Combination treatment for Netherton syndrome

Abstract

The present invention relates to a method for treating Netherton syndrome. In one embodiment, the method comprises administering to a patient (i) a serine protease inhibitor and (ii) an anti-inflammatory agent. In another embodiment, the method comprises (a) administering to the patient a serine protease inhibitor and an anti-inflammatory agent when the patient is experiencing Netherton syndrome, and (b) administering a serine protease inhibitor when the patient is in remission. The present invention also relates to a pharmaceutical composition comprising (i) a serine protease inhibitor and (ii) an anti-inflammatory agent.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 63 / 481,535, filed January 25, 2023, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to a method of treating Netherton syndrome (e.g., in a patient in need of treatment for Netherton syndrome), the method comprising administering to the patient a serine protease inhibitor and an anti-inflammatory agent. The present invention also relates to a pharmaceutical composition (e.g., a topical pharmaceutical composition) comprising the serine protease inhibitor and the anti-inflammatory agent. [Background technology]

[0003] Netherton syndrome is a disorder that affects the skin, hair, and immune system. Newborns with Netherton syndrome have red, scaly skin (piscine-like erythroderma), which may leak fluid. Some affected infants are born with a dense, transparent membrane covering their skin called a collodion membrane. This membrane usually passes during the first few weeks after birth. Without the protection of normal skin, newborns with this disorder are at risk of dehydration and developing skin or generalized infections (sepsis), which can be life-threatening. Affected newborns may also not grow or gain weight at the expected rate (failure to thrive). The health of older children and adults with Netherton syndrome usually improves, but they often remain underweight and short.

[0004] The severity of skin abnormalities from childhood onwards varies among individuals with Netherton syndrome and may fluctuate over time. The skin may remain red and scaly, particularly during the first few years of life. Some affected individuals experience the development of a distinctive skin abnormality called flexural linear ichthyosis, which has intermittent redness or patches of multiple circular lesions. The trigger for the onset is unknown, but researchers have suggested that stress or infection may be involved.

[0005] Itching is a common problem for affected individuals, and scratching can lead to frequent infections. Dead skin cells shed at an abnormal rate and often accumulate in the ear canal, which, if not regularly removed, can affect hearing. The skin absorbs substances such as lotions and ointments abnormally, which can lead to excessive blood levels of some topical medications. Because the skin's ability to protect against heat and cold is impaired, affected individuals may have difficulty regulating their body temperature.

[0006] Individuals with Netherton syndrome have brittle hair that breaks easily. Some hairs vary in diameter, with thicker and thinner patches. This feature is known as bamboo hair, trichorrhexis nodosa, or intussusceptible trichorrhexis. In addition to scalp hair, the eyelids and eyebrows may also be affected. The hair abnormalities of Netherton syndrome may not be visible during infancy, as newborns often have thinning hair.

[0007] Most individuals with Netherton syndrome have immune system-related problems such as food allergies, hay fever, asthma, or eczema.

[0008] U.S. Publication No. 2013 / 0338198 discloses certain skin disorder treatment compositions that include, inter alia, a serine protease inhibitor, a hydrophobic polymer / hydrophilic polymer complex including a poly(vinylpyrrolidone-alkylene) polymer, a release agent, and water.

[0009] New methods and compositions for treating Netherton syndrome are needed. Summary of the Invention

[0010] In one aspect, the invention relates to a method for treating Netherton syndrome in a patient (e.g., in a patient in need of treatment for Netherton syndrome), hi one embodiment, the method comprises administering to the patient (e.g., effective amounts of) (i) a serine protease inhibitor and (ii) an anti-inflammatory agent.

[0011] In one embodiment, a serine protease inhibitor and an anti-inflammatory agent are administered to a patient during an episode of Netherton syndrome.

[0012] Another aspect is a method of treating Netherton syndrome in a patient (e.g., in need of treatment for Netherton syndrome), the method comprising administering to the patient (e.g., an effective amount of) (a) serine protease inhibitors and anti-inflammatory agents if the patient has Netherton syndrome; and (b) administering a serine protease inhibitor if the patient is in remission.

[0013] In one embodiment, the occurrence of Netherton syndrome includes circumflex linear ichthyosis.

[0014] In another embodiment, if the patient is in remission, the anti-inflammatory agent is not administered along with the serine protease inhibitor.

[0015] In any of the methods described herein, the serine protease inhibitor, alone or in combination with an anti-inflammatory agent, is administered in an amount effective to suppress or inhibit Netherton syndrome or its symptoms.

[0016] In one embodiment of any of the methods described herein, the serine protease inhibitor and the anti-inflammatory agent are administered topically.

[0017] The serine protease inhibitor and the anti-inflammatory agent may be administered in a single dosage form (e.g., as a fixed-dose combination such as a gel, lotion, or cream) or in separate dosage forms, which may be administered simultaneously or sequentially by the same or different routes of administration. The dosage form(s) used may be a lotion, cream, gel, or liquid.

[0018] Yet another embodiment is a pharmaceutical composition (e.g., a topical pharmaceutical composition for use in treating Netherton syndrome) comprising (a) a serine protease inhibitor and (b) an anti-inflammatory agent.

[0019] In one embodiment of any of the methods (and compositions for use in treating Netherton syndrome in a patient) described herein, the patient has a SPINK5 mutation.

[0020] In a preferred embodiment of any of the methods and compositions described herein, the serine protease inhibitor is dipalmitoyl hydroxyproline or a pharmaceutically acceptable salt thereof.

[0021] In one embodiment of any of the methods described herein (and compositions for use in treating Netherton syndrome in a patient), the serine protease inhibitor and anti-inflammatory agent are applied topically to lesions on the arms and / or lower legs.

[0022] In one embodiment of any of the methods and compositions described herein, the anti-inflammatory agent is selected from nonsteroidal anti-inflammatory drugs (such as ibuprofen, meloxicam, and diclofenac), corticosteroids (such as prednisolone), TNF antagonists including TNFα and / or β inhibitors (such as adalimumab, infliximab, and etanercept), capsaicin, felbinac, ketoprofen, piroxicam, acetylsalicylic acid, glycyrrhetinic acid, pharmaceutically acceptable salts thereof, and any combination of any of the foregoing. In one embodiment, the anti-inflammatory agent is diclofenac, ketoprofen, pharmaceutically acceptable salts thereof, and any combination of any of the foregoing. In another embodiment, the anti-inflammatory agent is diclofenac or a pharmaceutically acceptable salt thereof (e.g., diclofenac sodium, diclofenac potassium, and diclofenac epolamine). In yet another embodiment, the anti-inflammatory agent is ketoprofen or a pharmaceutically acceptable salt thereof (eg, ketoprofen).

[0023] In one embodiment of any of the compositions described herein, the composition is a topical composition. DETAILED DESCRIPTION OF THE INVENTION

[0024] Detailed descriptions of certain aspects of the present application are disclosed herein. It will be understood that the disclosed embodiments are merely examples of ways in which certain aspects of the present application may be implemented and do not represent all of the ways in which the present application may be embodied.

[0025] definition It should be understood that throughout this specification, the terms "comprise" and "include," as well as variations such as "comprises," "comprising," "includes," "including," etc., are to be interpreted inclusively unless the context otherwise requires. The use of these words may imply the inclusion of element(s) not specifically listed.

[0026] As used herein, the term "treatment" or "treating" relates to curing or substantially curing a condition, as well as ameliorating, delaying, alleviating, suppressing, or alleviating at least one symptom of the condition, and encompasses prophylactic and therapeutic treatment. As will be understood by those skilled in the art, a treatment administered before the clinical manifestation of a condition is prophylactic (i.e., it protects the subject from developing the condition). If a treatment is administered after the manifestation of a condition, the treatment is therapeutic (i.e., intended to reduce, ameliorate, control, or maintain an existing condition and / or side effects associated with the condition).

[0027] The term "topical composition," as used herein, refers to a composition suitable for direct application to the skin, nails, or mucosal tissue, either by hand or with a suitable applicator. In one embodiment, the term "topical composition," as used herein, refers to a composition suitable for direct application to the skin.

[0028] As used herein, the term "patient" or "subject" refers to, but is not limited to, a human or an animal, including mammals (such as monkeys, guinea pigs, domestic pets such as cats and dogs, etc.).

[0029] As used herein, the term "about" when used to refer to a weight percent or other numerical value in a composition means plus or minus up to 20% (alternatively, up to 10% or 5%) of the reported value.

[0030] The phrases "wt %," "% by weight," and "% w / w," unless otherwise indicated, refer to the weight percentage(s) of a component based on the total weight of the composition containing that component.

[0031] As used herein, the term "pharmaceutically acceptable salt(s)" refers to salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamines, thiamine), salts of chiral bases (such as alkylphenylamines, glycinol, phenylglycinol), salts of naturally occurring amino acids (e.g., " refers to salts of amino acids such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, etc.), salts of unnatural amino acids (such as D-isomers or substituted amino acids), salts of guanidine, salts of substituted guanidines (where the substituents are selected from nitro, amino, alkyl, alkenyl, or alkynyl), ammonium salts, substituted ammonium salts, and aluminum salts. Other pharmaceutically acceptable salt(s) include acid addition salts (where appropriate) of sulfate, nitrate, phosphate, perchlorate, borate, hydrohalide, acetate, tartrate, maleate, citrate, fumarate, succinate, palmitate, methanesulfonate, benzoate, salicylate, benzenesulfonate, ascorbate, glycerophosphate, ketoglutarate, etc. Still other pharmaceutically acceptable salt(s) include, but are not limited to, quaternary ammonium salts of the compounds of the invention with alkyl halides or alkyl sulfates (e.g., Mel and (Me)SO). Pharmaceutically acceptable solvates may be hydrates or may include other solvents of crystallization such as alcohols.

[0032] Serine protease inhibitor(s) A suitable serine protease inhibitor is dipalmitoyl hydroxyproline.

[0033] The serine protease inhibitor can also be a LEKTI protein domain as described in U.S. Patent Publication No. 2021 / 0162029, which is incorporated herein by reference.

[0034] Anti-inflammatory agent(s) Suitable anti-inflammatory agents include nonsteroidal anti-inflammatory drugs (such as ibuprofen, meloxicam, and diclofenac), corticosteroids (such as prednisolone), TNF antagonists including TNF alpha and / or beta inhibitors (such as adalimumab, infliximab, and etanercept), capsaicin, felbinac, ketoprofen, piroxicam, acetylsalicylic acid, glycyrrhetinic acid, pharmaceutically acceptable salts thereof, and any combination of any of the foregoing.

[0035] In one embodiment, the anti-inflammatory agent is diclofenac, ketoprofen, pharmaceutically acceptable salts thereof, and any combination of any of the foregoing. In another embodiment, the anti-inflammatory agent is diclofenac or a pharmaceutically acceptable salt thereof (e.g., diclofenac sodium, diclofenac potassium, and diclofenac epolamine). In yet another embodiment, the anti-inflammatory agent is ketoprofen or a pharmaceutically acceptable salt thereof (e.g., ketoprofen).

[0036] Treatment method The serine protease inhibitor and anti-inflammatory agent can be administered by any route of administration, such as orally or topically.

[0037] In a preferred embodiment, the serine protease inhibitor is administered locally and the anti-inflammatory agent is administered by any route (eg, orally, parenterally, or topically).

[0038] In another preferred embodiment, both the serine protease inhibitor and the anti-inflammatory agent are administered topically. For example, the amount of serine protease inhibitor (such as dipalmitoyl hydroxyproline) provided in the topical composition can be at least 0.0001% by weight, such as about 0.2% to about 5% by weight, about 0.5% to about 3% by weight, or about 0.8% to about 2.5% by weight, based on the total weight of the topical composition.

[0039] In certain embodiments of any of the topical compositions described herein, the topical composition comprises about 0.5 to about 5% w / w diclofenac or a pharmaceutically acceptable salt thereof (e.g., diclofenac sodium, diclofenac potassium, and diclofenac epolamine), for example, about 1%, 1.3%, 1.5%, 2%, or 3% w / w diclofenac or a pharmaceutically acceptable salt thereof (e.g., diclofenac sodium, diclofenac potassium, and diclofenac epolamine).

[0040] In another embodiment, the topical composition comprises ketoprofen.

[0041] In certain embodiments, any of the topical compositions described herein is applied topically to the area of ​​the subject to be treated at least once daily, for example, two, three, or four times daily.

[0042] In certain embodiments, any of the topical compositions described herein is applied topically once daily to the area of ​​the subject to be treated.

[0043] In certain embodiments, any of the topical compositions described herein is applied topically to the area of ​​the subject to be treated twice daily.

[0044] In certain embodiments of any of the topical compositions described herein, the topical composition is an aqueous-based composition (i.e., a water-based composition that is free or substantially free of non-aqueous solvents). The term "substantially free of non-aqueous solvents" is intended to indicate that the formulation contains less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% non-aqueous solvents.

[0045] The topical composition can be applied to the skin tissue by spreading the composition on the skin tissue as a cream or lotion and rubbing the composition into the skin tissue. The rubbing action can include gentle or vigorous rubbing. In one embodiment, the composition can be characterized as having binding or almost adhesive properties to the skin tissue, although the composition is not the type of composition that would be considered an adhesive for bonding two substrates together, such as, for example, a hot melt adhesive.

[0046] In one embodiment, the anti-inflammatory agent is diclofenac or a pharmaceutically acceptable salt thereof (e.g., diclofenac sodium, diclofenac potassium, and diclofenac epolamine) and is administered orally. For example, about 100 to about 200 mg / day of diclofenac or a pharmaceutically acceptable salt thereof (e.g., diclofenac sodium, diclofenac potassium, and diclofenac epolamine) can be administered in accordance with the methods described herein.

[0047] In another embodiment, the anti-inflammatory agent is ketoprofen or a pharmaceutically acceptable salt thereof (e.g., ketoprofen) and is administered orally. For example, about 50 to about 300 mg per day (e.g., about 75 to about 300 mg per day) of ketoprofen or a pharmaceutically acceptable salt thereof (e.g., ketoprofen) can be administered by the methods described herein.

[0048] Pharmaceutical Composition When administered alone, the serine protease inhibitors can be incorporated into topical pharmaceutical compositions such as those described in US 2013 / 0338198.

[0049] The topical composition may also include an anti-inflammatory agent.

[0050] Any of the pharmaceutical compositions (e.g., topical pharmaceutical compositions) described herein may include one or more pharmaceutically acceptable excipients, such as, but not limited to, penetration enhancers, buffers, pH adjusters, surfactants, thickeners, conditioning agents, preservatives, chelating agents, gelling agents, emulsifiers, foaming agents, colorants, solvents, and any combination of any of the foregoing. Suitable excipients that may be used are also described in U.S. Publication No. 2013 / 0338198, which is incorporated herein by reference in its entirety.

[0051] Penetration enhancers suitable for use in any of the pharmaceutical compositions described herein include, but are not limited to, sulfoxides (e.g., DMSO), azones (e.g., laurocapram), pyrrolidones (e.g., 2-pyrrolidone), alcohols and alkanols (e.g., ethanol, decanol), oleic acid and its derivatives, glycols (e.g., propylene glycol), dimethylformamide (DMF), dimethylacetamide (DMAC), fatty alcohols (e.g., lauryl alcohol), fatty acid esters, fatty acids, fatty alcohol ethers (e.g., EO-2-oleyl ether), and terpenes, as well as any combination of any of the foregoing. In one embodiment, the penetration enhancer may be present at a concentration ranging from about 1% to about 20% by weight of the composition.

[0052] Suitable buffering agents for use in any of the pharmaceutical compositions described herein include, but are not limited to, phosphates such as sodium phosphate monobasic, sodium phosphate dibasic, lactates and citrates such as citric acid monohydrate, sodium citrate dihydrate, and any combination of any of the foregoing. The buffering agent may be present in a concentration ranging from about 0.01% to about 5% by weight of the composition.

[0053] Suitable pH adjusting agents for use in any of the pharmaceutical compositions described herein include, but are not limited to, acids such as hydrochloric acid, phosphoric acid, citric acid, and lactic acid, and suitable bases such as diethanolamine, triethanolamine, and sodium hydroxide, as well as any combination of any of the foregoing. The pH adjusting agent may be present at a concentration ranging from about 0.01% to about 5% by weight of the composition.

[0054] Suitable surfactants include anionic surfactants, nonionic surfactants, amphoteric surfactants, and any combination of any of the foregoing. Surfactants suitable for use in any of the pharmaceutical compositions described herein include, but are not limited to, sodium laureth sulfate, cocamidopropyl betaine, laureth 2, leuramide mea, chalauryl sulfate, disodium laureth sulfosuccinate, PEG-120 methyl glucose dioleate, sodium lauryl ether sulfate, lauryl alcohol, polyoxyethylene ethers, polyoxyethylene glycerol monostearate, stearic acid ester oxygen polyhydrocarbons, vitamin E succinic acid polyethylene glycol esters, sorbitan esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, organic esters (e.g., ethylene acetate), and polysorbate 80 (i.e., TWEEN® 80), as well as any combination of any of the foregoing. In one embodiment, the surfactant may be present at a concentration ranging from about 1% to about 25% by weight of the composition.

[0055] In another embodiment, any of the compositions described herein comprises at least 2% w / w surfactant, e.g., at least 5% w / w, at least 7.5% w / w, at least 10% w / w, at least 12.5% ​​w / w, at least 15% w / w, at least 17.5% w / w, at least 20% w / w, at least 22.5% w / w, at least 25% w / w, at least 27.5% w / w, at least 30% w / w, at least 35% w / w, or at least 40% w / w surfactant. In one embodiment, the surfactant comprises an anionic surfactant, an amphoteric surfactant, or a combination thereof. In another embodiment, the surfactant comprises an anionic surfactant and an amphoteric surfactant. In yet another embodiment, the surfactant comprises an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.

[0056] Suitable thickening agents for use in any of the pharmaceutical compositions described herein include, but are not limited to, polyquatenium-10, sodium chloride, natural vegetable starch, xanthan gum, gum arabic, guar gum, carrageenin, and sponge gel, as well as any combination of any of the foregoing. The thickening agent may be present in a concentration ranging from about 0.1% to about 10.0% by weight of the composition.

[0057] Conditioning agents (moisturizers) suitable for use in any of the pharmaceutical compositions described herein include, but are not limited to, citrimonium chloride, laurimonium hydroxypropyl hydrolyzed collagen, and silicone agents, as well as any combination of any of the foregoing. The conditioning agent may be present in a concentration ranging from about 0.1% to about 10.0% by weight of the composition.

[0058] Suitable preservatives for use in any of the pharmaceutical compositions described herein include, but are not limited to, chloro-m-cresol, citric acid, edetate disodium, ethoxylated alcohol, glycerin, 1,2,6-hexanetriol, methylparaben, parabens, potassium, sorbic acid esters, propyl gallate, propylene glycol, propylparaben, sodium bisulfate, sodium citrate, butylparaben, sodium metabisulfite, chlorocresol, sorbic acid, tannic acid, zinc stearate, butylated hydroxytoluene, butylated hydroxyanisole, benzoic acid, salicylic acid, propylparaben, dichlorobenzyl alcohol, formaldehyde, alpha-tocopherol, sodium ascorbate, ascorbic acid, ascorbyl phenol palmitate, m-cresol, bisphenol, cetrimide, benzalkonium chloride, sorbic acid, phenoxyethanol, iminea, benzyl alcohol, and benzoyl peroxide, as well as any combination of any of the foregoing. Preservatives may be present in concentrations ranging from about 0.1% to about 10.0% by weight of the composition.

[0059] Suitable chelating agents for use in any of the pharmaceutical compositions described herein include ethylenediaminetetraacetic acid (EDTA), citric acid, diethylenetriaminepentaacetic acid (DTPA), deferoxamine, deferasirox, deferiprone, pyridoxal isonicotinoyl hydrazone, rhodotorulinic acid, picolinic acid, nicotinic acid, neoaspergillic acid, methionine, lactic acid, N,N-ethylenebis[N-phosphonomethyl]glycine, tetraethylenepentamineheptaacetic acid (TPHA), tri(2-aminoethyl)aminehexaacetic acid (TAAHA), triethylenetetraminehexaacetic acid (TTA), and methylparaben. Chelating agents include, but are not limited to, acetic acid (TTHA), oxybis(ethinitrilo)tetraacetic acid (BAETA), trans-1,2-cyclohexanediaminetetraacetic acid, salicylic acid, tartaric acid, 2,3-dihydroxybenzoic acid, penicillamine, etidronic acid (1-hydroxyethane-1,1-diyl)bis(phosphonic acid), dimercaptosuccinic acid, dimercaptopropanesulfonate, dimercaprol, desferrithiocin (DFT), polycarboxylates, hydroxamates, catecholates, hydroxypyridates, and terphthalamide, as well as any combination of any of the foregoing. Chelating agents may be present in a concentration ranging from about 0.01% to about 5% by weight of the composition.

[0060] Suitable gelling agents for use in any of the pharmaceutical compositions described herein include, but are not limited to, carboxypolymethylene (Carbopol), carboxycellulose (such as sodium carboxymethylcellulose), hydroxycellulose (such as hydroxypropylcellulose and hydroxymethylcellulose), acrylates and alkyl acrylates (such as a mixture of crosslinked acrylates and C10-30 alkyl acrylate copolymers), carrageenan, alginate, dextrin, dextran, gelatin, and xanthan gum, as well as any combination of any of the foregoing. The gelling agent may be present at a concentration ranging from about 0.1% to about 5% by weight of the composition.

[0061] Suitable emulsifiers for use in any of the pharmaceutical compositions described herein include oleyl alcohol, polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, glyceryl stearate, PEG-100 stearate, PEG 75 lanolin, methyl myristate, isopropyl myristate, Arlacel Examples of emulsifiers include, but are not limited to, glyceryl stearate, PEG-100 stearate, steareth-2 and steareth-20, dimethicone copolyol, polysorbate 20 (Tween 20), cetyl esters wax, polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 80 (Tween 80), lauramide DEA, cocamide DEA, and cocamide MEA, phospholipid PTC, alginate, carrageenan, DO glycerin, methylcellulose, polyvinyl alcohol, carbopol, and carbomer, as well as any combination of any of the foregoing. The emulsifier may be present in a concentration ranging from about 0.1% to about 5% by weight of the composition.

[0062] Suitable effervescent agents for use in any of the pharmaceutical compositions described herein include, but are not limited to, coconut fatty acid diethanolamide, ethoxylated sorbitan stearate, palmitic acid, oleic acid, nonylphenol ethoxylate, and fatty alcohol ethoxylate, and any combination of any of the foregoing. The effervescent agent may be present in a concentration ranging from about 0.5% to about 10% by weight of the composition.

[0063] Suitable solvents for use in any of the pharmaceutical compositions described herein include, but are not limited to, water, butylene glycol, propylene glycol, propylene carbonate, caproyl 90, DMSO, ethyl acetate, and diethylene glycol monoethyl ether, and any combination of any of the foregoing.

[0064] Any of the pharmaceutical compositions described herein may further comprise a solubilizing agent. Suitable solubilizing agents for use in any of the pharmaceutical compositions described herein include, but are not limited to, butylene glycol, propylene glycol, propylene carbonate, propylene glycol caprylate (e.g., propylene glycol monocaprylate (Type II) (Caproyl 90, available from Gattefosse of Saint-Priest, France), DMSO, ethyl acetate, and diethylene glycol monoethyl ether, as well as any combination of any of the foregoing. The solubilizing agent may be present in a concentration ranging from about 0.1% to about 30% by weight of the composition.

[0065] In one embodiment, any of the topical compositions described herein further comprises a skin-binding polymer component, which holds the active agent together with the barrier component, and the barrier component is at least partially responsible for providing the barrier properties when the composition is applied to the skin.

[0066] A topical serine protease inhibitor-anti-inflammatory composition In one embodiment, the topical composition comprises: (a) about 0.0001% to about 5% by weight of a serine protease inhibitor; (b) an anti-inflammatory agent (e.g., about 0.0001% to about 25% by weight); (c) about 2% to about 10% by weight of a hydrophobic polymer / hydrophilic polymer composite comprising a poly(vinylpyrrolidone-alkylene) polymer where the alkylene group comprises at least 10 carbon atoms (e.g., a poly(vinylpyrrolidone-alkylene) polymer where the alkylene group comprises at least 10 carbon atoms and a poly(maleic acid / methyl vinyl ether) copolymer), and an optional cellulose-containing polymer; (d) about 0.5% to about 20% by weight of a barrier component or about 0.5% to about 5% by weight of a release agent; and (e) at least about 50% by weight of water.

[0067] The hydrophobic polymer / hydrophilic polymer complex (polymer component) of the topical composition can be provided as a component that exhibits a tendency to bind to skin tissue, holding the serine protease inhibitor in place and allowing the serine inhibitor to be released at a desired rate. When the polymer component is provided as a polymer that has a tendency to bind to skin tissue, the polymer component can be characterized as a skin-binding polymer component.

[0068] The polymer component can be prepared from a topical composition precursor. The topical composition precursor can be prepared by melt processing a hydrophobic polymer composition and a hydrophilic polymer composition to provide an interaction between the hydrophobic and hydrophilic polymer compositions. The term "melt processing" should be understood to refer to mixing the hydrophobic and hydrophilic polymer compositions under conditions that provide a fluid (i.e., liquid) state so that the hydrophobic and hydrophilic polymer components of the hydrophobic and hydrophilic polymer compositions are thoroughly mixed. When the polymers are thoroughly mixed, an interaction is believed to occur between the hydrophobic and hydrophilic polymer components. To allow this interaction to occur, the melt processing temperature can be at least about 50°C, and can be at least about 70°C. Furthermore, the melt processing temperature can be at least about 80°C or even greater than 90°C, but should not be so high as to cause polymer degradation.

[0069] The result of the interaction between the hydrophobic polymer component and the hydrophilic polymer component may be referred to as a hydrophobic polymer / hydrophilic polymer adduct. The term "adduct" is used to refer to the interaction between the hydrophobic polymer component and the hydrophilic polymer component. The interaction may be in the form of a complex, but this is merely a theory. Therefore, the term "adduct" is not intended to limit the polymer components to a particular interaction theory. However, this interaction extends the shelf life of emulsions containing the adduct compared to emulsions in which the adduct is not formed. Emulsions containing the adduct may exhibit enhanced resistance to partitioning into separate phases. It has been found that emulsions formed by simply mixing the hydrophobic and hydrophilic polymer compositions under conditions such that the adduct does not form result in compositions that are more prone to partitioning into separate phases.

[0070] In one embodiment, the interaction between the hydrophobic and hydrophilic polymeric components is achieved in the absence of water.

[0071] The polymer component may include a hydrophobic polymer / hydrophilic polymer adduct and may include other components. Polymer components that may be used in accordance with the present invention may include those taught in U.S. Patent No. 6,756,059, the entire disclosure of which is incorporated herein by reference.

[0072] The polymer component of the composition can be at least partially involved in retaining or isolating the serine protease inhibitor.By binding to skin tissue and retaining the serine protease inhibitor, the polymer component can help deliver the serine protease inhibitor to skin tissue and provide the desired level of activity for a desired period of time.For example, the composition can be provided to adhere or bind to skin tissue for at least about 1 hour, preferably at least about 2 hours, and retain the serine protease inhibitor for this period of time, so that the serine protease inhibitor maintains its activity for this period of time.

[0073] The hydrophobic polymer composition includes at least one hydrophobic polymer and can include a mixture of hydrophobic polymers. The hydrophobic polymer composition can include a component having repeating pyrrolidone / alkylene groups. Exemplary polymers having repeating pyrrolidone / alkylene groups include poly(vinylpyrrolidone / alkylene) polymers. Poly(vinylpyrrolidone / alkylene) polymers include polymers obtained by polymerizing alkylene-substituted vinylpyrrolidone. Poly(vinylpyrrolidone / alkylene) polymers can be represented by the following general formula: [ka] where R represents a carbon chain such as an alkylene group, and n represents the number of repeating units. The R group is preferably long enough so that the polymer remains relatively water-insoluble, but not so long that melt processing of the polymer becomes difficult. The alkylene group may contain at least about 10 carbon atoms and may contain less than about 30 carbon atoms. The alkylene group may contain from about 14 carbon atoms to about 22 carbon atoms, and may contain from about 15 carbon atoms to about 19 carbon atoms.

[0074] The poly(vinylpyrrolidone / alkylene) polymer can have a molecular weight high enough to maintain its water insolubility, but not so high that the polymer is difficult to melt process. The weight-average molecular weight of the poly(vinylpyrrolidone / alkylene) polymer can be from about 3,000 to about 400,000. Another way to characterize the size of a poly(vinylpyrrolidone / alkylene) polymer is by the number of repeating units (n). For a poly(vinylpyrrolidone / alkylene) polymer having a weight-average molecular weight of from about 6,000 to about 30,000, the poly(vinylpyrrolidone / alkylene) polymer can have from about 20 to about 80 repeating units, or from about 30 to about 50 repeating units. It is understood that repeating units refer to the residue of a vinylpyrrolidone / alkylene group.

[0075] Exemplary poly(vinylpyrrolidone / alkylene) polymers include poly(vinylpyrrolidone / 1-eicosene) and poly(vinylpyrrolidone / hexadecene). Poly(vinylpyrrolidone / 1-eicosene), sometimes referred to as PVPE, is commonly used in pharmaceutical and cosmetic preparations. An exemplary form of PVPE for use in accordance with the present invention contains about 43-44 repeating units in length, has a weight average molecular weight of about 17,000, and can be characterized as a paraffin-like solid. This particular PVPE is highly insoluble in water and has extremely low oral toxicity (LD). 50 >17000 mg / kg) and exhibits no demonstrable dermal toxicity. Poly(vinylpyrrolidone / 1-hexadecene) may be referred to as PVPH. An exemplary form of PVPH is a viscous yellow liquid that is insoluble in water and has low oral toxicity (LD 50 >64,000 mg / kg), has approximately 39-40 repeating units, a molecular weight of approximately 14,000, and exhibits no demonstrable skin toxicity.

[0076] PVPE and PVPH are widely used in the skin care industry, typically at concentrations below 1% by weight, due to their different hydrocarbon side chain lengths and their ability to bind to skin. Because the skin care industry generally prefers to apply active agents to the skin using water-based compositions, the use of PVPE and PVPH often requires solvents, surfactants, and emulsifiers to stabilize these polymers in aqueous emulsions. However, many of the solvents, surfactants, and emulsifiers used to stabilize PVPE and PVPH in aqueous emulsions lack the low skin toxicity of PVPE and PVPH. By themselves, PVPE and PVPH lack the sophisticated appeal of cosmetics when applied directly to the skin. They tend to be sticky and greasy.

[0077] The hydrophobic polymer composition can be provided as a single poly(vinylpyrrolidone / alkylene) polymer or as a mixture of different poly(vinylpyrrolidone / alkylene) polymers. The mixture of different poly(vinylpyrrolidone / alkylene) polymers can comprise at least 5 wt. % of the first poly(vinylpyrrolidone / alkylene) polymer, based on the weight of the hydrophobic polymer composition. The hydrophobic polymer composition can comprise from about 5 wt. % to about 54 wt. % of the first poly(vinylpyrrolidone / alkylene) polymer. The second poly(vinylpyrrolidone / alkylene) polymer can be provided in an amount of at least about 46 wt. % based on the weight of the hydrophobic polymer composition, and can range from about 46 wt. % to 95 wt. For hydrophobic polymer compositions containing a first poly(vinylpyrrolidone / alkylene) polymer and a second poly(vinylpyrrolidone / alkylene) polymer, the molar ratio of the first polymer to the second polymer can be from about 1:22 to about 1:1. When the hydrophobic polymer composition contains a mixture of different poly(vinylpyrrolidone / alkylene) polymers, the poly(vinylpyrrolidone / alkylene) polymers may be selected to provide improved properties compared to compositions having a hydrophobic polymer composition containing a single poly(vinylpyrrolidone / alkylene) polymer.

[0078] When the hydrophobic polymer composition is provided as a mixture of PVPH and PVPE, the PVPH may be provided in a range of about 46% to about 95% by weight, and the PVPE may be provided in a range of about 5% to about 65% by weight, based on the weight of the hydrophobic polymer composition.

[0079] The hydrophilic polymer composition may comprise a poly(maleic acid / methyl vinyl ether) copolymer or a mixture of poly(maleic acid / methyl vinyl ether) copolymers. The poly(maleic acid / methyl vinyl ether) copolymers that may be used may have a weight average molecular weight of at least about 50,000, and may have a weight average molecular weight of about 50,000 to about 4,000,000. The weight average molecular weight may be about 70,000 to 2,500,000. A general structural representation of a poly(maleic acid / methyl vinyl ether) copolymer is shown below: [ka] In the formula, n is the number of repeating units. The number n can be from about 200 to about 20,000.

[0080] The hydrophilic polymer composition may include a cellulose-containing polymer or a mixture of cellulose-containing polymers. Examples of cellulose-containing polymers that can be used include cellulose, carboxymethyl cellulose, or a mixture thereof. The molecular weight of the hydrophilic polymer should not be so high that it becomes difficult to process. The weight-average molecular weight of the hydrophilic polymer is preferably sufficient to provide solubility in water, but not so high that it becomes difficult to process. The cellulose that can be used may have a weight-average molecular weight of about 50,000 to about 15,000,000. An exemplary cellulose component that can be used includes cellulose gum.

[0081] The melting temperature refers to the temperature at which the polymer melts, and the maximum temperature refers to the temperature at which the polymer begins to decompose. Exemplary carboxymethyl cellulose polymers that can be used include those with a melting temperature range of about 55°C to about 60°C and a maximum temperature range of about 75°C to about 80°C.

[0082] The hydrophobic and hydrophilic polymer compositions can be combined and heated to provide a melt and mixture, which can be heated to at least about 50°C under mixing to form a complex between the hydrophobic and hydrophilic polymers. Preferably, the composition can be heated to at least about 70°C under mixing to form a complex between the hydrophobic and hydrophilic polymers. It should be understood that polymer melt refers to a polymer that flows or becomes a fluid or liquid when heated, and is not intended to refer to a polymer that forms a liquid as a result of being dissolved in a solvent.

[0083] The complexation step can be carried out in a relatively anhydrous environment. Once the desired level of complexation has occurred, the composition can be hydrated with water. It has been found that the presence of water during the complexation step can have a detrimental effect on the complexation process. The reason for this may be that water is ionic and, as a result, tends to reduce the interaction between the hydrophobic polymer component and the hydrophilic polymer component when they are melt-mixed. Therefore, it is desirable to limit the amount of water present during the complexation step to a level that does not significantly interfere with the complexation step or prevent the formation of the complex. Generally, this level is usually less than about 1% by weight of water. Preferably, the amount of water is limited to less than about 0.5% by weight. It should be understood that references to the amount of water refer to free water.

[0084] The hydrophobic and hydrophilic polymer compositions can be mixed in amounts sufficient to provide a ratio of pyrrolidone groups to hydrophilic groups of about 1:1 to about 5:1. The ratio of structures that cause the observed interaction between the hydrophobic and hydrophilic polymer compositions can be referred to as "functional group parity." The ratio of pyrrolidone groups to the combined carboxylic acid and hydroxyl groups can be about 1.5:1 to about 3:1. To drive the complexation reaction, it is desirable to provide an imbalance between the two types of groups. Therefore, it is generally desirable to provide more pyrrolidone groups than hydrophilic groups.

[0085] During the complex formation step, the amounts of hydrophobic and hydrophilic polymer compositions can be characterized on a weight percent basis. For example, about 2 wt. % to about 28 wt. % of the hydrophilic polymer composition can be combined with about 72 wt. % to about 98 wt. % of the hydrophobic polymer composition can be combined to form the complex. About 8 wt. % to about 25 wt. % of the hydrophilic polymer composition can be combined with about 72 wt. % to about 95 wt. % of the hydrophobic polymer composition can be combined to form the complex. During the complex formation step, the amount of available water in the composition can be less than about 1 wt. While the complex-forming composition can be relatively anhydrous, the amount of water is expected to be about 0.3 wt. % to about 1.0 wt. It should be understood that the amount of water refers to free water.

[0086] After the hydrophobic polymer and hydrophilic polymer have sufficiently reacted or interacted to form a complex, water can be added to the composition to provide a stable aqueous composition that can be further hydrated relatively easily. Initial hydration of the topical composition precursor has been found to be the most difficult hydration step due to the need to control the hydration conditions. After initial hydration to a water content of at least about 30% by weight, further hydration to higher water contents is expected to be relatively easy and can be achieved by simply mixing the composition with water. Therefore, the amount of water provided in the composition when available as a shipping concentrate is preferably about 30% to about 45% by weight. When the composition contains about 30% to about 45% by weight of water, it is expected that the composition can contain about 3% to about 10% by weight of the hydrophilic polymer composition and about 30% to about 50% by weight of the hydrophobic polymer composition.

[0087] Water can be added to the relatively anhydrous composition by mixing the water with the relatively anhydrous composition at a temperature and for a time sufficient to hydrate the composition without significantly losing the interaction between the hydrophobic and hydrophilic polymeric compositions. The relatively anhydrous composition can be hydrated by heating to at least 60°C and adding water during mixing. The composition can be heated to at least about 65°C and at least about 70°C. An exemplary temperature range is from about 65°C to about 80°C.

[0088] Relatively anhydrous compositions can be referred to as topical composition precursors, and generally refer to hydrophobic polymer / hydrophilic polymer adducts containing less than about 1.0% water by weight, if any. The polymer component of the composition can refer to a composition containing only the hydrophobic polymer / hydrophilic polymer adduct, or to a composition in which the hydrophobic polymer / hydrophilic polymer adduct is diluted with water. Generally, it is desirable for the polymer component to have a sufficient amount of water to allow the polymer component to be formulated into a composition containing a cationic pharmaceutically active ingredient according to the present invention. If the polymer component contains too little water, the composition may be difficult to formulate. For example, the polymer component can contain up to about 95% water by weight, and can contain up to about 97% water by weight. The polymer component can have a water concentration of about 30% to about 45% by weight.

[0089] Additional components may be added to the hydrophobic polymer / hydrophilic polymer adduct. For example, it may be desirable to add ingredients that help stabilize the hydrophobic polymer / hydrophilic polymer adduct and help preserve and / or maintain the composition.

[0090] An exemplary polymer component that can be used is available from Skinvisible Pharmaceuticals, Inc. under the name Invisicare™ C-5 composition. The Invisicare™ C-5 composition contains a mixture of poly(vinylpyrrolidone / eicosene) and poly(vinylpyrrolidone / hexadecene), and carboxymethylcellulose. Another exemplary polymer component that can be used is available from Skinvisible Pharmaceuticals, Inc. under the name Invisicare™ M-1 composition. The Invisicare™ M-1 composition contains a mixture of poly(vinylpyrrolidone / eicosene) and poly(vinylpyrrolidone / hexadecene), and poly(maleic acid / methyl vinyl ether) copolymer. In one embodiment, the polymer component contains poly(maleic acid / methyl vinyl ether) copolymer because it helps to aid in the release of the serine protease inhibitor. In another embodiment, when the composition is provided at a neutral pH, polymer components containing poly(maleic acid / methyl vinyl ether) copolymer tend to exhibit a negative charge. The negative charge on the polymer component facilitates the release of the negatively charged active agent.

[0091] The polymer component may be provided in the composition in an amount of about 2% to about 10% by weight, based on the weight of the composition. Additionally, the polymer component may be provided in the treatment composition in an amount of about 3% to about 8% by weight, 4% to about 7% by weight, and about 5% to about 6% by weight.

[0092] The composition can comprise a barrier component to provide the composition with barrier properties.The presence of a barrier component is desirable for treating dermatitis or incontinence.For example, the barrier component can help reduce the passage of bodily excretions such as urine and feces, and can help reduce the contact between urine and feces and skin tissue.

[0093] An exemplary barrier component is a silicone barrier component such as Dow Corning 9045. When a silicone barrier component is provided in a dermatitis treatment composition, it may be provided in an amount of about 0.5% to about 20% by weight based on the weight of the composition. Preferably, the dermatitis treatment composition contains about 0.6% to about 5% by weight of the silicone barrier component based on the weight of the composition. Other exemplary barrier components include allatoin, aluminum hydroxide gel, calamine, cocoa butter, dimethicone, glycerin, kaolin, petrolatum, shark liver oil, white petrolatum, zinc acetate, zinc carbonate, and zinc oxide. When allatoin is used as a barrier component, it may be provided in an amount of about 0.5% to about 2% by weight based on the weight of the composition. When aluminum hydroxide gel is provided as a barrier component, it may be provided in an amount of about 0.15% to about 5% by weight. When calamine is provided as a barrier component, it may be provided in an amount of about 1% to about 25% by weight. When cocoa butter is the barrier component, it may be provided in an amount of 50% to about 90% by weight. When dimethicone is provided as the barrier component, it may be provided in an amount of about 1% to about 30% by weight. When glycerin is provided as the barrier component, it may be provided in an amount of 20% to about 45% by weight. When kaolin is provided as the barrier component, it may be provided in an amount of about 4% to about 20% by weight. When petrolatum is provided as the barrier component, it may be provided in an amount of about 30% to about 90% by weight. When shark liver oil is provided as the barrier component, it may be provided in an amount of about 2% to about 5% by weight. When white petrolatum is provided as the barrier component, it may be provided in an amount of 30% to about 90% by weight. When zinc oxide is provided as the barrier component, it may be provided in an amount of about 0.1% to about 2% by weight. When zinc carbonate is provided as the barrier component, it may be provided in an amount of about 0.2% to about 2% by weight. When zinc oxide is provided as a barrier component, it may be provided in an amount of about 1% to about 25% by weight. It is understood that mixtures of various barrier components may be provided.

[0094] In one embodiment, the topical composition comprises a barrier component.

[0095] In another embodiment, the topical composition does not include a barrier component.

[0096] The composition may contain a sufficient amount of water to provide the desired coverage on the skin tissue while applying the composition to the skin tissue. The water component may be provided as deionized water, filtered water, distilled water, reverse osmosis water, or tap water. If the water contains hardness or other components, it may be desirable to include builders, sequestering agents, and chelating agents to address the water hardness. Generally, the composition may contain at least about 50% water by weight. Furthermore, if too much water is present, it is expected that the emulsion may become unstable. Generally, the amount of water in the composition may be less than about 95% by weight. The amount of water in the composition may be from about 65% to about 93% by weight.

[0097] The composition can include a pH adjuster, buffer, or neutralizer to provide the composition with a pH that helps stabilize the serine protease inhibitor. Exemplary pH adjusters that can be used include sodium hydroxide, potassium hydroxide, triethanolamine, acetic acid, propionic acid, citric acid, succinic acid, and mixtures thereof.

[0098] The polymer component of the composition (such as lotion, cream, gel, or liquid) can at least partially contribute to reducing the irritation of the composition.For example, it is believed that the polymer component can help reduce the irritation of skin tissue.The composition can be provided without a pH adjuster if necessary.However, generally, a buffering agent is incorporated into the composition to help control the pH of the composition.Furthermore, the buffering agent is typically selected as a buffering agent that is compatible with skin problems or does not harm skin tissue.

[0099] Thickeners that can be incorporated into the composition include ingredients that thicken or increase the viscosity of the composition so that it can be easily applied to the skin. Thickeners that can be used in the composition include ingredients often referred to as viscosity control agents.

[0100] Exemplary thickeners or viscosity control agents that can be provided in the hand sanitizing composition include cellulose gum, alkanetriols; acrylates; substituted celluloses such as hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and hydroxypropyl cellulose; cetyl alcohol; gums such as natural or synthetic rubbers; long-chain alcohols, for example, those having about 9 to about 24 carbon atoms; polyglycols such as polyethylene glycol, polypropylene glycol, polybutylene glycol, polyethylene propylene glycol, or mixtures thereof; waxes such as natural or synthetic waxes; hydrogenated oils; glycol esters; fatty acid esters; long-chain acids; acid amides; silicates; and mixtures thereof. An exemplary thickener that can be used is hydroxyethyl cellulose. An exemplary thickener that can be used is a polyacrylic acid thickener available under the name Carbopol, such as Carbopol Ultrez-10 from Lipscom.

[0101] The composition may or may not contain a thickener. When the composition contains a thickener, the thickener can be provided in an amount that provides a desired level of thickening. The composition may contain the thickener in an amount of at least about 0.1% by weight, or at least about 0.4% by weight. Furthermore, the thickener may be provided in an amount of less than about 4% by weight, or less than about 2% by weight.

[0102] The composition may include a release agent that aids in sustained release of the serine protease inhibitor over an extended period of time. The release agent may be provided as a surfactant. A surfactant may also be present to help maintain the composition as an emulsion. Generally, an emulsion refers to a composition that does not phase separate after being left at room temperature for several months. Generally, the composition is preferably stored in a warehouse or storage facility for at least two months, and can remain as an emulsion for those two months. Preferably, the composition can remain as an emulsion for at least one year or at least two years. The ability of the composition to remain as an emulsion can be tested according to an accelerated stability test in which the composition is kept at 40°C for 120 days. This 120-day accelerated stability test is expected to roughly correspond to a period of about two years at room temperature. Generally, the composition is expected to remain as an emulsion after being left at room temperature for two years.

[0103] Exemplary surfactants that can be used as the surfactant component include nonionic surfactants, which help stabilize the emulsion and generally uniformly disperse the cationic pharmaceutically active ingredient. Exemplary nonionic surfactants that can be used include glycerol, such as glycerol monostearate, polysorbates available under the names Tween 80 and Polysorbate 60, and polyoxyethylene stearates. Additionally, mixtures of nonionic surfactants can be included, including mixtures of polysorbates and glycerol stearate. Additional nonionic surfactants that can be used include ethoxylated surfactants, propoxylated surfactants, or ethoxy / propoxylated surfactants. Exemplary ethoxy / propoxylated surfactants include the 10-carbon chain and 9-carbon PO / EO surfactants available under the name Lutensol XP-90 from BASF. Additional nonionic surfactants include sorbitan monolaurate and sorbitan monostearate. Additional surfactants that can be used include those generally characterized as Pluronic surfactants, such as poloxamers. Exemplary surfactants that can be used include Pluronic F-87NF and Pluronic L44NF manufactured by BASF. In one embodiment, the composition does not contain anionic surfactants because they can cause irritation.

[0104] The composition may include a surfactant component in an amount sufficient to provide the composition with the desired emulsion stability and a sufficiently low viscosity without foaming. The amount of surfactant component in the composition may be from about 0.2% to about 7% by weight, from about 0.5% to about 6% by weight, and from about 1% to about 5% by weight. It should be understood that the composition may be provided without any added surfactant component, if desired.

[0105] The composition may contain a release agent that aids in the sustained release of the serine protease inhibitor over a long period of time. The sustained release of the serine protease inhibitor refers to release over a period of time, and this release provides the desired properties. Generally, it is desirable that the composition provides a relatively consistent release of the serine protease inhibitor after the composition is applied to skin tissue. A relatively consistent release can be characterized as a release rate at 1 hour that is within about 50% of the release rate at 30 minutes. A relatively consistent release rate can also be characterized as a release rate at 2 hours that is within about 50% of the release rate at 30 minutes. Preferably, these release rates can be provided within about 25%, more preferably within about 15%.

[0106] Providing a sustained release rate or a relatively consistent release rate over a long period of time can provide at least two advantages.For example, by continuously releasing the serine protease inhibitor over a long period of time, it is possible to extend the pharmaceutical effectiveness of the composition after application to skin tissue.It is expected that extending the pharmaceutical effectiveness of the composition can achieve improved performance.In addition, by controlling the release of the serine protease inhibitor so that the serine protease inhibitor is not released all at once, it is possible to reduce or minimize skin irritation.

[0107] The composition may include a non-surfactant release agent in an amount of about 0.2% to about 7% by weight.

[0108] The composition may contain an emollient to improve the texture of the composition. An emollient is an oily or oily substance that helps to smooth and soften the skin and may also reduce roughness, cracking, or irritation. Exemplary suitable emollients include mineral oil, lanolin oil, coconut oil, cocoa butter, olive oil, almond oil, macadamia nut oil, synthetic jojoba oil, natural jojoba oil, safflower oil, corn oil, liquid lanolin, aloe vera, cottonseed oil, and peanut oil, all having a viscosity ranging from 50 to 500 centipoise (cps).

[0109] Other suitable emollients include squalane, castor oil, polybutene, odorless mineral spirits, sweet almond oil, avocado oil, clophyllum oil, ricin oil, vitamin E acetate, olive oil, linoleic acid alcohol, coconut oil, oleyl alcohol, cereal germ oils such as wheat germ oil, isopropyl palmitate, isopropyl myristate, hexadecyl stearate, butyl stearate, decyl oleate, acetyl glycerides, (C 12 ~C 15 ) octanoates and benzoates of alcohols, octanoates and decanoates of alcohols and polyalcohols such as glycol and glycerol, lysine oleates of alcohols and polyalcohols, for example, isopropyl adipate, hexyl laurate, and octyl dodecanoate.

[0110] Other suitable emollients that are solid or semi-solid at room temperature or ambient temperature may be used in an amount sufficient to provide a liquid topical composition.Such solid or semi-solid cosmetic emollients include hydrogenated lanolin, hydroxylated lanolin, acetylated lanolin, petrolatum, isopropyl lanolate, butyl myristate, cetyl myristate, myristyl myristate, myristyl lactate, cetyl alcohol, isostearyl alcohol and isocetyl lanolate.Exemplary emollients include natural and synthetic esters of stearic acid, stearyl alcohol, palmitic acid, coconut oil, etc.

[0111] The composition may contain an emollient in an amount sufficient to provide a smooth feel.An exemplary range of the emollient in the composition may be at least about 0.5% by weight.Furthermore, the composition may contain an emollient in an amount less than about 3% by weight.It should be understood that the emollient is an optional component of the composition.The composition may be provided without an emollient if necessary.

[0112] The composition can contain a moisturizing agent to provide desired moisturizing effect to skin tissue.The moisturizing agent can be provided as a humectant.Generally, the humectant is a moisturizing agent that promotes water retention due to its moisture-absorbing properties.Exemplary humectants include polymer glycols such as glycerin, polyethylene glycol and polypropylene glycol, and sorbitol such as sorbitol solution, pyrrolidone carboxylic acid, urea, or a mixture thereof.The composition can be provided without a moisturizing agent.

[0113] When the composition includes a humectant, it may be included in an amount of at least about 0.5% by weight. Further, the composition may include a humectant in an amount of less than about 5% by weight.

[0114] An additional ingredient that may be provided as part of the composition is a skin soothing agent, which may also be referred to as a skin protectant. Exemplary skin soothing agents include allatoin, kaolin, cocoa butter, glycerin, shark liver oil, peltratum, zinc oxide, zinc carbonate, zinc acetate, aluminum hydroxide, calamine, and mixtures thereof.

[0115] The skin soothing agent may be provided in the composition in an amount of from about 0.2% to about 2% by weight, preferably from about 0.5% to about 1% by weight.

[0116] The composition may contain a preservative to prevent bacterial, fungal, and / or yeast contamination. Exemplary preservatives that may be used in hand disinfection compositions include phenoxyethanol, benzoic acid, derivatives and salts of benzoic acid, parabens, oxazolidine, chlorinated aromatic compounds and phenols, hydantoin, cresol and derivatives, imidazolinol diurea, iodopropanol butylcarbamate, sulfites, and bisulfites. The composition may contain any preservative commonly used or known to be suitable for topical applications. Exemplary commercially available preservatives include liquid Germal Plus (diazolidinyl urea and iodopropynyl butylcarbamate) and Germaben 11 (diazolidinyl urea and methylparaben and propylparaben).

[0117] The composition can be formulated without preservatives.Preservatives are expected to extend the shelf life of the composition by reducing or preventing the growth of bacteria, fungi, and / or yeast.When the composition contains a preservative, the preservative is preferably provided in an amount sufficient to provide a desired level of protection from the growth of bacteria, fungi, and / or yeast.

[0118] Generally, for most preservatives, it is expected that the amount of preservative may be provided at a level of from about 0.1% to about 1.0% by weight, and may be provided at a level of from about 0.2% to about 0.5% by weight, based on the weight of the composition.

[0119] The composition may contain an antioxidant to extend the shelf life of the composition and provide desired properties when applied to skin tissue.Exemplary antioxidants that can be used include vitamins such as vitamin E, vitamin E acetate, vitamin C, and vitamin D, and their derivatives.Exemplary antioxidants include alpha-tocopherol, which can be characterized as natural or synthetic vitamin E.Additional exemplary antioxidants include propyl, octyl, and dodecyl esters of gallic acid, butylated hydroxyanisole (BHA) (usually as a mixture of ortho- and meta-isomers), butylated hydroxytoluene (BHT), and nordihydroguaiaretic acid, and alkylated parabens such as methylparaben and propylparaben.

[0120] The composition can be formulated without an antioxidant. If the composition includes an antioxidant, the antioxidant can be provided in an amount that provides antioxidant properties to the composition. Generally, the antioxidant can be provided in an amount of about 0.2% to about 2% by weight, and is expected to be provided in an amount of about 0.7% to about 1.5% by weight, based on the weight of the composition. In the case of vitamin E, vitamin E can be included in the composition in an amount of about 0.1% to about 1% by weight, and is expected to be included in an amount of about 0.3% to about 0.8% by weight.

[0121] Chelating agents are substances used to chelate or bind metal ions to certain heterocyclic structures, so that the ions are held in place by chemical bonds from each participating ring. Suitable chelating agents include ethylenediaminetetraacetic acid (EDTA), trisodium EDTA, tetrasodium EDTA, calcium disodium edetate, trisodium EDTA, tetrasodium EDTA, and dipotassium EDTA. One or more chelating agents may be included in the emulsion in an amount ranging from about 0.001 to about 0.1 weight percent. It should be understood that the composition may be provided without a chelating agent.

[0122] Fragrances are aromatic compounds that can impart an aesthetically pleasing fragrance to a composition. Typical fragrances include aromatic substances extracted from plant sources (i.e., rose petals, gardenia flowers, jasmine flowers, etc.), which can be used alone or in any combination to produce essential oils. Alternatively, alcoholic extracts may be prepared to incorporate the fragrance. One or more fragrances may be included in the composition in an amount ranging from about 0.001 to about 10 percent by weight, preferably from about 0.05 to about 5 percent. It should be understood that the composition may be provided without fragrance.

[0123] The composition may also contain non-toxic pharmaceutically and dermatologically acceptable carriers, diluents, and excipients suitable for topical application, as is well known.See, for example, Merck Index, Merck & Co., Rahway, NJ, Bioreversible Carriers in Drug Design, Theory and Application, Roche (ed.), Pergamon Press, (1987); Gilman et al., (eds) (1990) Goodman and Gilman's: The Pharmacological Bases of Therapeutics, 8th Ed., Pergamon Press; Novel Drug Delivery Systems, 2nd Ed., Norris (ed.), Marcel Dekker Inc., (1989); and Remington's Pharmaceutical Sciences.For the standard dosages of conventional pharmacological agents, see, for example, Physicians' Desk Reference (1997 Edition) and American Medical Association (1997) Drug Evaluations (Subscription).

[0124] The above specification, examples, and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention resides in the claims hereinafter appended. [Example]

[0125] Topical compositions according to the present invention may comprise the following ingredients:

[0126] Example 1 [Table 1]

[0127] Example 2 [Table 2]

[0128] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that many modifications may be made to the exemplary embodiments and other arrangements may be devised without departing from the spirit and scope of the invention as set forth above.

[0129] All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. 1. A method for treating Netherton syndrome in a patient in need thereof, comprising administering to the patient effective amounts of (i) a serine protease inhibitor and (ii) an anti-inflammatory agent.

2. 10. The method of claim 1, wherein the serine protease inhibitor and the anti-inflammatory agent are administered to the patient during an occurrence of Netherton syndrome.

3. 3. The method of claim 1 or 2, wherein the method comprises administering effective amounts of a serine protease inhibitor and an anti-inflammatory agent to suppress Netherton syndrome.

4. 1. A method of treating Netherton syndrome in a patient in need thereof, comprising: (a) administering a serine protease inhibitor and an anti-inflammatory agent to the patient when the patient develops Netherton syndrome; and (b) administering a serine protease inhibitor when the patient is in remission; The method comprising:

5. 10. The method of any one of the preceding claims, wherein the patient has a SPINK5 mutation.

6. 6. The method of claim 4 or 5, wherein the method comprises administering effective amounts of a serine protease inhibitor and an anti-inflammatory agent to suppress the occurrence of Netherton syndrome.

7. 6. The method of claim 4 or 5, wherein the method comprises administering an effective amount of a serine protease inhibitor to suppress or inhibit the Netherton syndrome or a symptom thereof.

8. 10. The method of any one of the preceding claims, wherein the serine protease inhibitor is dipalmitoyl hydroxyproline or a pharmaceutically acceptable salt thereof.

9. 10. The method of any one of the preceding claims, wherein the serine protease inhibitor is dipalmitoyl hydroxyproline.

10. 10. The method of any one of the preceding claims, wherein the serine protease inhibitor and the anti-inflammatory agent are applied topically to lesions on the arms and / or legs.

11. 10. The method of any one of the preceding claims, wherein the anti-inflammatory agent is selected from a nonsteroidal anti-inflammatory drug, a corticosteroid, a TNF antagonist, capsaicin, felbinac, ketoprofen, piroxicam, acetylsalicylic acid, glycyrrhetinic acid, or a pharmaceutically acceptable salt thereof, or any combination of any of the foregoing.

12. 10. The method of any one of the preceding claims, wherein the anti-inflammatory agent is selected from diclofenac, ketoprofen, pharmaceutically acceptable salts thereof, or any combination of any of the foregoing.

13. 13. The method of claim 12, wherein the anti-inflammatory agent is diclofenac or a pharmaceutically acceptable salt thereof.

14. 13. The method of claim 12, wherein the anti-inflammatory agent is ketoprofen or a pharmaceutically acceptable salt thereof.

15. A topical pharmaceutical composition comprising (a) a serine protease inhibitor and (b) an anti-inflammatory agent.

16. 16. The topical pharmaceutical composition of claim 15, wherein the serine protease inhibitor is dipalmitoyl hydroxyproline or a pharmaceutically acceptable salt thereof.

17. 17. The topical pharmaceutical composition of claim 15 or claim 16, wherein the serine protease inhibitor is dipalmitoyl hydroxyproline.

18. 18. The topical pharmaceutical composition of any one of claims 15 to 17, wherein the anti-inflammatory agent is selected from a nonsteroidal anti-inflammatory drug, a corticosteroid, a TNF antagonist, capsaicin, felbinac, ketoprofen, piroxicam, acetylsalicylic acid, glycyrrhetinic acid, or a pharmaceutically acceptable salt thereof, or any combination of any of the foregoing.

19. 19. The topical pharmaceutical composition of any one of claims 15 to 18, wherein the anti-inflammatory agent is selected from diclofenac, ketoprofen, a pharmaceutically acceptable salt thereof, or any combination of any of the foregoing.

20. 20. The topical pharmaceutical composition of any one of claims 15 to 19, wherein the anti-inflammatory agent is diclofenac or a pharmaceutically acceptable salt thereof.

21. The topical pharmaceutical composition of any one of claims 15 to 19, wherein the anti-inflammatory agent is ketoprofen or a pharmaceutically acceptable salt thereof.

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