Tunable Nitric Oxide-Releasing Macromolecules Having Multiple Nitric Oxide Donor Structures"; dendrimers or NO release metal structures as described in U.S. Publication No. 2009/0214618; nitric oxide release coatings as described in U.S. Publication No. 2011/0086234; and compounds as described in U.S. Publication No. 2010/0098733. The descriptions of each of the references in this paragraph are hereby incorporated by reference in their entirety. In addition, NO release macromolecules may be manufactured as described in International Patent Application No.PCT / US2012 / 022048 entitled "Temperature Controlled Sol- Gel Co-Condensation "deposited on January 20, 2012, the description of which is incorporated herein by way of reference in its entirety.
[0062] As an example, in some embodiments of the invention, NO release particles include precipitated NO charged silica. The NO-charged precipitated silica can be formed from silane monomers modified with a nitric oxide donor in a co-condensed siloxane network. In one embodiment of the invention, the nitric oxide donor is an N-diazeniodiolate.
[0063] In some embodiments, the nitric oxide donor can be formed from an aminoalkoxysilane using a preload method, and the co-condensed siloxane network can be synthesized from the condensation of a silane mixture that includes a alkoxysilane and aminoalkoxysilane to form a modified co-condensed siloxane network with nitric oxide donor. As used herein, the "preload method" means that the aminoalkoxysilane is "pre-treated" or "preloaded" with nitric oxide prior to co-condensation with alkoxysilane. In some embodiments, nitric oxide preload can be performed using chemical methods. In another embodiment, the "preload" method can be used to create more densely functionalized co-condensed siloxane networks and materials with NO donors.
[0064] The co-condensed siloxane network can be uniformly sized silica particles, a collection of silica particles with a variety of sizes, amorphous silica, a smoked silica, a nanocrystalline silica, ceramic silica, colloidal silica, a silica coating, a silica film, organically modified silica, mesoporous silica, silica gel, bioactive glass or any other suitable form or state of silica.
[0065] In some embodiments, the alkoxysilane is tetraalkoxysilane having the formula Si (OR) 4, where R is an alkyl group. The R groups can be the same or different. In some embodiments, tetraalkoxysilane is selected as tetramethyl orthosilicate (TMOS) or tetraethyl orthosilicate (TEOS). In some embodiments, the aminoalkoxysilane has the formula: R "- (NH-R ') n- Si (OR) 3, where R is alkyl, R' is alkylene, branched alkylene or aralkylene, n is 1 or 2, and R "is selected from the group consisting of alkyl, cycloalkyl, aryl and alkylamine.
[0066] In some embodiments, the aminoalkoxysilane can be selected from N- (6-aminoexyl) aminopropyltrimethoxysilane (AHAP3); N- (2-aminoethyl) -3-aminopropyltrimethoxysilane (AEAP3); (3-trimethoxysilylpropyl) di-ethylenetriamine (DET3); (aminoethylaminomethyl) phenethyltrimethoxysilane (AEMP3); [3- (methylamino) propyl] trimethoxysilane (MAP3); N-butylamino-propyltrimethoxysilane (n-BAP-3); t-butylamino-propyltrimethoxysilane (t-BAP3); N-ethylaminoisobutyltrimethoxysilane (EAiB3); N-phenylamino-propyltrimethoxysilane (PAP3); and N-cyclohexylaminopropyltrimethoxysilane (cHAP3).
[0067] In some embodiments, the aminoalkoxysilane has the formula: NH [R'-Si (OR) 3] 2, where R is alkyl and R 'is alkylene. In some embodiments, the aminoalkoxysilane can be selected from bis (3-triethoxysilylpropyl) amine, bis- [3- (trimethoxysilyl) propyl] amine and bis- [(3-trimethoxysilyl) propyl] ethylenediamine.
[0068] In some embodiments, as described above, the aminoalkoxysilane is preloaded to release NO and the amino group is replaced by a diazeniodiolate. Thus, in some modalities, the aminoalkoxysilane has the formula: R "- N (NONO-X +) - R'-Si (OR) 3, where R is alkyl, R 'is alkylene or aralkylene, R" is alkyl or alkylamine and X + is a cation selected from the group consisting of Na +, K + and Li +.
[0069] The composition of the siloxane network (for example, quantity or chemical composition of the aminoalkoxysilane) and the charge conditions for nitric oxide (for example, the solvent and base) can be varied to optimize the quantity and duration of release of nitric oxide. Thus, in some embodiments, the composition of the silica particles can be modified to regulate the NO release half-life of silica particles.
[0070] In another embodiment, the amino group of aminoalkoxysilane is replaced with a diazeniodiolate and the aminoalkoxysilane having the formula of R "-N (NONO-X +) - R'-Si (OR) 3, where: R is alkyl, R 'is alkylene or aralkylene, R "is alkyl or alkylamine and X + is a cation selected from the group consisting of Na + and K +.
[0071] In some embodiments of the invention, the particle size of the NO release particles is in the range of 20 nm and 10 pm. The particle size can be chosen especially to minimize or prevent toxicity and penetration through the epidermis (or compromised dermis) and into the blood vessels. In particular embodiments, the particle size is distributed around an average particle size of less than about 10 pm to allow the particle size to enter a follicle. In additional embodiments, the particle size is distributed around an average particle size of less than about 8 pm. In other embodiments, the particle size is distributed around a particle size greater than about 10 pm to prevent the particle from entering the follicle.
[0072] In additional embodiments, a mixture of particles with average particle sizes distributed around two or more average particle sizes can be provided. For example, a mixture of particles having a particle size distributed around an average particle size of less than about 10 pm to allow the particle to enter a follicle can be mixed with particles having a particle size distributed around an average particle size of more than about 10 pm to prevent the particle from entering the follicle. The particles may have the same nitric oxide release profiles or different nitric oxide release profiles. For example, smaller particles may have a release profile made especially to increase their ability to moderate sebum production and / or abnormal keratinization and the larger particles may have a release profile specially designed to increase their ability to kill bacteria, promote wound healing, reduce scarring and other desirable therapeutic effects provided by nitric oxide. Other combinations and multiple combinations could also be provided.
[0073] A pharmaceutical composition of the present invention can be prepared by any suitable method. However, in some embodiments, a composition of the present invention can be manufactured using a method described in U.S. Provisional Patent Applications Nos. Series 61 / 504,626 and 61 / 610,179 (Attorney Document No. 9729-26PR2), both entitled "Methods of Manufacturing Topical Compositions and Apparatus for Same", filed on July 5, 2011 and March 13, 2012, respectively, which are incorporated herein by reference in their entirety.
[0074] In certain embodiments of the present invention, a method of preparing a pharmaceutical composition of the present invention comprises homogenizing a first excipient composition comprising a hydrophobic base, an amphiphilic compound and optionally a co-solvent. A mechanical suspended stirring device can be used to mix a first excipient composition until the desired uniformity and / or consistency is achieved. The homogenization rate and / or rate can be constant, varied, increased and / or decreased to obtain the desired uniformity and / or consistency. In particular embodiments of the present invention, a first excipient composition of the present invention is mixed until the composition is visually uniform. In some embodiments of the present invention, the method further comprises separately homogenizing a second excipient composition comprising a hydrophobic base, an active pharmaceutical ingredient and optionally a humectant. The first excipient composition and the second excipient composition can then be combined to form a pharmaceutical composition of the present invention.
[0075] Figure 1 is a flow chart of operations for an exemplary embodiment of the present invention. As seen in Figure 1, operations begin by distributing raw materials for use in the process (block 100). Then the temperature of the mixing vessels is adjusted (block 110). A hydrophobic base and an amphiphilic compound are added to a container (block 120) optionally with a co-solvent (block 125) to form a first excipient composition. The homogenization parameters (for example, homogenization rate, time, etc.) are then adjusted and homogenization of the first excipient composition is started (block 130). In particular embodiments of the present invention, after adding the components of the first excipient composition, the homogenization rate is increased compared to the initial rate and maintained until a visually uniform composition is obtained. In a separate container, a hydrophobic base and an active pharmaceutical ingredient (API) such as, but not limited to, a moisture activated API, are optionally combined (block 140) with a humectant (block 145) to form a second excipient composition . The homogenization parameters (for example, homogenization rate, time, etc.) are then adjusted and homogenization of the second excipient composition is started (block 150). Then, the first and second excipient compositions are combined and homogenized until the desired uniformity is obtained (block 160).
[0076] Any suitable homogenization mechanism can be used. Examples of homogenization devices include mechanical suspended agitation such as propellant homogenizers, anchor, blade pitch, rotor-stator, rotating blades, ultrasonic, in-line and high pressure devices. Either of these methods can be used, and multiple methods can be used in combination in some modalities. Homogenization of premix compositions can provide a final topical composition that has desirable API stability and mixing homogeneity. invention, in-line homogenizer can be used. In particular embodiments of the present invention, a homogenization method and / or device can be used, which keeps an active pharmaceutical ingredient (for example, a moisture activated active pharmaceutical ingredient) below a temperature at which the active pharmaceutical ingredient would degrade. An active pharmaceutical ingredient can degrade at a particular temperature if kept at that temperature for a specific length of time. Thus, in some embodiments of the present invention, the length of time that an active pharmaceutical ingredient is maintained at a particular temperature is below the period of time that the active ingredient would degrade at this temperature. In certain embodiments of the present invention, for the entire homogenization process, the active pharmaceutical ingredient is maintained at a temperature that does not exceed the temperature at which the active pharmaceutical ingredient would degrade.
[0077] In some embodiments of the present invention, homogenization is carried out at a temperature in the range of from about -15 ° C to about 30 ° C or any range thereof. In particular embodiments of the present invention, homogenization is carried out at room temperature. In some embodiments of the present invention, homogenization is carried out in an inert, dry atmosphere, so that water and oxygen are substantially absent from the homogenization vessel.
[0078] A pharmaceutical composition of the present invention can be used to treat an individual's skin by topically administering the pharmaceutical composition. In this way, another aspect of the present invention comprises a method of treating an individual's skin, the method comprising topically administering a pharmaceutical composition of the present invention to an individual's skin. In some embodiments of the present invention, when a moisture-activated active pharmaceutical ingredient is present in a pharmaceutical composition of the present invention, the method may further comprise contacting moisture (e.g., water) with the composition and / or application to the site before, after and / or during the stage of topically administering the composition. In some embodiments of the present invention, moisture, such as, but not limited to, water and / or a body fluid, is already present at the application site prior to administration of a pharmaceutical composition of the present invention.
[0079] Any portion of an individual's skin can be treated, including, but not limited to, a mucosal membrane (including a body cavity), nail and / or scalp of the individual. However, in some embodiments of the present invention, one or more appendages of the individual are treated using a method described herein. Still, in some embodiments of the present invention, the individual's torso is treated using a method described here.
[0080] The present invention finds use in both veterinary and medical applications. Suitable individuals to be treated with an embodiment of the method of the invention include, but are not limited to, avian individuals and mammals. Mammals of the present invention include, but are not limited to, canines, felines, cattle, goats, horses, sheep, porcines, rodents (eg, rats and mice), lagomorphs, primates (eg, apes and humans), non-primates humans (for example, monkeys, baboons, chimpanzees, gorillas) and the like and mammals in utero. Any mammalian individual needing to be treated in accordance with the present invention is suitable. Human individuals of both genders and any stage of development (i.e., neonatal, infantile, juvenile, adolescent, adult) can be treated in accordance with the present In some embodiments of the present invention, the individual is a mammal and in certain embodiments the individual is a human. Human subject includes both male and female genders of all ages including fetal, neonatal, infant, juvenile, adolescent, adult and geriatric as well as pregnant individuals. In particular embodiments of the present invention, the individual is a teenager and / or human adult.
Illustrative birds according to the present invention include chickens, ducks, turkeys, geese, quail, pheasants, ratites (for example, ostrich) and domesticated birds (for example, parrots and canaries) and birds in ovo.
[0082] The methods of the present invention can also be performed on animal subjects, particularly human subjects such as mice, rats, dogs, cats, livestock and horses for veterinary purposes and / or for drug evaluation and drug development purposes .
[0083] In particular embodiments of the present invention, the individual is "in need of" the methods of the present invention, for example, the individual has been diagnosed with, is at risk for and / or is believed to have a disease or disorder that can be treated using the methods of the present invention. In some embodiments of the present invention, the individual has a skin disorder such as, but not limited to, atopic dermatitis and / or psoriasis. In other embodiments of the present invention, the individual has a wound such as, but not limited to, a sore, a burn and / or a diabetic foot ulcer. In some embodiments of the present invention, the individual has an inflammatory skin condition or disorder.
[0084] "Treating", "treating" or "treating" (and its grammatical variations) as used herein refers to any type of treatment that provides a benefit to an individual and may mean that the severity of the individual's condition is reduced , at least partially improved and / or that some relief, mitigation or decrease in at least one clinical symptom is obtained and / or there is a delay in the progression of the disease or disorder. In particular embodiments of the invention, the severity of the skin disorder is reduced in an individual compared to the severity of the skin disorder in the absence of the methods of the present invention. In other embodiments of the present invention, the methods of the present invention improve wound healing and / or prevent infection.
[0085] The present invention is explained in more detail in the following non-limiting Examples. Examples Example 1
[0086] Tables 1 and 2 show various pharmaceutical compositions prepared according to the modalities of the present invention. Table 1: Pharmaceutical compositions comprising formulation 1

Table 2: Pharmaceutical compositions comprising formulation 2
Example 2
[0087] Ointment formulations with Nitricil® 2% comprising MAP3 as described in US Publication No. 2009/0214618 and in International Patent Application No.PCT / US2012 / 022048 entitled "Temperature Controlled Sol-Gel Co-Condensation" deposited on 20 January 2012 were prepared. Tables 3-6 show the formulations of the ointments and gels produced. The ointment formulations in Tables 4 and 5 were prepared as described here. A version of the ointment in Table 4 was also prepared without active ingredient Nitricil®, with the active ingredient replaced with Mineral Oil and Light Mineral Oil. The ointment described in Table 3 was prepared as described in United States Patent Application Serial No. 12 / 860,457. The topical gel in Table 6 was produced as described in United States Provisional Patent Application Serial No. 61 / 504,628. Table 3: Ointment comprising formulation 11-15-12
Table 4: Ointment comprising formulation T PO-005
Table 5: Ointment comprising formulation TO-006
Table 6: Alcohol Gel

[0088] The efficacy of the ointment formulations in Tables 4 and 5 were compared with an alcohol gel formulation (known to be bactericidal against Pseudomonas aeruginosa) shown in Table 6 and an anterior ointment formulation shown in Table 3. All formulations contained Nitricil ® 2% as described above and were tested at a 50 mg / mL dilution in PBS for testing (equivalent to a Nitricil® concentration of 1 mg / mL). Figure 2 shows the test results. Ointment formulation T0-005 was bactericidal against P. aeruginosa within one hour. Figure 3 compares the time of death of the T0-005 formulation with and without Nitricil®. The vehicle formulation T0-005 did not exhibit any antibacterial activity (Figure 3, bottom). Example 3
[0089] Nitricil® was produced as described in Example 2. A formulation as described in Table 7 was prepared as described here.Table 7: Ointment comprising formulation T0-2

[0090] A vehicle version of the T0 formulation replacing Nitricil® with Light Mineral Oil. -2 was prepared
[0091] All formulations contained Nitricil® 2% as described above and were tested at a 50 mg / mL dilution in PBS for testing (equivalent to a Nitricil® concentration of 1 mg / mL) for P. death time. aeruginosa. Figure 4 shows the test results. The T0-2 ointment formulation was bactericidal against P. aeruginosa within an hour while the vehicle was not. Example 4
[0092] The efficacy of topical ointments according to the concept of the present invention in reducing Pseudomonas aeruginosa in wounds has been evaluated in a porcine animal model. Ointments were prepared as described here with respect to formulations 2% and 4% as shown in Table 1. Ointment without Nitricil® was used as the vehicle control.
[0093] Rectangular wounds measuring 10 mm x 7 mm x 0.5 mm deep were made in the paravertebral and thoracic areas of three animals. The wounds were separated from each other by 15 mm uncut skin. A 25 µl suspension containing 106 cfu / mL of Pseudomonas aeruginosa was inoculated into each wound. All wounds were then covered with a polyurethane film dressing (Tegaderm; 3M, St. Paul, MN) within 30 minutes of inoculation and left in place for 48 hours.
[0094] After 48 hours, the polyurethane film dressings were removed and three of the wounds were recovered for baseline bacterial counts. The remaining wounds were divided into four groups of eight wounds each, treated with = 200 mg to cover the injured area and skin without surrounding wounds. The treatments were spread smoothly with a sterile Teflon spatula and were again treated with a film dressing.
[0095] The dressings were replaced daily after applying the treatment. Four wounds from each group were recovered prior to daily dressing changes as described in the "Recovery Section" below starting on day 4 after the wound.
[0096] Three wounds were cultured 48 hours after inoculation to enumerate the baseline bacteria. Four wounds for each treatment group were recovered after treatment on days 4 and 7. To recover bacteria from the wounds, a sterile surgical stainless steel cylinder (internal diameter 22 mm) was placed around the wound area.One (1) mL of neutralizing solution for all purpose was pipetted into the cylinder and the site was rubbed with a sterile Teflon spatula for 30 seconds.
[0097] Serial dilutions were made of all culture samples and the degree of biological contamination assessed using the Spiral Plater System (Spiral Biotech, Norwood, MA). Pseudomonas agar base with SN supplement was used to isolate P. aeruginosa from the wounds. All plates were incubated aerobically overnight (24 hours) at 37 ° C, after which the number of viable colonies was counted.
[0098] Table 8 shows the results of the counts on Day 4 and Day 7 for the 2% and 4% ointment formulations, vehicle control and untreated control. As seen in Table 8, both 2% and 4% ointments achieved significant pathogen reduction on day 7.Table 8: Efficacy of the ointment against Pseudomonas aeruginosa
Example 5
[0099] The formulations of Example 4 were also tested for efficacy against MRSA of Staphylococcus aureus in the same porcine animal models using 2 animals. The experimental procedure was as described in Example 4, except for the change in provocation pathogen. Table 9 shows the results for Days 4 and 7 for ointment 2%, ointment 4%, vehicle control and untreated control. As seen in Table 9, both 2% and 4% ointments prevented pathogen growth and reduced counts on day 7. Table 9: Efficacy of the ointment against Staphylococcus aureus MRSA
Example 6
[00100] Macromolecular nitric oxide release compound (Nitricil® NVN1) comprising MAP3 was manufactured as described in United States Patent Application Publication No. 2009/0214618 and PCT Patent Application Number PCT / US12 / 22048 filed on 20 January 2012, entitled "Temperature Controlled Sol-Gel Co-Condensation", whose descriptions are hereby incorporated by reference in their entirety for reference. The resulting macromolecular particles were ball milled to provide an average particle size of 8 to 10 pm to provide an active pharmaceutical ingredient (API).
[00101] Figure 5 is a graph of the release profiles for Nitricil® NVN1 and NVN4 at pH 7.4 and 37 ° C for the first 200 minutes of release. Nitricil® NVN4 is a macromolecular nitric oxide release compound comprising AEP3 / TEOS in a 1: 1 ratio and was manufactured as described in United States Patent Application Publication No. 2009/0214618 and PCT Patent Application Number PCT / US12 / 22048 filed on January 20, 2012, entitled "Temperature Controlled Sol-Gel Co-Condensation" to provide an API. The general release kinetics of Nitricil® NVN1 are provided in Table 10 below. Table 10: Nitricil® NVN1 half-life and potency at pH 7.4 and 37 ° C

[00102] Nitricil® NVN1 was formulated in two finished dosage forms of an ointment as shown in Table 11. Table 11: Nitricil® NVN1 ointment formulations

[00103] The placebo ointment was formulated with the weight of the API being replaced by an increase in the amount of mineral oil. Example 7
[00104] Male mice derived from BALB / c, weighing 22 ± 2 g, were provided by BioLasco Taiwan (under Charles River Laboratories Technology Licensee). The animals were housed in individually ventilated cage shelves (IVC Racks, 36 Mini Isolator Systems) under a clean area during the experiment. Each 5 mice were kept in an animal cage (in cm, 26.7 length x 20.7 width x 14.0 height) sterilized with autoclave and kept under temperature (20 - 24 ° C) and humidity (50% - 80 %) controlled with 12-hour light / dark cycles. The animals had free access to standard sterile laboratory food [MF-18 (Oriental Yeast Co., Ltd. Japan)] and sterile tap water ad libitum. All aspects of this work, that is, accommodation, experimentation and disposal of animals, were carried out in accordance with the Care and Use of Laboratory Animals (National Academy Press, Washington, D.C., 2010).
[00105] Groups of 5 male BALB / c mice weighing 22 ± 2 g were used. The animals were sensitized by applying oxazolone (100 pL, 1.5% in acetone) to their pre-shaved abdominal surface. Seven days later, test substances (20 mg / ear) and vehicle (20 pL / ear) were applied topically to the anterior and posterior surfaces of the right ear 30 minutes before and 15 minutes after oxazolone challenge (1%, 20 pL / ear) ). Ear swelling was measured with a Dyer micrometer 24 hours after challenge with oxazole as an inflammation index. Ear edema was calculated by subtracting the thickness of the left ear (normal control) from the right ear (treated ear). The percentage inhibition was calculated according to the formula: (Ic-It) / Ic x 10, where Ic and It refers to increased ear thickness (mm) in control and treated mice, respectively. One-way ANOVA and Dunnett tests were used to determine the statistical significance between vehicle and treated control groups. Significance is adjusted at P <0.05.
[00106] The test articles (Unguento Nitricil® NVN1 0.2% and 2%) described in Example 6 were evaluated for possible anti-inflammatory activity in the ear swelling test induced by oxazolone in BALB / c mice, a model of allergic contact dermatitis. The test substances and vehicles were each administered topically (TOP) 30 minutes before and 15 minutes after challenge with the second application of oxazolone. The effects of test substances on ear swelling were measured 24 hours later and the results are summarized in Table 12 below.Table 12: In vivo anti-inflammatory efficacy of NO release compositions
Note: Negative values indicate no inhibition or stimulation. ANOVA One-way and Dunnett tests were used to verify the difference between vehicle control (or respective placebo control) and treated groups. * P <0.05, vs. Vehicle A or its placebo control.
[00107] Topical administrations of Nitricil® NVN1 0.2% and 2% ointment were not associated with significant inhibition vs. the control of vehicle A (acetone / ethanol: 1/1) and placebo ointment. Treatment with placebo ointment did not exhibit a significant effect on oxazolone-induced ear swelling. Dexamethasone (0.1 mg / ear x2), the positive control, was associated with significant inhibition of oxazolone-induced swelling in the ear. Example 8
[00108] Using a cold process, ointment formulations were prepared as described in Table 13. These formulations were selected for enlargement.Table 13: Nitricil® NVN1 Ointment Formulations (TO-007 and TO-008)

[00109] The laboratory scale process used during the development of the formulations provided in Table 13 has been extended to the 5.5 kg scale using a Ross Dual Shaft Mixer, Model No .: CDA-2 with an 8L mixing vessel. The agitation and homogenization system contained two independently activated top entry agitators, as described below: 1. A Three Vane Anchor Shaker driven in a speed range of approximately 23-225 rpm. The anchor is designed with a triangular cross section and includes fixed Teflon scrapers for cleaning the side wall and the bottom of the mixing can. 2. A High Speed Dispersion Apparatus, 5.08 cm (2 ") diameter blade, operated at a speed range of approximately 1,000-10,000 rpm. Four batches of ointment were manufactured to determine the order of material addition , as well as suitable mixing speeds (anchor-type agitator and high-speed dispersion apparatus) and mixing times for the small scale process. A summary of the development of batch formulations is provided in Table 14 and the flowchart for manufacturing is provided in Figure 6.Table 14: Batch formulas for topical ointments

[00110] Analytical batch results are provided in Tables 15 and 16. Table 15: Analytical results for placebo ointment
Table 16: Analytical results for Nitricil® NVN1 Ointments 2%, 6%, 12% and 20%

Example 9
[00111] A Nitricil® ointment was evaluated in BALB / c mice to determine the potential anti-inflammatory properties of the Nitricil® ointment in vivo. Male mice derived from BALB / c, weighing 22 ± 2 g, were provided by BioLasco Taiwan (under Charles Rivers Laboratories Technology License). The animals were housed in Individually Ventilated Cage Shelves (IVC Racks, 36 Mini Isolator systems) under a clean area during the experiment. Each 5 mice were kept in an animal cage (in cm, 26.7 cm long x 20.7 cm wide x 14.0 high) sterilized with an autoclave and kept under temperature (20-24 ° C) and humidity ( 50% - 80%) controlled with 12-hour light / dark cycles. The animals had free access to standard sterile laboratory feed [MF-18 (Oriental Yeast Co., Ltd. Japan)] and sterile tap water ad libitum. All aspects of this work, that is, accommodation, experimentation and disposal of animals, were carried out in general agreement with the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, D.C., 2011).
[00112] Topical Nitricil® ointment (1% and 4%) and placebo ointment were tested throughout the study. The compositions of the topical Nitricil® and placebo ointment formulations are provided in Table 17. Dexamethasone (0.1 mg / ear) was used as a positive control. Dexamethasone is a potent glucocorticoid steroid that is used to treat various inflammatory and autoimmune disorders. Table 17. Composition of ointment formulations used in this study


[00113] The test system used was a 7-day oxazolone-induced ear swelling test. Oxazolone-induced ear swelling is useful as a model of inflammation. Oxazolone is an allergen that induces delayed-type hypersensitivity, and is therefore primarily useful as a model of inflammation directed by the adaptive immune response (eg, allergic contact dermatitis, psoriasis, etc.). In this trial, the mice (5 per group) were sensitized to oxazolone (100 pL, 1.5% in acetone) through a topical application of oxazolone on the surface of their pre-shaved abdomen. Seven days later, the animals were challenged with a second application of oxazolone to the ear. Test articles (20 mg / mouse) and vehicle (20 pL / ear) were administered topically (TOP) to the anterior and posterior surfaces of the right ear 30 minutes before and 15 minutes after the second challenge with oxazolone (1%, 20 pL / ear) (elicitation phase). Ear swelling was measured with a Dyer micrometer 24 hours after challenge with oxazolone as an inflammation index. Ear edema was calculated by subtracting the thickness of the left ear (normal control) from the right ear (treated ear) (Table 18). An additional group was treated with dexamethasone, a known anti-inflammatory agent, (positive control) to verify the validity of the assay.
[00114] The percentage inhibition was calculated according to the formula: (Ic - It) / Ic x 100, where Ic and It refer to increased ear thickness (mm) in control and treated mice, respectively. One-way ANOVA and Dunnett tests were used to determine statistical significance between vehicle control and treated groups. Significance is adjusted at P <0.05. Table 18: Treatment information and swelling results
Note: One-way ANOVA and Dunne tt tests were used to verify difference between placebo / vehicle control and treatment groups. * P <0.05, vs. Vehicle (Acetone: Ethanol / 1: 1) t P <0.05, vs. Placebo ointment.
[00115] Topical administrations of Topical Nitricil® NVN1 1% and Topical Nitricil® NVN1 4% were both associated with significant inhibition (P <0.05) of oxazolone-induced ear swelling versus both vehicle control ointment ( acetone: ethanol: 1/1) and placebo. Nitricil® NVN1 Topical Ointment 1% inhibited swelling in the ear in 57% versus acetone / ethanol vehicle and in 58% versus placebo ointment. Nitricil® NVN1 Topical Ointment 4% inhibited swelling in the ear by 59% versus acetone / ethanol vehicle and by 60% versus placebo ointment. The placebo ointment had no effect on ear swelling with respect to the acetone / ethanol vehicle. Dexamethasone (positive control) inhibited swelling of the ear by 86% with respect to the acetone / ethanol vehicle.
[00116] Topical administration of topical 1% and 4% Nitricil® ointment caused significant inhibition (P <0.05) of oxazolone-induced ear swelling compared to the control or placebo ointment vehicle (Acetone / Ethanol: 1 /1). Thus, topical ointment Nitricil® 1% and 4% significantly inhibited inflammation in an in vivo model of allergic contact dermatitis. Topical Nitricil® NVN1 4% was not significantly more effective than Topical Nitricil® NVN1 1% under the conditions of this test. The placebo ointment group had no effect with respect to vehicle control (Acetone / Ethanol: 1/1). Dexamethasone (0.1 mg / mouse x 2), the positive control, was associated with significant inhibition of oxazolone-induced ear swelling in mice. Table 19 shows a comparison of the percent inhibition of oxazolone-induced ear swelling results from this study, the study described in Example 7, and a subsequent study with Nitricil® ointment formulations as described in Example 8 for an ethanol / vehicle formulation. acetone or a placebo formulation. For Nitricil® NVN4 ointment formulations, the formulations were similar to those provided in Example 8 for Nitricil® NVN1 ointment formulations with minor adjustments made for light mineral oil to match the difference in the amount of Nitricil® in the formulation. Table 19: Comparison of percent inhibition of oxazolone-induced ear swelling results from several studies
* Significant inhibition (P <0.05) versus formulation of ethanol / acetone or placebo vehicle. Example 10 Study of Wound Healing in a Partial Thickness Wound Model of Pig
[00117] Using Nitricil® NVN1 ointments, such as TO-007 ointment formulations described in Example 8, partial thickness wounds were treated in a porcine model. Partial thickness wounds were treated with the following formulations: ointment formulations containing Nitricil® NVN1 0.1%, 0.5%, 1% or 4%, vehicle ointment, Tegaderm for standard occlusion as a positive control or left exposed to air as a negative control.
[00118] The results of the wound healing study of eight animals are shown in Figure 7. The smaller doses, Nitricil® NVN1 0.1% and 0.5%, showed much faster rates of reepithelization. All 20 wounds at the lowest dose (0.1%) were completely healed on Day 6, 2 whole days faster than the corresponding vehicle ointment or the Tegaderm occlusive care standard. Although these data were not collected in a thermal injury model, they clearly demonstrate the ability of nitric oxide to stimulate faster healing.
[00119] Two biopsies were obtained from all animals in each treatment group on Days 2, 4 and 7 post-injury. Wedge biopsies for histology were obtained through the center of the wounds including normal adjacent skin on both sides. Puncture biopsies were obtained from the other half of the wound for RNA isolation and subsequent RT-PCR analysis.
[00120] Any differences in epithelial thickness were observed for any of the treatment groups, showing a regulated healing process and no excessive proliferation of cells in the epithelium. Wounds treated with 0.5% Nitricil® NVN1 ointment expressed a high level of IL-8 mRNA on Day 2 compared to the other treatment groups (Figure 8). The expression of IL-8, a neutrophil chemoattract, was significantly induced in wounds following 2 days of treatment with 0.5% Nitricil® NVN1 (p <0.05). Nitric oxide can activate the IL-8 promoter and IL-8 in turn can suppress the expression of iNOS in neutrophils. This signaling effect was sufficient to promote healing, but it did not facilitate recruitment of excess neutrophils and caused a sustained inflammatory response (Figure 9). The white cell infiltrate measured via histology was not statistically different for any of the treatments.
[00121] The above is illustrative of the present invention and should not be considered as limiting it. The invention is defined by the claims that follow, with equivalents of the claims being included therein. All publications, patent applications, patents, patent publications and other references mentioned here are incorporated by reference in their entirety as to the teachings relevant to the sentence and / or paragraph where the reference is presented.

权利要求:
Claims (18)
[0001]
1. Pharmaceutical composition for topical administration of a moisture-activated active pharmaceutical ingredient, characterized by the fact that it comprises: the moisture-activated active pharmaceutical ingredient, which comprises a co-condensed silica particle of nitric oxide release; a hydrophobic base; and an amphiphilic compound, which comprises a polyethylene glycol capric / caprylic glyceride (PEG), with water being present in the composition at a concentration of less than 2% by weight of the composition.
[0002]
2. Pharmaceutical composition, according to claim 1, characterized by the fact that: the hydrophobic base is present in the composition in a concentration of from 35% to 90%; and the amphiphilic compound is present in the composition at a concentration of from 1% to 30%.
[0003]
3. Pharmaceutical composition according to claim 1, characterized by the fact that the amphiphilic compound has a hydrophilic-lipophilic balance (HLB) value of 12 to 20.
[0004]
4. Pharmaceutical composition according to claim 1, characterized by the fact that the amphiphilic compound comprises a capric / caprylic glyceride of PEG-6.
[0005]
5. Pharmaceutical composition according to claim 1, characterized by the fact that the amphiphilic compound absorbs moisture and does not substantially absorb vaporous moisture.
[0006]
6. Pharmaceutical composition according to claim 1, characterized by the fact that the hydrophobic base comprises at least one of mineral oil and a hydrophobic polymer.
[0007]
7. Pharmaceutical composition, according to claim 1, characterized by the fact that the pharmaceutical composition further comprises a co-solvent and the co-solvent is present in the composition in a concentration of 1% to 30%.
[0008]
Pharmaceutical composition according to claim 7, characterized in that the co-solvent comprises a fatty acid ester.
[0009]
Pharmaceutical composition according to claim 7, characterized by the fact that the co-solvent comprises a caprylic / capric triglyceride.
[0010]
10. Pharmaceutical composition, according to claim 1, characterized by the fact that it also comprises a humectant, and the humectant is present in the composition in a concentration of 1% to 25%.
[0011]
11. Pharmaceutical composition according to claim 10, characterized by the fact that the humectant comprises a polyhydric alcohol.
[0012]
12. Pharmaceutical composition, according to claim 1, characterized by the fact that the active pharmaceutical ingredient activated by moisture is present in the composition in a concentration of 0.1% to 70%.
[0013]
Pharmaceutical composition according to claim 1, characterized by the fact that the co-condensed silica particle of nitric oxide release comprises a diazeniodiolate functional group.
[0014]
Pharmaceutical composition according to claim 13, characterized in that the co-condensed silica particle has an average particle size of less than 10 pm.
[0015]
15. Pharmaceutical composition according to claim 1, characterized by the fact that it comprises: the active pharmaceutical ingredient activated by moisture present in the composition in a concentration of 0.1% to 35%; the hydrophobic polymer present in the composition in a concentration of 30% to 60%; a mineral oil present in the composition in a composition of 1% to 30%; the amphiphilic compound present in the composition in a concentration of 1% to 20%; a co-solvent present in the composition at a concentration of 1% to 25%; and a humectant present in the composition at a concentration of 1% to 25%.
[0016]
16. Pharmaceutical composition, according to claim 1, characterized by the fact that it comprises an ointment.
[0017]
Pharmaceutical composition according to any one of claims 1 to 16, characterized by the fact that it is for use in treating an individual's skin.
[0018]
18. Pharmaceutical composition, according to claim 17, characterized by the fact that said treatment comprises contact of water with the pharmaceutical composition before, after and / or during the stage of topically administering the composition.

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法律状态:
2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-10-30| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2019-11-19| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2020-04-07| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-09-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-12-08| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 28/02/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US201261610563P| true| 2012-03-14|2012-03-14|

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US61/610,563|2012-03-14|

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PCT/US2013/028223|WO2013138075A1|2012-03-14|2013-02-28|Nitric oxide releasing pharmaceutical compositions|

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