Treatment for particular skin disorders with rapamycin

Abstract

The present invention relates to methods of treating a microcystic lymphatic malformation, angiofibroma or venous malformation (e.g., in a patient in need thereof) by topically administering to the patient a topical composition comprising rapamycin or a pharmaceutically acceptable salt thereof and a hydrophobic polymer / hydrophilic polymer adduct or diethylene glycol monoethyl ether.

Description

161737-01401TREATMENT FOR PARTICULAR SKIN DISORDERS WITH RAPAMYCIN

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 764,218, filed February 27, 2025, which is hereby incorporated by reference.Field of the Invention

[0002] The present invention relates to methods of treating a microcystic lymphatic malformation, angiofibroma, or venous malformation (e.g., in a patient in need thereof) by topically administering to the patient a topical composition comprising rapamycin or a pharmaceutically acceptable salt thereof and a hydrophobic polymer / hydrophilic polymer adduct or diethylene glycol monoethyl ether.Background of the Invention

[0003] Microcystic lymphatic malformation (MLM) is a disorder that affects the skin, lymph nodes and throat. Newborns with MLM have cysts that appear diffuse and grow without clear borders. The microcystic cysts are fluid-filled vesicles that appear as blisters or blood blisters. Complications from this disease include infections around the malformations, especially within the neck and mouth area and leakage of lymphatic fluid from the malformations. Bleeding into these malformations can cause pain and discomfort. MLMs in visible sites can cause disfigurement and patients with these lesions are self-conscious and impacted psychologically. Additional complications include malformations in the respiratory system causing trouble with breathing, eating, drinking, and speech, malformations in the chest causing heart and breathing complications, and malformations in the gastrointestinal tract causing chronic diarrhea and loss of important proteins.

[0004] Currently, there is no cure for MLM as most malformations cannot be completely removed by surgery. Treatment options include observation, compression therapy, sclerotherapy, drug therapy such as topical creams, laser therapy and surgical excision of smaller malformations.1161737.01401 / 156261385v.3

[0005] Garcia-Montero et al., J Am Acad Dermatol., 2019, 80:508-515, disclose a study in which 11 patients having superficial lymphatic malformations and an average age of 10.5 years were treated with a 0.1, 0.4, or 0.8% topical rapamycin formulation.

[0006] Venous malformations occur when veins do not form normally, and are the most common type of vascular anomaly. Venous malformations can be isolated from normal veins or can drain into them. They can occur anywhere on the body, but are most common on the head and neck. Venous malformations can look like a bruise on the skin or a growth under the skin. They typically have a bluish color if in or near the skin.

[0007] Angiofibromas are benign skin tumors made up of blood vessels and fibrous tissue. Angiofibromas can present as a firm, flesh-colored dome-shaped papule less than 5 mm in diameter. Complications of angiofibromas may include itchiness and bleeding.

[0008] U.S. Patent Publication No. 2020 / 0000778 discloses an anhydrous composition which includes one or more mTOR inhibitors, one or more solvents, one or more gelling agents, and one or more antioxidants, and methods of treating skin disorders using such a composition.

[0009] There is a current need for improved treatments of MLM, angiofibromas, and venous malformations.Summary of the Invention

[0010] In one aspect, the present invention relates to a topical composition comprising (a) rapamycin, a prodrug thereof (e.g., temsirolimus), or a pharmaceutically acceptable salt thereof and (b) a hydrophobic polymer / hydrophilic polymer adduct or diethylene glycol monoether.

[0011] In another aspect, the present invention relates to a method of treating a microcystic lymphatic malformation, angiofibroma (e.g., facial angiofibroma), or venous malformation (e.g., in a patient in need thereof) comprising topically administering to the patient a topical composition comprising rapamycin or a pharmaceutically acceptable salt thereof and a hydrophobic polymer / hydrophilic polymer adduct. In one embodiment, an effective amount of the topical composition is administered.2161737.01401 / 156261385v.3

[0012] In one embodiment, the topical composition is rapamycin or a pharmaceutically acceptable salt thereof. In another embodiment, the topical composition is rapamycin. In yet another embodiment, the topical composition is temsirolimus or a pharmaceutically acceptable salt thereof.

[0013] In one embodiment, the polymer adduct comprises a poly(vinylpyrrolidone-alkylene) polymer and cellulose. The poly(vinylpyrrolidone-alkylene) polymer may comprise a polymer having an alkylene group containing about 10 carbon atoms to about 30 carbon atoms. In one embodiment, the cellulose has an average molecular weight of about 50,000 to about 15,000,000. The cellulose may be, for example, carboxymethyl cellulose. In one embodiment, the hydrophobic polymer / hydrophilic polymer adduct comprises about 2 wt. % to about 28 wt. % of the hydrophilic polymer and about 72 wt. % to about 98 wt. % of the hydrophobic polymer.

[0014] In one embodiment, the topical composition comprises about 0.1 to about 8 wt. % of rapamycin or a pharmaceutically acceptable salt thereof. In another embodiment, the topical composition comprises about 0.5 to about 6 wt. % of rapamycin or a pharmaceutically acceptable salt thereof. In yet another embodiment, the topical composition comprises about 3 to about 6 wt. % of rapamycin or a pharmaceutically acceptable salt thereof. In one embodiment, the topical composition comprises rapamycin.

[0015] In one embodiment, the topical composition includes from about 50% and about 95% solvent, such as from about 50 to about 92%, from about 70 to about 90%, or from about 80 to about 90% solvent, based upon the total weight of the composition.

[0016] In one embodiment, the topical composition is aqueous. The topical composition may comprise at least about 50 wt. % water.

[0017] In one embodiment, the aqueous topical composition includes di ethylene glycol monoethyl ether and water. In one particular embodiment, the ratio of diethylene glycol monoethyl ether to water ranges from about 5:1 to about 1:1, such as from about 3:1 to about 1:1. In one embodiment, the aqueous topical composition includes from about 30 to about 70 wt. % (such as about 40 to about 65 wt.%) of diethylene glycol monoethyl ether. The aqueous topical composition may include from about 10 to about 45 wt. % (such as about 20 to about 40 wt. %) of water. The aqueous topical composition may include from about 1 to about 10 wt. % (such as about 3 to about 8 wt. %) of medium chain triglycerides. The aqueous topical 3161737.01401 / 156261385v.3composition may further include one or more of (or all of) (i) about 0.2 wt. % to about 6 wt. % (such as about 0.2 to about 3 wt. %) of a surfactant (e.g., poloxamer, such as poloxamer 407), (ii) about 0.1 wt. % to about 10 wt. % (such as about 2 wt. % to about 8 wt. %, about 3 wt. % to about 8 wt. %, or about 4 wt. % to about 7 wt. %) of a thickener or viscosity modifier (such as methyl vinyl ether and maleic acid copolymer, carbomer (e.g., carbomer homopolymer type B), hexadecyl povidone, eicosyl povidone, or any mixture of any of the foregoing), and (iii) about 0.1 wt. % to about 5 wt. % (such as about 0.2 to about 1 wt. %) of a moisturizer (e.g., allantoin). The composition may further include one or more of (or all of) (i) about 0.01 to about 1 wt. %, such as 0.02 to about 0.5 wt. %, of a chelator, such as edetate disodium, and (ii) about 0.1 to about 2 wt. % (such as about 0.2 to about 1 wt. %) of a preservative, such as phenoxyethanol. The aqueous topical composition may include about 2 to about 5 wt. % rapamycin, such as 2, 2.5, 3, 3.5, or 4% wt. % rapamycin, a prodrug thereof (e.g., temsirolimus), or a pharmaceutically acceptable salt thereof (e.g., rapamycin). The aqueous topical composition may be a lotion.

[0018] In another embodiment, the aqueous topical composition includes about 30 to about 70 wt. % (such as about 40 to about 65 wt. %) of diethylene glycol monoethyl ether and about 1 to about 20 wt. % water, such as about 2 to about 8 wt. % water. In one particular embodiment, the ratio of di ethylene glycol monoethyl ether to water ranges from about 20:1 to about 2:1, such as from about 15 : 1 to about 5:1. The aqueous topical composition may include from about 10 to about 50 wt. % (such as about 20 to about 40 wt. % or about 25 to about 35 wt. %) of medium chain triglycerides. In one embodiment, the aqueous topical composition includes from about 40 to about 65 wt. % (such as about 45 to about 60 wt.%) of diethylene glycol monoethyl ether. The aqueous topical composition may include from about 2 to about 10 wt. % (such as about 3 to about 8 wt. %) of water. The aqueous topical composition may further include one or more of (or all of) (i) about 0.2 wt. % to about 6 wt. % (such as about 0.2 to about 3 wt. %) of a surfactant (e.g., poloxamer, such as poloxamer 407), (ii) about 0.1 to about 5 wt. % (such as about 0.3 to about 3 wt. %) of an emulsifier (such as polysorbate 60), (iii) about 0.1 wt. % to about 12 wt. % (such as about 2 wt. % to about 10 wt. %, about 3 wt. % to about 9 wt. %, or about 5 wt. % to about 7 wt. %) of a thickener or viscosity modifier (such as methyl vinyl ether and maleic acid copolymer, methyl hydroxy propyl cellulose (MHPC), hexadecyl povidone, eicosyl povidone, or any mixture of any of the foregoing), and (iv) about 0.1 wt. % to about 5 wt. % (such as about 0.2 to about 1 wt. %) of a moisturizer (e.g., allantoin). The composition may further include one or more of (or all of) (i) about 0.01 to about 1 wt. %,4161737.01401 / 156261385v.3such as 0.02 to about 0.5 wt. %, of a chelator, such as edetate disodium, (ii) about 0.1 to about 2 wt. % (such as about 0.2 to about 1 wt. %) of a preservative, such as phenoxyethanol, and (iii) about 0.01 to about 3 wt. % (such as 0.02 to about 0.5 wt. %) of an antioxidant, such as butylated hydroxytoluene (BHT). The aqueous topical composition may include about 2 to about 5 wt. % rapamycin, such as 2, 2.5, 3, 3.5, or 4% wt. % rapamycin, a prodrug thereof (e.g., temsirolimus), or a pharmaceutically acceptable salt thereof (e.g., rapamycin). The aqueous topical composition may be a lotion.

[0019] In one embodiment, the composition comprises one or more of (i) about 0.5 wt. % to about 6 wt. % of a surfactant, (ii) about 0.1 wt. % to about 4 wt. % (such as about 0.1 wt. % to about 3 wt. % or 2 wt. %) of a thickener or viscosity modifier, or (iii) about 0.5 wt. % to about 5 wt. % of a moisturizer.

[0020] In one embodiment, the topical composition is a lotion. In another embodiment, the topical composition is a gel.

[0021] In one embodiment, the topical composition is anhydrous and includes rapamycin, a prodrug thereof (e.g., temsirolimus), or a pharmaceutically acceptable salt thereof (e.g., rapamycin) in a solvent comprising diethylene glycol monoethyl ether. In one embodiment, the composition includes from about 30 to about 70 wt. % (such as about 40 to about 65 wt.%) of diethylene glycol monoethyl ether. The topical composition may include additional solvents, such as polyethylene glycol (e.g., PEG 400), isopropyl alcohol, diisopropyl adipate, propylene glycol di capryl ate / di caprate or any combination of any of the foregoing. For example, the topical composition may include about 10 to about 20 wt. % polyethylene glycol (e.g., PEG 400), about 10 to about 20 wt. % isopropyl alcohol, about and 10 to about 20 wt. % diisopropyl adipate or propylene glycol dicaprylate / dicaprate. The composition may be a gel and further include a gelling agent, such as hydroxypropyl cellulose. The gelling agent may be present in an amount ranging from about 0.2 to about 7 wt. %, such as about 0.5 to about 5 wt. %. The composition may further an antioxidant or preservative, such as butylated hydroxytoluene. The antioxidant and / or preservative may be present in an amount ranging from about 0.02 to about 2 wt. %, such as from about 0.05 to about 0.5 wt. %. The aqueous topical composition may include about 2 to about 5 wt. % rapamycin, such as 2, 2.5, 3, 3.5, or 4% wt. % rapamycin, a prodrug thereof (e.g., temsirolimus), or a pharmaceutically acceptable salt thereof (e.g., rapamycin).5161737.01401 / 156261385v.3

[0022] In one embodiment, the method comprises once daily administration of the topical composition. In another embodiment, the method comprises twice daily administration of the topical composition.

[0023] In one embodiment, the topical composition is applied to blisters on the patient. In another embodiment, the topical composition is applied to venous malformations on the patient. In another embodiment, the topical composition is applied to angiofibromas on the patient. In yet another embodiment, the topical composition is applied all over the body.

[0024] In one embodiment, the patient suffers from microcystic lymphatic malformation.

[0025] In another embodiment, the patient suffers from venous malformation.

[0026] In another embodiment, the patient suffers from angiofibromas.Brief Description of the Drawings

[0027] In order that the present disclosure may be readily understood, aspects of the invention are illustrated by the way of examples in the accompanying drawings.

[0028] Figures 1A and IB are graphs of rapamycin-loaded lotion of Example 4 where Figure 1A is the Flow sweep rheological profile showing shear stress (triangles) and viscosity (squares) as a function of shear rate (1 / s) and Figure IB is the rheological profile showing the storage modulus (G’, triangles), loss modulus (G”, squares), and complex viscosity (q*, circles) as a function of angular frequency (rad / s).Detailed Description of the Invention

[0029] Disclosed herein are detailed descriptions of specific aspects of the present application. It will be understood that the disclosed embodiments are merely examples of the way in which certain aspects of the application can be implemented and do not represent an exhaustive list of all of the ways the application may be embodied.6161737.01401 / 156261385v.3Definitions

[0030] Throughout this specification it is to be understood that the words "comprise" and "include" and variations such as "comprises," "comprising," "includes," "including" are to be interpreted inclusively, unless the context requires otherwise. The use of these words may imply the inclusion of an element or elements not specifically recited.

[0031] As used herein, the terms “treatment” or “treating” relate to curing or substantially curing a condition, as well as ameliorating, delaying, relieving, inhibiting, or reducing at least one symptom of the condition, and are inclusive of prophylactic treatment and therapeutic treatment. As would be recognized by one or ordinary skill in the art, treatment that is administered prior to clinical manifestation of a condition is prophylactic (i.e., it protects the subject against developing the condition). If the treatment is administered after manifestation of the condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, control, or maintain the existing condition and / or side effects associated with the condition).

[0032] Microcystic lymphatic malformations generally refers to lymphatic cysts that are smaller than 2 cm without clear borders and appear diffuse. Cysts typically appear as blisters or blood blisters.

[0033] Venous malformations generally refers to abnormal collections of enlarged, thinwalled veins that may occur anywhere in the body.

[0034] Angiofibroma generally refers to benign skin tumors characterized by the presence of fibrovascular tissue.

[0035] The term "topical composition" as used herein refers to a composition suitable for application directly to the skin, nail, or mucosal tissue, either by hand or through a suitable applicator. In one embodiment, the term "topical composition" as used herein refers to a composition suitable for application directly to the skin.

[0036] Rapamycin is also known as sirolimus.

[0037] The term “patient” or “subject” as used herein refers to, but is not limited to, a human or an animal including mammals (such as monkeys, guinea pig, domestic pets, for instance, cats and dogs).7161737.01401 / 156261385v.3

[0038] As used herein, the term “about” when used to refer to weight % in composition or other numeral amounts means plus or minus up to 20% (alternatively, up to 10% or 5%) of the reported value.

[0039] The phrases "weight %" “% by weight” and "% w / w" describe the weight percentage(s) of an ingredient based on the total weight of a composition containing the ingredient, unless otherwise indicated.

[0040] The term “pharmaceutically acceptable salt(s)” as used herein means 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, trialkylamine, thiamine, and the like), salts of chiral bases (such as alkylphenylamine, glycinol, phenyl glycinol and the like), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, and the like), salts of non-natural amino acids (such as D-isomers or substituted amino acids), salts of guanidine, salts of substituted guanidine (wherein 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) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like. Yet other pharmaceutically acceptable salt(s) include, but are not limited to, quaternary ammonium salts of the compounds of the present invention with alkyl halides or alkyl sulphates (such as Mel and (Me)2SO4). Pharmaceutically acceptable solvates may be hydrates or comprise other solvents of crystallization such as alcohols.

[0041] In some embodiments, any of the topical compositions or transdermal compositions described herein are topically applied to the area of the subject to be treated at least once a day, such as two, three or four times a day.

[0042] In some embodiments, any of the topical compositions or transdermal compositions described herein are topically applied to the area of the subject to be treated once a day.

[0043] In some embodiments, any of the compositions described herein are topically applied to the area of the subject to be treated twice a day.8161737.01401 / 156261385v.3

[0044] In some embodiments of any of the topical compositions described herein, the topical composition is an aqueous based composition (i.e., a water-based composition, which is free or substantially free of non-water solvent.) The term “substantially free of non-water solvent” 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% of non-water solvent.

[0045] The topical composition can be applied to skin tissue as a result of applying the composition as a cream or lotion to the skin tissue and rubbing onto the skin tissue. The action of rubbing may include gentle rubbing or vigorous rubbing. In some embodiments, although the composition is sometimes characterized as having a binding or almost adhesive property with respect to skin tissue, the composition is not the type of composition that one would consider to be an adhesive that holds two substrates together such as, for example, a hot melt adhesive. In some embodiments, the topical composition is an adhesive for applying to the skin.

[0046] In some embodiments of any of the transdermal compositions described herein, the transdermal composition is an adhesive.

[0047] The transdermal composition can be applied to skin tissue as a result of applying the composition as an adhesive comprising a component that goes underneath the skin. In some embodiments, the component comprises a pharmaceutical composition that is released underneath the skin.Pharmaceutical Compositions

[0048] The rapamycin or pharmaceutically acceptable salt thereof when administered alone may be incorporated in a topical pharmaceutical composition, such as those described in U.S. Patent No. 2013 / 0338198 or U.S. Patent No. 8,318,818, both of which are hereby incorporated by reference.

[0049] Any of the pharmaceutical compositions (e.g., topical pharmaceutical compositions) described herein may comprise one or more pharmaceutically acceptable excipients, such as, but not limited to, one or more of a penetration enhancer, a buffering agent, a pH modifier, a surfactant, a thickener, a conditioning agent, a preservative, a chelating agent, a gelling agent,9161737.01401 / 156261385v.3an emulsifier, a foaming agent, a colorant, a solvent, 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 hereby incorporated by reference in its entirety.

[0050] In some embodiments, suitable penetration enhancers 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 derivatives thereof, 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, and any combination of any of the foregoing. In some instances, the penetration enhancer may present in a concentration ranging from about 1% to about 20% by weight of the composition.

[0051] In some embodiments, suitable buffering agents for use in any of the pharmaceutical compositions described herein include, but are not limited to, phosphates, such as monobasic sodium phosphate, dibasic sodium phosphate, lactates, and citrates such as citric acid monohydrate, sodium citrate dihydrate, and any combination of any of the foregoing. In some embodiments, the buffering agent may be present in an amount of from about 0.01% to about 5% wt%, based on the total weight of the composition.

[0052] In some embodiments, suitable pH modifiers 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, and any combination of any of the foregoing. The pH modifier may be present in an amount of from about 0.01% to about 5% wt%, based on the total weight of the composition.

[0053] In some embodiments, suitable surfactants include anionic surfactants, non-ionic surfactants, amphoteric surfactants, and any combination of any of the foregoing. In some embodiments, suitable surfactants 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, TEA lauryl sulfate, disodium laureth sulfosuccinate, PEG-120 methyl glucose dioleate, sodium lauryl ether sulfate, lauryl alcohol, polyoxyethylene ether, polyoxyethylene glycerol monostearate, stearic acid ester oxygen polyhydrocarbon, vitamin E succinate polyethylene glycol ester, sorbitan esters, polyoxyethylene castor oil,10161737.01401 / 156261385v.3polyoxyethylene hydrogenated castor oil, poloxamer, organic esters (e.g. ethylene acetate), and polysorbate (such as polysorbate 60 or polysorbate 80 (i.e., TWEEN® 80)), and any combination of any of the foregoing. In some embodiments, the surfactant is present in an amount of from about 1% to about 25% wt%, based on the total weight of the composition. In some instances, the surfactant is present in an amount of from about 0.01 to about 25 wt%, based on the total weight of the composition.

[0054] In some embodiments, any of the compositions described herein contain 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 some embodiments, the surfactant comprises an anionic surfactant, an amphoteric surfactant, or a combination thereof. In some embodiments, the surfactant comprises an anionic surfactant and an amphoteric surfactant. In some embodiments, the surfactant comprises an anionic surfactant, an amphoteric surfactant, and a non-ionic surfactant. In some embodiments, the surfactant comprises an anionic surfactant and a nonionic surfactant.

[0055] In some embodiments, suitable thickeners and viscosity modifiers for use in any of the pharmaceutical compositions described herein include, but are not limited to, polyquatemium-10, methyl vinyl ether and maleic acid copolymer (such as Gantrez™ S-97 HSU available from ISP Chemicals LLC, UK), carbomer (e.g., carbomer homopolymer type B also known as allyl pentaerythritol crosslinked), hexadecyl povidone (available as Ganex™ V-216 from ISP Freetown Fine Chemical Inc, USA), eicosyl povidone (available as Ganex™ V-220 from ISP Freetown Fine Chemical Inc, USA), sodium chloride, natural plant starch, xanthan gum, arabic gum, guar gum, carrageenin and seaweed gel, and any combination of any of the foregoing. In some embodiments, the thickener may be present in an amount of from about 0.1 % to about 10.0 % wt%, based on the total weight of the composition.

[0056] In some embodiments, suitable conditioning agents (moisturizers) for use in any of the pharmaceutical compositions described herein include, but are not limited to, citrimonium chloride, laurdimonium hydroxypropyl hydrolyzed collagen and silicone agents, and any combination of any of the foregoing. In some embodiments, the conditioning agent may be present in an amount of from about 0.1% to about 10.0% wt%, based on the total weight of the composition.11161737.01401 / 156261385v.3

[0057] In some embodiments, suitable preservatives for use in any of the pharmaceutical compositions described herein include, but are not limited to, chloro-m-cresol, citric acid, disodium edetate (also known as edetate disodium), ethoxylated alcohol, glycerin, 1,2,6-hexanetriol, methylparaben, parabens, potassium, sorbate, 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, di chlorobenzyl alcohol, formaldehyde, alpha-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. In some embodiments, the preservative may be present in an amount of from about 0.1% to about 10.0% wt%, based on the total weight of the composition.

[0058] In some embodiments, suitable chelating agents for use in any of the pharmaceutical compositions described herein include, but are not limited to, ethylenediaminetatraacetic acid (EDTA), citric acid, diethylenetriaminepentaacetic acid (DTP A), deferoxamine, deferasirox, deferiprone, pyridoxal isonicotinoyl hydrazone, rhodotorulic acid, picolinic acid, nicotinic acid, neoaspergillic acid, methionine, lactic acid, N,N-ethylene bis[N-phopsphonomethyl]glycine, tetraethylenepentaamine heptaacetic acid (TPHA), tri(2-aminoethyl)aminehexaacetic acid (TAAHA), triethylenetetraaminehexaacetic acid (TTHA), oxybis(ethylenenitrilo)tetraacetic acid (BAETA), trans- 1,2-cy cl ohexaneediaminetetraacetic acid, salicyclic acid, tartaric acid, 2,3 -dihydroxybenzoic acid, penicillamine, etidronic acid (1-hydroxyethan-l,l-diyl)bis(phosphonic acid), dimercaptosuccinic acid, dimercapto-propane sulfonate, dimercaprol, desferrithiocin (DFT), polycarboxylates, hydroxamates, catecholates, hydroxypyridonates, and teraphthalamides, and any combination of any of the foregoing. In some embodiments, the chelating agent may be present in an amount of from about 0.01% to about 5% wt%, based on the total weight of the composition.

[0059] In some embodiments, suitable gelling agents for use in any of the pharmaceutical compositions described herein include, but are not limited to, carboxypolymethylene (Carbopol), carboxycelluloses (such as sodium carboxymethylcellulose), hydroxycelluloses (such as hydroxypropylcellulose and hydroxymethylcellulose), acrylates and alkyl acrylates (such as mixtures of cross-linked acrylate and C10~30 alkyl acrylate copolymers), acrylate copolymers, carrageenin, alginates, dextrins, dextrans, gelatins and xanthan gum, and any 12161737.01401 / 156261385v.3combination of any of the foregoing. In some embodiments, the gelling agent may be present in an amount of from about 0.1% to about 5% wt%, based on the total weight of the composition.

[0060] In some embodiments, suitable emulsifiers for use in any of the pharmaceutical compositions described herein include, but are not limited to, 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 165, 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 8010), lauramide DEA, cocamide DEA, and cocamide MEA, Phospholipid PTC, alginate, carrageenan, Glucate DO, methylcellulose, polyvinyl alcohol, Carbopol and Carbomer, and any combination of any of the foregoing. In some embodiments, the emulsifier is Captex 355 EP / NF (a medium-chain triglyceride). In some embodiments, the emulsifier may be present in an amount of from about 0.1% to about 8% wt% and alternatively from about 0.1 to about 5 wt%, based on the total weight of the composition.

[0061] In some embodiments, suitable foaming agents for use in any of the pharmaceutical compositions described herein include, but are not limited to, coconut fatty acid di ethanol ami de, ethoxylated sorbitan stearate, palmitate, oleate, nonyl phenol ethoxylates and fatty alcohol ethoxylates, and any combination of any of the foregoing. In some embodiments, the foaming agent may be present in an amount of from about 0.5% to about 10% wt%, based on the total weight of the composition.

[0062] In some embodiments, suitable solvents for use in any of the pharmaceutical compositions described herein include, but are not limited to, water, isopropyl alcohol, diisopropyl adipate, butylene glycol, propylene glycol, propylene carbonate, caproyl 90, DMSO, ethyl acetate and diethylene glycol monoethyl ether, medium-chain triglycerides (such as Miglyol® 812 N available from IOI Oleochemical pharma, Germany), paraffin, and any combination of any of the foregoing.

[0063] In some embodiments, any of the pharmaceutical composition described herein may further comprise a solubilizing agent. In some embodiments, 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 (such as 13161737.01401 / 156261385v.3propylene glycol monocaprylate (type II) (Caproyl 90 available from Gattefosse of Saint-Priest, France)), DMSO, ethyl acetate and diethylene glycol monoethyl ether (Transcutol® P available from Sigma Aldrich, Ireland), polyvinyl caprolactam-polyvinyl acetate-poly ethylene glycol (Soluplus® available from BASF SE, Germany), and any combination of any of the foregoing. In some embodiments, the solubilizing agent may be present in an amount of from about 0.1% to about 70% wt%, alternatively from about 0.1 to about 60 wt%, and alternative from about 10 to about 60 wt%, based on the total weight of the composition.

[0064] In some embodiments, 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 agents together with the barrier component, and the barrier component is at least in part responsible for providing barrier properties when the composition is applied to skin.

[0065] In some embodiments, the topical composition comprises (a) about 0.0001 wt. % to about 8 wt. % of rapamycin or a pharmaceutically acceptable salt thereof, and (b) about 2 wt. % to about 10 wt. % of a hydrophobic polymer / hydrophilic polymer complex comprising a poly(vinylpyrrolidone-alkylene) polymer wherein the alkylene group contains at least 10 carbon atoms (e.g., a poly(vinylpyrrolidone-alkylene polymer wherein the alkylene group contains at least 10 carbon atoms and a poly (maleic acid / methylvinylether) copolymer) and optionally a cellulose containing polymer, (e) about 0.5 wt. % to about 20 wt. % of a barrier component or about 0.5 wt. % to about 5 wt. % of a release agent, and (f) at least about 50 wt. % water, based on the total weight of the composition.

[0066] In some embodiments, the hydrophobic polymer / hydrophilic polymer complex (polymer component) of the topical composition can be provided as a component that exhibits a tendency to bond to skin tissue and hold the rapamycin in place and allow the rapamycin to be released at a desired rate. When the polymer component is provided as a polymer that has an ability to bond to skin tissues, the polymer component can be characterized as a skin bonding polymer component.

[0067] In some embodiments, 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 14161737.01401 / 156261385v.3composition. It should be understood that the phrase “melt processing” refers to mixing the hydrophobic polymer composition and the hydrophilic polymer composition under conditions that provide 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 sufficiently mix. When the polymers are sufficiently mixed, it is believed that an interaction forms between the hydrophobic polymer component and the hydrophilic polymer component. In some embodiments, the melt processing temperature can be at least about 50° C. and can be at least about 70° C. to generate this interaction. In some embodiments, the melt processing temperature can be at least about 80° C. or at least above 90° C, but should not be so high that it causes degradation of the polymers.

[0068] 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. The interaction may be a form of complexing, but that is only theory. Accordingly, the term “adduct” is not meant to limit the polymer component to a particular theory of interaction. The interaction, however, provides an emulsion containing the adduct with an enhanced shelflife compared with an emulsion where an adduct has not been formed. An emulsion containing the adduct can exhibit enhanced resistance to splitting into separate phases. It has been found that an emulsion formed by simply mixing the hydrophobic polymer composition and the hydrophilic polymer composition under conditions so that the adduct is not formed results in a composition that has a greater tendency to split into separate phases.

[0069] In some embodiments, the interaction between the hydrophobic polymer component and the hydrophilic polymer component is achieved in the absence of water.

[0070] The polymer component can include a hydrophobic polymer / hydrophilic polymer adduct and can include other components. Polymer components that can be used according to the invention can include the polymer components disclosed in U.S. Pat. No. 6,756,059. The entire disclosure of U.S. Pat. No. 6,756,059 is incorporated herein by reference.

[0071] In some embodiments, the polymer component of the composition can be, at least in part, responsible for holding or isolating the rapamycin. By binding to skin tissue and holding on to the rapamycin, the polymer component can help deliver the rapamycin to the skin tissue 15161737.01401 / 156261385v.3to provide a desired level of activity for a desired length of time. In some embodiments, for example, the composition can be provided so that it adheres or binds to skin tissue for at least about one hour, and preferably at least about two hours, and holds the rapamycin for that length of time so that the rapamycin remains active for that length of time.

[0072] In some embodiments, the hydrophobic polymer composition includes at least one hydrophobic polymer and can include a mixture of hydrophobic polymers. In some instances, the hydrophobic polymer composition can include components having repeating pyrrolidone / alkylene groups. In some embodiments, exemplary polymers having repeating pyrrolidone / alkylene groups 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:wherein R represents a carbon chain such as an alkylene group and n represents the number of repeating units. The R group is preferably sufficiently long so that the polymer remains relatively water insoluble and should not be too long so that the polymer is difficult to melt process. In some embodiments, the alkylene group can contain at least about 10 carbon atoms and can contain less than about 30 carbon atoms. In some embodiments, the alkylene group can contain about 14 carbon atoms to about 22 carbon atoms and can contain about 15 carbon atoms to about 19 carbon atoms.

[0073] In some embodiments, the poly(vinylpyrrolidone / alkylene) polymers can have a molecular weight that is sufficiently high so that the polymer maintains its water insolubility, but the molecular weight should not be so high that it becomes difficult to melt process the polymer. In some embodiments, 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 16161737.01401 / 156261385v.3number of repeating units (n). In the case of a poly(vinylpyrrolidone / alkylene) polymer having a weight average molecular weight of about 6,000 to about 30,000, the poly(vinylpyrrolidone / alkylene) polymer can have about 20 to about 80 repeating units, and can have about 30 to about 50 repeating units. It should be understood that repeating units refer to the residues of vinylpyrrolidone / alkylene groups.

[0074] In some embodiments, exemplary poly(vinylpyrrolidone / alkylene) polymers include poly(vinylpyrrolidone / l-eicosene) and poly(vinylpyrrolidone / hexadecene). Poly(vinylpyrrolidone / l-eicosene) can be referred to as PVPE and is commonly used in pharmaceutical and cosmetic preparations. In some embodiments, an exemplary form of PVPE for use according to the invention includes about 43 to 44 repeating units in length and 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 an extremely low oral toxicity (LD5O>17OOO mg / kg) and exhibits no demonstrable dermal toxicity. Poly(vinylpyrrolidone / 1-hexadecene) can be referred to as PVPH. In some embodiments, an exemplary form of PVPH is available as a viscous yellow liquid that is insoluble in water and has a low oral toxicity (LD5O>64OOO mg / kg), has about 39 to 40 repeating units, a molecular weight of about 14,000, and exhibits no demonstrable dermal toxicity.

[0075] PVPE and PVPH differ in the length of the hydrocarbon side chain, and are used extensively in the skin care industry, usually at concentrations of less than 1% by weight, because of their ability to bind to skin. Because the skin care industry generally prefers to apply actives to skin using a water-based composition, the use of PVPE and PVPH often requires solvents, surfactants, and emulsifiers to stabilize these polymers in a water emulsion. However, many of the solvents, surfactants and emulsifiers used to stabilize PVPE and PVPH in a water emulsion lack the low dermal toxi cities of PVPE and PVPH. PVPE and PVPH by themselves lack a cosmetically elegant appeal when applied directly to the skin. They tend to be sticky and greasy.

[0076] In some embodiments, the hydrophobic polymer composition can be provided as a single poly(vinylpyrrolidone / alkylene) polymer or as a mixture of different poly(vinylpyrrolidone / alkylene) polymers. In some embodiments, the mixture of different poly(vinylpyrrolidone / alkylene) polymers can include at least 5 wt. % of a first poly(vinylpyrrolidone / alkylene) polymer based on the weight of the hydrophobic polymer composition. In some embodiments, the hydrophobic polymer composition can include about 17161737.01401 / 156261385v.35 wt. % to about 54 wt. % of the first poly(vinylpyrrolidone / alkylene) polymer. In some embodiments, the second poly(vinylpyrrolidone / alkylene) polymer can be provided in an amount of at least about 46 wt. % and can be in a range of about 46 wt. % to 95 wt. % based on the weight of the hydrophobic polymer composition. In some embodiments, for a hydrophobic polymer composition containing a first poly(vinylpyrrolidone / alkylene) polymer and a second poly(vinylpyrrolidone / alkylene) polymer, the mole ratio of the first polymer to the second polymer can be about 1:22 to about 1:1. In some embodiments, 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 composition having a hydrophobic polymer composition containing a single poly(vinylpyrrolidone / alkylene) polymer.

[0077] In some embodiments, when the hydrophobic polymer composition is provided as a mixture of PVPH and PVPE, the PVPH can be provided in a range of about 46 wt. % to about 95 wt. % and the PVPE can be provided in a range of about 5 wt. % to about 65 wt. %, based upon the weight of the hydrophobic polymer composition.

[0078] In some embodiments, the hydrophilic polymer composition can include a poly(maleic acid / methylvinylether) copolymer or a mixture of poly(maleic acid / methylvinylether) copolymers. Poly(maleic acid / methylvinylether) copolymers that can be used can have a weight average molecular weight of at least about 50,000, and can have a weight average molecular weight of about 50,000 to about 4,000,000. In some embodiments, the weight average molecular weight can be about 70,000 to 2,500,000. A general structural representation of a poly(maleic acid / methylvinylether) copolymer is shown below:wherein n is the number of repeating units. The number n can be about 200 to about 20,000.18161737.01401 / 156261385v.3

[0079] In some embodiments, the hydrophilic polymer composition can include a cellulose containing polymer and can include a mixture of cellulose containing polymers. Cellulose containing polymers that can be used include cellulose, carboxymethyl cellulose, or mixtures thereof. The hydrophilic polymer should have a molecular weight that is not too high so that the hydrophilic polymer becomes difficult to process. The weight average molecular weight of the hydrophilic polymers is preferably sufficient to provide solubility in water but not too high to become difficult to process. In some embodiments, cellulose that can be used can 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.

[0080] In some embodiments, additional hydrophilic polymers that can be used according to the invention include starch, derivatives of starch, polyvinyl alcohol, cellulose, derivatives of cellulose, carboxymethyl cellulose, cyclodextrins, and dextrans. In some embodiments, exemplary starches include amylopectin and polyglucose. In some embodiments, the weight average molecular weight of the hydrophilic polymers is preferably sufficient to provide solubility in water but not too high to become difficult to process. Starches that can be used according to the invention preferably have a weight average molecular weight of between about 50,000 and about 20,000,000. In some embodiments, a derivative of starch that can be used according to the invention includes partially hydrolized starch. In some embodiments, cellulose that can be used according to the invention preferably has a weight average molecular weight of between about 50,000 and about 15,000,000. In some embodiments, polyglucose that can be used according to the invention can be characterized as low fraction polyglucose having a weight average molecular weight of between about 60,000 and about 90,000, and high fraction polyglucose having a weight average molecular weight of between about 90,000 and about 300,000. In some embodiments, an exemplary low fraction polyglucose material that can be used according to the invention is available under the name Dextran-70. In general, this type of polyglucose has all alpha 1-6 linkages. In some embodiments, starch derivatives that can be used according to the invention include those starch derivatives having alpha 1-4 linkages. In some embodiments, an example of this type of starch derivative includes cyclodextrins. Preferred cyclodextrins that can be used according to the invention are those that act to provide a cavity within the molecule large enough to contain components desirable for topical applications. In some embodiments, preferably, the cyclodextrins that can be used according to the invention have a molecular weight of between about 900 and about 1,400. In some19161737.01401 / 156261385v.3embodiments, polyvinyl alcohols that can be used according to the invention preferably have a weight average molecular weight of between about 50,000 and about 200,000.

[0081] In some embodiments, the hydrophilic polymer is present in the composition in an amount ranging of from about 0.1 to about 8 wt% and alternatively from about 0.1 to about 5 wt%, based on the total weight of the composition.

[0082] 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. In some embodiments, 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.

[0083] In some embodiments, exemplary hydrophilic polymers that can be used according to the invention include those polymers having the following melting temperature range and the following maximum temperature range beyond which it is expected decomposition of the polymer will occur. In some embodiments, exemplary poly (maleic acid / methylvinylether) copolymers that can be used include those having a melting temperature range of between about 60° C. and about 65° C. and a maximum temperature range of between about 80° C. and about 90° C. In some embodiments, exemplary polyacrylic acid polymers that can be used include those having a melting temperature range of between about 65° C. and about 70° C. and a maximum temperature range of between about 80° C. and about 90° C. In some embodiments, exemplary carboxymethyl cellulose polymers that can be used include those having a melting temperature range of between about 55° C. and about 60° C. and a maximum temperature range of between about 75° C. and about 80° C. In some embodiments, exemplary polyvinyl alcohol polymers that can be used include those having a melting temperature range of between about 50° C. and about 55° C. and a maximum temperature range of between about 65° C. and about 70° C. In some embodiments, exemplary starches that can be used include those having a melting temperature range of between about 40° C. and about 45° C. and a maximum temperature range of between about 50° C. and about 55° C. In some embodiments, exemplary dextrans that can be used include those having a melting temperature range of between about 37° C. and about 40° C. and a maximum 10 temperature range of between about 45° C. and about 50° C. In some embodiments, exemplary P-cyclodextrins that can be used according to the invention include those having a melting temperature range of between about20161737.01401 / 156261385v.340° C. and about 45° C. and a maximum temperature range of between about 65° C. and about 70° C.

[0084] In some embodiments, the hydrophobic polymer composition and the hydrophilic polymer composition can be combined and heated to provide a melt and mixed. They can be heated to at least about 50° C. under mixing to form a complex between the hydrophobic and hydrophilic polymers. In some embodiments, 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 a polymer melt refers to a polymer that flows or becomes fluid or liquid when heated and is not meant to refer to a polymer that forms a liquid as a result of being dissolved in a solvent.

[0085] In some embodiments, 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 deleterious effect on the complex formation process. The reason for this may be that water is ionic and, as a result, can have a tendency to reduce the interaction between the hydrophobic polymer component and the hydrophilic polymer component when they are melt mixed. Accordingly, it is desirable to limit the amount of water present during the complex formation step to a level that does not significantly interfere with the complex formation step or prevent the formation of a complex. In some embodiments, this level is typically less than about 1 wt. % water. In some embodiments, preferably, the amount of water is limited to less than about 0.5 wt. %. It should be understood that the reference to the amount of water refers to free water.

[0086] In some embodiments, the hydrophobic polymer composition and the hydrophilic polymer composition can be mixed together in amounts sufficient to provide a ratio of pyrrolidone groups to hydrophilic groups of about 1:1 to about 5:1. The ratio of the structures causing the observed interaction between the hydrophobic polymer composition and the hydrophilic polymer composition can be referred to as “functional group parity.” In some embodiments, the ratio of pyrrolidone groups to the combination of carboxylic acid groups and hydroxyl groups can be 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. In some embodiments, it is generally desirable to provide more of the pyrrolidone groups than the hydrophilic groups.21161737.01401 / 156261385v.3

[0087] During the complex formation step, the amounts of hydrophobic polymer composition and hydrophilic polymer composition can be characterized on a weight percent basis. In some embodiments, for example, about 2 wt. % to about 28 wt. % hydrophilic polymer composition and about 72 wt. % to about 98 wt. % hydrophobic polymer composition can be combined to provide for complex formation. In some embodiments, about 8 wt. % to about 25 wt. % hydrophilic polymer composition and about 72 wt. % to about 95 wt. % hydrophobic polymer composition can be combined to form the complex. In some embodiments, during the complex formation step, the amount of water available in the composition can be less than about 1 wt. %. In some embodiments, although the complex forming composition 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 refers to free water.

[0088] Once the hydrophobic polymers and the hydrophilic polymers 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 relatively easily further hydrated. It has been found that the first hydration of the topical composition precursor is the most difficult hydration step because of the need to control the conditions of hydration. In some embodiments, after the first hydration to a water content of at least about 30 wt. %, it is expected that further hydrations to higher water contents are relatively easy and can be accomplished by simply mixing the composition with water. In some embodiments, accordingly, the amount of water provided in the composition when made available as a concentrate for shipment is preferably between about 30 wt. % and about 45 wt. %. In some embodiments, when the composition includes about 30 wt. % to about 45 wt. % water, it is expected that the composition can include about 3 wt. % to about 10 wt. % hydrophilic polymer composition and about 30 wt. % to about 50 wt. % hydrophobic polymer composition.

[0089] Water can be added to the relatively anhydrous composition by mixing water and the relatively anhydrous composition at a temperature and for a time sufficient to allow the composition to become hydrated without losing significant amounts of interaction between the hydrophobic polymer composition and the hydrophilic polymer composition. In some embodiments, the relatively anhydrous composition can be hydrated by heating to at least 60° C. and adding water while mixing. In some embodiments, the composition can be heated to at least about 65° C. and to at least about 70° C. In some embodiments, an exemplary temperature range is about 65° C. to about 80° C.22161737.01401 / 156261385v.3

[0090] In some embodiments, the relatively anhydrous composition can be referred to as the topical composition precursor and generally refers to the hydrophobic polymer / hydrophilic polymer adduct containing less than about 1.0 wt. % water if any water is present. The polymer component for the composition can refer to a composition that contains only the hydrophobic polymer / hydrophilic polymer adduct, and it can refer to a composition wherein the hydrophobic polymer / hydrophilic polymer adduct is diluted with water. In general, it is desirable to have a sufficient amount of water in the polymer component that allows one to formulate the polymer component into the cationic pharmaceutically active ingredient containing composition according to the invention. If there is too little water in the polymer component, it may become difficult to formulate the composition. In some embodiments, for example, the polymer component can contain water in an amount of up to about 95 wt. % and may contain water in an amount up to about 97 wt. %. In some embodiments, the polymer component can have a water concentration of about 30 wt. % to about 45 wt. %.

[0091] In some embodiments, additional components can be added to the hydrophobic polymer / hydrophilic polymer adduct. In some embodiments, for example, it may be desirable to add a component that helps stabilize the hydrophobic polymer / hydrophilic polymer adduct, and to help preserve and / or maintain the composition.

[0092] In some embodiments, an exemplary polymer component that can be used is available under the name Invisicare™ C-5 composition from Skinvisible Pharmaceuticals, Inc. Invisicare™ C-5 composition contains a mixture of poly(vinylpyrrolidone / eicosene) and poly(vinylpyrrolidone / hexadecene), and carboxymethyl cellulose. The Invisicare C-5 polymer can be characterized as a polymer adduct containing about 40 wt. % water and about 60 wt. % polymer adduct prepared from carboxymethyl cellulose and a mixture of poly(vinylpyrrolidone / l-eicosene) and poly(vinylpyrrolidone / hexadecene). In some embodiments, another exemplary polymer component that can be used is available under the name Invisicare™ M-l composition from Skinvisible Pharmaceuticals, Inc. Invisicare™ M-l composition contains a mixture of poly(vinylpyrrolidone / eicosene) and poly(vinylpyrrolidone / hexadecene), and poly(maleic acid / methylvinylether) copolymer. In some embodiments, the polymer component contains poly(maleic acid / methylvinylether) copolymer as it helps assist with the release of the rapamycin. In some embodiments, when the composition is provided at a neutral pH, the polymer component containing poly(maleic23161737.01401 / 156261385v.3acid / methylvinylether) copolymer tends to exhibit a negative charge. The negative charge on the polymer component helps facilitate release of a negatively charged active agent.

[0093] In some embodiments, the polymer component can be provided in the composition in an amount of about 2 wt. % to about 10 wt. % based on the weight of the composition. In some embodiments, the polymer component can be provided in the treatment composition in an amount of about 3 wt. % to about 8 wt. %, 4 wt. % to about 7 wt. %, and about 5 wt. % to about 6 wt. %.

[0094] The composition may contain a barrier component to provide the composition with barrier properties. The presence of a barrier component is desirable for treating dermatitis or incontinence. In some embodiments, for example, the barrier component can help reduce the passage of body waste such as urine and feces therethrough to help reduce contact of the urine and feces with skin tissue.

[0095] In some embodiments, an exemplary barrier component is a silicone barrier component such as Dow Corning 9045. In some embodiments, when a silicone barrier component is provided in the dermatitis treatment composition, it can be provided in an amount of from about 0.5 wt. % to about 20 wt. % based on the total weight of the composition. In some embodiments, preferably, the dermatitis treatment composition includes a silicone barrier component in an amount of from about 0.6 wt. % to about 5 wt. % based on the total weight of the composition. In some embodiments, 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. In some embodiments, when allantoin is used as the barrier component, it can be provided in an amount of from about 0.5 wt. % to about 2 wt. % based on the total weight of the composition. In some instances, allantoin is present in an amount of from about 0.01 to about 5 wt%, based on the total weight of the composition. In some embodiments, when aluminum hydroxide gel is provided as the barrier component, it can be provided in an amount of from about 0.15 wt. % to about 5 wt. %, based on the total weight of the composition. In some embodiments, when calamine is provided as the barrier component, it can be provided in an amount of from about 1 wt. % to about 25 wt. %, based on the total weight of the composition. In some embodiments, when cocoa butter is the barrier component, the cocoa butter can be provided in an amount of from 50 wt. % to about 90 wt. %, based on the total weight of the composition. In some embodiments, when dimethicone is provided as a barrier component, it can be provided in an 24161737.01401 / 156261385v.3amount of from about 1 wt. % to about 30 wt. %, based on the total weight of the composition. In some embodiments, when glycerin is provided as a barrier component, it can be provided in an amount of from 20 wt. % to about 45 wt. %, based on the total weight of the composition. In some embodiments, when kaolin is provided as a barrier component, it can be provided in an amount of from about 4 wt. % to about 20 wt. %, based on the total weight of the composition. In some embodiments, when petrolatum is provided as a barrier component, it can be provided in amount of from about 30 wt. % to about 90 wt. %, based on the total weight of the composition. In some embodiments, when shark liver oil is provided as a barrier component, it can be provided in amount of from about 2 wt. % to about 5 wt. %, based on the total weight of the composition. In some embodiments, when white petrolatum is provided as a barrier component, it can be provided in an amount of from 30 wt. % to about 90 wt. %, based on the total weight of the composition. In some embodiments, when zinc oxide is provided as a barrier component, it can be provided in amount of from about 0.1 wt. % to about 2 wt. %, based on the total weight of the composition. In some embodiments, when zinc carbonate is provided as a barrier component, it can be provided in an amount of from about 0.2 wt. % to about 2 wt. %, based on the total weight of the composition. In some embodiments, when zinc oxide is provided as a barrier component it can be provided in an amount of from about 1 wt. % to about 25 wt. %, based on the total weight of the composition. It should be appreciated that mixtures of various barrier components can be provided.

[0096] In some embodiments, the topical composition includes a barrier component.

[0097] In some embodiments, the topical composition does not include a barrier component.

[0098] In some embodiments, the composition can include water in an amount sufficient to allow the composition to be applied to skin tissue while providing the desired coverage over the skin tissue. In some embodiments, the water component can be provided as deionized water, filtered water, distilled water, reverse osmosis water, or tap water. In some embodiments, in the event that the water includes hardness or other components, it may be desirable to include builders, sequestrants, and chelating agents to handle the water hardness. In some embodiments, the composition can include at least about 50 wt. % water. In addition, it is expected that if there is too much water, the emulsion might become unstable. In some embodiments, the amount of water in the composition can be less than about 95 wt. %. In some embodiments, the amount of water in the composition can be about 65 wt. % to about 93 wt.25161737.01401 / 156261385v.3

[0099] In some embodiments, the composition can include pH adjusting agents, buffering agents, or neutralizing agents to provide the composition with a pH that helps stabilize the rapamycin. In some embodiments, exemplary pH adjusting agents that can be used include sodium hydroxide, potassium hydroxide, triethanolamine, acetic acid, propionic acid, citric acid, succinic acid, and mixtures thereof. In one embodiment, the composition does not include trolamine.

[0100] In some embodiments, the polymer component of the composition (such as a lotion, cream, gel, or liquid) may be at least in part responsible for reducing the irritability of the composition. In some embodiments, for example, it is believed that the polymer component may help reduce irritation of skin tissue. In some embodiments, the composition can be provided without any pH modifier, if desired. In some embodiments, 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 issue or that does not harm skin tissue.

[0101] In some embodiments, thickeners that can be incorporated into the composition include those components that thicken or increase the viscosity of the composition so that the composition can be readily applied to skin. In some embodiments, thickeners that can be used in the composition include those components often referred to as viscosity controlling agents.

[0102] In some embodiments, exemplary thickeners or viscosity controlling agents include cellulose gum, alkane triols; acrylates; substituted celluloses such as hydroxy ethyl cellulose, carboxymethyl cellulose, methylcellulose, and hydroxypropyl cellulose; cetyl alcohol; allyl pentaerythritol crosslinked, eicosyl povidone, gums such as natural gums or synthetic gums; long chain alcohols such as those having about 9 to about 24 carbon atoms; polyglycols such as polyethylene glycols, polypropylene glycols, polybutylene glycols, polyethylene propylene glycols, or mixtures thereof; waxes such as natural waxes or synthetic waxes; hydrogenated oils; glycol esters; fatty acid esters; long chain acids; acid amides; silicates; and mixtures thereof. In some embodiments, exemplary thickeners that can be used is hydroxyethyl cellulose. In some embodiments, an exemplary thickener that can be used is a polyacrylic acid thickeners available under the name Carbopol, such as, Carbopol Ultrez-10, from Lipscomb.

[0103] In some embodiments, the composition does not include a thickener. In some embodiments, the composition includes a thickener. In some embodiments, the thickener can 26161737.01401 / 156261385v.3be provided in an amount that provides the desired level of thickening. In some embodiments, the composition comprises a thickener in an amount of at least about 0.1 wt. %, based on the total weight of the composition. In some embodiments, the composition comprises at least one thickener in an amount of at least about 0.4 wt. %, based on the total weight of the composition. In some embodiments, the thickener can be provided in an amount of less than about 4 wt. %, and, alternatively, can be provided in an amount of less than about 2 wt. %, based on the total weight of the composition.

[0104] In some embodiments, the composition can include a release agent to assist with the sustained release of the rapamycin over a prolonged period of time. In some embodiments, the release agent can be provided as a surfactant. In some embodiments, a surfactant can additionally be present to help maintain the composition as an emulsion. In general, an emulsion refers to a composition that resists phase separation after sitting at room temperature for a couple of months. In some embodiments, it is desirable for the composition to be stored in a warehouse or in a storage closet for at least two months and can remain as an emulsion during that two-month period. In some embodiments, the composition can remain as an emulsion for at least one year or at least two years. In some embodiments, the ability of the composition to remain as an emulsion can be tested according to an accelerated stability test where the composition is held at 40° C. for 120 days. In some embodiments, it is expected that this accelerated stability test for 120 days roughly corresponds to a period of about two years at room temperature. In general, it is expected that the composition can remain as an emulsion after sitting for two years at room temperature.

[0105] In some embodiments, exemplary surfactants that can be used as the surfactant component include nonionic surfactants that help stabilize the emulsion and provide a generally even distribution of the cationic pharmaceutically active ingredient containing component. In some embodiments, exemplary nonionic surfactants that can be used include glycerol stearate such as glycerol monostearate, polysorbate such as that available under the name Tween 80 and Polysorbate 60, polyoxyethylene stearate. In some embodiments, mixtures of nonionic surfactants can be included including mixtures of polysorbate and glycerol stearate. In some embodiments, an additional nonionic surfactant that can be used includes an ethoxy surfactant, a propoxy surfactant, or an ethoxy / propoxy surfactant. In some embodiments, an exemplary ethoxy / propoxy surfactant includes a 10-carbon chain and 9 POZEO surfactant available under the name Lutensol XP-90 from BASF. In some embodiments, additional nonionic surfactants27161737.01401 / 156261385v.3include sorbitan monolaurate and sorbitan monostearate. In some embodiments, additional surfactants that can be used include those that are generally characterized as Pluronic surfactants such as poloxamers. In some embodiments, exemplary surfactants that can be used include Pluronic F-87NF and Pluronic L44NF from BASF. In some embodiments, the surfactant is poloxamer 407 from Sigma Aldrich, Ireland. In one embodiment, the composition does not include anionic surfactants as they may cause irritation.

[0106] In some embodiments, exemplary surfactants that can be used as the surfactant component include anionic surfactants. In some instances, the anionic surfactant is carboxylic salts or sulfonate salts.

[0107] In some embodiments, exemplary surfactants that can be used as the surfactant component include cationic surfactants. In some instances, the cationic surfactant is an amide. In some instances, the amide is a cocoamide.

[0108] In some embodiments, the composition can include an amount of surfactant component sufficient to provide the composition with a desired emulsion stability and sufficiently low viscosity without foaming. In some embodiments, the amount of the surfactant component in the composition, can be about 0.2 wt. % to about 7 wt. %, about 0.5 wt. % to about 6 wt. %, and about 1 wt. % to about 5 wt. %. In some embodiments, it should be understood that the composition can be provided without any surfactant component, if desired.

[0109] In some embodiments, the composition can contain a release agent to assist with the sustained release of the rapamycin over a prolonged period of time. In some embodiments, a sustained release of the rapamycin refers to a release, over the time period, wherein the release provides desired properties. In some embodiments, in general, it is desirable for the composition to provide a relatively consistent release of the rapamycin after application of the composition to skin tissue. In some embodiments, a relatively consistent release can be characterized as a release rate at one hour that is within about 50% of the release rate at 30 minutes. In some embodiments, in addition, a relatively consistent release rate can be characterized as a release rate at two hours that is within about 50% of the release rate at 30 minutes. In some embodiments, preferably, these release rates can be provided within about 25%, and more preferably can be provided within about 15%.

[0110] At least two advantages can be obtained by providing a sustained release rate or a relatively constant release rate over a prolonged period of time. In some embodiments, for 28161737.01401 / 156261385v.3example, by providing a sustained release of the rapamycin over a prolonged period of time, it is possible to prolong the pharmaceutical efficacy of the composition after application to skin tissue. In some embodiments, by prolonging the pharmaceutical efficacy of the composition, it is expected that enhanced performance can be achieved. In some embodiments, by controlling the release of the rapamycin so that it is not released at one instant in time, it is possible to reduce or minimize skin irritation.

[0111] In some embodiments, the composition can include a non-surfactant release agent in an amount of about 0.2 wt. % to about 7 wt. %.

[0112] In some embodiments, the composition can include an emollient for improving the texture of the composition. In some embodiments, an emollient is an oleaginous or oily substance which helps to smooth and soften the skin, and may also reduce its roughness, cracking, or irritation. In some embodiments, exemplary suitable emollients include mineral oil, having a viscosity in the range of 50 to 500 centipoise (cps), lanolin oil, coconut oil, cocoa butter, olive oil, almond oil, macadamia nut oil, synthetic jojoba oils, natural sonora jojoba oils, safflower oil, com oil, liquid lanolin, aloe vera, cottonseed oil, and peanut oil.

[0113] In some embodiments, 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, linolenic alcohol, coconut oil, oleyl alcohol, the oil of cereal germs such as the oil of wheat germ, isopropyl palmitate, isopropyl myristate, hexadecyl stearate, butyl stearate, decyl oleate, acetyl glycerides, the octanoates and benzoates of (C12-C15) alcohols, the octanoates and decanoates of alcohols and polyalcohols such as those of glycol and glycerol, ricin oleates of alcohols and poly alcohols such as those of isopropyl adipate, hexyl laurate and octyl dodecanoate.

[0114] In some embodiments, other suitable emollients which are solids or semi-solids at room or ambient temperatures may be used in amounts sufficient to provide liquid topical compositions. In some embodiments, such solid or semi-solid cosmetic emollients include hydrogenated lanolin, hydroxylated lanolin, acetylated lanolin, petrolatum, isopropyl lanolate, butyl myristate, cetyl myristate, myristyl myrislate, myristyl lactate, cetyl alcohol, isostearyl alcohol and isocetyl lanolate. In some embodiments, exemplary emollients include stearic acid, stearyl alcohol, palmitic acid enters natural and synthetic esters such as coconut oil.29161737.01401 / 156261385v.3

[0115] In some embodiments, the composition can include the emollient in an amount sufficient to provide a silky feel. In some embodiments, an exemplary range of the emollient in the composition can be at least about 0.5 wt. %, based on the total weight of the composition. In some embodiments, in addition, the composition can include an emollient in an amount of less than about 3 wt. %, based on the total weight of the composition. In some embodiments, the emollient is an optional component of the composition. In some embodiments, the composition can be provided without an emollient, if desired.

[0116] In some embodiments, the composition can include a moisturizer to provide a desired moisturizing effect to skin tissue. In some embodiments, the moisturizer can be provided as a humectant. In some embodiments, in general, a humectant is a moistening agent that promotes retention of water due to its hydroscopic properties. In some embodiments, exemplary humectants include glycerin, polymeric glycols such as polyethylene glycol and polypropylene glycol, and sorbitols such as a sorbitol solution, pyrrolidone carboxylic acid, urea, or mixtures thereof. The composition can be provided without a moisturizer.

[0117] In some embodiments, when the composition includes a moisturizer, it can be included in an amount of at least about 0.5 wt. %, based on the total weight of the composition. In some embodiments, the composition can include a moisturizer in an amount of less than about 5 wt. %, based on the total weight of the composition.

[0118] In some embodiments, an additional component that can be provided as part of the composition is a skin soothing agent or component which can also be referred to as a skin protectant. In some embodiments, exemplary skin soothing agents include allantoin, kaolin, cocoa butter, glycerin, shark liver oil, petrolatum, zinc oxide, zinc carbonate, zinc acetate, aluminum hydroxide, calamine, and mixtures thereof.

[0119] In some embodiments, the skin soothing agent can be provided in the composition in an amount of from about 0.2 wt. % to about 2 wt. %, and preferably about 0.5 wt. % to about 1 wt.%, based on the total weight of the composition.

[0120] In some embodiments, the composition can include preservatives for prevention of bacterial, fungal, and / or yeast contamination. In some embodiments, exemplary preservatives that can be used include phenoxyethanol, benzoic acid, derivatives and salts of benzoic acid, parabens, oxazolidines, chlorinated aromatic compounds and phenols, hydantoins, cresols and derivatives, imiazolindinyl urea, iodopropanol butylcarbamate, sulfites, and bisulfites. In some 30161737.01401 / 156261385v.3embodiments, the composition can include any of the preservatives commonly used or known to be suitable for topically applied compositions. Exemplary commercially available preservatives include liquid Germal Plus (diazolidinyl urea and iodopropynyl butylcarbamate) and Germaben 11 (diazolidinyl urea and methylparaben and propylparaben).

[0121] In some embodiments, the composition can be formulated without a preservative. In some embodiments, it is expected that the preservative will increase the shelf life of the composition by reducing or preventing the growth of bacteria, fungus, and / or yeast. In some embodiments, when the composition includes a preservative, the preservative is preferably provided in an amount sufficient to provide a desired level of protection from growth of bacteria, fungus, and / or yeast.

[0122] In some embodiments, in general, for most preservatives, it is expected that the amount of preservative can be provided at a level of form about 0.1 wt. % to about 1.0 wt. %, and can be provided at a level of about 0.2 wt. % to about 0.5 wt. %, based on the total weight of the composition.

[0123] In some embodiments, the composition can include antioxidants to help increase the shelf life of the composition and to 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 derivatives thereof. Exemplary antioxidants include a-tocopherols 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.

[0124] In some embodiments, the composition can be formulated without an antioxidant. In some embodiments, the composition can be formulated with an antioxidant. In some instances, the antioxidant can be provided in an amount that provides antioxidant properties in the composition. In some embodiments, the antioxidant can be provided in an amount of from about 0.2 wt. % to about 2 wt. %, and can be provided in an amount of from about 0.7 wt. % to about 1.5 wt. %, based on the total weight of the composition. In some embodiments, vitamin E can be included in the composition in an amount of from about 0.1 wt % to about 1 wt. %,31161737.01401 / 156261385v.3and can be included in an amount of from about 0.3 wt. % to about 0.8 wt. %, based on the total weight of the composition.

[0125] Chelating agents are substances used to chelate or bind metallic ions with a certain heterocyclic ring structure so that the ion is held by chemical bonds from each of the participating rings. In some embodiments, the composition comprises a chelating agent. In some instances, the chelating agents is ethylene diaminetetraacetic acid (EDTA), EDTA trisodium, EDTA tetrasodium, calcium disodium edetate, disodium edetate, EDTA trisodium, EDTA tetrasodium and EDTA dipotassium. In some embodiments, one or more chelating agents can be included in the emulsion in an amount of from about 0.001 to about 0.1 wt %, based on the total weight of the composition. In some embodiments, it should be appreciated that the composition can be provided without a chelating agent.

[0126] Fragrances are aromatic compounds which can impart an aesthetically pleasing aroma to the composition. In some embodiments, the composition comprises a fragrance. In some embodiments, fragrances include aromatic materials extracted from botanical sources (i.e., rose petals, gardenia blossoms, jasmine flowers, etc.) which can be used alone or in any combination to create essential oils. In some embodiments, alcoholic extracts may be prepared for compounding fragrances. In some embodiments, one or more fragrances can optionally be included in the composition in an amount of from about 0.001 to about 10 wt%, preferably about 0.05 to about 5 wt%, based on the total weight of the composition. In some embodiments, it should be appreciated that the composition can be provided without a fragrance.

[0127] In some embodiments, the composition may also include non-toxic, pharmaceutically and dermatologically acceptable carriers, diluents and excipients, suitable for topical application, as are well known, 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 Ed., Pergamon Press, Novel Drug Delivery Systems, 2nd Ed., Norris (ed.) Marcel Dekker Inc., (1989), and Remington's Pharmaceutical Sciences. For standard dosages of conventional pharmacological agents, see, e.g., Physicians Desk Reference (1997 Edition); and American Medical Association (1997) Drug Evaluations (Subscriptions).

[0128] In some embodiments, the pharmaceutical composition is placed in an organic polymer. In some embodiments, the organic polymer is PDMS. In some instances, the organic 32161737.01401 / 156261385v.3polymer is in the form of a patch or an adhesive patch. In some instances, the organic polymer comprises a component that is transdermal to the skin. In some instances, the component is dissolvable, which can, for example, release the pharmaceutical composition. In some instances, the component is a needle, spike, or other object that is able to pierce the skin. In some instances, the pharmaceutical composition is inside the component. In some instances, the component dissolves underneath the skin releasing the pharmaceutical composition.

[0129] 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.ExamplesEXAMPLE 1

[0130] The topical formulation may be prepared by mixing the components of Table 1.Table 1EXAMPLE 2

[0131] The topical formulation may be prepared by mixing the components of Table 2.33161737.01401 / 156261385v.3Table 2Example 3

[0132] The topical formulation may be prepared by mixing the components of Table 3.Table 334161737.01401 / 156261385v.3Example 4: Semi-Solid Formulation

[0133] The formulation in Table 4 can be prepared as follows. Rapamycin is mixed with a sufficient amount of diethylene glycol monoethyl ether (Transcutol® P) to solubilize 4% w / w rapamycin, with purified water. To account for variability and ensure accuracy, calculations were based on the lowest solubility value within the standard deviation range (75 mg / mL). On this basis, 53.3% w / w di ethylene glycol monoethyl ether was required to solubilize 4% w / w rapamycin. This amount replaced a large proportion of the aqueous phase, reducing water content from 77.85% w / w in the original drug-free formulation to 24.52% w / w in the rapamycin-loaded formulation and 28.52% w / w in the placebo formulation.

[0134] The final composition of the drug-free formulation and drug formulation is presented in Table 4, and was prepared as followed:

[0135] Oil phase: In a porcelain vessel medium-chain triglycerides (Miglyol ® 812 N) are heated to 65 ± 2 °C under continuous stirring. Polysorbate 60, poloxamer 407, hexadecyl povidone (Ganex™ V 216), and eicosyl povidone (Ganex™ V 220) are then added sequentially. Allantoin is dissolved in the mixture, followed by the addition of phenoxyethanol, with mixing maintained for at least 5 minutes.

[0136] Aqueous phase: Rapamycin is mixed with diethylene glycol monoethyl ether (Transcutol® P) and edetate disodium to form a mixture. In parallel, purified water is added in a separate vessel followed by gradual addition of carbomer homopolymer Type B under increasing stirring speed. This mixture is then heated to 65 ± 2 °C while continuing to add the mixture of rapamycin and diethylene glycol monoethyl ether (Transcutol® P) then mix for 60 minutes. Then, methyl vinyl ether and maleic acid copolymer (Gantrez™ S 97) is incorporated and stirred for an additional 10 minutes.

[0137] Emulsification and cooling: Once both phases reached 65 ± 2 °C, the oil phase is slowly introduced into the aqueous phase with stirring. The mixture is then homogenized using an Ultra-Turrax® at 10,000 rpm for 5 minutes. After emulsification, stirring is continued while cooling to 45 °C.35161737.01401 / 156261385v.3

[0138] pH Measurement - The pH of the formulation is measured using Jenway® 3510 pH meter.

[0139] Viscosity and rheological properties: The viscosity and storage and loss moduli of the formulation were measured using a Discovery HR-1 rheometer equipped with a 40.0 mm parallel plate and a Peltier plate made of stainless steel. Both moduli are reported as the formulation is a viscoelastic system (exhibiting both elastic and viscous properties); the internal structure of a system responsible for the elastic behavior is represented by the storage modulus G', and the viscous part by the loss modulus G”.

[0140] For all measurements, 2 mL of the sample was carefully loaded onto the instrument, and the gap was adjusted to 500 pm with any excess material removed. The temperature was maintained at 25°C throughout the test. Prior to analysis a soaking time of 3 minutes was employed. Firstly, to determine the shear thinning behavior of the gel, the change in viscosity with increase in shear rate was determined. Data were collected across a shear rate range of 1.0 s1to 100 s with 10 data points recorded per decade. Secondly, to determine gel structural strength a frequency sweep was performed. Measurements were recorded over an angular frequency range of 100 rad / s to 0.1 rad / s, with 10 data points collected per decade.

[0141] Drug content uniformity: The actual drug loading in the formulation was determined by sampling three different regions of the lotion to ensure representative analysis. Each 0.5 g sample was mixed with 1 mL of methanol, vortexed for 5 minutes, and centrifuged for 10 minutes. The supernatant was collected, diluted 20-fold with methanol, and filtered.Table 436161737.01401 / 156261385v.3

[0142] The rapamycin formulation was acidic, with a measured pH of 4.01, and the extracted rapamycin content from the 50 g lotion was 1.95g ± 0.03 (3.9 ± 0.0 %) with an extraction efficiency of 97.4 ± 1.5%.

[0143] The viscosity of the rapamycin sample decreased from 6.45 Pa- s at a shear rate of 1 s ' to 0.396 Pa s at a shear rate of 100 s ', while the corresponding shear stress increased from 9.71 x |06MPa to 3.96 x IO5MPa, demonstrating shear-thinning behavior (FIGs. 1A and IB). The storage modulus remained constant at low frequencies, starting at 1.07 x IO5Pa, and began to increase gradually after an angular frequency of approximately 12.6 rad / s, reaching 2.90 x |05Pa at the highest frequency. This gradual increase reflects the development of 37161737.01401 / 156261385v.3elastic characteristics at higher deformation rates. The complex viscosity demonstrated a clear shear-thinning trend, decreasing from 107.13 Pa s at the lowest frequency to 0.39 Pa s at the highest frequency. Throughout the measurement of the rapamycin formula, the loss modulus remained higher than the storage modulus, indicating a dominant viscous response across the entire frequency range.

[0144] Rapamycin was successfully incorporated into the lotion formulation at a target concentration of ~4% w / w. The rheological profile of the rapamycin formulation confirmed viscoelastic fluid behavior, with a predominantly viscous response at low frequencies and a gradual increase in elasticity at higher frequencies. The pronounced shear-thinning behavior observed in the flow sweep further supports the rapamycin formulation’s suitability for topical application. High viscosity at low shear rates contributes to rapamycin formulation stability during storage, while reduced viscosity under shear facilitates easy spreading upon application. Overall, these characteristics reflect a well -structured and stable semi-solid system with desirable handling properties and structural integrity.Example 5: Lotion Formulation

[0145] The formulation in Table 5 is prepared. Rapamycin is mixed with a sufficient amount of diethylene glycol monoethyl ether (Transcutol® P) to solubilize 4% w / w rapamycin, with purified water. To account for variability and ensure accuracy, calculations were based on the lowest solubility value within the standard deviation range (75 mg / mL). On this basis, 53.3% w / w diethylene glycol monoethyl ether was required to solubilize 4% w / w rapamycin. This amount replaced a large proportion of the aqueous phase, reducing water content from 77.85% w / w in the original drug-free formulation to 24.52% w / w in the rapamycin-loaded formulation and 28.52% w / w in the placebo formulation.Table 538161737.01401 / 156261385v.3Example 6: Gel Formulation

[0146] The gel formulations in Table 6 are prepared.39161737.01401 / 156261385v.3

[0147] 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 numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.

[0148] 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 herein by reference.161737.01401 / 156261385v.3

Claims

WHAT IS CLAIMED:

1. A method of treating a microcystic lymphatic malformation, angiofibroma, or venous malformation in a patient in need thereof comprising topically administering to the patient an effective amount of a topical composition comprising (a) rapamycin, a prodrug thereof, or a pharmaceutically acceptable salt thereof and (b) a hydrophobic polymer / hydrophilic polymer adduct or diethylene glycol monoethyl ether.

2. The method of claim 1, wherein the topical composition comprises rapamycin or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the topical composition comprises rapamycin.

4. The method of claim 1, wherein the topical composition comprises temsirolimus or a pharmaceutically acceptable salt thereof.

5. The method of any one of the preceding claims, wherein the polymer adduct comprises a poly(vinylpyrrolidone-alkylene) polymer and cellulose.

6. The method of claim 5, wherein the poly(vinylpyrrolidone-alkylene) polymer comprises a polymer having an alkylene group containing about 10 carbon atoms to about 30 carbon atoms.

7. The method of claim 5 or 6, wherein the cellulose has an average molecular weight of about 50,000 to about 15,000,000.

8. The method of any one of claims 5-7, wherein the cellulose comprises carboxymethyl cellulose.

9. The method of any one of the preceding claims, wherein the hydrophobic polymer / hydrophilic polymer adduct comprises about 2 wt. % to about 28 wt. % of the hydrophilic polymer and about 72 wt. % to about 98 wt. % of the hydrophobic polymer.

10. The method of any one of the preceding claims, wherein the topical composition comprises about 0.1 to about 8 wt. % of rapamycin or a pharmaceutically acceptable salt thereof.41161737.01401 / 156261385v.

311. The method of any one of the preceding claims, wherein the topical composition comprises at least about 50 wt. % water.

12. The method of any one of the preceding claims, wherein the composition comprises one or more of (i) about 0.5 wt. % to about 6 wt. % of a surfactant, (ii) about 0.1 wt. % to about 2 wt. % of a thickener, or (iii) about 0.5 wt. % to about 5 wt. % of a moisturizer.

13. The method of any of the preceding claims, wherein the topical composition is aqueous.

14. The method of any of the preceding claims, wherein the topical composition is a lotion.

15. The method of any of the preceding claims, wherein the topical composition is a gel.

16. The method of any one of the preceding claims, wherein the method comprises once daily administration of the topical composition.

17. The method of any one of the preceding claims, wherein the method comprises twice daily administration of the topical composition.

18. The method of any one of the preceding claims, wherein the topical composition is applied to blisters on the patient.

19. The method of any one of the preceding claims, wherein the topical composition is applied to venous malformations or angiofibroma on the patient.

20. The method of any of the preceding claims, wherein the topical composition is applied all over the body.

21. A topical composition comprising (a) rapamycin, a prodrug thereof, or a pharmaceutically acceptable salt thereof and (b) hydrophobic polymer / hydrophilic polymer adduct.

22. The topical composition of claim 21, wherein the topical composition comprises rapamycin or a pharmaceutically acceptable salt thereof.42161737.01401 / 156261385v.

323. The topical composition of claim 21, wherein the topical composition comprises rapamycin.

24. The topical composition of claim 21, wherein the topical composition comprises temsirolimus or a pharmaceutically acceptable salt thereof.

25. The topical composition of any one of claims 21-24, wherein the polymer adduct comprises a poly(vinylpyrrolidone-alkylene) polymer and cellulose.

26. The topical composition of claim 25, wherein the poly(vinylpyrrolidone-alkylene) polymer comprises a polymer having an alkylene group containing about 10 carbon atoms to about 30 carbon atoms.

27. The topical composition of claim 25 or 26, wherein the cellulose has an average molecular weight of about 50,000 to about 15,000,000.

28. The topical composition of any one of claims 25-27, wherein the cellulose comprises carboxymethyl cellulose.

29. The topical composition of any one of claims 21-28, wherein the hydrophobic polymer / hydrophilic polymer adduct comprises about 2 wt. % to about 28 wt. % of the hydrophilic polymer and about 72 wt. % to about 98 wt. % of the hydrophobic polymer.

30. The topical composition of any one of claims 21-29, wherein the topical composition comprises about 0.1 to about 8 wt. % of rapamycin or a pharmaceutically acceptable salt thereof.

31. The topical composition of any one of claims 21-30, wherein the topical composition comprises at least about 50 wt. % water.

32. The topical composition of any one of claims 21-31, wherein the composition comprises one or more of (i) about 0.5 wt. % to about 6 wt. % of a surfactant, (ii) about 0.1 wt. % to about 2 wt. % of a thickener, or (iii) about 0.5 wt. % to about 5 wt. % of a moisturizer.

33. An aqueous topical composition comprising(a) about 2 to about 5 wt. % rapamycin, a prodrug thereof (e.g., temsirolimus), or a pharmaceutically acceptable salt thereof (such as about 3 to about 4 wt. %43161737.01401 / 156261385v.3rapamycin);(b) (i) diethylene glycol monoethyl ether and water, wherein the ratio of di ethylene glycol monoethyl ether to water is from about 5: 1 to about 1:1, such as from about 3 : 1 to about 1:1, and (ii) from about 1 to about 10 wt. % (such as about 3 to about 8 wt. %) of medium chain triglycerides.

34. The aqueous topical composition of claim 33, wherein the composition comprises about 40 to about 65 wt.% of diethylene glycol monoethyl ether and about 20 to about 40 wt. % of water.

35. The aqueous topical composition of claim 33 or 34, further comprising one or more of (or all of):(c) about 0.2 wt. % to about 6 wt. % (such as about 0.2 to about 3 wt. %) of a surfactant (e.g., pol oxamer, such as pol oxamer 407);(d) about 0.1 wt. % to about 10 wt. % (such as about 2 wt. % to about 8 wt. %, about 3 wt. % to about 8 wt. %, or about 4 wt. % to about 7 wt. %) of a thickener or viscosity modifier (such as methyl vinyl ether and maleic acid copolymer, carbomer (e.g., carbomer homopolymer type B), hexadecyl povidone, eicosyl povidone, or any mixture of any of the foregoing), and(e) about 0.1 wt. % to about 5 wt. % (such as about 0.2 to about 1 wt. %) of a moisturizer (e.g., allantoin).

36. The aqueous topical composition of any one of claims 33-35, further comprising one or more of (or all of):(f) about 0.01 to about 1 wt. %, such as 0.02 to about 0.5 wt. %, of a chelator, such as edetate di sodium, and(g) about 0.1 to about 2 wt. % (such as about 0.2 to about 1 wt. %) of a preservative, such as phenoxyethanol.

37. The aqueous topical composition of any one of claims 33-36, wherein the composition comprises about 2 to 5 wt. % rapamycin, such as 2, 2.5, 3, 3.5, or 4% wt. % rapamycin.

38. An aqueous topical composition comprising(a) about 2 to about 5 wt. % rapamycin, a prodrug thereof (e.g., temsirolimus), or a pharmaceutically acceptable salt thereof (such as about 3 to about 4 wt. %44161737.01401 / 156261385v.3rapamycin);(b) (i) about 30 to about 70 wt. % diethylene glycol monoethyl ether and about 1 to about 20 wt. % water, and (ii) from about 10 to about 50 wt. % (such as about 20 to about 40 wt. %) of medium chain triglycerides.

39. The aqueous topical composition of claim 38 wherein the composition comprises about 40 to about 65 wt.% of diethylene glycol monoethyl ether and about 2 to about 8 wt. % of water.

40. The aqueous topical composition of claim 38 or 39, further comprising one or more of (or all of):(c) about 0.2 wt. % to about 6 wt. % (such as about 0.2 to about 3 wt. %) of a surfactant (e.g., pol oxamer, such as pol oxamer 407);(d) about 0.1 to about 5 wt. % (such as about 0.3 to about 3 wt. %) of an emulsifier (such as polysorbate 60);(e) about 0.1 wt. % to about 12 wt. % (such as about 2 wt. % to about 10 wt. %, about 3 wt. % to about 9 wt. %, or about 5 wt. % to about 7 wt. %) of a thickener or viscosity modifier (such as methyl vinyl ether and maleic acid copolymer, methyl hydroxy propyl cellulose (MHPC), hexadecyl povidone, eicosyl povidone, or any mixture of any of the foregoing), and(f) about 0.1 wt. % to about 5 wt. % (such as about 0.2 to about 1 wt. %) of a moisturizer (e.g., allantoin).

41. The aqueous topical composition of any one of claims 38-40, further comprising one or more of (or all of):(g) about 0.01 to about 1 wt. %, such as 0.02 to about 0.5 wt. %, of a chelator, such as edetate di sodium;(h) about 0.1 to about 2 wt. % (such as about 0.2 to about 1 wt. %) of a preservative, such as phenoxyethanol; and(i) about 0.01 to about 3 wt. % (such as 0.02 to about 0.5 wt. %) of an antioxidant, such as butylated hydroxytoluene (BHT).

42. The aqueous topical composition of any one of claims 38-41, wherein the composition comprises about 2 to 5 wt. % rapamycin, such as 2, 2.5, 3, 3.5, or 4% wt. % rapamycin.45161737.01401 / 156261385v.

343. A method of treating a microcystic lymphatic malformation, angiofibroma, or venous malformation in a patient in need thereof comprising topically administering to the patient an effective amount of a topical composition of any one of claims 33-42.46161737.01401 / 156261385v.3

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