Combination therapy of internal therset

Abstract

The invention relates to a method for treating internal sephton syndrome. In one embodiment, the method comprises administering to the 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's internal sephson syndrome attacks, and (b) administering a serine protease inhibitor when the patient is in a remission state. The invention also relates to a pharmaceutical composition comprising (i) a serine protease inhibitor and (ii) an anti-inflammatory agent.

Description

[0001] Cross - reference to related applications

[0002] This application claims the priority of U.S. Patent Application No. 63 / 481,535, filed on January 25, 2023, the entire content of which is incorporated herein by reference. Technical field

[0003] The present invention relates to methods of treating Netherton syndrome (e.g., in a patient in need thereof). The methods include administering a serine protease inhibitor and an anti - inflammatory agent to the patient. The present invention also relates to pharmaceutical compositions (e.g., topical pharmaceutical compositions) that comprise a serine protease inhibitor and an anti - inflammatory agent. Background art

[0004] Netherton syndrome is a disorder that affects the skin, hair, and immune system. Newborns with Netherton syndrome have red, scaly skin (ichthyosiform erythroderma), and the skin may exude fluid. Some affected infants are born with a tight, transparent sheath called a collodion membrane covering their skin. This membrane usually sheds during the first few weeks of life. Because newborns with this disorder lack the protection provided by normal skin, they are at risk of dehydration and skin or systemic infections (sepsis), which can be life - threatening. Affected infants may also fail to grow and gain weight at the expected rate (failure to thrive). The health of older children and adults with Netherton syndrome generally improves, although they often remain underweight and short.

[0005] After infancy, the severity of skin abnormalities in people with Netherton syndrome varies and may fluctuate over time. The skin may remain red and scaly, especially during the first few years after birth. Some affected individuals have intermittent redness or experience an outbreak of a unique skin abnormality called ichthyosis linearis circumflexa, which involves patches of multiple circular lesions. The causes of disease outbreaks are unknown, but researchers believe stress or infection may be involved.

[0006] 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 can affect hearing if not removed regularly. The skin abnormally absorbs substances such as lotions and ointments, which can lead to overly high blood levels of certain topical medications. Because the skin's ability to resist heat and cold is impaired, affected individuals may have difficulty regulating their body temperature.

[0007] Individuals with Netherton syndrome have hair that is fragile and prone to breakage. Some hair strands vary in diameter, being thick or thin. This characteristic is known as bamboo hair, trichorrhexis nodosa, or trichorrhexis invaginata. In addition to the hair on the scalp, the eyelashes and eyebrows may also be affected. The hair abnormalities of Netherton syndrome may not be noticed in infancy because infants often have sparse hair.

[0008] Most individuals with Netherton syndrome have immune system-related problems such as food allergies, hay fever, asthma, or eczema.

[0009] U.S. Publication No. 2013 / 0338198 discloses a specific therapeutic composition for skin disorders, which comprises a serine protease inhibitor, a hydrophobic polymer / hydrophilic polymer complex comprising a poly(vinylpyrrolidone-alkylene) polymer, a releasing agent, and water.

[0010] There is a need for new methods and compositions for treating Netherton syndrome. SUMMARY OF THE INVENTION

[0011] In one aspect, the present invention relates to a method of treating Netherton syndrome in a patient (e.g., a patient in need). In one embodiment, the method comprises administering to the patient (e.g., an effective amount of) (i) a serine protease inhibitor and (ii) an anti-inflammatory agent.

[0012] In one embodiment, the serine protease inhibitor and the anti-inflammatory agent are administered to the patient during an episode of Netherton syndrome.

[0013] Another aspect is a method of treating Netherton syndrome in a patient (e.g., a patient in need), which comprises administering to the patient (e.g., their effective amounts of)

[0014] (a) a serine protease inhibitor and an anti-inflammatory agent when the patient has an episode of Netherton syndrome; and

[0015] (b) a serine protease inhibitor when the patient is in remission.

[0016] In one embodiment, an episode of Netherton syndrome includes ichthyosis linearis circumflexa.

[0017] In another embodiment, when the patient is in remission, the anti-inflammatory agent is not administered together with the serine protease inhibitor.

[0018] In any of the methods described herein, the serine protease inhibitor is administered alone or in combination with an anti-inflammatory agent in an amount effective to suppress or inhibit Netherton syndrome or its symptoms.

[0019] In one embodiment of any of the methods described herein, a serine protease inhibitor and an anti-inflammatory agent are administered topically.

[0020] The serine protease inhibitor and the anti-inflammatory agent can 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 can be administered concomitantly or sequentially by the same or different routes of administration. The dosage form used can be a lotion, cream, gel, or liquid.

[0021] Another aspect is a pharmaceutical composition (such as a topical pharmaceutical composition, e.g., a pharmaceutical composition for treating Netherton syndrome), which comprises (a) a serine protease inhibitor and (b) an anti-inflammatory agent.

[0022] In one embodiment of any of the methods described herein (and the composition for treating Netherton syndrome in a patient), the patient has a SPINK5 mutation.

[0023] 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.

[0024] In one embodiment of any of the methods described herein (and the composition for treating Netherton syndrome in a patient), the serine protease inhibitor and the anti-inflammatory agent are topically applied to the lesions on the arms and / or calves.

[0025] In one embodiment of any of the methods and compositions described herein, the anti-inflammatory agent is selected from non-steroidal 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, their pharmaceutically acceptable salts, and any combination of any of the foregoing. In one embodiment, the anti-inflammatory agent is diclofenac, ketoprofen, their pharmaceutically acceptable salts, and any combination of any of the foregoing. In another embodiment, the anti-inflammatory agent is diclofenac or its pharmaceutically acceptable salt (e.g., sodium diclofenac, potassium diclofenac, and diclofenac epolamine). In yet another embodiment, the anti-inflammatory agent is ketoprofen or its pharmaceutically acceptable salt (e.g., ketoprofen).

[0026] In one embodiment of any of the compositions described herein, the composition is a topical composition. Detailed Description

[0027] A detailed description of specific aspects of the present application is disclosed herein. It will be understood that the disclosed embodiments are merely examples of ways in which certain aspects of the present application can be implemented and do not represent an exhaustive list of all ways in which the present application can be implemented.

[0028] Definition

[0029] Throughout the specification, it should be understood that unless the context requires otherwise, the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" shall be construed as inclusive. The use of these words may imply the inclusion of one or more elements not specifically recited.

[0030] As used herein, the terms "treatment" or "treating" refer to curing or substantially curing a medical condition, as well as improving, delaying, alleviating, suppressing, or reducing at least one symptom of the medical condition, and include prophylactic treatment and therapeutic treatment. As recognized by those of ordinary skill in the art, treatment performed prior to the clinical manifestation of a medical condition is prophylactic (i.e., it protects the subject from developing the medical condition). If treatment is performed after the medical condition has occurred, the treatment is therapeutic (i.e., it is intended to reduce, improve, control, or maintain the existing medical condition and / or side effects associated with the medical condition).

[0031] As used herein, the term "topical composition" refers to a composition adapted to be applied directly to the skin, nails, or mucosal tissue by hand or by means of a suitable applicator. In one embodiment, as used herein, the term "topical composition" refers to a composition adapted to be applied directly to the skin.

[0032] As used herein, the terms "patient" or "subject" refer to, but are not limited to, humans or animals, including mammals (such as monkeys, guinea pigs, domestic pets, e.g., cats and dogs).

[0033] As used herein, the term "about", when used to refer to weight % or other numerical amounts in a composition, means plus or minus up to 20% (alternatively, up to 10% or 5%) of the reported value.

[0034] Unless otherwise specified, the phrases "weight %", "weight percentage", and " %w / w" describe the weight percentage of a component based on the total weight of the composition containing the component.

[0035] As used herein, the term "pharmaceutically acceptable salt" means salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), organic bases (such as N,N'-diacetyldiethylenetriamine, glucosamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, thiamine, etc.), chiral bases (such as alkylphenylamine, glycidol, phenylglycidol, etc.), natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, etc.), unnatural amino acids (such as D-isomers or substituted amino acids), salts of guanidine, substituted guanidines (where the substituent is selected from nitro, amino, alkyl, alkenyl, or alkynyl), ammonium salts, substituted ammonium salts, and aluminum salts. Other pharmaceutically acceptable salts include acid addition salts (if appropriate), such as sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmitates, mesylates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates, etc. Other pharmaceutically acceptable salts include, but are not limited to, quaternary ammonium salts of the compounds of the present invention with alkyl halides or alkyl sulfates (such as Mel and (Me)2SO4). Pharmaceutically acceptable solvates can be hydrates or include other crystalline solvents, such as alcohols.

[0036] Serine protease inhibitor

[0037] A suitable serine protease inhibitor is dipalmitoyl hydroxyproline.

[0038] 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.

[0039] Anti-inflammatory agent

[0040] Suitable anti-inflammatory agents include non-steroidal 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, biphenylacetic acid, ketoprofen, piroxicam, acetylsalicylic acid, glycyrrhetinic acid, their pharmaceutically acceptable salts, and any combination of any of the foregoing.

[0041] In one embodiment, the anti-inflammatory agent is diclofenac, ketoprofen, a pharmaceutically acceptable salt 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., sodium diclofenac, potassium diclofenac, and epomediol diclofenac). In yet another embodiment, the anti-inflammatory agent is ketoprofen or a pharmaceutically acceptable salt thereof (e.g., ketoprofen).

[0042] Therapeutic method

[0043] The serine protease inhibitor and the anti-inflammatory agent can be administered by any route of administration, such as orally or topically.

[0044] In a preferred embodiment, the serine protease inhibitor is administered topically and the anti-inflammatory agent is administered by any route (e.g., orally, parenterally, or topically).

[0045] In another preferred embodiment, both the serine protease inhibitor and the anti-inflammatory agent are administered topically. For example, based on the total weight of the topical composition, the amount of the 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.

[0046] In certain embodiments of any of the topical compositions described herein, the topical composition comprises about 0.5 to about 5% w / w of diclofenac or a pharmaceutically acceptable salt thereof (e.g., sodium diclofenac, potassium diclofenac, and epomediol diclofenac), such as about 1%, 1.3%, 1.5%, 2%, or 3% w / w of diclofenac or a pharmaceutically acceptable salt thereof (e.g., sodium diclofenac, potassium diclofenac, and epomediol diclofenac).

[0047] In another embodiment, the topical composition comprises ketoprofen.

[0048] In certain embodiments, any of the topical compositions described herein is topically applied to the area to be treated of a subject at least once a day, such as two, three, or four times a day.

[0049] In certain embodiments, any of the topical compositions described herein is topically applied to the area to be treated of a subject once a day.

[0050] In certain embodiments, any of the compositions described herein is topically applied to the area to be treated of a subject twice a day.

[0051] In certain embodiments of any of the topical compositions described herein, the topical composition is an aqueous-based composition (i.e., an aqueous-based composition that contains no or substantially no non-aqueous solvents). The term "substantially free of non-aqueous solvents" means that the formulation contains less than about 2%, less than about 1%, less than about 0.5%, or less than about 0.1% of non-aqueous solvents.

[0052] As a result of applying the composition as a cream or lotion to the skin tissue and rubbing it into the skin tissue, the topical composition can be applied to the skin tissue. The act of rubbing can include gentle rubbing or vigorous rubbing. In one embodiment, although the composition is sometimes characterized as having adhesive or nearly adhesive properties to the skin tissue, the composition is not the type of composition that one would consider to be an adhesive (such as, for example, a hot melt adhesive) that holds two substrates together.

[0053] In one embodiment, the anti-inflammatory agent is diclofenac or a pharmaceutically acceptable salt thereof (e.g., sodium diclofenac, potassium diclofenac, and epolamine diclofenac), which is administered orally. For example, about 100 to about 200 mg / day of diclofenac or a pharmaceutically acceptable salt thereof (e.g., sodium diclofenac, potassium diclofenac, and epolamine diclofenac) can be administered in the methods described herein.

[0054] In another embodiment, the anti-inflammatory agent is ketoprofen or a pharmaceutically acceptable salt thereof (e.g., ketoprofen), which is administered orally. For example, about 50 to about 300 mg / day (e.g., about 75 to about 300 mg / day) of ketoprofen or a pharmaceutically acceptable salt thereof (e.g., ketoprofen) can be administered in the methods described herein.

[0055] Pharmaceutical composition

[0056] Serine protease inhibitors can be incorporated into topical pharmaceutical compositions when administered alone, such as those described in U.S. Patent No. 2013 / 0338198.

[0057] The topical composition can also contain an anti-inflammatory agent.

[0058] Any of the pharmaceutical compositions described herein (e.g., topical pharmaceutical compositions) can contain one or more pharmaceutically acceptable excipients, such as, but not limited to, one or more of the following: penetration enhancers, buffers, pH regulators, surfactants, thickeners, conditioners, preservatives, chelating agents, gelling agents, emulsifiers, foaming agents, colorants, solvents, and any combination of any of the foregoing. Suitable excipients that can be used are also described in U.S. Publication No. 2013 / 0338198, the entire content of which is incorporated herein by reference.

[0059] Suitable penetration enhancers for 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, diols (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, and any combination of any of the foregoing. In one embodiment, the penetration enhancer may be present at a concentration of about 1% to about 20% by weight of the composition.

[0060] Suitable buffering agents for any of the pharmaceutical compositions described herein include, but are not limited to, phosphates such as sodium dihydrogen phosphate, disodium hydrogen phosphate, 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 at a concentration of about 0.01% to about 5% by weight of the composition.

[0061] Suitable pH regulators for 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, and any combination of any of the foregoing. The pH regulator may be present at a concentration of about 0.01% to about 5% by weight of the composition.

[0062] Suitable surfactants include anionic surfactants, nonionic surfactants, zwitterionic surfactants, and any combination of any of the foregoing. Suitable surfactants for any of the pharmaceutical compositions described herein include, but are not limited to, sodium lauryl polyether sulfate, cocamidopropyl betaine, laureth-2, lauramide mea, tea lauryl sulfate, disodium lauryl polyether sulfosuccinate, PEG-120 methyl glucose dioleate, sodium lauryl ether sulfate, lauryl alcohol, polyoxyethylene ethers, polyoxyethylene monostearate glycerol, stearate oxy polyhydrocarbons, polyethylene glycol ester of vitamin E succinate, sorbitan esters, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, organic esters (e.g., vinyl acetate), and polysorbate 80 (i.e., 80), and any combination of any of the foregoing. In one embodiment, the surfactant is present at a concentration of about 1% to about 25% by weight of the composition.

[0063] In another embodiment, any one of the compositions described herein contains at least 2% w / w of a surfactant, such as 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 of a 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 non-ionic surfactant.

[0064] Suitable thickeners for any one of the pharmaceutical compositions described herein include, but are not limited to, polyquaternium-10, sodium chloride, natural plant starches, xanthan gum, gum arabic, guar gum, carrageenan and alginate, and any combination of any of the foregoing. The thickener may be present at a concentration of from about 0.1% to about 10.0% by weight of the composition.

[0065] Suitable conditioning agents (humectants) for any one of the pharmaceutical compositions described herein include, but are not limited to, ammonium chloride citrate, hydrolyzed collagen hydroxypropyl laurylammonium and silicone reagents, and any combination of any of the foregoing. The conditioning agent may be present at a concentration of from about 0.1% to about 10.0% by weight of the composition.

[0066] Suitable preservatives for any one of the pharmaceutical compositions described herein include, but are not limited to, chlorocresol, citric acid, disodium edetate, ethoxylated alcohols, glycerol, 1,2,6-hexanetriol, methyl paraben, parabens, potassium, sorbic acid, propyl gallate, propylene glycol, propyl paraben, sodium bisulfate, sodium citrate, butyl paraben, sodium metabisulfite, chlorocresol, sorbic acid, tannic acid, zinc stearate, butylated hydroxytoluene, butylated hydroxyanisole, benzoic acid, salicylic acid, propyl paraben, dichlorobenzyl alcohol, formaldehyde, α-tocopherol, sodium ascorbate, ascorbic acid, ascorbyl palmitate phenol, m-cresol, bisphenol, cetrimide, benzalkonium chloride, sorbic acid, phenoxyethanol, imidurea, benzyl alcohol and benzoyl peroxide, and any combination of any of the foregoing. The preservative may be present at a concentration of from about 0.1% to about 10.0% by weight of the composition.

[0067] Suitable chelating agents for any of the pharmaceutical compositions described herein include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), citric acid, diethylenetriaminepentaacetic acid (DTPA), desferrioxamine, deferasirox, deferiprone, pyridoxal isonicotinoyl hydrazone, rubiginic acid, picolinic acid, nicotinic acid, neoechinulinic acid, methionine, lactic acid, N,N'-ethylenebis[N-(phosphonomethyl)glycine], tetraethylenepentamineheptaacetic acid (TPHA), tris(2-aminoethyl)amine hexaacetic acid (TAAHA), triethylenetetraminehexaacetic acid (TTHA), oxydiacetic acid bis(ethylenedinitrile) (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, desferrithiozine (DFT), polycarboxylates, hydroxamates, catecholates, hydroxypicolinate, and terephthalamide, and any combination of any of the foregoing. The chelating agent may be present at a concentration of from about 0.01% to about 5% by weight of the composition.

[0068] Suitable gelling agents for any of the pharmaceutical compositions described herein include, but are not limited to, carboxypolymethylene (Carbopol), carboxymethylcellulose (such as sodium carboxymethylcellulose), hydroxycellulose (such as hydroxypropyl cellulose and hydroxymethyl cellulose), acrylates and alkyl acrylates (such as a mixture of crosslinked acrylate and acrylate C10-30 alkyl ester copolymer), carrageenan, alginate, dextrin, dextran, gelatin, and xanthan gum, and any combination of any of the foregoing. The gelling agent may be present at a concentration of from about 0.1% to about 5% by weight of the composition.

[0069] Suitable emulsifiers for any of the pharmaceutical compositions described herein include, but are not limited to, oleyl alcohol, polyoxyethylene oleyl ether, PEG-40 stearate, cetostearyl alcohol polyether-12, cetostearyl alcohol polyether-20, cetostearyl alcohol polyether-30, glyceryl stearate, PEG-100 stearate, PEG 75 lanolin, methyl myristate, isopropyl myristate, Arlacel 165, glyceryl stearate, PEG-100 stearate, steareth-2 and steareth-20, dimethicone copolyol, polysorbate 20 (Tween 20), cetyl esters wax, polysorbate 40 (Tween40), polysorbate 60 (Tween 60), polysorbate 80 (Tween 80), lauramide DEA, cocamide DEA and cocamide MEA, phospholipid PTC, alginate, carrageenan, gluconate DO, methylcellulose, polyvinyl alcohol, Carbopol and Carbomer, and any combination of any of the foregoing. The emulsifier may be present at a concentration of from about 0.1% to about 5% by weight of the composition.

[0070] Suitable foaming agents for any of the pharmaceutical compositions described herein include, but are not limited to, coconut fatty acid diethanolamide, ethoxylated sorbitan stearate, palmitate, oleate, nonylphenol ethoxylate and fatty alcohol ethoxylate, and any combination of any of the foregoing. The foaming agent may be present at a concentration of from about 0.5% to about 10% by weight of the composition.

[0071] Suitable solvents for 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.

[0072] Any of the pharmaceutical compositions described herein may further comprise a solubilizer. Suitable solubilizers for any of the pharmaceutical compositions described herein include, but are not limited to, butylene glycol, propylene glycol, propylene carbonate, propylene glycol caprylate (such as propylene glycol monocaprylate (Type II) (Caproyl 90, available from Gattefossé of Saint Priest, France)), DMSO, ethyl acetate and diethylene glycol monoethyl ether, and any combination of any of the foregoing. The solubilizer may be present at a concentration of from about 0.1% to about 30% by weight of the composition.

[0073] In one embodiment, any of the topical compositions described herein further comprises a skin-bonding polymer component and a barrier component. The skin-bonding polymer component holds the active agent together with the barrier component, and when the composition is applied to the skin, the barrier component is at least partially responsible for providing the barrier properties.

[0074] A topical serine protease inhibitor-anti-inflammatory agent composition

[0075] In one embodiment, the topical composition comprises (a) from about 0.0001 wt% to about 5 wt% serine protease inhibitor, (b) an anti-inflammatory agent (e.g., from about 0.0001 wt% to about 25 wt%), (c) from about 2 wt% to about 10 wt% of a hydrophobic polymer / hydrophilic polymer complex comprising a poly(vinylpyrrolidone-alkylene) polymer wherein the alkylene contains at least 10 carbon atoms (e.g., a poly(vinylpyrrolidone-alkylene) polymer wherein the alkylene contains at least 10 carbon atoms and a poly(maleic acid / methyl vinyl ether) copolymer), and optionally a cellulose-containing polymer, (d) from about 0.5 wt% to about 20 wt% of a barrier component or from about 0.5 wt% to about 5 wt% of a releasing agent, and (e) at least about 50 wt% water.

[0076] The hydrophobic polymer / hydrophilic polymer complex (polymer component) of the topical composition can be provided as a component that exhibits a tendency to adhere to skin tissue and holds the serine protease inhibitor in place and allows the serine protease inhibitor to be released at a desired rate. When the polymer component is provided as a polymer having a tendency to adhere to skin tissue, the polymer component can be characterized as a skin-bonding polymer component.

[0077] 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 polymer composition and the hydrophilic polymer composition. It should be understood that the phrase "melt-processing" refers to mixing the hydrophobic polymer composition and the hydrophilic polymer composition under conditions such that the hydrophobic polymer component of the hydrophobic polymer composition and the hydrophilic polymer component of the hydrophilic polymer composition are in a fluid (i.e., liquid) state so that they are thoroughly mixed. When the polymers are thoroughly mixed, it is believed that an interaction is formed between the hydrophobic polymer component and the hydrophilic polymer component. The melt-processing temperature can be at least about 50°C and can be at least about 70°C to produce such an interaction. Additionally, the melt-processing temperature can be at least about 80°C or at least higher than 90°C, but should not be so high as to cause polymer degradation.

[0078] The result of the interaction between the hydrophobic polymer component and the hydrophilic polymer component can 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. This interaction may be a form of complexation, but that is only theoretical. Thus, the term "adduct" does not imply restricting the polymer components to a specific interaction theory. However, this interaction gives the emulsion containing the adduct a longer storage period compared to an emulsion in which no adduct is formed. The emulsion containing the adduct can exhibit an enhanced ability to resist phase separation of the components. It has been found that an emulsion formed by simply mixing a hydrophobic polymer composition and a hydrophilic polymer composition under conditions such that no adduct is formed results in a composition that is more prone to phase separation of the components.

[0079] In one embodiment, the interaction between the hydrophobic polymer component and the hydrophilic polymer component is achieved in the absence of water.

[0080] The polymer component can include the hydrophobic polymer / hydrophilic polymer adduct and can include other components. The polymer components that can be used according to the present invention can include the polymer components disclosed in U.S. Patent No. 6,756,059. The entire disclosure of U.S. Patent No. 6,756,059 is incorporated herein by reference.

[0081] The polymer component of the composition can be at least partially responsible for retaining or sequestering a 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 the skin tissue to provide a desired level of activity for a desired length of time. For example, a composition can be provided such that it adheres or binds to the skin tissue for at least about one hour, and preferably at least about two hours, and retains the serine protease inhibitor for that length of time such that the serine protease inhibitor remains active for that length of time.

[0082] The hydrophobic polymer composition comprises at least one hydrophobic polymer and can comprise a mixture of hydrophobic polymers. The hydrophobic polymer composition can comprise a component having repeating pyrrolidone / alkylene. Exemplary polymers having repeating pyrrolidone / alkylene include poly(vinylpyrrolidone / alkylene) polymers. Poly(vinylpyrrolidone / alkylene) polymers include those polymers obtained by polymerizing alkylene-substituted vinylpyrrolidone. Poly(vinylpyrrolidone / alkylene) polymers can be represented by the following general formula:

[0083]

[0084] Wherein 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 such that the polymer remains relatively insoluble in water and should not be so long that the polymer is difficult to melt process. The alkylene group can contain at least about 10 carbon atoms and can contain less than about 30 carbon atoms. The alkylene group can contain from about 14 carbon atoms to about 22 carbon atoms and can contain from about 15 carbon atoms to about 19 carbon atoms.

[0085] The poly(vinylpyrrolidone / alkylene) polymer can have a high enough molecular weight such that the polymer retains its water insolubility, but the molecular weight should not be so high that it is difficult to melt process the polymer. The weight average molecular weight of the poly(vinylpyrrolidone / alkylene) polymer can be between about 3,000 and about 400,000. Another way to characterize the size of the poly(vinylpyrrolidone / alkylene) polymer is by the number of repeating units (n). In the case of poly(vinylpyrrolidone / alkylene) polymers having a weight average molecular weight of about 6,000 to about 30,000, the poly(vinylpyrrolidone / alkylene) polymer can have from about 20 to about 80 repeating units and can have from about 30 to about 50 repeating units. It should be understood that the repeating unit refers to the residue of vinylpyrrolidone / alkylene.

[0086] Exemplary poly(vinylpyrrolidone / alkylene) polymers include poly(vinylpyrrolidone / 1-eicosen-1-ene) and poly(vinylpyrrolidone / hexadecene). Poly(vinylpyrrolidone / 1-eicosen-1-ene) may be referred to as PVPE and is commonly used in pharmaceutical and cosmetic formulations. An exemplary form of PVPE used according to the present invention includes from about 43 to 44 lengths of repeating units, has a weight average molecular weight of about 17,000, and can be characterized as a waxy solid. This particular PVPE is highly insoluble in water and has extremely low oral toxicity (LD 50 > 17000 mg / kg), and no significant skin toxicity. Poly(vinylpyrrolidone / 1-hexadecene) can 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 > 64000 mg / kg), has from about 39 to 40 repeating units, a molecular weight of about 14,000, and does not exhibit significant skin toxicity.

[0087] PVPE and PVPH differ in the length of their hydrocarbon side chains and are widely used in the skin care industry, typically at concentrations less than 1 wt% because they can adhere to the skin. Since the skin care industry generally prefers to use water-based compositions to apply active substances to the skin, the use of PVPE and PVPH typically requires solvents, surfactants, and emulsifiers to stabilize these polymers in water emulsions. However, many of the solvents, surfactants, and emulsifiers used to stabilize PVPE and PVPH in water emulsions lack the low skin toxicity of PVPE and PVPH. When applied directly to the skin, PVPE and PVPH themselves lack aesthetic appeal. They tend to be sticky and greasy.

[0088] The hydrophobic polymer composition can be provided as a single poly(vinylpyrrolidone / alkylene) polymer or as a mixture of different poly(vinylpyrrolidone / alkylene) polymers. Based on the weight of the hydrophobic polymer composition, the mixture of different poly(vinylpyrrolidone / alkylene) polymers can contain at least 5 wt% of a first poly(vinylpyrrolidone / alkylene) polymer. The hydrophobic polymer composition can contain from about 5 wt% to about 54 wt% of the first poly(vinylpyrrolidone / alkylene) polymer. Based on the weight of the hydrophobic polymer composition, the second poly(vinylpyrrolidone / alkylene) polymer can be provided in an amount of at least about 46 wt% and can range from about 46 wt% to 95 wt%. For a hydrophobic polymer composition 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 can be selected to provide improved properties compared to a hydrophobic polymer composition having a single poly(vinylpyrrolidone / alkylene) polymer.

[0089] When the hydrophobic polymer composition is provided as a mixture of PVPH and PVPE, based on the weight of the hydrophobic polymer composition, PVPH can be provided in the range of about 46 wt% to about 95 wt%, and PVPE can be provided in the range of about 5 wt% to about 65 wt%.

[0090] 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) copolymer that can 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. The general structure of the poly(maleic acid / methyl vinyl ether) copolymer is represented as follows:

[0091]

[0092] where n is the number of repeating units. The number n may be about 200 to about 20,000.

[0093] The hydrophilic polymer composition may comprise a cellulose-containing polymer, and may include a mixture of cellulose-containing polymers. The cellulose-containing polymers that can be used include cellulose, carboxymethyl cellulose, or a mixture thereof. The hydrophilic polymer should have a molecular weight that is not too high such that the hydrophilic polymer 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 as to be 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. Exemplary cellulose components that can be used include cellulose gum.

[0094] 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 having 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.

[0095] The hydrophobic polymer composition and the hydrophilic polymer composition may be combined and heated to provide a melt and mixed. They may be heated to at least about 50°C under mixing to form a complex between the hydrophobic polymer and the hydrophilic polymer. Preferably, the composition may be heated to at least about 70°C under mixing to form a complex between the hydrophobic polymer and the hydrophilic polymer. It should be understood that a polymer melt refers to a polymer that flows or becomes fluid or liquid when heated, rather than a polymer that forms a liquid due to dissolution in a solvent.

[0096] The complex formation step can be carried out in a relatively anhydrous environment. Once the desired level of complex formation has occurred, the composition can be hydrated with water. It has been found that the presence of water during the complex formation step can have a detrimental effect on the complex formation process. The reason may be that water is ionic and thus, when the hydrophobic polymer component and the hydrophilic polymer component are melt-mixed, the interaction between them may be reduced. Therefore, it is desirable to limit the amount of water present during the complex formation step to a level that does not significantly interfere with or prevent the complex formation step. Generally, this level is typically less than about 1 wt% water. Preferably, the amount of water is limited to less than about 0.5 wt%. It should be understood that the amount of water referred to is free water.

[0097] The hydrophobic polymer composition and the hydrophilic polymer composition can be mixed together in an amount sufficient to provide a ratio of pyrrolidone groups to hydrophilic groups of from about 1:1 to about 5:1. The ratio of the structures that give rise to the observed interaction between the hydrophobic polymer composition and the hydrophilic polymer composition can be referred to as "functional group parity". The ratio of the pyrrolidone groups to the combination of carboxylic acid groups and hydroxyl groups can be from about 1.5:1 to about 3:1. In order to drive the complex formation reaction, it is desirable to provide an imbalance between the two types of groups. Thus, it is generally desirable to provide more pyrrolidone groups than hydrophilic groups.

[0098] During the complex formation step, the amounts of the hydrophobic polymer composition and the hydrophilic polymer composition can be characterized based on weight percentages. For example, from about 2 wt% to about 28 wt% of the hydrophilic polymer composition and from about 72 wt% to about 98 wt% of the hydrophobic polymer composition can be combined to provide for complex formation. From about 8 wt% to about 25 wt% of the hydrophilic polymer composition and from 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 water available in the composition can be less than about 1 wt%. Although the composition for forming the complex can be relatively anhydrous, it is expected that the amount of water can be between about 0.3 wt% and about 1.0 wt%. It should be understood that the amount of water is free water.

[0099] Once the hydrophobic polymer and the 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. It has been found that the first hydration of the topical composition precursor is the most difficult hydration step because the conditions of hydration need to be controlled. After the first hydration to at least about 30% by weight of water content, it is expected that further hydration to a higher water content is relatively easy and can be accomplished by simply mixing the composition with water. Thus, when used as a concentrate for transportation, the amount of water provided in the composition is preferably between about 30% and 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.

[0100] Water can be added to the relatively anhydrous composition by mixing water and the relatively anhydrous composition at a certain temperature and for a time sufficient to hydrate the composition without significant loss of interaction between the hydrophobic polymer composition and the hydrophilic polymer composition. 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. Exemplary temperature ranges are from about 65 °C to about 80 °C.

[0101] The relatively anhydrous composition can be referred to as a topical composition precursor and generally refers to a hydrophobic polymer / hydrophilic polymer adduct containing less than about 1.0% by weight of water (if any). The polymer component of the composition can refer to a composition containing only the hydrophobic polymer / hydrophilic polymer adduct, and it can refer to a composition in which the hydrophobic polymer / hydrophilic polymer adduct is diluted with water. Generally, it is desirable to have a sufficient amount of water in the polymer component such that one can formulate the polymer component into a composition containing a cationic drug active ingredient according to the present invention. If there is too little water in the polymer component, it may be difficult to formulate the composition. For example, the polymer component can contain up to about 95% by weight of water and can contain up to about 97% by weight of water. The polymer component can have a water concentration of about 30% to about 45% by weight.

[0102] Additional components can be added to the hydrophobic polymer / hydrophilic polymer adduct. For example, it may be desirable to add components that help stabilize the hydrophobic polymer / hydrophilic polymer adduct and that help preserve and / or maintain the composition.

[0103] An exemplary polymer component that can be used can be named Invisicare TMThe C-5 composition is obtained from Skinvisible Pharmaceuticals, Inc. Invisicare TM The C-5 composition contains a mixture of poly(vinylpyrrolidone / eicosenylene) and poly(vinylpyrrolidone / hexadecenylene), and carboxymethyl cellulose. Another exemplary polymer component that can be used can be named Invisicare TM The M-1 composition is obtained from Skinvisible Pharmaceuticals, Inc. Invisicare TM The M-1 composition contains a mixture of poly(vinylpyrrolidone / eicosenylene) and poly(vinylpyrrolidone / hexadecenylene), and a poly(maleic acid / methyl vinyl ether) copolymer. In one embodiment, the polymer component comprises a poly(maleic acid / methyl vinyl ether) copolymer as it aids in the release of serine protease inhibitors. In another embodiment, when the composition is provided at neutral pH, the polymer component containing the poly(maleic acid / methyl vinyl ether) copolymer tends to exhibit a negative charge. The negative charge on the polymer component aids in the release of negatively charged active agents.

[0104] Based on the weight of the composition, the polymer component can be provided in the composition in an amount of about 2 wt% to about 10 wt%. Additionally, the polymer component can be provided in the therapeutic composition in amounts of about 3 wt% to about 8 wt%, 4 wt% to about 7 wt%, and about 5 wt% to about 6 wt%.

[0105] The composition can contain a barrier component to provide a composition with barrier properties. The presence of the barrier component is desirable for treating dermatitis or incontinence. For example, the barrier component can help reduce the passage of body wastes such as urine and feces, thus helping to reduce the contact of urine and feces with skin tissue.

[0106] Exemplary barrier components are silicone barrier components, such as Dow Corning 9045. When a silicone barrier component is provided in a dermatitis treatment composition, it can be provided in an amount of about 0.5 wt% to about 20 wt% based on the weight of the composition. Preferably, based on the weight of the composition, the dermatitis treatment composition contains about 0.6 wt% to about 5 wt% of the silicone barrier component. Other exemplary barrier components include allantoin, aluminum hydroxide gel, calamine, cocoa butter, dimethicone, glycerin, kaolin, petrolatum, shark liver oil, white petrolatum, zinc acetate, zinc carbonate, and zinc oxide. When allantoin is used as a barrier component, it can be provided in an amount of about 0.5 wt% to about 2 wt% based on the weight of the composition. When aluminum hydroxide gel is provided as a barrier component, it can be provided in an amount of about 0.15 wt% to about 5 wt%. When calamine is provided as a barrier component, it can be provided in an amount of about 1 wt% to about 25 wt%. When cocoa butter is a barrier component, it can be provided in an amount of 50 wt% to about 90 wt%. When dimethicone is provided as a barrier component, it can be provided in an amount of about 1 wt% to about 30 wt%. When glycerin is provided as a barrier component, it can be provided in an amount of 20 wt% to about 45 wt%. When kaolin is provided as a barrier component, it can be provided in an amount of about 4 wt to about 20 wt%. When petrolatum is provided as a barrier component, it can be provided in an amount of about 30 wt% to about 90 wt%. When shark liver oil is provided as a barrier component, it can be provided in an amount of about 2 wt% to about 5 wt%. When white petrolatum is provided as a barrier component, it can be provided in an amount of 30 wt% to about 90 wt%. When zinc oxide is provided as a barrier component, it can be provided in an amount of about 0.1 wt% to about 2 wt%. When zinc carbonate is provided as a barrier component, it can be provided in an amount of about 0.2 wt% to about 2 wt%. When zinc oxide is provided as a barrier component, it can be provided in an amount of about 1 wt% to about 25 wt%. It should be understood that mixtures of various barrier components can be provided.

[0107] In one embodiment, the topical composition contains a barrier component.

[0108] In another embodiment, the topical composition does not contain a barrier component.

[0109] The composition may contain a sufficient amount of water to allow the composition to be applied to skin tissue while providing a desired coverage on the skin tissue. The water component may be provided as deionized water, filtered water, distilled water, reverse osmosis water, or tap water. In cases where the water includes hardness or other components, it may be necessary to add detergents, polyvalent chelating agents, and chelating agents to control the hardness of the water. Generally, the composition may contain at least about 50% by weight of water. Additionally, it is expected that if there is too much water, 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.

[0110] The composition may contain a pH regulator, buffer, or neutralizing agent to provide a pH to the composition that helps to stabilize the serine protease inhibitor. Exemplary pH regulators that may be used include sodium hydroxide, potassium hydroxide, triethanolamine, acetic acid, propionic acid, citric acid, succinic acid, and mixtures thereof.

[0111] The polymeric component of the composition (such as a lotion, cream, gel, or liquid) may be at least partially responsible for reducing the irritation of the composition. For example, it is believed that the polymeric component can help reduce irritation of the skin tissue. If desired, a composition may be provided that does not contain any pH regulator. However, generally, incorporating a buffer into the composition helps to control the pH of the composition. Additionally, a buffer is typically selected as one that is compatible with or does not harm the skin tissue.

[0112] Thickeners that may be incorporated into the composition include those components that thicken or increase the viscosity of the composition such that the composition can be easily applied to the skin. Thickeners that can be used in the composition include those components that are commonly referred to as viscosity control agents.

[0113] Exemplary thickeners or viscosity control agents that may be provided in the hand sanitizing composition include cellulose gums, alkanetriols; acrylates; substituted celluloses such as hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, and hydroxypropyl cellulose; cetyl alcohol; gums such as natural gums or synthetic gums; long-chain alcohols such as those having from about 9 to about 24 carbon atoms; polyglycols such as polyethylene glycol, polypropylene glycol, polybutylene glycol, polypropylene glycol, or mixtures thereof; waxes such as natural waxes or synthetic waxes; hydrogenated oils; glycol esters; fatty acid esters; long-chain acids; amides; silicates; and mixtures thereof. An exemplary thickener that may be used is hydroxyethyl cellulose. An exemplary thickener that may be used is a polyacrylic acid thickener that can be obtained under the name Carbopol, such as Carbopol Ultrez-10 from Lipscomb.

[0114] The composition may or may not contain a thickening agent. When the composition contains a thickening agent, the thickening agent may be provided in an amount that provides the desired level of thickening. The composition may contain the thickening agent in an amount of at least about 0.1% by weight, and may contain the thickening agent in an amount of at least about 0.4% by weight. Additionally, the amount of the thickening agent may be provided in an amount less than about 4% by weight, and may be less than about 2% by weight.

[0115] The composition may contain a release agent to assist in the sustained release of the serine protease inhibitor over an extended period of time. The release agent may be provided as a surfactant. Additional surfactants may be present to help maintain the composition as an emulsion. Generally, an emulsion refers to a composition that resists phase separation after being stored at room temperature for several months. Generally, it is desirable for the composition to be stored in a warehouse or storage room for at least two months, and to remain an emulsion during these two months. Preferably, the composition may remain an emulsion for at least one year or at least two years. The ability of the composition to remain an emulsion can be tested according to an accelerated stability test, in which the composition is maintained at 40 °C for 120 days. It is expected that this 120-day accelerated stability test roughly corresponds to a period of about two years at room temperature. Generally, it is expected that the composition can remain an emulsion after being stored at room temperature for two years.

[0116] Exemplary surfactants that can be used as surfactant components include nonionic surfactants, which help to stabilize the emulsion and provide a generally uniform distribution of the components containing the cationic pharmaceutical active ingredient. Exemplary nonionic surfactants that can be used include glyceryl stearates, such as glyceryl monostearate, polysorbates, such as polyoxyethylene stearates obtained under the names Tween 80 and polysorbate 60. Additionally, mixtures of nonionic surfactants can be included, including mixtures of polysorbates and glyceryl stearates. Additional nonionic surfactants that can be used include ethoxylated surfactants, propoxylated surfactants, or ethoxylated / propoxylated surfactants. Exemplary ethoxylated / propoxylated surfactants include those having a 10-carbon chain and 9 PO / EO and that can be obtained 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 surfactants generally characterized as Pluronic surfactants (such as poloxamers). Exemplary surfactants that can be used include Pluronic F-87NF and Pluronic L44NF from BASF. In one embodiment, the composition does not contain anionic surfactants because they may cause irritation.

[0117] The composition may comprise an amount of surfactant component sufficient to provide the desired emulsion stability and a low enough viscosity without foaming. The amount of surfactant component in the composition can be from about 0.2 wt% to about 7 wt%, from about 0.5 wt% to about 6 wt%, and from about 1 wt% to about 5 wt%. It should be understood that a composition without any surfactant component can be provided if desired.

[0118] The composition may contain a release agent to assist in the sustained release of the serine protease inhibitor over an extended period of time. Sustained release of the serine protease inhibitor refers to release over a period of time, where the release provides the desired properties. Generally, after the composition is applied to skin tissue, it is desirable for the composition to provide a relatively consistent release of the serine protease inhibitor. Relatively consistent release can be characterized as a release rate at one hour within about 50% of the release rate at 30 minutes. Additionally, relatively consistent release rate can be characterized as a release rate at two hours within about 50% of the release rate at 30 minutes. Preferably, these release rates can be provided within about 25%, and more preferably within about 15%.

[0119] At least two advantages can be obtained by providing a sustained release rate or a relatively constant release rate over an extended period of time. For example, by providing sustained release of the serine protease inhibitor over an extended period of time, it is possible to extend the efficacy of the composition after it is applied to skin tissue. By extending the efficacy of the composition, enhanced performance is expected. Additionally, by controlling the release of the serine protease inhibitor such that it is not released in a single instant, it is possible to reduce or minimize skin irritation.

[0120] The composition may comprise from about 0.2 wt% to about 7 wt% of a non-surfactant release agent.

[0121] The composition may comprise an emollient for improving the texture of the composition. An emollient is an oily or greasy substance that helps to smooth and soften the skin and can also reduce skin roughness, cracking, or irritation. Exemplary suitable emollients include mineral oil with a viscosity of 50 to 500 centipoise (cps), lanolin oil, coconut oil, cocoa butter, olive oil, almond oil, macadamia nut oil, synthetic jojoba oil, natural Sonoran jojoba oil, safflower oil, corn oil, liquid lanolin, aloe vera, cottonseed oil, and peanut oil.

[0122] Other suitable emollients include squalane, castor oil, polybutene, odorless mineral spirits, sweet almond oil, avocado oil, dichlorophyllum oil, ricinoleic acid oil, vitamin E acetate, olive oil, linolenyl alcohol, coconut oil, oleyl alcohol, cereal germ oil (such as wheat germ oil), isopropyl palmitate, isopropyl myristate, cetyl stearate, butyl stearate, decyl oleate, acetyl glycerides, octanoates and benzoates of (C 12 -C 15 ) alcohols, octanoates and decanoates of alcohols and polyols (such as those of ethylene glycol and glycerol), ricinoleic acid esters of alcohols and polyols (such as those of isopropyl adipate, hexyl laurate and octyl laurate).

[0123] Other suitable emollients that are solid or semi-solid at room temperature or ambient temperature can 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 isoaetyl lanolate. Exemplary emollients include stearic acid, stearyl alcohol, palmitic acid, natural and synthetic esters such as coconut oil.

[0124] The composition can contain an amount of emollient sufficient to provide a smooth feel. An exemplary range of emollient in the composition can be at least about 0.5% by weight. Additionally, the composition can contain less than about 3% by weight of emollient. It should be understood that emollient is an optional component of the composition. If desired, the composition can be free of emollient.

[0125] The composition can contain a humectant to provide the desired moisturizing effect to skin tissue. The humectant can act as a hydrating agent. Generally, a hydrating agent is a wetting agent that promotes the retention of moisture due to its water-absorbing properties. Exemplary hydrating agents include glycerin, polymeric glycols (such as polyethylene glycol and polypropylene glycol), and sorbitol (such as sorbitol solution, pyrrolidone carboxylic acid, urea, or mixtures thereof). The composition can be free of humectant.

[0126] When the composition contains a humectant, its content can be at least about 0.5% by weight. Additionally, the composition can contain less than about 5% by weight of humectant.

[0127] Additional components that can be provided as part of the composition are skin soothers or components, which can also be referred to as skin protectants. Exemplary skin soothers include allantoin, kaolin, cocoa butter, glycerin, shark liver oil, petrolatum, zinc oxide, zinc carbonate, zinc acetate, aluminum hydroxide, calamine, and mixtures thereof.

[0128] The skin soother can be provided in the composition in an amount of about 0.2% to about 2% by weight, preferably about 0.5% to about 1% by weight.

[0129] The composition can include a preservative to prevent contamination by bacteria, fungi, and / or yeast. Exemplary preservatives useful in the hand sanitizing composition include phenoxyethanol, benzoic acid, derivatives and salts of benzoic acid, parabens, oxazolidines, chlorinated aromatic compounds and phenols, hydantoins, cresols and derivatives, imidazolidinyl urea, iodopropynyl butylcarbamate, sulfites and bisulfites. The composition can include any commonly used or known preservative suitable for topically applied compositions. Exemplary commercially available preservatives include Liquid Germal Plus (diazolidinyl urea and iodopropynyl butylcarbamate) and Germaben II (diazolidinyl urea and methylparaben and propylparaben).

[0130] The composition can be formulated without a preservative. It is expected that the preservative will increase the shelf life of the composition by reducing or preventing the growth of bacteria, fungi, and / or yeast. When the composition includes a preservative, the preservative is preferably provided in an amount sufficient to provide the desired level of prevention of the growth of bacteria, fungi, and / or yeast.

[0131] Generally, for most preservatives, based on the weight of the composition, it is expected that the amount of the preservative can be provided at a level of about 0.1% to about 1.0% by weight, and can be provided at a level of about 0.2% to about 0.5% by weight.

[0132] The composition can include an antioxidant to help increase the shelf life of the composition and provide the 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 α-tocopherol, which is characterized by natural or synthetic vitamin E. Additional exemplary antioxidants include propyl, octyl, and dodecyl esters of gallic acid, butylated hydroxyanisole (BHA) (usually a mixture of ortho and meta isomers), butylated hydroxytoluene (BHT), and nordihydroguaiaretic acid, and alkylated parabens such as methylparaben and propylparaben.

[0133] The composition can be formulated without an antioxidant. When the composition contains an antioxidant, the antioxidant can be provided in an amount that provides antioxidant properties in the composition. Generally, based on the weight of the composition, it is expected that the antioxidant can be provided in an amount of about 0.2% to about 2% by weight, and can be provided in an amount of about 0.7% to about 1.5% by weight. In the case of vitamin E, it is expected that vitamin E can be included in the composition in an amount of about 0.1% to about 1% by weight, and can be included in an amount of about 0.3% to about 0.8% by weight.

[0134] Chelating agents are substances used to chelate or bind metal ions with a specific heterocyclic structure such that the ion is held by the chemical bonds of each participating ring. Suitable chelating agents include ethylenediaminetetraacetic acid (EDTA), trisodium EDTA, tetrasodium EDTA, calcium disodium EDTA, trisodium EDTA, tetrasodium EDTA, and dipotassium EDTA. One or more chelating agents can optionally be included in the emulsion in an amount of about 0.001% to about 0.1% by weight. It should be understood that a composition without chelating agents can be provided.

[0135] Fragrances are aromatic compounds that can impart an aesthetically pleasing fragrance to the composition. Typical fragrances include aromatic substances extracted from plant sources (i.e., rose petals, gardenia, jasmine, etc.), which can be used alone or in any combination to make essential oils. Alternatively, alcohol extracts can be prepared to blend fragrances. One or more fragrances can optionally be included in the composition in an amount of about 0.001% to about 10% by weight, preferably about 0.05% to about 5% by weight. It should be understood that the composition can be fragrance-free.

[0136] It is well known that the composition may also contain non-toxic, pharmaceutically and dermatologically acceptable carriers, diluents and excipients suitable for topical application. See, for example, Merck Index, Merck & Co., Rahway, N.J., 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 Edition, Pergamon Press, Novel Drug Delivery Systems, 2nd Edition, Norris (ed.) Marcel Dekker Inc., (1989) and Remington's Pharmaceutical Sciences. For standard doses of conventional pharmaceuticals, see, for example, Physicians Desk Reference (1997 Edition); and American Medical Association (1997) Drug Evaluation (subscription).

[0137] The foregoing description, examples and data provide a complete description of the manufacture and use of the compositions of the present invention. Since many embodiments of the present invention can be made without departing from the spirit and scope of the present invention, the present invention resides in the claims appended hereto.

[0138] Example

[0139] The topical composition according to the present invention may comprise the following components.

[0140] Example 1

[0141]

[0142]

[0143] Example 2

[0144] Ingredient Function Serine protease inhibitor Activity Anti-inflammatory agent Activity Carbopol-Ultrez-10 Thickener Polysorbate 60 Release agent EDTA Chelating agent Pluronic F-87NF Release agent <![CDATA[Invisicare TM C-5 Composition]]> Skin-bonding polymer Allantoin Skin-soothing agent Stearic acid Emollient Coconut oil Emollient Triethanolamine pH regulator Phenoxyethanol Preservative

[0145] Although the present invention has been described herein with reference to specific embodiments, it should be understood that these embodiments merely illustrate the principles and applications of the present invention. Accordingly, it should be understood that various modifications can be made to the exemplary embodiments without departing from the spirit and scope of the present invention as set forth above, and other arrangements can be designed.

[0146] All publications and patent applications cited in this application are hereby incorporated by reference as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference herein.

Claims

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

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

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

4. 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 Netherton syndrome occurs in the patient; and (b) administering a serine protease inhibitor while the patient is in remission.

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

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

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

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

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

10. A method as claimed in any preceding claim wherein the serine protease inhibitor and anti-inflammatory agent are applied topically to lesions on the arms and / or lower legs.

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

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

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

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

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

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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