WATERLESS COMPOSITIONS OF MTOR Inhibitors AND METHODS FOR USE

Description

TECHNICAL FIELD

[0001] The field of invention generally relates to compositions for topical delivery of mTOR inhibitors, as well as said compositions for use in treating skin disorders.BACKGROUND

[0002] US2013317053A1 discloses topical compositions comprising rapamycin. WO99 / 24036A1 discloses anhydrous topical compositions comprising rapamycin. WO2008 / 015539A2 discloses a topical anhydrous ointment comprising rapamycin.SUMMARY

[0003] In one claimed embodiment, a topical anhydrous composition consisting of: rapamycin at 3.9 wt% of the composition; isopropyl alcohol at 15 wt% of the composition; polyethylene glycol 400 at 55.3 wt% of the composition; diisopropyl adipate at 15 wt% of the composition; glycerol at 10 wt% of the composition; hydroxypropyl cellulose at 0.75 wt% of the composition; propyl gallate at 0.05 wt% of the composition; ascorbyl palmitate at 0.02 wt% of the composition; alpha-tocopherol at 0.002 wt% of the composition is provided. In another claimed embodiment a topical anhydrous composition consisting of: rapamycin at 3.9 wt% of the composition; isopropyl alcohol at 15 wt% of the composition; polyethylene glycol 400 at 51 wt% of the composition; polypropylene glycol at 1.5 wt% of the composition; diisopropyl adipate at 15 wt% of the composition; glycerol at 10 wt% of the composition; benzyl alcohol at 2 wt% of the composition; oleyl alcohol at 0.75 wt% of the composition; hydroxypropyl cellulose at 0.75 wt% of the composition; propyl gallate at 0.05 wt% of the composition; ascorbyl palmitate at 0.02 wt% of the composition; alpha-tocopherol at 0.002 wt% of the composition is provided.

[0004] In additional claimed embodiments, a topical anhydrous composition consisting of: rapamycin at 3.9 wt% of the composition; isopropyl alcohol at 15 wt% of the composition; polyethylene glycol 400 at 55.3 wt% of the composition; diisopropyl adipate at 15 wt% of the composition; glycerol at 10 wt% of the composition; hydroxypropyl cellulose at 0.75 wt% of the composition; propyl gallate at 0.05 wt% of the composition; ascorbyl palmitate at 0.02 wt% of the composition; alpha-tocopherol at 0.002 wt% of the composition for use in treating a skin disorder in a subject is provided. In another additional claimed embodiment a topical anhydrous composition consisting of: rapamycin at 3.9 wt% of the composition; isopropyl alcohol at 15 wt% of the composition; polyethylene glycol 400 at 51 wt% of the composition; polypropylene glycol at 1.5 wt% of the composition; diisopropyl adipate at 15 wt% of the composition; glycerol at 10 wt% of the composition; benzyl alcohol at 2 wt% of the composition; oleyl alcohol at 0.75 wt% of the composition; hydroxypropyl cellulose at 0.75 wt% of the composition; propyl gallate at 0.05 wt% of the composition; ascorbyl palmitate at 0.02 wt% of the composition; alpha-tocopherol at 0.002 wt% of the composition for use in treating a skin disorder in a subject is provided.BRIEF DESCRIPTION OF FIGURES

[0005] FIG. 1 depicts total mean deposition of rapamycin (ng) in the tissue (combined epidermis and dermis) following application of rapamycin compositions (O3, NA21, NA22, NA23, NA17, NA19, NA25, AG14, NA 26, NA24, TD201). Each error bar is determined using 1 standard deviation from the mean (n=5). FIG. 2 depicts total mean amount of rapamycin (ng) recovered from epidermis and dermis, separately, following application of rapamycin compositions (O3, NA21, NA22, NA23, NA17, NA19, NA25, AG14, NA 26, NA24, TD201). Each error bar is determined using 1 standard deviation from the mean (n=5). FIG. 3 depicts total mean deposition of rapamycin (ng) in the tissue (combined epidermis and dermis) following application of rapamycin compositions (NA22, NA28, NA33, NA34, 011, TD201). Each error bar is determined using 1 standard deviation from the mean (n=5). FIG. 4 depicts total mean amount of rapamycin (ng) recovered from epidermis and dermis, separately, following application of rapamycin compositions (NA22, NA28, NA33, NA34, 011, TD201). Each error bar is determined using 1 standard deviation from the mean (n=5). DETAILED DESCRIPTION

[0006] As used in this application and in the claims, the singular forms "a," "an," and "the" include the plural forms unless the context clearly dictates otherwise. Additionally, the term "includes" means "comprises."

[0007] The term "patient" and "subject" are interchangeable and may be taken to mean any living organism which may be treated with compounds of the present invention. As such, the terms "patient" and "subject" may include, but is not limited to, any non-human mammal, primate or human. In some embodiments, the "patient" or "subject" is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans. In some embodiments, the patient or subject is an adult, child or infant. In some embodiments, the patient or subject is a human.

[0008] "Administering" when used in conjunction with the mTOR inhibitor means to administer mTOR inhibitor to a patient whereby the mTOR inhibitor positively impacts the tissue to which it is targeted. The mTOR inhibitors described herein can be administered either alone or in combination (concurrently or serially) with other pharmaceutically active agents. For example, the mTOR inhibitors can be administered in combination with other anti-cancer or anti-neoplastic agents, or in combination with other therapies for treating skin disorders. In some embodiments, the mTOR inhibitors described herein can also be administered in combination with (i.e., as a combined composition or as separate compositions) other therapeutics.

[0009] An "effective amount" of a composition is a predetermined amount calculated to achieve the desired effect, i.e., to ameliorate, prevent or improve an unwanted condition, disease or symptom of a patient. The activity contemplated by the present methods may include both therapeutic and / or prophylactic treatment, as appropriate. The specific dose of the agent administered according to this invention to obtain therapeutic and / or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the condition being treated. The effective amount administered may be determined by a physician in the light of the relevant circumstances including the condition to be treated, the choice of the compound to be administered, and the chosen route of administration.

[0010] The term "carrier" as used herein encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical, cosmetic or other agent across a tissue layer such as the stratum corneum or stratum spinosum.

[0011] The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the claimed invention. In embodiments or claims where the term comprising is used as the transition phrase, such embodiments can also be envisioned with replacement of the term "comprising" with the terms "consisting of" or "consisting essentially of."

[0012] The term "treating" is used herein, for instance, in reference to methods of treating a skin disorder or a systemic condition, and generally includes the administration of a compound or composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition or enhance the texture, appearance, color, sensation, or hydration of the intended tissue treatment area of the tissue surface in a subject relative to a subject not receiving the compound or composition. This can include reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in a manner to improve or stabilize a subject's condition.

[0013] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0014] The weight percentages disclosed herein are weight-to-weight percentages.

[0015] Disclosed herein are anhydrous compositions of an mTOR inhibitor, which is rapamycin. The anhydrous compositions comprise the mTOR inhibitor, solvents, a gelling agent, and antioxidants.

[0016] A disclosed but not claimed anhydrous composition of mTOR inhibitor has a Cmax of about 120-990 micromolar in the epidermis, and about 36-350 micromolar in the dermis. Disclosed but not claimed herein, the anhydrous composition of mTOR inhibitor has a Tmax of about 15-24 hours in the epidermis.

[0017] The anhydrous composition comprises the mTOR inhibitor rapamycin (sirolimus). Other mTOR inhibitors, which are disclosed but do not form part of the claimed invention are everolimus, pimecrolimus, ridaforolimus, temsirolimus, zotarolimus, rapamycin prodrug AP-23573, AP-23481, torin-1, torin-2, WYE-354, dactolisib, voxtalisib, omipalisib, apitolisib, vistusertib, gedatolisib, WYE-125132, BGT226, palomid 529, GDC-0349, XL388, CZ415, CC-223, ABT-578, SF1126, PKI-587, INK128, AZD8055, NVPBE235, AZD2014, biolimus A9 (umirolimus), GSK2126458, OSI027, PP121, WYE-687, WAY-600, XL765, PI-103, BEZ235, KU-0063794, Torkinib (PP242), PF-04691502, and pharmaceutically acceptable salts, hydrates, solvates, or amorphous solid thereof, and combinations thereof.

[0018] Disclosed but not claimed herein, mTOR inhibitors also include specific inhibitors of TOR complex 1, specific inhibitors of TOR complex 2, and the like. Disclosed but not claimed herein, agents that can be used to inhibit TOR complex 2 include but are not limited to small molecules, nucleic acids, proteins, and antibodies. Small molecules include but are not limited to pyridinonequinolines, pyrazolopyrimidines, and pyridopyrimidines. Disclosed herein but not claimed , small molecules that inhibit TOR complexes 1 and 2 include Torin 1, Torin 2, torkinib (PP242), PP30, KU-0063794, WAY-600, WYE-687, WYE-354, AZD8055, INK128, OS1027, AZD2014, omipalisib, wortmannin, LY294002, PI-103, BGT226, XL765, and NVP-BEZ235. Disclosed but not claimed herein, the inhibitors include but is not limited to antisense oligonucleotide, siRNA, shRNA, and combinations thereof. Disclosed but not claimed herein, the agent that inhibits TOR complex 2 would not inhibit TOR complex 1.

[0019] Disclosed but not claimed herein, the anhydrous composition may further comprise other compounds regulating mTOR pathway, such as tacrolimus, metformin, and the like.

[0020] The compositions according to the claimed invention comprise 3.9 wt% rapamycin.

[0021] The anhydrous compositions contain solvents that facilitate solubilization of mTOR inhibitors. Solvents according to the claimed invention are those recited in claims 1 or 2. All other solvents mentioned below do not form part of the claimed invention. Disclosed but not necessarily claimed herein, solvents include alcohols, polyols, amides, esters, propylene glycol ethers and mixtures thereof. Non-limiting examples of alcohol or polyol include ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, PEG 400, PEG 3350, SR-PEG 400, SR-DMI, oleyl alcohol, castor oil, miglyol 810, liquid paraffin, propylene glycol dicaprylate / dicaprate, butanediols and isomers thereof, glycerol, glycerol triacetate, pentaerythritol, sorbitol, mannitol, Transcutol ®< P (diethylene glycol monoethyl ether), Transcutol HP, diisopropyl adipate, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives, and mixtures thereof. Examples of amide include 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof. Examples of an ester include ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof, and mixtures thereof.

[0022] Disclosed but not necessarily claimed herein, the solvents include benzyl alcohol, DMSO, diglycol, propylene glycol monocaprylate (Capryol 90), diethylene glycol monoethylether (Transcutol ®< ), tetrahydrofurfurylalcohol polyethylene glycol ether (glycofurol), butylene glycol, propylene glycol, diethylene glycol, triethylene glycol, and combinations thereof. Disclosed but not necessarily claimed herein, solvents include propylene glycol monocaprylate, benzyl alcohol, tetrahydrofurfurylalcohol polyethylene glycol ether, and combinations thereof. The anhydrous compositions do not contain ethanol. Disclosed but not claimed herein, the anhydrous compositions contain benzyl alcohol less than 10 wt%, less than 8 wt%, less than 6 wt%, less than 4 wt%, or less than 2 wt%. In the first embodiment according to claim 1, the anhydrous composition does not contain benzyl alcohol.

[0023] The anhydrous compositions comprise hydroxypropyl cellulose (KLUCEL) as gelling agent. Disclosed but not part of the claimed invention, are other gelling agents, such as poloxamers and carbomers. Examples of poloxamers are poloxamer P-188, poloxamer P-138, poloxamer P-237, poloxamer P-288, poloxamer P-124, poloxamer P-338, and poloxamer P-407. Other block copolymers, such as poly(ethylene glycol / DL lactide Co-glyceride) poly(□-caprolactum), glyceryl tris 12-hydroxy stearate, hydroxy stearin, propylene carbonate, and polyvinyl pyrolidine. Examples of carbomers that may be used are carbomer 981, carbomer 934, carbomer 934P, carbomer 940, carbomer 941, carbomer 1342, polycarbophil, and calcium polycarbophil. Disclosed but not claimed herein, the gelling agent is selected from carbomer 981, carbomer 934P, glyceryl tris 12-hydroxy stearate, hydroxy stearin, propylene carbonate, polyvinyl pyrolidine, and combinations thereof. Disclosed but not claimed herein, the gelling agent is present from about 0.1 wt% to about 5 wt% of the total composition, about 0.1 wt% to about 4 wt% of the total composition, about 0.1 wt% to about 3 wt% of the total composition, about 0.1 wt% to about 2 wt% of the total composition, or about 0.1 wt% to about 1 wt% of the total composition.

[0024] The anhydrous compositions comprise three antioxidants, i.e. 0.05 wt% propyl gallate, 0.02 wt% ascorbyl palmitate and 0.002 wt% alpha-tocopherol. Also disclosed but not part of the claimed invention are ascorbic acid, vitamin E and its derivatives (except for alpha-tocopherol, which is part of the claimed invention), ψ-tocopherol, δ-tocopherol, octyl gallate, dodecyl gallate, butylated hydroxy anisole (BHA) and butylated hydroxy toluene (BHT), and D-α-tocopheryl polyethylene glycol 1000 succinate.

[0025] The anhydrous compositions of mTOR inhibitor comprise the polymeric surfactant hydroxypropyl cellulose. Other polymers having surfactant properties (polymeric surfactant), which are disclosed but do not form part of the claimed invention are, hydrophobically modified polyacrylic acid (trade name Pemulen ™< TR-I and TR-2), copolymers based on acrylamidoalkyl sulfonic acid and cyclic N-vinylcarboxamides (tradename Aristoflex ®< AVC), copolymers based on acrylamidoalkyl sulfonic acid and hydrophobically modified methacrylic acid (tradename Aristoflex ®< HMB), a homopolymer of acrylamidoalkyl sulfonic acid (tradename Granthix APP), hydrophobically-modified, crosslinked, anionic acrylic copolymers, including random polymers, but may also exist in other forms such as block, star, graft, and the like. Disclosed but not claimed herein, the hydrophobically modified, crosslinked, anionic acrylic copolymer may be synthesized from at least one acidic monomer and at least one hydrophobic ethylenically unsaturated monomer. Examples of suitable acidic monomers include those ethylenically unsaturated acid monomers that may be neutralized by a base. Examples of suitable hydrophobic ethylenically unsaturated monomers include those that contain a hydrophobic chain having a carbon chain length of at least about 3 carbon atoms. Other materials that may be suitable polymeric surfactants can include ethylene oxide / propylene oxide block copolymers, sold under the trade name PLURONIC ®< , modified cellulose polymers such as those modified cellulose polymers described by the trade name KLUCEL ®< (hydroxypropyl cellulose), monomeric anionic surfactants, monomeric amphoteric surfactants, betaine, and combinations thereof. Other suitable polymeric surfactants include copolymers based on acrylamidoalkylsulfonic acids and cyclic N-vinylcarboxamides and / or linear N- vinylcarboxamides (e.g., Aristoflex ®< AVC and Aristoflex ®< HMB) and a betaine. Disclosed but not claimed herein, the polymeric surfactants include poloxamer P-188, poloxamer P-138, poloxamer P-237, poloxamer P-288, poloxamer P-124, poloxamer P-338, poloxamer P-407, D-α-Tocopheryl polyethylene glycol 1000 succinate, Brij 020, and combinations thereof. Disclosed but not claimed herein, the polymeric surfactant is present from about 0.1 wt% to about 50 wt% of the total composition, about 0.1 wt% to about 40 wt% of the total composition, about 0.1 wt% to about 30 wt% of the total composition, about 0.1 wt% to about 20 wt% of the total composition, or about 0.1 wt% to about 10 wt% of the total composition.

[0026] Disclosed but not claimed herein, the anhydrous compositions of mTOR inhibitor may further comprise one or more moisturizing agents or an emollient component, for example mineral oil, dimethicone, cyclomethicone, cholesterol, or combinations thereof. Disclosed but not claimed herein, the anhydrous composition includes liquid emollients such as polyhydric alcohols, polyols, saccharides, triglycerides, hydrocarbons, silicones, fatty acids, fatty, esters, fatty alcohols, and blends thereof. Disclosed but not claimed herein, the moisturizing agent is present from about 0.5 wt% to about 10 wt% of the total composition, about 0.5 wt% to about 8 wt% of the total composition, about 0.5 wt% to about 6 wt% of the total composition, about 0.5 wt% to about 4 wt% of the total composition, or about 0.5 wt% to about 1 wt% of the total composition.

[0027] Disclosed but not claimed herein, the anhydrous compositions of mTOR inhibitor comprise one or more cooling agents, such as L-menthol, p-menthane-3,8-diol, isopulegol, menthoxypropane-1,2,-diol, menthyl lactate (such as Frescolat ®< ML), gingerol, icilin, tea tree oil, methyl salicylate, camphor, peppermint oil, N-ethyl-p-menthane-3-carboxamide, ethyl 3-(p-menthane-3-carboxamido)acetate, 2-isopropyl-N,2,3-trimethylbutyramide, menthone glycerol ketal, menthone glyerine acetal, coolact 10; WS3, WS5, WS23, menthyl glutarate, and mixtures thereof. Disclosed but not claimed herein, the cooling agent is present from about 0.5 wt% to about 10 wt% of the total composition, about 0.5 wt% to about 8 wt% of the total composition, about 0.5 wt% to about 6 wt% of the total composition, about 0.5 wt% to about 4 wt% of the total composition, or about 0.5 wt% to about 2 wt% of the total composition.

[0028] The anhydrous compositions disclosed herein do not contain water.

[0029] The second embodiment of the present invention comprises benzyl alcohol as a preservative to prevent the growth of harmful microorganisms.

[0030] The disclosed but not claimed anhydrous composition of mTOR inhibitors may comprise further ingredients as required. For example, it may contain a further active ingredient, e.g. a corticosteroid, an antibiotic, an antimycotic, and / or an antiviral agent. Moreover, it may comprise one or more further excipients, such as permeation enhancers (DMSO, Transcutol ®< , menthol, oleic acid, n-alkanols, 1-alkyl-2-pyrrolidones, N,N-dimethlyalkanamides, and 1,2-alkanediols, etc.), and the like.

[0031] Disclosed but not claimed herein, the compositions may further comprise other skin care agents, including, but not limited to, retinol, steroids, sunblock, salicylate, minocycline, antifungals, peptides, antibodies, lidocaine, and the like and combinations thereof. Disclosed but not claimed herein, other skin care agents include N-acyl amino acid compounds including, for example, N-acyl phenylalanine, N-acyl tyrosine, and the like, their isomers, including their D and L isomers, salts, derivatives, and mixtures thereof. An example of a suitable N-acyl amino acid is N-undecylenoyl-L-phenylalanine is commercially available under the tradename SEPIWHITE ®< . Other skin active agents include, but are not limited to, Lavandox, Thallasine 2, Argireline NP, Gatuline In-Tense and Gatuline Expression, Myoxinol LS 9736, Syn-ake, and Instensyl ®< , Sesaflash ™< , N- acetyl D-glucosamine, panthenol (for example, DL panthenol available from Alps Pharmaceutical Inc.), tocopheryl nicotinate, benzoyl peroxide, 3-hydroxy benzoic acid, flavonoids (for example, flavanone, chalcone), farnesol, phytantriol, glycolic acid, lactic acid, 4-hydroxy benzoic acid, acetyl salicylic acid, 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, cis- retinoic acid, trans-retinoic acid, retinol, retinyl esters (for example, retinyl propionate), phytic acid, N-acetyl-L-cysteine, lipoic acid, tocopherol and its esters (for example, tocopheryl acetate: DL-a- tocopheryl acetate available from Eisai), azelaic acid, arachidonic acid, tetracycline, ibuprofen, naproxen, ketoprofen, hydrocortisone, acetominophen, resorcinol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, 2,4,4'-trichloro-2'-hydroxy diphenyl ether, 3,4,4'- trichlorocarbanilide, octopirox, lidocaine hydrochloride, clotrimazole, miconazole, ketoconazole, neomycin sulfate, theophylline, and mixtures thereof. Of the listed agents, only alpha-tocopherol falls under the scope of the claimed invention.

[0032] One or more sunscreens may be incorporated into the anhydrous compositions, but such compositions do not form part of the claimed invention. A variety of sunscreens may be employed including the p-aminobenzoic acid derivatives such as p-(2-ethylhexyl)dimethylaminobenzoate, and benzophenone derivatives such as (2-hydroxy-4-methoxyphenyl)phenylmethanone, Mexoryl ™< SX, and Mexoryl ™< XL, terephthalylidene dicamphor sulfonic acid, and drometrizole trisiloxane. Other non-limiting examples include benzophenones (oxybenzone and sulisobenzone), cinnamates (octylmethoxy cinnamate and cinoxate), salicylates (homomethyl salicylate) anthranilates, TiO 2 , avobenzone, bemotrizinol, bisoctrizole, 3-(4-methylbenzylidene)-camphor, cinoxate, diethylamino hydroxybenzoyl hexyl benzoate, dioxybenzone, drometrizole trisiloxane, ecamsule, ethylhexyl triazone, homosalate, menthyl anthranilate, octocrylene, octyl salicylate, iscotrizinol, isopentenyl-4-methoxycinnamate, octyl- dimethyl-p-aminobenzoic acid, octyl-methoxycinnamate, oxybenzone, polysilicone-15, trolamine salicylate, and ZnO. The exact amount of sunscreen employed in the present compositions will vary depending on the degree of protection desired from the sun's harmful rays.

[0033] The anhydrous compositions may also comprise one or more pigments to color the composition, and a fragrance, such as Firmenich and Co. 66.001 / NY / G fragrance oil, to make the composition soothing to the olfactory system, but such compositions do not form part of the claimed invention. The amount of these ingredients present in the composition will depend on the specific effect desired.

[0034] The mTOR inhibitor in the compositions disclosed herein are stable for extended periods of time. For example, the mTOR inhibitor in the compositions may be stable at temperature ranges from about 4 °C to about 50 °C for a period of 12-36 months, at temperature ranges from about 4 °C to about 45 °C for a period of 12-36 months, at temperature ranges from about 4 °C to about 40 °C for a period of 12-36 months at temperature ranges from about 4 °C to about 35 °C for a period of 12-36 months, or at temperature ranges from about 4 °C to about 30 °C for a period of 12-36 months.

[0035] The compositions are for use in methods to treat a skin disorder in a subject, whereby the method comprises topically administering a composition according to claims 1 or 2 topically.

[0036] Any reference to a method of treatment in this specification is to be constructed as a composition for use in such a method.

[0037] In one claimed embodiment, a topical anhydrous composition consisting of: rapamycin at 3.9 wt% of the composition; isopropyl alcohol at 15 wt% of the composition; polyethylene glycol 400 at 55.3 wt% of the composition; diisopropyl adipate at 15 wt% of the composition; glycerol at 10 wt% of the composition; hydroxypropyl cellulose at 0.75 wt% of the composition; propyl gallate at 0.05 wt% of the composition; ascorbyl palmitate at 0.02 wt% of the composition; alpha-tocopherol at 0.002 wt% of the composition for use in treating a skin disorder in a subject is provided. In another claimed embodiment a topical anhydrous composition consisting of: rapamycin at 3.9 wt% of the composition; isopropyl alcohol at 15 wt% of the composition; polyethylene glycol 400 at 51 wt% of the composition; polypropylene glycol at 1.5 wt% of the composition; diisopropyl adipate at 15 wt% of the composition; glycerol at 10 wt% of the composition; benzyl alcohol at 2 wt% of the composition; oleyl alcohol at 0.75 wt% of the composition; hydroxypropyl cellulose at 0.75 wt% of the composition; propyl gallate at 0.05 wt% of the composition; ascorbyl palmitate at 0.02 wt% of the composition; alpha-tocopherol at 0.002 wt% of the composition for use in treating a skin disorder in a subject is provided.

[0038] In some claimed embodiments, the skin disorder is selected from the group consisting of plantar hyperkeratosis, epidermolysis bullosa, lichenoid keratoses, epidermolytic ichthyosis, Olmsted syndrome, actinic keratosis, pachyonychia congenita, warts, psoriasis, basal cell carcinoma, melanoma, venous malformation, lupus, infantile hemangiomas, angiofibroma, basal cell nevus syndrome, Birt-Hogg-Dube syndrome, Blue rubber bleb nevus syndrome, cutaneous T-cell lymphoma, lymphatic malformations, epidermolysis bullosa simplex, Kaposi sarcoma, Kaposiform hemangioendothelioma, Muir-Torre syndrome, neurofibromatosis, graft-versus-host disease, Pemphigus vulgaris, hemangioendotheliomas in Maffucci syndrome, and combinations thereof.

[0039] Disclosed but not claimed examples of skin disorder that may be treated by the anhydrous compositions include blisters, tuberous sclerosis, seborrheic keratosis, keratosis pilaris, multiple minute digitate hyperkeratosis, hyperkeratosis lenticularis perstans, stasis dermatitis, focal acral hyperkeratosis, follicular hyperkeratosis, chronic erosive oral lichen, Conradi-Eltinermann, erythrokeratoderma variabilis, ichthyosis hystrix, KID syndrome, Netherton syndrome, Refsum disease, Sjogren-Larsson Syndrome, hyperhidrosis, calluses, dermatitis (contact dermatitis, drug-induced dermatitis, allergic dermatitis, nummular dermatitis, perioral dermatitis, neurodermatitis, seborrheic dermatitis, and atopic dermatitis), acne, carbunculosis, cellulitis, furunculosis, granuloma, acanthosis nigricans, athlete's foot, bacterial vaginosis, balanitis, dermatofibrosarcoma protruberans, squamous cell carcinoma, melanoma, merkel cell carcinoma, keloid, cystic lymphangioma, Cavernous lymphangioma, venous malformation, epidermal nevi, bromhidrosis, dermatophytosis, candidiasis, onychomycosis, tinea (tinea alba, tinea pedis, tinea unguium, tinea manuum, tinea cruris, tinea corporis, tinea capitis, tinea faciei, tinea barbae, tinea imbricata, tinea nigra, tinea versicolor, tinea incognito), eczema, dyshydrotic eczema, decubitous ulcer, ecthyma, erysipalus, erythema multiforme, impetigo, insect bites, genital warts, hemangioma, herpes, hives, hyperhidrosis, filariasis, lentigines, lupus, miliaria, milker's nodules, molluscum contagiosum, myiasis, scabies, cutaneous larva migrans, furuncular myiasis, migratory myiasis, pediculosis, nevus araneus, panniculitis, paronychia, pemphigoid, pityriasis, pruritis vulvae, rosacea, trichomoniasis, vaginal yeast infection, vitiligo, xeroderma, angiofibroma, Bannayan-Riley-Ruvalcaba syndrome, basal cell nevus syndrome, Cowden disease, diffuse microcystic extramammary paget, familial multiple discoid fibromas, Hailey-Hailey disease, infantile hemangiomas, juvenile polyposis syndrome, Keloid scar disease, Lhermitte-Duclos syndrome, metastatic melanoma, nonmelanoma skin cancer, Peutz-Jeghers syndrome, Port-wine stains, Proteus syndrome, Proteus-like Syndrome, Sturge-weber syndrome, hereditary footpad hyperkeratosis (HFH) in canines, cutaneous sarcoidosis, cutaneous Castleman Disease, Bullous Pemphigoid, and combinations thereof.

[0040] In some claimed embodiments, the skin disorder that is treated is angiofibroma. In some claimed embodiments, the skin disorder that is treated is pachyonychia congenita.

[0041] In claimed embodiments, administration of the composition is by topical application.

[0042] The anhydrous composition of mTOR inhibitor is administered topically, and the mTOR inhibitor may reach epidermal and dermal layer through absorption. Optionally, the topical application of the anhydrous composition does not result in systemic absorption of the mTOR inhibitors.

[0043] The topical administration of the anhydrous compositions results in delivery of the mTOR inhibitor to epidermis of the skin or to epidermis and dermis.

[0044] The anhydrous compositions can be topically applied to the skin, preferably by manually rubbing the applied amount over the skin to thoroughly coat the skin. The rubbing action preferably is a gentle rubbing or massaging for a period of at least about 5 second, preferably about 5 to about 30 seconds to spread all over the skin. The moisture or water present on the skin may emulsify the anhydrous composition due to continuous rubbing and massaging, resulting in the formation of an emulsion in situ on the skin.

[0045] Disclosed but not claimed herein is a method of treating hair loss in a subject. Disclosed but not claimed herein, the method of treating hair loss includes administering to the subject in need thereof an effective amount of an anhydrous composition comprising an effective amount one or more mTOR inhibitors, one or more solvents, one or more gelling agents, and one or more antioxidants. Disclosed but not claimed herein, treatment of diseases related to hair, hair shaft, hair follicles, hair bulbs, oil glands, and components thereof, include, for example, hair loss, dandruff, seborrheic dermatitis, alopecia areata, hair disease, ringworm, tinea capitis, folliculitis, pattern hair loss, telogen effluvium, cradle cap, trichotillomania, traction alopecia, trichorrhexis nodosa, folliculitis decalvans, head lice infestation, frontal fibrosing alopecia, non-scarring hair loss, pityriasis amiantacea, dissecting cellulitis of the scalp, acne keloidalis nuchae, monilethrix, pediculosis, alopecia totalis, pseudopelade of Brocq, bubble hair deformity, hair casts, hypertrichosis, ingrown hair, monilethrix, premature greying of hair, pattern hair loss, trichorrhexis invaginata, and the like.

[0046] The compositions disclosed herein may be applied topically to a selected area of the body from which it is desired to reduce hair growth. For example, the composition can be applied to the face, particularly to the beard area of the face, i.e., the cheek, neck, upper lip, and chin. The composition also may be used as an adjunct to other methods of hair removal including shaving, waxing, mechanical epilation, chemical depilation, electrolysis and laser-assisted hair removal. Other actions that make their concept appearance are concurrent skin benefits in addition to hair reduction. The composition can also be applied to the legs, arms, torso or armpits. The composition is suitable, for example, for reducing the growth of unwanted hair in women. In humans, the composition may be applied once or twice a day, or even more frequently, to achieve a perceived reduction in hair growth. Reduction in hair growth is demonstrated when, for example, the rate of hair growth is slowed, the need for removal is reduced, the subject perceives less hair on the treated site, or quantitatively, when the weight of hair removed (i.e., hair mass) is reduced.

[0047] Disclosed but not claimed herein is a method of treating dry eye syndrome in a subject. Disclosed but not claimed herein, the method of treating dry eye syndrome includes administering to the subject in need thereof an effective amount of an anhydrous composition comprising one or more mTOR inhibitors, one or more solvents, one or more gelling agents, and one or more antioxidants.

[0048] The composition may, for example, be applied to a plaster, patch, bandage, or a film. Topical delivery may be aided by the use of ultrasound technology. The ultrasound energy is applied over the tissue and to assist the diffusion of the composition past the tissue.

[0049] Disclosed but not claimed herein, the compositions disclosed herein can be in the form of transdermal patches. The transdermal patches can be in any conventional form such as, for example, a strip, a gauze, a film, and the like. Patch material may be nonwoven or woven (e.g., gauze dressing). Layers may also be laminated during processing. It may be nonocclusive or occlusive, but the latter is preferred for backing layers. The patch is preferably hermetically sealed for storage (e.g., foil packaging). The patch can be held onto the skin and components of the patch can be held together using various adhesives. For example, the transdermal patch can be in the form of a band-aid type device, or it may be packaged in a small metal or plastic "cup", which is strapped onto the appropriate site using an adhesive, tape, or an outer fabric or leather strap, similar to that worn as part of a watch. The entire patch may be disposable or may be refillable. In some embodiments, the compositions disclosed herein can be coated on bandages, mixed with bioadhesives, or included in dressings.

[0050] A hand pump may be used to dispense the mTOR inhibitor anhydrous compositions. For example, the hand pump may be configured to dispense the required dose of mTOR inhibitor within a tolerance specified by a corresponding label approved by a government regulatory agency. The hand pump may deliver 0.5-10 mL of the composition per pump action, such as 1, 2, 3, 4, or 5 mL of the composition per pump action. In some embodiments, the mTOR inhibitor compositions may be packaged along with a pharmaceutically acceptable hand pump.

[0051] Disclosed but not claimed herein, the anhydrous compositions may be administered in a conventional manner by any route by which they retain activity. For example, the anhydrous composition of mTOR inhibitors may be administered by routes including, but not limited to, topical, transdermal, or percutaneous. Thus, modes of administration for the compounds (either alone or in combination with other pharmaceuticals) can be, but are not limited to, sublingual, or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, and percutaneous and topical forms such as patches and creams, lotions, gels.

[0052] The particular quantity of composition administered, of course, will be determined by the particular circumstances surrounding its use, including the composition administered, the condition of the skin, the age of the user, the degree of the skin disorder, and similar considerations. For example, the dosage may depend on the particular animal treated, the age, weight, and health of the subject, the types of concurrent treatment, if any, and frequency of treatments. Many of these factors can be easily determined by one of skill in the art (e.g., by the clinician). Typically, a single application of the composition will be applied topically to cover adequately the affected area of the skin. Subsequent applications may be made as needed to deliver the desired level of mTOR inhibitors.

[0053] The composition can be administered one, two, three, four, five or more times each day, and applying can be carried out for a period of at least 1 month, 2 months, 3 months, 4 months, 6 months, 8 months or 12 months.

[0054] The composition may be administered once, as needed, once daily, twice daily, three times a day, once a week, twice a week, every other week, every other day, or the like for one or more dosing cycles. A dosing cycle may include administration for about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks. After this cycle, a subsequent cycle may begin approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks later. The treatment regime may include 1, 2, 3, 4, 5, or 6 cycles, each cycle being spaced apart by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks.

[0055] The method of treating a skin disorder may comprise administering the anhydrous composition described herein, wherein the method does not further include any additional medical or therapeutic intervention for treatment of the skin disorder.

[0056] The method of treating a skin disorder may comprise administering the anhydrous compositions described herein, wherein the mTOR inhibitor is the only active agent administered for treating the skin disorder.

[0057] The methods may include a variety of additional steps including, for example, cleaning the surface tissue at the site of applying and the like.

[0058] The methods may further include descaling or debriding of the tissue surface before, during or after administration of the compositions described herein. Methods for descaling or debriding tissue surface may include electromagnetic radiation, laser, dermal abrasion, chemical peel, ultrasound, heating, cooling, or by a needle.

[0059] The tissue surface may be descaled or debrided with abrasion. Abrasion of the outer layer or epidermis of the skin (dermal abrasion) is desirable to smooth or blend scars, blemishes, or other skin conditions that may be caused by, for example, acne, sun exposure, and aging. Standard techniques used to abrade the skin have generally been separated into two fields referred to as dermabrasion and microdermabrasion. Both techniques remove portions of the epidermis called the stratum corneum, which the body interprets as a mild injury. The body then replaces the lost skin cells, resulting in a new outer layer of skin. Additionally, despite the mild edema and erythema associated with the procedures, the skin looks and feels smoother because of the new outer layer of skin.

[0060] The tissue surface may be descaled or debrided with microdermabrasion. Microdermabrasion refers generally to a procedure in which the surface of the skin is removed due to mechanical rubbing by a handpiece emitting a stream of sand or grit. For example, a handpiece can be used to direct an air flow containing tiny crystals of aluminum oxide, sodium chloride, or sodium bicarbonate. The momentum of the grit tends to wear away two to three cell layers of the skin with each pass of the handpiece. Alternatively, new "crystal-free" microdermabrasion techniques utilize a diamond-tipped handpiece without a stream of grit.

[0061] The tissue surface may be descaled or debrided with electromagnetic radiation, for instance using a so-called fractional laser treatment. By way of example, such methods employ electromagnetic radiation (EMR) having one or more wavelengths of between approximately 1,850 to 100,000 nanometers and with pulse widths of between approximately 1 femtosecond (1×10-15 s) to 10 milliseconds (10×10-3 s) with fluence in the range of from approximately 1 J / cm2 to 300 J / cm2. In other examples, the tissue is descaled or debrided with electromagnetic radiation having one or more wavelengths of between approximately 2,200 to 5,000 nanometers. In still other examples, the tissue is descaled or debrided with electromagnetic radiation having one or more wavelengths of between approximately 190 to 320 nanometers with fluence in the range of from 1 J / cm2 to 300 J / cm2. Optionally, conditions selected for debriding portions of the tissue minimize the coagulation zone of tissue damage, for instance by keeping the coagulation zone to a relatively small diameter surrounding the ablated void.

[0062] Electromagnetic radiation (EMR), particularly in the form of laser light or other optical radiation, has been used in a variety of cosmetic and medical applications, including uses in dermatology, dentistry, ophthalmology, gynecology, otorhinolaryngology and internal medicine. For most dermatological applications, EMR treatment can be performed with a device that delivers the EMR to the surface of the targeted tissue(s). EMR treatment is typically designed to (a) deliver one or more particular wavelengths (or a particular continuous range of wavelengths) of energy to a tissue to induce a particular chemical reaction, (b) deliver energy to a tissue to cause an increase in temperature, or (c) deliver energy to a tissue to damage or destroy cellular or extracellular structures, such as for skin remodeling. Examples of devices that have been used to treat the skin during cosmetic procedures such as skin rejuvenation include the Palomar ®< LuxIR, the Palomar ®< 1540, 1440 and 2940 Fractional Handpieces, the Reliant Fraxel ®< SR Laser and similar devices by Lumenis, Alma Lasers, Sciton and many others.

[0063] The methods may further include photodynamic therapy before, during or after administration of the compositions described herein. Photodynamic therapy is a minimally invasive two-step medical procedure that uses photoactivatable drugs called photosensitizers to treat a range of diseases. First, a photosensitizer is administered and, once it has permeated the target tissue, the photosensitizer is then activated by exposure to a dose of electromagnetic (usually light) radiation at a particular wavelength. The compositions disclosed herein may contain a photosensitizer. In embodiments, any suitable photosensitizing agent or mixture of agents may be used herein. Generally, these will absorb radiation in the range of from about 380 nm to about 900 nm. As used herein, "photosensitizer" or "photosensitizing agent" preferably means a chemical compound which, when contacted by radiation of a certain wavelength, forms singlet oxygen or thermal energy. Non-limiting examples of photosensitizers include aminolevulinic acid esters, porphyrins, porphyrin derivatives, bacteriochlorins, isobacteriochlorins, phthalocyanine, naphthalocyanines, pyropheophorbides, sapphyrins, texaphyrins, tetrahydrochlorins, purpurins, porphycenes, phenothiaziniums, and metal complexes such as, but not limited to, tin, aluminum, zinc, lutetium, and tin ethyl etiopurpurin (SnET2), and combinations thereof.

[0064] The compositions of the present invention can also be administered in combination with other active ingredients, or other compatible drugs or compounds where such combination is seen to be desirable or advantageous in achieving the desired effects of the methods described herein.

[0065] This invention and embodiments illustrating the method and materials used may be further understood by reference to the following non-limiting examples.EXAMPLESComparative Example 1:

[0066] A comparative anhydrous composition is described below: Component wt % Role tetrahydrofurfurylalcohol polyethylene glycol ether34.55%drug solventTranscutol ®< 15%co-solventpropylene glycol monocaprylate20%co-solventPropylene Glycol5%skin penetration enhancer / solventPoloxamer 40710 %surfactantWS51.05%cooling agentrapamycin1.2%APIcholesterol0.95%emollientSilicones10%emollientKlucel ®< 2.25%gelling agent Comparative Example 2

[0067] A comparative anhydrous composition is described below: Component wt % Role tetrahydrofurfurylalcohol polyethylene glycol ether29.42%drug solventTranscutol ®< 9%co-solventPEG40035%co-solventPropylene Glycol5%skin penetration enhancer / solventWS51.05%cooling agentrapamycin2.4 %APICholesterol0.90%emollientCyclomethicone10%emollientDimethicone5%emollientKlucel ®< 2.23%gelling agent Comparative Example 3

[0068] A comparative anhydrous composition is described below: Component wt % Role Capryilic / Capric Triclycerides30.45%drug solventTranscutol10%co-solventGlycofural25%co-solventPropylene Glycol5%skin penetration enhancer / solventIsopropyl myristate8 %emollient / thickening agentWS51.05%cooling agentrapamycin2.2%APIAscorbyl Palmitate0.3%antioxidantCyclomethicone10%emollientDimethicone5%emollientCarbopol3%gelling agent Comparative Example 4:

[0069] A comparative anhydrous composition (NA 17) is described below: component Wt% Role Rapamycin3.26APIIsopropyl alcohol15solventPEG40055.668solventTranscutol P15penetration enhancer / solventGlycerol10solventKlucel ®< 1gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Comparative Example 5:

[0070] A comparative anhydrous composition (NA 19) is described below: component Wt% Role Rapamycin3.26APIIsopropyl alcohol15solventPEG40055.388solventTranscutol P15penetration enhancer / solventGlycerol10solventKlucel ®< 1gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidantpeppermint oil0.2cooling agentmenthol0.08cooling agent Comparative Example 6:

[0071] A comparative anhydrous composition (NA 21) is described below: component Wt% Role Rapamycin4.54APIIsopropyl alcohol15solventPEG40044.388solventTranscutol P25penetration enhancer / solventGlycerol10solventKlucel ®< 1gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Example 7:

[0072] An exemplary anhydrous composition (NA 22) is described below: component Wt% Role Rapamycin3.9APIIsopropyl alcohol15solventPEG40055.3solventdiisopropyl adipate15solventGlycerol10solventKlucel ®< 0.75gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Comparative Example 8:

[0073] A comparative anhydrous composition (NA 23) is described below: component Wt% Role Rapamycin4.51APIethanol15solventPEG40054.418solventdiisopropyl adipate15solventGlycerol10solventKlucel ®< 1gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Comparative Example 9:

[0074] A comparative anhydrous composition (NA 24) is described below: component Wt% Role Rapamycin2.384APIIsopropyl alcohol15solventPEG40056.548solventPropylene glycol15penetration enhancer / solventGlycerol10solventKlucel ®< 1gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Comparative Example 10:

[0075] A comparative anhydrous composition (NA 25) is described below: component Wt% Role Rapamycin2.69APIIsopropyl alcohol15solventPEG40026.238solventPropylene glycol15penetration enhancer / solventTranscutol P25penetration enhancer / solventDiisopropyl adipate15solventKlucel ®< 1gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Comparative Example 11:

[0076] A comparative anhydrous composition (NA 26) is described below: component Wt% Role Rapamycin3.254APIIsopropyl alcohol15solventPEG40047.608solventPropylene glycol15penetration enhancer / solventTranscutol P10penetration enhancer / solventGlycerol10solventKlucel ®< 1gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Comparative Example 12:

[0077] A comparative ointment composition (O3) is described below: component Wt% Role Rapamycin4.59APIPEG40034.34solventTranscutol P47.998penetration enhancer / solventPEG 335013solventPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Comparative Example 13:

[0078] A comparative aqueous composition (TD201) is described below: component Wt% Rapamycin1water87.95Pemulen TR-10.28Carbopol Ultrez 100.76Propylene glycol2.87Oleic acid1.43Mineral oil0.95Triethanol amine (q.s to pH 5-7)ca. 0.76Benzyl alcohol4 Example 14:

[0079] An exemplary anhydrous composition (NA 28) is described below: component Wt% Role Rapamycin3.9APIIsopropyl alcohol15solventPEG40051solventPropylene glycol1.5penetration enhancer / solventDiisopropyl adipate15solventGlycerol10solventBenzyl alcohol2solventOleyl alcohol0.75solventKlucel ®< 0.75gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Comparative Example 15:

[0080] A comparative anhydrous composition (NA 33) is described below: component Wt% Role Rapamycin3.9APIPEG40028.3solventPropylene glycol15penetration enhancer / solventTranscutol P15Penetration enhancer / solventDiisopropyl adipate15solventGlycerol10solventBenzyl alcohol2solventOleyl alcohol10solventKlucel ®< 0.75gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Comparative Example 16:

[0081] A comparative anhydrous composition (NA 34) is described below: component Wt% Role Rapamycin3.2APIPEG40051.7solventPropylene glycol1.5penetration enhancer / solventTranscutol P15Penetration enhancer / solventDiisopropyl adipate15solventGlycerol10solventBenzyl alcohol2solventOleyl alcohol0.75solventKlucel ®< 0.75gelling agentPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Comparative Example 17:

[0082] A comparative ointment composition (O 11) is described below: component Wt% Role Rapamycin2.5APIPEG40043solventPropylene glycol1.5penetration enhancer / solventTranscutol P29.45Penetration enhancer / solventWater7.8solventBenzyl alcohol2solventOleyl alcohol0.75solventPEG 335013solventPropyl gallate0.05antioxidantAscorbyl palmitate0.02antioxidanta-tocopherol0.002antioxidant Example 18: Ex vivo skin permeation experiment

[0083] Human donor skin was placed between upper and lower compartments. The lower compartment was filled with receiver fluid. Various rapamycin compositions were applied on the surface of the skin facing the upper compartment (11 formulations (i.e., O3, NA21, NA22, NA21, NA17, TD201, NA19, NA25, AG14, NA26 and NA24), n =6 replicates, dosage 10 mg / cm 2< ) and left for 24 hrs. A positive displacement pipette was used to apply the formulation (~ 10 mg / cm2) to the plunger of a 1 mL syringe. The formulation (10 + / - 0.5mg) was applied to the skin surface and spread over the diffusion area using the plunger. Prior to and after the application the weight of the plunger was recorded, from which the dose per cell was calculated. NA22 is an example of a claimed composition, other compositions are for comparative purposes.

[0084] Following the time period, the excess rapamycin compositions were wiped from the skin surface and the skin layers were separated into stratum corneum, epidermis, and dermis. The Stratum corneum was removed from the human skin using a tape stripping procedure. The epidermis was separated from the dermis by dry heating at 60°C for 2 min. Rapamycin was extracted from each layer by 90:10 v / v ethanol: water solvent mixture, and quantified. The receiver fluid in the lower compartment was also analyzed for the presence of rapamycin.

[0085] As would be expected, the greatest amount of rapamycin was found on the surface of the skin after 24 hours. Further, there appeared to be more of the drug residing in the epidermis than either the stratum corneum or dermal layer. Furthermore, over time there was an increase in the amount of rapamycin quantified in both the epidermis and dermis. Rapamycin was not detected in the receiver fluid at any of the time points across the experimental period, suggesting that rapamycin did not fully pass through the skin layers.

[0086] As shown in FIGs. 1 and 2, results from the penetration experiment revealed similarity of epidermal drug recoveries following application of all formulations when compared to TD201, with the exception of NA24, where amounts of drug recovered from the skin from TD201 were eightfold higher. Significantly higher amounts of drug in the dermis were observed from O3 when compared to TD201 (p<0.02), however all other formulations were statistically comparable but NA21, NA22 and NA23 exhibited higher average dermis levels than those observed in TD201. When delivery of the drug to the total tissue, i.e. the epidermis and dermis in combination was considered, all formulations exhibited drug recoveries statistically similar to TD201.

[0087] Further, as shown in FIGs. 3 and 4, results of the penetration experiment indicated that significantly higher amounts of rapamycin were delivered to the epidermis following application of NA22, NA33 and NA28 when compared to O11 (p < 0.05) while all other comparisons were statistically similar (i.e. TD201 performed similarly to all anhydrous formulations). Furthermore, NA22 was shown to outperform TD201, NA34 and O11 when levels of dermal drug delivery were considered, with significantly higher deposition in this skin layer than the aforementioned formulations (p < 0.05). The results suggest that NA22 demonstrated enhanced drug delivery to the dermis and comparable delivery to the epidermis when compared to the formulation TD201. NA22 and NA28 are examples of a claimed composition, other compositions are for comparative purposes.

[0088] In summary, anhydrous compositions showed significant amount of rapamycin deposition in the skin layers, when compared to aqueous compositions, AG14 and TD201.Example 19: Evaluating Topical Bioavailability

[0089] The following Example can be used to assess the claimed compositions.Dermatopharmacokinetic (DPK) Studies

[0090] The dermatopharmacokinetic (DPK) approach is comparable to a blood, plasma, urine PK approach applied to the stratum corneum. DPK encompasses drug concentration measurements with respect to time and provides information on drug uptake, apparent steady-state levels, and drug elimination from the stratum corneum based on a stratum corneum concentration-time curve.

[0091] Application and Removal of Test and Reference Products: The treatment areas will be marked using a template without disturbing or injuring the stratum corneum / skin. The size of the treatment area will depend on multiple factors including drug strength, analytical sensitivity, the extent of drug diffusion, and exposure time. The stratum corneum is highly sensitive to certain environmental factors. To avoid bias and to remain within the limits of experimental convenience and accuracy, the treatment sites and arms will be randomized. Uptake, steady-state, and elimination phases, as described in more detail below, may be randomized between the right and left arms in a subject. Exposure time points in each phase may be randomized among various sites on each arm. The test and reference products for a particular exposure time point may be applied on sites to minimize differences. Test and reference products should be applied concurrently on the same subjects according to a SOP that has been previously developed and validated. The premarked sites will be treated with predetermined amounts of the products (e.g., 5 mg / sq cm) and covered with a nonocclusive guard. Occlusion will be used only if recommended in product labeling. Removal of the drug product will be performed according to SOPs at the designated time points, using multiple cotton swabs or Q-tips with care to avoid stratum corneum damage. In case of certain oily preparations such as ointments, washing the area with a mild soap may be needed before skin stripping. If washing is carried out, it will be part of an SOP.

[0092] Sites and Duration of Application: The bioavailability / bioequivalence (BA / BE) study will include measurements of drug uptake into the stratum corneum and drug elimination from skin. A minimum of eight sites will be employed to assess uptake / elimination from each product. The time to reach steady state in the stratum corneum will be used to determine timing of samples. For example, if the drug reaches steady-state in three hours, 0.25, 0.5, 1 and 3 hours posttreatment may be selected to determine uptake and 4, 6, 8 and 24 hours may be used to assess elimination. A zero time point (control site away from test sites) on each subject will be selected to provide baseline data. If the test / reference drug products are studied on both forearms, randomly selected sites on one arm may be designated to measure drug uptake / steady-state. Sites on the contralateral arm may then be designated to measure drug elimination. During drug uptake, both the excess drug removal and stratum corneum stripping times are the same so that the stratum corneum stripping immediately follows the removal of the excess drug. In the elimination phase, the excess drug will be removed from the sites at the steady-state time point, and the stratum corneum will be harvested at succeeding times over 24 hours to provide an estimate of an elimination phase.

[0093] Collection of Sample: Skin stripping proceeds first with the removal of the first 1-2 layers of stratum corneum with two adhesive tapes strip / disc applications, using a commercially available product (e.g., D-Squame, Transpore). These first two tape-strip(s) contain the generally unabsorbed, as opposed to penetrated or absorbed, drug and therefore will be analyzed separately from the rest of the tape-strips. The remaining stratum corneum layers from each site will be stripped at the designated time intervals. This is achieved by stripping the site with an additional 10 adhesive tape-strips. All ten tape strips obtained from a given time point will be combined and extracted, with drug content determined using a validated analytical method. The values will be generally expressed as amounts / area (e.g., ng / cm2) to maintain uniformity in reported values. Data may be computed to obtain full drug concentration-time profiles, Cmax-ss, Tmax-ss, and AUCs for the test and reference products.Procedure for Skin Stripping:

[0094] To assess drug uptake: The test and / or reference drug products will be applied concurrently at multiple sites. After an appropriate interval, the excess drug from a specific site will be removed by wiping three times lightly with a tissue or cotton swab. Using information from the pilot study, the appropriate times of sample collection to assess drug uptake will be determined. The application of adhesive tape two times will be repeated, using uniform pressure, discarding these first two tape strips. Stripping will be continued at the same site to collect ten more stratum corneum samples. Care will be taken to avoid contamination with other sites. The procedure will be repeated for each site at other designated time points. The drug will be extracted from the combined ten skin strippings and the concentration will be determined using a validated analytical method. The results will be expressed as amount of drug per square cm treatment area of the adhesive tape.

[0095] To assess drug elimination: The test and reference drug product will be applied concurrently at multiple sites chosen based on the results of the pilot study. Sufficient exposure period to reach apparent steady-state level will be allowed. Excess drug from the skin surface will be removed as described previously, including the first two skin strippings. The skin stripping samples will be collected using ten successive tape strips at time intervals based on the pilot study and drug content will be analyzed.

[0096] Metrics and Statistical Analyses: A plot of stratum corneum drug concentration versus a time profile will be constructed to yield stratum corneum metrics of Cmax, Tmax and AUC. The two one-sided hypotheses at the α= 0.05 level of significance will be tested for AUC and Cmax by constructing the 90 percent confidence interval (CI) for the ratio between the test and reference averages. Individual subject parameters, as well as summary statistics (average, standard deviation, coefficient of variation, 90% CI) will be reported. For the test product to be BE, the 90 percent CI for the ratio of means (population geometric means based on log-transformed data) of test and reference treatments will fall within 80-125 percent for AUC and 70- 143 percent for Cmax.In vivo Dermal Open Flow Microperfusion

[0097] In dermal open-flow microperfusion (dOFM), a thin, hollow tube will be inserted just under the skin surface, running through a section of the skin a few inches wide and then exiting. A liquid similar to body fluid will be injected into the tubing; a portion of the tube under the skin is porous, so any drug that has been applied and absorbed through the skin's outer layer enters the flowing liquid, which will be then collected for analysis. dOFM can reliably measure the changing amounts of drug in the skin after topical application of a dermatological drug product.

Claims

1. A topical anhydrous composition consisting of: rapamycin at 3.9 wt% of the composition; isopropyl alcohol at 15 wt% of the composition; polyethylene glycol 400 at 55.3 wt% of the composition; diisopropyl adipate at 15 wt% of the composition; glycerol at 10 wt% of the composition; hydroxypropyl cellulose at 0.75 wt% of the composition; propyl gallate at 0.05 wt% of the composition; ascorbyl palmitate at 0.02 wt% of the composition; alpha-tocopherol at 0.002 wt% of the composition.

2. A topical anhydrous composition consisting of: rapamycin at 3.9 wt% of the composition; isopropyl alcohol at 15 wt% of the composition; polyethylene glycol 400 at 51 wt% of the composition; polypropylene glycol at 1.5 wt% of the composition; diisopropyl adipate at 15 wt% of the composition; glycerol at 10 wt% of the composition; benzyl alcohol at 2 wt% of the composition; oleyl alcohol at 0.75 wt% of the composition; hydroxypropyl cellulose at 0.75 wt% of the composition; propyl gallate at 0.05 wt% of the composition; ascorbyl palmitate at 0.02 wt% of the composition; alpha-tocopherol at 0.002 wt% of the composition.

3. A topical anhydrous composition for use in treating a skin disorder in a subject, wherein the topical anhydrous composition is according to claim 1 or 2 and is applied topically.

4. The topical anhydrous composition for use according to claim 3, wherein the skin disorder is selected from the group consisting of plantar hyperkeratosis, epidermolysis bullosa, lichenoid keratoses, epidermolytic ichthyosis, Olmsted syndrome, actinic keratosis, pachyonychia congenita, warts, psoriasis, basal cell carcinoma, melanoma, venous malformation, lupus, infantile hemangiomas, angiofibroma, basal cell nevus syndrome, Birt-Hogg-Dube syndrome, Blue rubber bleb nevus syndrome, cutaneous T-cell lymphoma, lymphatic malformations, epidermolysis bullosa simplex, Kaposi sarcoma, Kaposiform hemangioendothelioma, Muir-Torre syndrome, neurofibromatosis, graft-versus-host disease, Pemphigus vulgaris, hemangioendotheliomas in Maffucci syndrome, and combinations thereof.