Anhydrous composition of mTOR inhibitor and method of using the same

Abstract

To provide anhydrous compositions and methods for topical delivery of mTOR inhibitors.SOLUTION: In one embodiment, an anhydrous composition includes one or more mTOR inhibitors, one or more solvents, one or more gelling agents, and one or more antioxidants.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 443,117, filed on January 6, 2017, entitled "Anhydrous Compositions of mTOR Inhibitors and Methods of Use Thereof," which is incorporated herein by reference in its entirety.

Summary of the Invention

Means for Solving the Problems

[0002] Compositions and methods for the topical delivery of mTOR inhibitors are disclosed herein. In one embodiment, the anhydrous composition comprises an effective amount of one or more mTOR inhibitors, one or more solvents, one or more gelling agents, and one or more antioxidants. In some embodiments, the mTOR inhibitor is present at about 0.1 wt% to about 20 wt% of the total composition. In some embodiments, the solvent is present at about 1 wt% to about 99.9 wt% of the total composition. In some embodiments, the gelling agent is present at about 0.1 wt% to about 5 wt% of the total composition. In some embodiments, the antioxidant is present at about 0.001 wt% to about 1 wt% of the total composition.

[0003] In a further embodiment, a method of treating a skin disease in a subject in need thereof comprises topically administering an effective amount of an anhydrous composition comprising an effective amount of one or more mTOR inhibitors, one or more solvents, one or more gelling agents, and one or more antioxidants. In some embodiments, the mTOR inhibitor is present at about 0.1 wt% to about 20 wt% of the total composition. In some embodiments, the solvent is present at about 1 wt% to about 99.9 wt% of the total composition. In some embodiments, the gelling agent is present at about 0.1 wt% to about 5 wt% of the total composition. In some embodiments, the antioxidant is present at about 0.001 wt% to about 1 wt% of the total composition. As prior art document information related to the invention of this application, there are the following (including documents cited at the international stage after the international filing date and documents cited when transferred to other countries for national phase). (Prior art document) (Patent document) (Patent Document 1) U.S. Patent No. 10,130,707 (Patent Document 2) U.S. Patent No. 10,172,789 (Patent Document 3) U.S. Patent No. 10,456,383 (Patent Document 4) U.S. Patent Application Publication No. 2001 / 0031769 (Patent Document 5) U.S. Patent Application Publication No. 2002 / 0015702 (Patent Document 6) U.S. Patent Application Publication No. 2002 / 0016625

Brief Description of the Drawings

[0004]

Figure 1

Figure 2

Figure 3

Figure 4

Modes for Carrying Out the Invention

[0005] When a range of values is provided, each value that lies between the upper and lower limits of that range, as well as other recited or intervening values within the recited range, is intended to be encompassed within the present disclosure. For example, if a range of 1 μm to 8 μm is recited, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μm are also intended to be explicitly disclosed, as are ranges of values greater than or equal to 1 μm and less than or equal to 8 μm.

[0006] As used in this application and the claims, the singular forms “a,” “an,” and “the” include the plural unless the context clearly dictates otherwise. Further, the term “comprising” means “having.”

[0007] As used herein, all recited numerical terms should be read as being preceded by the term “about,” which means plus or minus 10% of the numerical value of the number being used. Thus, a claim for “50%” means “about 50%” and encompasses the range of 45% to 55%.

[0008] The terms “patient” and “subject” are interchangeable and can be interpreted to mean any organism that can be treated with the compounds of the present invention. As such, the terms “patient” and “subject” can include, but are not limited to, any non-human mammal, primate, or human. In some embodiments, the “patient” or “subject” is a mammal such as a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, primate, or human. In some embodiments, the patient or subject is an adult, child, or infant. In some embodiments, the patient or subject is a human.

[0009] As used herein, "administering" when used in combination with an mTOR inhibitor means that the mTOR inhibitor is administered to a patient, whereby the mTOR inhibitor actively affects the tissue it targets. The mTOR inhibitors described herein can be administered alone or in combination with other pharmaceutically active agents (simultaneously or sequentially). For example, the mTOR inhibitor can be administered in combination with other anti-cancer or anti-neoplastic agents, or in combination with other therapies for treating skin diseases. In some embodiments, the mTOR inhibitors described herein can also be administered in combination with other therapeutic agents (i.e., as a combined composition or as separate compositions).

[0010] An "effective amount" of a composition is a predetermined amount calculated to achieve a desired effect, i.e., to alleviate, prevent, or improve an undesirable condition, disease, or symptom in a patient. The activities contemplated by the methods can, if desired, include both therapeutic and / or prophylactic treatments. The specific dosage of the agent administered in accordance with the present invention to obtain a therapeutic and / or prophylactic effect will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, and the disease being treated. The effective amount to be administered can be determined by a physician taking into account the relevant circumstances, including the symptoms being treated, the choice of compound administered, and the selected route of administration.

[0011] As used herein, the term "carrier" includes carriers, excipients, and diluents, and means a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, composition, or vehicle involved in the conveyance or transport of other agents across tissue layers such as pharmaceutical, cosmetic, or tissue layers such as the stratum corneum or stratum spinosum.

[0012] The transitional term "comprising", which is synonymous with "including" or "characterized by", is inclusive or open-ended and does not exclude additional elements or method steps not recited. In contrast, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the scope of the claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the invention claimed. In embodiments or claims where the term "comprising" is used as a transitional term, it is also contemplated that such embodiments may also be replaced with the terms "consisting of" or "consisting essentially of".

[0013] The term "treating" as used herein, for example, with respect to methods of treating a skin disorder or a systemic condition, generally includes the administration of a compound or composition that, compared to a subject not receiving the compound or composition, decreases the frequency of a medical condition, or delays the onset of symptoms of a medical condition, or enhances the texture, appearance, color, sensation, or hydration of an intended tissue treatment area of the tissue surface of the subject. This includes reversing, reducing, or preventing the symptoms, clinical signs, and underlying pathology of the condition to improve or stabilize the symptoms of the subject.

[0014] As used in this disclosure, the term "disorder" is used to mean and is used interchangeably with the terms disease, condition, or illness, unless otherwise specified.

[0015] The weight percentages disclosed herein can be weight-to-weight or weight-to-volume percentages, as appropriate.

[0016] Anhydrous compositions of mTOR inhibitors are disclosed herein. In some embodiments, the anhydrous composition comprises one or more mTOR inhibitors, one or more solvents, one or more gelling agents, and one or more antioxidants.

[0017] In some embodiments, the anhydrous composition of the mTOR inhibitor has a Cmax of about 120 to 990 micromoles in the epidermis and about 36 to 350 micromoles in the dermis. In some embodiments, the anhydrous composition of the mTOR inhibitor has a Tmax of about 15 to 24 hours in the epidermis. In some embodiments, the anhydrous composition is considered to be biologically equivalent or substantially biologically equivalent to the anhydrous composition containing the mTOR inhibitor described herein when measured by an approved local bioavailability study.

[0018] In some embodiments, the anhydrous composition comprises at least one mTOR inhibitor. Non-limiting examples of mTOR inhibitors include rapamycin (sirolimus), everolimus, pimecrolimus, ridarolimus, temsirolimus, zotarolimus, rapamycin prodrug AP-23573, AP-23481, Torin-1, Torin-2, WYE-354, dactolisib, bimiralisib, omipalisib, apitolisib, bisuvelitinib, gedatolisib, WYE-125132, BGT226, palomid 529, GDC-0349, XL388, CZ415, CC-223, ABT-578, SF1126, PKI-587, INK128, AZD8055, NVPBE235, AZD2014, biolimus A9 (umbralisib), GSK2126458, OSI027, PP121, WYE-687, WAY-600, XL765, PI-103, BEZ235, KU-0063794, torquinib (PP242), PF-04691502, and pharmaceutically acceptable salts, hydrates, solvates, or amorphous solids thereof, and combinations thereof.

[0019] In some embodiments, the mTOR inhibitor also includes a specific inhibitor of TOR complex 1, a specific inhibitor of TOR complex 2, etc. In one embodiment, drugs that can be used to inhibit TOR complex 2 include, but are not limited to, small molecules, nucleic acids, proteins, and antibodies. Examples of small molecules include, but are not limited to, pyridinone quinoline, pyrazolopyrimidine, and pyridopyrimidine. In a further aspect, small molecules that inhibit TOR complex 1 and 2 include Torin 1, Torin 2, Torquinib (PP242), PP30, KU-0063794, WAY-600, WYE-687, WYE-354, AZD8055, INK128, OS1027, AZD2014, Omipalisib, Wortmannin, LY294002, PI-103, BGT226, XL765, and NVP-BEZ235. In a further aspect, the inhibitor includes, but is not limited to, antisense oligonucleotides, siRNA, shRNA, and combinations thereof. In a further aspect, the drug that inhibits TOR complex 2 does not inhibit TOR complex 1.

[0020] In some embodiments, the anhydrous composition may further include other compounds that regulate the mTOR pathway, such as tacrolimus and metformin.

[0021] In some embodiments, the mTOR inhibitor is present in about 0.1 wt% to about 20 wt%, about 0.1 wt% to about 15 wt%, about 0.1 wt% to about 10 wt%, about 0.1 wt% to about 4.5 wt%, about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt% of the total composition, and any individual amount or any range between any two of these values. In some embodiments, the weight percentages disclosed herein can be weight - to - weight or weight - to - volume percentages. Non - limiting examples include about 0.1 wt%, about 0.5 wt%, about 0.8 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, about 5 wt%, about 10 wt%, about 15 wt%, or about 20 wt%. In some embodiments, the mTOR inhibitor is rapamycin and is present in about 0.1 wt% to about 10 wt% of the total composition.

[0022] In some embodiments, the compound that modulates the mTOR pathway is present in about 0.1 wt% to about 20 wt%, about 0.1 wt% to about 15 wt%, about 0.1 wt% to about 10 wt%, about 0.1 wt% to about 4.5 wt%, about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt% of the total composition, and any individual amount or any range between any two of these values. In some embodiments, the weight percentages disclosed herein can be weight - to - weight or weight - to - volume percentages. Non - limiting examples include about 0.1 wt%, about 0.5 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt%, about 5 wt%, about 10 wt%, about 15 wt%, or about 20 wt%.

[0023] In some embodiments, the anhydrous composition may include one or more solvents that facilitate solubilization of the mTOR inhibitor. In some embodiments, the solvents include alcohols, polyols, amides, esters, propylene glycol ethers, and mixtures thereof. Non-limiting examples of alcohols or polyols include ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, PEG400, PEG3350, SR-PEG400, SR-DMI, oleyl alcohol, castor oil, Miglyol 810, liquid paraffin, propylene glycol dicaprylate / dicaprate, butanediol and its isomers, glycerol, glycerol triacetate, pentaerythritol, sorbitol, mannitol, Transcutol® P (diethylene glycol monoethyl ether), Transcutol HP, diisopropyl adipate, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivatives, and mixtures thereof. Examples of amides include 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide, polyvinylpyrrolidone, and mixtures thereof. Examples of esters include ethyl propionate, tributyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers, δ-valerolactone and its isomers, β-butyrolactone and its isomers, and mixtures thereof.

[0024] In some embodiments, the solvent includes benzyl alcohol, DMSO, diglycol, propylene glycol monocaprylate (caprylol 90), diethylene glycol monoethyl ether (transcutol (registered trademark)), tetrahydrofurfuryl alcohol polyethylene glycol ether (glycofurol), butylene glycol, propylene glycol, diethylene glycol, triethylene glycol, and combinations thereof. More preferably, in some embodiments, the solvent includes propylene glycol monocaprylate, benzyl alcohol, tetrahydrofurfuryl alcohol polyethylene glycol ether, and combinations thereof. In some embodiments, the anhydrous composition does not contain ethanol. In some embodiments, the anhydrous composition contains less than 10 wt%, less than 8 wt%, less than 6 wt%, less than 4 wt%, or less than 2 wt% benzyl alcohol. In some embodiments, the anhydrous composition does not contain benzyl alcohol.

[0025] In some embodiments, the solvent is present in about 1 wt% to about 99.9 wt%, about 1 wt% to about 90 wt%, about 1 wt% to about 80 wt%, about 1 wt% to about 70 wt%, about 1 wt% to about 60 wt%, about 1 wt% to about 50 wt%, about 1 wt% to about 40 wt%, about 1 wt% to about 30 wt%, about 80 wt% to about 99.9 wt%, about 85 wt% to about 99.9 wt%, about 90 wt% to about 99.9 wt%, or about 95 wt% to about 99.9 wt% of the total composition. Non-limiting examples include about 1 wt%, about 25 wt%, about 40 wt%, about 50 wt%, about 60 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 92 wt%, about 94 wt%, about 95 wt%, about 96 wt%, about 97 wt%, about 99 wt%, or about 99.9 wt%.

[0026] In some embodiments, the anhydrous composition includes one or more gelling agents such as poloxamers and carbomers. Non-limiting 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(ε-caprolactam), and hydroxypropyl cellulose (KLUCEL®), glyceryl tris 12-hydroxystearate, hydroxystearin, propylene carbonate, polyvinyl pyrrolidine can also be used as gelling agents. Non-limiting examples of carbomers that can be used are carbomer 981, carbomer 934, carbomer 934P, carbomer 940, carbomer 941, carbomer 1342, polycarbophil, and calcium polycarbophil. In a preferred embodiment, the gelling agent is selected from hydroxypropyl cellulose, carbomer 981, carbomer 934P, glyceryl tris 12-hydroxystearate, hydroxystearin, propylene carbonate, polyvinyl pyrrolidine, and combinations thereof. In some embodiments, the gelling agent is present at about 0.1 wt% to about 5 wt%, about 0.1 wt% to about 4 wt%, about 0.1 wt% to about 3 wt%, about 0.1 wt% to about 2 wt%, or about 0.1 wt% to about 1 wt% of the total composition.

[0027] In some embodiments, the anhydrous composition comprises one or more antioxidants such as ascorbic acid, vitamin E and its derivatives, α-tocopherol, ψ-tocopherol, δ-tocopherol, ascorbyl palmitate, propyl gallate (PG), octyl gallate, dodecyl gallate, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT), and D-α-tocopheryl polyethylene glycol 1000 succinate. In some embodiments, the antioxidant is present at about 0.001 wt% to about 1 wt%, about 0.001 wt% to about 0.5 wt%, about 0.001 wt% to about 0.1 wt%, about 0.001 wt% to about 0.05 wt%, or about 0.001 wt% to about 0.01 wt% of the total composition.

[0028] In some embodiments, the anhydrous composition comprises an effective amount of one or more mTOR inhibitors present at about 0.1 wt% to about 20 wt% of the total composition, one or more solvents present at about 1 wt% to about 99 wt% of the total composition, one or more gelling agents present at about 0.1 wt% to about 5 wt% of the total composition, and one or more antioxidants present at about 0.001 wt% to about 1 wt% of the total composition.

[0029] In some embodiments, the anhydrous composition comprises an effective amount of one or more mTOR inhibitors present at about 0.1 wt% to about 10 wt% of the total composition, one or more solvents present at about 1 wt% to about 70 wt% of the total composition, one or more gelling agents present at about 0.1 wt% to about 4 wt% of the total composition, and one or more antioxidants present at about 0.01 wt% to about 1 wt% of the total composition.

[0030] In some embodiments, the anhydrous composition comprises an effective amount of one or more mTOR inhibitors present at about 1 wt% to about 10 wt% of the total composition, one or more solvents present at about 10 wt% to about 70 wt% of the total composition, one or more gelling agents present at about 1 wt% to about 5 wt% of the total composition, and one or more antioxidants present at about 0.01 wt% to about 0.5 wt% of the total composition.

[0031] In some embodiments, the anhydrous composition comprises an effective amount of one or more mTOR inhibitors present at about 1 wt% to about 5 wt% of the total composition, one or more solvents present at about 10 wt% to about 50 wt% of the total composition, one or more gelling agents present at about 1 wt% to about 4 wt% of the total composition, and one or more antioxidants present at about 0.001 wt% to about 0.01 wt% of the total composition.

[0032] In some embodiments, the anhydrous composition comprises one or more effective amounts of mTOR inhibitors, one or more solvents, and one or more antioxidants, and does not contain a gelling agent.

[0033] In some embodiments, the anhydrous composition of the mTOR inhibitor further comprises a polymeric surfactant, a humectant, a coolant, a rheology modifier, a pH adjuster, a preservative, and combinations thereof.

[0034] In some embodiments, the anhydrous composition of the mTOR inhibitor comprises one or more polymeric surfactants. Polymers having surfactant properties (polymeric surfactants) include, but are not limited to, hydrophobically modified polyacrylic acids (trade names Pemulen™ TR-1 and TR-2), copolymers based on acrylamide alkylsulfonic acid and cyclic N-vinylcarboxamide (trade name Aristoflex™ AVC), copolymers based on acrylamide alkylsulfonic acid and hydrophobically modified methacrylic acid (trade name Aristoflex™ HMB), and homopolymers of acrylamide alkylsulfonic acid (trade name Granthix APP). Another type of polymeric emulsifier of note includes hydrophobically modified crosslinked anionic acrylic copolymers containing random polymers, although other forms such as block, star, graft, etc. may also be present. In one embodiment, the hydrophobically modified crosslinked anionic acrylic copolymer can be synthesized from at least one acidic monomer and at least one hydrophobic ethylenically unsaturated monomer. Examples of suitable acidic monomers include ethylenically unsaturated acid monomers that may be neutralized by a base. Examples of suitable hydrophobic ethylenically unsaturated monomers include those containing a hydrophobic chain having a carbon chain length of at least about 3 carbon atoms. Other materials that can be suitable polymeric surfactants include ethylene oxide / propylene oxide block copolymers sold under the trade name PLURONIC™, modified cellulose polymers such as those described under the trade name KLUCEL™ (hydroxypropylcellulose), monomeric anionic surfactants, monomeric amphoteric surfactants, betaines, and combinations thereof. Other suitable polymeric surfactants include copolymers based on acrylamide alkylsulfonic acid and cyclic N-vinylcarboxamide and / or linear N-vinylcarboxamide (e.g., Aristoflex™ AVC and Aristoflex™ HMB) and betaines.In a preferred embodiment, the polymeric surfactant includes 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, Brij020, and combinations thereof. In some embodiments, the polymeric surfactant is present at about 0.1 wt% to about 50 wt%, about 0.1 wt% to about 40 wt%, about 0.1 wt% to about 30 wt%, about 0.1 wt% to about 20 wt%, or about 0.1 wt% to about 10 wt% of the total composition.

[0035] In some embodiments, the anhydrous composition of the mTOR inhibitor may further include one or more humectants or emollient components, such as mineral oil, dimethicone, cyclomethicone, cholesterol, or combinations thereof. In some embodiments, the anhydrous composition includes liquid emollients such as polyhydric alcohols, polyols, saccharides, triglycerides, hydrocarbons, silicones, fatty acids, fats, esters, fatty alcohols, and mixtures thereof. In some embodiments, the humectant is present at about 0.5 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.5 wt% to about 6 wt%, about 0.5 wt% to about 4 wt%, or about 0.5 wt% to about 1 wt% of the total composition.

[0036] In some embodiments, the anhydrous composition of the mTOR inhibitor comprises 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, ishirin, tea tree oil, methyl salicylate, camphor, peppermint oil, N-ethyl-p-menthane-3-carboxamide, ethyl 3-(p-menthane-3-carboxamide)acetate, 2-isopropyl-N,2,3-trimethylbutyramide, mentonglycerol ketal, mentonglycerol acetal, Coolact 10; WS3, WS5, WS23, menthyl glutarate, and mixtures thereof. In some embodiments, the cooling agent is present at about 0.5 wt% to about 10 wt%, about 0.5 wt% to about 8 wt%, about 0.5 wt% to about 6 wt%, about 0.5 wt% to about 4 wt%, or about 0.5 wt% to about 2 wt% of the total composition.

[0037] In some embodiments, the anhydrous composition disclosed herein does not contain water. In some embodiments, the anhydrous composition disclosed herein is substantially free of water. In some embodiments, the anhydrous composition disclosed herein contains less than 1% water in the total composition. In some embodiments, the anhydrous composition disclosed herein contains less than 0.5% water in the total composition. In some embodiments, the anhydrous composition disclosed herein contains less than 0.1% water in the total composition.

[0038] In some embodiments, the anhydrous composition of the mTOR inhibitor further comprises a rheology modifier, a pH adjuster, a preservative, and combinations thereof.

[0039] The composition of the present invention may further comprise a polymer (rheology modifier) having thickening properties. In one embodiment, the polymer having thickening properties may be a hydrophobically modified crosslinked acrylate copolymer (Carbopol® Ultrez20). Other polymers having similar properties may also be used. Non-limiting examples of the polymer having thickening properties include PEG-150 distearate, PEG-7 glyceryl cocoate, PEG-200 hydrogenated glyceryl palmitate, PEG-120 methyl glucose dioleate, carboxymethylene polymer, carboxyvinyl polymer, acrylate, C10-C30 alkyl acrylate crosspolymer, isopropyl myristate, and combinations thereof. In some embodiments, the polymer having thickening properties can account for about 0.1 wt% to about 3 wt%. In another embodiment, the polymer having thickening properties can be present in an amount of 0.4 wt% to about 1.0 wt% of the total composition. In one embodiment, the polymer having thickening properties occupies about 0.5 wt% to about 0.75 wt% of the total composition. In some embodiments, the thickening polymer can be mixed with a surfactant polymer.

[0040] In some embodiments, the composition of the present invention may further comprise a non-aqueous pH adjuster or a non-aqueous buffer present in the composition to neutralize and / or activate the thickening polymer to facilitate the formation of a composition having desirable rheological properties. Any anhydrous base or buffer system known in the art and suitable for use in skin contact applications can be used. In one embodiment, the base may include triethanolamine, sodium ethylenediaminetetraacetate (EDTA), alkali metal hydroxides such as sodium hydroxide (NaOH), ammonium lactate, sodium citrate, salts of weak acids such as sodium ascorbate, or mixtures thereof. The base component also provides utility in that it can adjust the pH of the entire composition to a range beneficial for minimizing skin irritation due to pH effects. In some embodiments, the composition of the present invention may also include an anhydrous acid or the acid component of a buffer system, and any acid known in the art and suitable for human skin contact can be used. Examples of acids useful in the present composition and commonly used to adjust the pH of topical compositions include, but are not limited to, citric acid, lactic acid, ascorbic acid, tartaric acid, and hydrochloric acid, as well as combinations of these and similar acids. In some embodiments, a phosphate buffer system is used in the composition. In some embodiments, the composition further comprises a phosphate buffer system and Brij020. In some embodiments, a phosphate / citric acid buffer system is used in the composition. In some embodiments, the composition comprises a phosphate / citric acid buffer and Brij020. Specific examples of the pH level of the composition include about pH 4, about pH 4.5, about pH 5, about pH 5.6, about pH 6, about pH 7, about pH 7.4, about pH 8, and ranges between any two of these values.

[0041] The compositions disclosed herein may further contain a preservative to prevent the growth of harmful microorganisms. While microorganisms tend to grow when in the aqueous phase, they can also be present in the oil phase. Therefore, preservatives having oil solubility are preferably used in the compositions of the present invention. Generally, 1 / 10 to 1% by weight of the preservative is appropriate. Traditional preservatives for cosmetics and pharmaceuticals are alkyl esters of para-hydroxybenzoic acid. Other preservatives that have come into use only recently include hydantoin derivatives, propionates, cationic surfactants such as benzalkonium chloride, benzyl alcohol, sorbic acid, and various quaternary ammonium compounds. Cosmetic chemists are knowledgeable about suitable preservatives and routinely select preservatives to satisfy preservative loading tests and provide product stability. Particularly preferred preservatives for the preferred anhydrous compositions of the present invention are phenoxyethanol, phenethyl alcohol, methyl and propyl parahydroxybenzoate, imidazolidinyl urea, and quaternium-15. The preservatives should be selected taking into account the use of the composition and possible incompatibilities that may occur between the preservatives and other components in the composition.

[0042] In some embodiments, the anhydrous composition is a sustained release composition for the controlled release of an mTOR inhibitor to reduce the rapid uptake and systemic absorption of the applied drug. Sustained (or controlled) release refers to the gradual release of the mTOR inhibitor from the composition over a period of time. There may be an initial burst phase, but in some embodiments, the release exhibits a relatively linear kinetics, preferably providing a constant supply of the mTOR inhibitor over the release period. The release period can vary from about 1 hour to about 8 hours, depending on the skin disease and its intended use. The composition may further comprise various biodegradable polymers for promoting sustained release, such as polylactide (PLA), polyglycolide (PGA), polybutylene succinate (PBS), polyhydroxyalkanoate (PHA), polycaprolactone (PCL), polyhydroxybutyrate (PHB), polyhydroxyvalerate (PHV), PHB and PHV copolymer (PHBV), and polylactic acid (PLA)-polyethylene glycol (PEG) copolymer (PLEG). In some embodiments, the preferred polymer is Pluronic® 127.

[0043] In some embodiments, the viscosity of the anhydrous compositions disclosed herein is generally that of a thick liquid or gel, but can reach a paste-like consistency. Generally, the viscosity can range from a minimum of about 5,000, 10,000, or 15,000, preferably about 20,000, to a maximum of about 12,000,000, 2,000,000, or even about 600,000 cP.

[0044] The anhydrous composition of the mTOR inhibitor may optionally contain further components. For example, the anhydrous composition may include additional active ingredients such as corticosteroids, antibiotics, antifungal agents, and / or antiviral agents. Further, the anhydrous composition may contain one or more additional excipients such as penetration enhancers (e.g., DMSO, Transcutol®, menthol, oleic acid, n-alkanols, 1-alkyl-2-pyrrolidone, N,N-dimethylalkanamide, and 1,2-alkanediols).

[0045] In some embodiments, the composition may further include other skin care agents including, but not limited to, retinol, steroids, sunscreen agents, salicylates, minocycline, antifungal agents, peptides, antibodies, lidocaine, and combinations thereof. In some embodiments, other skin care agents include, for example, N-acyl amino acid compounds including N-acyl phenylalanine, N-acyl tyrosine, etc., 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, which is commercially available under the trade name SEPIWHITE®.Other skin active agents include, but are not limited to, Lavandox, Thallasine2, Aldi Relin NP, Gatuline Intense and Gatuline Expression, Myoxinol LS9736, Syn-ake, and Instensyl (registered trademark), Cesaflash (trademark), N-acetyl-D-glucosamine, panthenol (e.g., DL-panthenol available from Alps Pharmaceutical Inc.), tocopheryl nicotinate, benzoyl peroxide, 3-hydroxybenzoic acid, flavonoids (e.g., flavanone, chalcone), farnesol, phytantriol, glycolic acid, lactic acid, 4-hydroxybenzoic acid, acetylsalicylic acid, 2-hydroxybutanoic acid, 2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, cis-retinoic acid, trans-retinoic acid, retinol, retinyl ester (e.g., retinyl propionate), phytic acid, N-acetyl-L-cysteine, lipoic acid, tocopherol and its esters (e.g., tocopheryl acetate available from Eisai: DL-α-tocopheryl acetate), azelaic acid, arachidonic acid, tetracycline, ibuprofen, naproxen, ketoprofen, hydrocortisone, acetaminophen, resorcinol, phenoxyethanol, phenoxypropanol, phenoxyisopropanol, 2,4,4’-trichloro-2’-hydroxydiphenyl ether, 3,4,4’-trichlorocarbanilide, octopirox, lidocaine hydrochloride, clotrimazole, miconazole, ketoconazole, neomycin sulfate, theophylline, and mixtures thereof.

[0046] One or more sunscreen agents may be incorporated into the anhydrous composition of the present invention. Various sunscreen agents can be used, including p-aminobenzoic acid derivatives such as p-(2-ethylhexyl)dimethylaminobenzoate, benzophenone derivatives such as (2-hydroxy-4-methoxyphenyl)phenylmethanone, Mexoryl (trademark) SX, and Mexoryl (trademark) XL, terephthalylidene dicamphor sulfonic acid, and droxmetrizole trisiloxane. Other non-limiting examples include benzophenone (oxybenzone and sulisobenzone), cinnamate (octyl methoxycinnamate and cinoxate), salicylate (homomethyl salicylate) anthranilate, TiO2, avobenzone, bemotrizinol, bisoctrizole, 3-(4-methylbenzylidene)-camphor, cinoxate, diethylamino hydroxybenzoyl hexyl benzoate, dioxybenzone, droxmetrizole trisiloxane, ecamsule, ethylhexyl triazone, homosalate, menthyl anthranilate, octocrylene, octyl salicylate, isoctrizinol, isopentenyloxy-4-methoxycinnamate, octyl-dimethyl-p-aminobenzoic acid, octyl-methoxycinnamate, oxybenzone, polysilicone-15, trolamine salicylate, and ZnO. The exact amount of the sunscreen agent used in the composition will vary depending on the desired degree of protection from the sun's harmful rays.

[0047] The anhydrous composition of the present invention may also contain one or more pigments for coloring the composition and a fragrance such as Firmenich and Co. 66.001 / NY / G fragrance oil to soothe the olfactory system. The amounts of these components present in the composition will depend on the particular desired effect.

[0048] In embodiments, the anhydrous composition can be a topical dosage form including, but not limited to, solutions, powders, liquid suspensions, semi-solids, ointments, pastes, creams, lotions, gels, jellies, and foams, and a solid dosage form including, but not limited to, solutions, suspensions, and parenteral dosage forms including dry powders. The active ingredient can be included in a composition having pharmaceutically acceptable diluents, extenders, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, emulsifiers, buffers, wetting agents, humectants, solubilizers, preservatives, and the like. The pharmaceutical composition of the compound can also include a suitable solid or gel phase carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, gelatin, and polymers such as polyethylene glycol.

[0049] In some embodiments, the anhydrous compositions disclosed herein can be in the form of pastes, liquids, lotions, sprays, aerosols, powders, ointments, creams, mouthwashes, toothpastes, foams, gels, solid sticks, and combinations thereof. In some embodiments, the compositions disclosed herein are spreadable, rapidly absorbed, moisturizing, non-greasy, non-irritating to the patient's skin, aesthetically pleasing to use, and have a cooling effect.

[0050] In embodiments, the compositions described herein can be formulated as liquids. Liquid dosage forms for topical administration can include diluents such as, for example, alcohols, glycols, oils, and the like. Such compositions can also include wetting agents or emulsifiers. In some embodiments, the compositions of the embodiments can be formulated as water-in-oil or oil-in-water emulsions. Creams can be water-in-oil (w / o) emulsions in which the aqueous phase is dispersed in the oil phase, or oil-in-water (o / w) emulsions in which the oil is dispersed in the aqueous base. Ointments generally refer to more viscous oil-in-water creams. Traditional ointment bases (i.e., carriers) include hydrocarbons (petrolatum, beeswax, etc.), vegetable oils, fatty alcohols (cholesterol, lanolin, wool alcohol, stearyl alcohol, etc.), or silicones. Insoluble solids such as starch, zinc oxide, calcium carbonate, or talc can also be used in ointments and creams. The gel form of the above compositions can be formed by trapping a large amount of aqueous or aqueous-alcoholic liquid in a network of polymer or colloidal solid particles. Such polymers or colloids (gelling agents or thickeners) are typically present at a concentration of less than 10% w / w and include carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium alginate, alginic acid, pectin, tragacanth, carrageenan, agar, clay, aluminum silicate, carbomer, and the like.

[0051] In some embodiments, the mTOR inhibitor in the compositions disclosed herein is stable over a long period of time. For example, in some embodiments, the mTOR inhibitor in the composition is stable for 12 to 36 months in a temperature range of about 4°C to about 50°C. In some embodiments, the mTOR inhibitor in the composition is stable for 12 to 36 months in a temperature range of about 4°C to about 45°C. In some embodiments, the mTOR inhibitor in the composition is stable for 12 to 36 months in a temperature range of about 4°C to about 40°C. In some embodiments, the mTOR inhibitor in the composition is stable for 12 to 36 months in a temperature range of about 4°C to about 35°C. In some embodiments, the mTOR inhibitor in the composition is stable for 12 to 36 months in a temperature range of about 4°C to about 30°C.

[0052] Also disclosed herein is a method of treating a skin disease in a subject. In some embodiments, the method of treating a skin disease in a subject comprises topically administering an effective amount of an anhydrous composition comprising an effective amount of one or more mTOR inhibitors, one or more solvents, one or more gelling agents, and one or more antioxidants.

[0053] In some embodiments, the method of treating a skin disease in a subject comprises topically administering an effective amount of an anhydrous composition comprising an effective amount of one or more mTOR inhibitors, one or more solvents, and one or more antioxidants.

[0054] Non-limiting examples of skin diseases that can be treated by the anhydrous composition include plantar keratosis, blisters, tuberous sclerosis, seborrheic keratosis, porokeratosis, epidermolysis bullosa, multiple minute digitate hyperkeratosis, lenticular keratosis, stasis dermatitis, circumscribed acrokeratosis, follicular keratosis, lichenoid keratosis (lichen planus, lichen sclerosus), chronic erosive oral lichen planus, Conradi-Hünermann, epidermolytic ichthyosis, erythrokeratodermia variabilis, ichthyosis, KID syndrome, Netherton syndrome, Olmsted syndrome, Refsum disease, Sjogren-Larsson syndrome, actinic keratosis, congenital hypertrophy of the nails, hyperhidrosis, warts, keratosis, dermatitis (contact dermatitis, drug-induced dermatitis, allergic dermatitis, nummular dermatitis, perioral dermatitis, neurodermatitis, seborrheic dermatitis, and atopic dermatitis), psoriasis, acne, calcinosis, cellulitis, abscess, granuloma, melasma, athlete's foot, bacterial vaginitis, balanitis, dermatofibrosarcoma protuberans, basal cell carcinoma, squamous cell carcinoma, melanoma, Merkel cell carcinoma, keloid, cystic lymphangioma, cavernous lymphangioma, venous malformation, epidermal nevus, bromhidrosis, dermatophytosis, candidiasis, onychomycosis, tinea (tinea alba, tinea pedis, tinea unguium, tinea manus, tinea corporis, tinea capitis, tinea faciei, tinea barbae, tinea imbricata, tinea nigra, vitiligo, tinea incognitoincognito), eczema, dyshidrotic eczema, decubitus ulcer, pustule, erysipelas, erythema multiforme, impetigo, insect bite, genital wart, angioma, herpes, urticaria, hyperhidrosis, filariasis, nevus, lupus, miliaria, nodule of lactating woman, molluscum contagiosum, myiasis, scabies, cutaneous larva migrans, setiferous fly larva disease, migratory myiasis, pediculosis, stellate angioma, panniculitis, paronychia, pemphigoid, pityriasis, vulvar pruritus, rosacea, trichomoniasis, vaginal yeast infection, leukoplakia, xeroderma, angiofibroma, Bannayan-Riley-Ruvalcaba syndrome, basal cell nevus syndrome, Birt-Hogg-Dube syndrome, blue rubber bleb nevus syndrome, Cowden disease, cutaneous T-cell lymphoma, diffuse glomerular lymphangiomatosis, simplex epidermal blistering disease, extramammary Paget, familial multiple discoid fibroma, Hailey-Hailey disease, infantile hemangioma, juvenile polyposis syndrome, Kaposi sarcoma, Kaposi-type angioendothelioma, keloid scar disease, Remitting acroparesthesia syndrome, metastatic melanoma, Muir-Torre syndrome, neurofibromatosis, non-melanoma skin cancer, oral graft-versus-host disease, pemphigus vulgaris, Peutz-Jeghers syndrome, port-wine stain, Proteus syndrome, Proteus-like syndrome, intractable angioendothelioma of Maffucci syndrome, Sturge-Weber syndrome, hereditary footpad hyperkeratosis (HFH) of dog, cutaneous sarcoidosis, cutaneous Castleman disease, bullous pemphigoid, and combinations thereof are included.

[0055] In some embodiments, the skin disease to be treated is angiofibroma. In some embodiments, the skin disease to be treated is congenital nail hypertrophy. In some embodiments, the symptoms of congenital nail hypertrophy are treated, and the symptoms are selected from pain, itching, or combinations thereof.

[0056] In some embodiments, the administration of the composition is by topical application.

[0057] In some embodiments, the anhydrous composition of the mTOR inhibitor is topically administered, and the mTOR inhibitor reaches the epidermal layer and the dermal layer by absorption. In some embodiments, the topical application of the anhydrous composition does not result in systemic absorption of the mTOR inhibitor.

[0058] In some embodiments, topical administration of the anhydrous composition results in delivery of the mTOR inhibitor to the epidermis of the skin. In some embodiments, topical administration of the anhydrous composition results in delivery of the mTOR inhibitor to the epidermis and dermis.

[0059] In some embodiments, the method of treating the skin disease comprises topically administering an anhydrous composition comprising one or more mTOR inhibitors present at about 0.1 wt% to about 20 wt% of the total composition, one or more solvents present at 1 wt% to about 99 wt% of the total composition, one or more gelling agents present at about 0.1 wt% to about 5 wt% of the total composition, and one or more antioxidants present at about 0.001 wt% to about 1 wt% of the total composition. In some embodiments, the composition may further comprise a polymeric surfactant, a humectant, a cooling agent, a rheology modifier, a pH adjuster, a preservative, and combinations thereof. In some embodiments, the anhydrous composition does not contain a gelling agent.

[0060] In some embodiments, the anhydrous composition can be topically applied to the skin, preferably by rubbing the amount applied to the skin by hand to completely coat the skin. This rubbing action is preferably a gentle rubbing or massage for at least about 5 seconds, preferably about 5 to about 30 seconds, so as to spread over the entire skin. Moisture or water present on the skin can emulsify the anhydrous composition for continuous rubbing and massage, resulting in the formation of an in-situ emulsion on the skin.

[0061] Some embodiments of the present invention relate to methods of treating hair loss in a subject. In some embodiments, the method of treating hair loss comprises administering to a subject in need thereof an effective amount of an anhydrous composition comprising an effective amount of one or more mTOR inhibitors, one or more solvents, one or more gelling agents, and one or more antioxidants. In embodiments, the treatment of hair, hair shafts, hair follicles, hair bulbs, sebaceous glands, and diseases associated with these components includes, for example, hair loss, dandruff, seborrheic dermatitis, alopecia areata, hair diseases, tinea corporis, tinea capitis, folliculitis, alopecia, telogen effluvium, neonatal cephalic dermatitis, trichotillomania, traction alopecia, nodular trichoschisis, folliculitis decalvans, pediculosis capitis, frontal fibrosing alopecia, non-scarring alopecia, pityriasis amiantacea, scalp dissecting cellulitis, nuchal polypoid folliculitis, moniliform hair, pediculosis, total alopecia, atrophic alopecia, bubble hair deformity, hair sheath, hirsutism, ingrown hair, moniliform hair, premature gray hair, alopecia, piling trichoschisis, etc.

[0062] The compositions disclosed herein can be applied topically to selected areas of the body where it is desired to reduce hair growth. For example, the composition can be applied to the face, particularly the beard area of the face, i.e., the cheeks, neck, upper lip, and chin. The composition can also be used as an adjunct to other hair removal methods including shaving, waxing, mechanical hair removal, chemical hair removal, electrolysis, and laser-assisted hair removal. Other actions that give rise to those concepts have beneficial effects on the skin in addition to hair removal. The composition can also be applied to the legs, arms, torso, or underarms. The composition is suitable, for example, for suppressing unwanted hair growth in women. In humans, the composition may be applied once or twice a day, or more frequently, to achieve a perceived reduction in hair growth. A reduction in hair growth is demonstrated, for example, when the hair growth rate slows, the need for removal decreases, the subject perceives less hair at the treatment site, or the weight (i.e., hair volume) of the removed hair decreases quantitatively.

[0063] Some embodiments of the present invention relate to methods of treating dry eye syndrome in a subject. In some embodiments, the method of treating dry eye syndrome comprises administering to a 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.

[0064] In some embodiments, the anhydrous composition of the present invention can be applied, for example, to a plaster, patch, bandage, or film. In some embodiments, topical delivery is assisted by the use of ultrasonic technology. Ultrasonic energy is applied across the tissue to help the composition diffuse through the tissue.

[0065] In embodiments, the composition disclosed herein can be in the form of a transdermal patch. The transdermal patch can be in any conventional form such as, for example, a strip, gauze, film, etc. The patch material can be a non-woven or woven fabric (e.g., a gauze bandage). Layers can also be laminated during processing. It can be non-sealed or sealed, although the latter is preferred for the support layer. The patch is preferably hermetically sealed for storage (e.g., in a foil package). The patch can be held on the skin, and the 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 can be packaged in a small metal or plastic "cup", which is fastened to the appropriate site using an outer cloth or leather strap in the same manner as an adhesive, tape, or something worn as part of a watch. The entire patch can be disposable or refillable. In some embodiments, the composition disclosed herein can be coated on a bandage, mixed with a bioadhesive, or included in a bandage.

[0066] In some embodiments, a hand pump can be used to dispense the mTOR inhibitor anhydrous composition. For example, the hand pump may be configured to dispense the required amount of the mTOR inhibitor within the tolerance specified by the corresponding label approved by the government regulatory agency. The hand pump can deliver from 0.5 to 10 mL of the composition per pump actuation, such as 1, 2, 3, 4, or 5 mL of the composition per pump actuation. In some embodiments, the mTOR inhibitor composition can be packaged together with a pharmaceutically acceptable hand pump.

[0067] In some embodiments, the anhydrous compositions can be administered by conventional methods by any route by which they retain their activity. For example, the anhydrous compositions of mTOR inhibitors can be administered by routes including, but not limited to, topical or transdermal routes. Thus, the method of administration of the compounds (alone or in combination with other pharmaceuticals) can be, but is not limited to, sublingual administration, or by the use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, and transdermal and topical forms such as patches and creams, lotions, gels.

[0068] The specific amount of the composition to be administered will, of course, be determined by the particular circumstances surrounding its use, including, but not limited to, the composition being administered, the condition of the skin, the age of the user, the extent of the skin disease, and like considerations. For example, the dosage may depend on the particular animal being treated, the age, weight, and health status of the subject, the type of co-therapy, if any, and the frequency of treatment. Many of these factors can be readily determined by one of ordinary skill in the art (e.g., a clinician). Typically, a single application of the composition will be applied topically to adequately cover the affected area of the skin. Subsequent applications can be made as needed to deliver the desired level of the mTOR inhibitor.

[0069] In some embodiments, the composition can be administered once, twice, three times, four times, five times or more per day, and the application can be carried out over a period of at least 1 month, 2 months, 3 months, 4 months, 6 months, 8 months, or 12 months.

[0070] In some embodiments, the composition can be administered in one or more dosing cycles once, optionally once a day, twice a day, three times a day, once a week, twice a week, every other week, every other day, etc. The dosing cycle can include dosing 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, the next cycle can be started about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks later. The treatment plan can include 1, 2, 3, 4, 5, or 6 cycles, with each cycle spaced about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks apart.

[0071] In an embodiment, there is provided a method for treating a skin disease having a step of administering the anhydrous composition described herein, the method further not including any additional medical or therapeutic intervention for the treatment of the skin disease.

[0072] In an embodiment, a method for treating a skin disease includes a step of administering the anhydrous composition described herein, and the mTOR inhibitor is the only active agent administered for treating the skin disease.

[0073] In some embodiments, the method can include various additional steps, such as, for example, cleaning the surface tissue of the application site.

[0074] In an embodiment, the method can further include scale removal or wound wiping of the tissue surface before, during, or after administration of the composition described herein. In an embodiment, the method for scale removal or wound wiping of the tissue surface can include those by electromagnetic radiation, laser, dermabrasion, chemical peel, ultrasound, heating, cooling, or needles.

[0075] In some embodiments, the tissue surface is scale removed or wound wiped along with abrasion. Abrasion of the outer layer of the skin or the epidermis (dermabrasion) is desirable to smooth or integrate scars, wounds, or other skin conditions that can be caused, for example, by acne, sun exposure, and aging. Standard techniques used to abrade the skin are generally divided into two areas called dermabrasion and microdermabrasion. Both techniques remove a portion of the epidermis called the stratum corneum, which the body interprets as a minor injury. The body then replaces the lost skin cells, creating a new outer layer of skin. In addition, despite the minor swelling and erythema associated with the treatment, the skin looks and feels smoother thanks to the new outer layer of skin.

[0076] In an embodiment, the tissue surface is scale removed or wound wiped using microdermabrasion. Microdermabrasion generally refers to a procedure in which the surface of the skin is removed by mechanical rubbing with a handpiece that emits a stream of sand or grit. For example, a handpiece can be used to direct an air stream containing small crystals of aluminum oxide, sodium chloride, or sodium bicarbonate. The force of the grit tends to abrade two to three cell layers of the skin each time it passes through the handpiece. Alternatively, in a new "crystal-free" microdermabrasion technique, a diamond tip handpiece without a stream of grit is used.

[0077] In an embodiment, the tissue surface is scale removed or wound wiped with electromagnetic radiation using, for example, so-called fractional laser treatment. By way of example, such a method has one or more wavelengths of about 1,850 to 100,000 nanometers and a fluence of about 1 J / cm 2 ~300 J / cm 2 at about 1 femtosecond (1 × 10 -15 s) to 10 milliseconds (10 × 10 -3Electromagnetic radiation (EMR) having a pulse width of (s) is used. In other examples, the tissue is abraded or wound debrided with electromagnetic radiation having one or more wavelengths of about 2200 - 5000 nanometers. In still other examples, the tissue is abraded or wound debrided with electromagnetic radiation having one or more wavelengths of about 190 - 320 nanometers at a fluence of 1 J / cm 2 ~ 300 J / cm 2 . Optionally, the conditions selected to wound debride a portion of the tissue minimize the coagulation zone of tissue damage, for example, by keeping the coagulation zone to a relatively small diameter surrounding the excised void.

[0078] Electromagnetic radiation (EMR), particularly in the form of laser light or other optical radiation, is used in a variety of cosmetic and medical applications, including use in dermatology, dentistry, ophthalmology, gynecology, otolaryngology, and internal medicine. In most cutaneous applications, EMR treatment can be performed using a device that delivers EMR to the surface of the target tissue. EMR treatment typically (a) supplies energy at one or more specific wavelengths (or a specific continuous range of wavelengths) to the tissue to induce a particular chemical reaction, (b) supplies energy to the tissue to cause a temperature rise, or (c) supplies energy to the tissue to damage or destroy cells 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 Palomar® LuxIR, Palomar® 1540, 1440, and 2940 fractional handpieces, Reliant Fraxel® SR laser, and similar devices by Lumenis, Alma Lasers, Sciton, and many other vendors.

[0079] In an embodiment, the method 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 a photoactivating agent called a photosensitizer to treat various diseases. First, the photosensitizer is administered, and once it has penetrated the target tissue, the photosensitizer is then activated by exposure to a predetermined amount of electromagnetic (usually light) radiation of a specific wavelength. The compositions disclosed herein may contain a photosensitizer. In embodiments, any suitable photosensitizer or mixture of agents may be used herein. Generally, these will absorb radiation in the range of about 380 nm to about 900 nm. As used herein, "photosensitizer" or "photosensitizing agent" preferably means a compound that forms singlet oxygen or thermal energy upon contact with radiation of a specific wavelength. Non-limiting examples of photosensitizers include aminolevulinic acid esters, porphyrins, porphyrin derivatives, bacteriochlorins, isobacteriochlorins, phthalocyanines, naphthalocyanines, pyropheophorbides, sapphyrins, texaphyrins, tetrahydrochlorins, purpurins, porphycenes, phenothiazinium, and, without limitation thereto, aluminum, zinc, lutetium, and tin ethyl etiopurpurin (SnET2), and combinations thereof, among others.

[0080] The compositions of the present invention may also be administered in combination with other active ingredients, or other compatible drugs or compounds such that such combinations are desirable or appear to be advantageous for achieving the desired effects of the methods described herein.

[0081] The present invention and embodiments, which describe the methods and materials used, may be further understood by reference to the following non-limiting examples.

[0082] Examples

Examples

[0083] Exemplary anhydrous compositions are shown below.

[0084]

Table 1

Examples

[0085] Exemplary anhydrous compositions are shown below.

[0086]

Table 2

Examples

[0087] Exemplary anhydrous compositions are shown below.

[0088]

Table 3

Examples

[0089] Exemplary anhydrous composition (NA17) is shown below.

[0090]

Table 4

Examples

[0091] Exemplary anhydrous composition (NA19) is shown below.

[0092]

Table 5

Examples

[0093] Exemplary anhydrous composition (NA21) is shown below.

[0094]

Table 6

Example

[0095] An exemplary anhydrous composition (NA22) is shown below.

[0096]

Table 7

Example

[0097] An exemplary anhydrous composition (NA23) is shown below.

[0098]

Table 8

Example

[0099] An exemplary anhydrous composition (NA24) is shown below.

[0100]

Table 9

Example

[0101] An exemplary anhydrous composition (NA25) is shown below.

[0102]

Table 10

Example

[0103] An exemplary anhydrous composition (NA26) is shown below.

[0104]

Table 11

Example

[0105] The exemplary ointment composition (O3) is shown below.

[0106]

Table 12

Examples

[0107] The exemplary aqueous composition (TD201) is shown below.

[0108]

Table 13

Examples

[0109] The exemplary anhydrous composition (NA28) is shown below.

[0110]

Table 14

Examples

[0111] The exemplary anhydrous composition (NA33) is shown below.

[0112]

Table 15

Examples

[0113] The exemplary anhydrous composition (NA34) is shown below.

[0114]

Table 16

Examples

[0115] The exemplary ointment composition (O11) is shown below.

[0116]

Table 17

Example

[0117] In vitro skin permeation experiment Human donor skin was placed between the upper and lower compartments. The lower compartment was filled with the receiver solution. Various rapamycin compositions were applied to the skin surface facing the upper compartment (11 formulations (i.e., O3, NA21, NA22, NA21, NA17, TD201, NA19, NA25, AG14, NA26, and NA24), n = 6 replicates, dose 10 mg / cm 2 ), and left for 24 hours. Using a volumetric pipette, the formulation (~10 mg / cm 2 ) was applied to the plunger of a 1 mL syringe. The formulation (10 ± 0.5 mg) was applied to the skin surface and spread over the diffusion area using the plunger. Before and after this application, the weight of the plunger was recorded, and the dose per cell was calculated from this value.

[0118] After this period, the excess rapamycin composition was wiped off the skin surface, and the skin layer was separated into the stratum corneum, epidermis, and dermis. The stratum corneum was removed from human skin using a tape stripping procedure. The epidermis was separated from the dermis by dry heat at 60 °C for 2 minutes. Rapamycin was extracted and quantified from each layer with a 90:10 v / v ethanol:water solvent mixture. The receiver solution in the lower compartment was also analyzed for the presence of rapamycin.

[0119] As expected, the maximum amount of rapamycin was seen on the skin surface after 24 hours. Furthermore, more drug appeared to be present in the epidermis than in the stratum corneum or dermis layer. Furthermore, over time, the amount of rapamycin quantified in both the epidermis and dermis increased. Rapamycin was not detected in the receiver solution at any point during the experiment, suggesting that rapamycin did not completely pass through the skin layer.

[0120] As shown in FIGS. 1 and 2, the results of the penetration experiments showed a similarity in the epidermal drug recovery rate after application of all formulations when compared to TD201, except for NA24, in which the amount of drug recovered from the skin was 8-fold higher than that from TD201. When compared to TD201, a significantly higher amount of drug was observed in the dermis from O3 (p<0.02), while all other formulations were statistically comparable, although NA21, NA22, and NA23 showed higher average dermal levels than those observed with TD201. Considering drug delivery to the whole tissue, i.e., the combination of epidermis and dermis, all formulations showed a statistically similar drug recovery rate to TD201.

[0121] Also, as shown in FIGS. 3 and 4, the results of the penetration experiments showed that significantly higher amounts of rapamycin were delivered to the epidermis after application of NA22, NA33, and NA28 when compared to O11 (p<0.05), while all other comparisons were statistically similar (i.e., TD201 was performed similarly to all anhydrous formulations). Furthermore, when considering the level of dermal drug delivery, NA22 was shown to be superior to TD201, NA34, and O11, and the deposition in this skin layer was significantly higher than that of the aforementioned formulations (p<0.05). This result suggests that, when compared to formulation TD201, NA22 demonstrated enhanced drug delivery to the dermis and comparable delivery to the epidermis.

[0122] In summary, the anhydrous compositions showed a significant amount of rapamycin deposition in the skin layers when compared to the aqueous composition AG14 and TD201.

Example

[0123] Evaluation of Local Bioavailability Skin Drug Pharmacokinetics (DPK) Test The skin drug pharmacokinetics (DPK) approach corresponds to the PK approach for blood, plasma, and urine applied to the stratum corneum. DPK involves the measurement of drug concentration over time and provides information on drug uptake from the stratum corneum, apparent steady-state levels, and drug disappearance based on the stratum corneum concentration-time curve.

[0124] Application and Removal of Test and Reference Products: The treatment area is marked using a template without disturbing or damaging the stratum corneum / skin. The size of the treatment area varies depending on multiple factors including drug strength, assay sensitivity, extent of drug diffusion, and exposure time. The stratum corneum is very sensitive to certain environmental factors. To avoid bias and stay within the limits of experimental convenience and accuracy, the treatment sites and treatment groups are randomized. As described in more detail below, the uptake, steady-state, and elimination phases can be randomized between the left and right arms of the subject. The exposure time points for each phase may be randomized at various sites on each arm. The test and reference products for a given exposure time point can be applied on-site to minimize differences. The test and reference products should be applied simultaneously to the same subject according to previously developed and validated SOPs. The pre-marked sites are treated with a predetermined amount (e.g., 5 mg / cm 2 ) of the product and covered with a non-occlusive guard. Occlusion is used only if recommended in the product labeling. Removal of the drug product is performed according to the SOP at the designated time point using multiple cotton swabs or Q-tips, taking care to avoid damage to the stratum corneum. In the case of certain oily preparations such as ointments, it may be necessary to wash the area with a low-irritant detergent before stripping the skin. If washing is performed, it becomes part of the SOP.

[0125] Application Site and Application Period: Bioavailability / Bioequivalence (BA / BE) studies involve measuring drug uptake into the stratum corneum and drug disappearance from the skin. To evaluate uptake / disappearance from each product, a minimum of eight sites are employed. The time to reach steady state in the stratum corneum is used to determine the timing of samples. For example, if the drug reaches steady state in 3 hours, 0.25, 0.5, 1, and 3 hours post-treatment can be selected to determine uptake, and 4, 6, 8, and 24 hours can be used to evaluate disappearance. A zero-time point (control site away from the test site) for each subject is selected to obtain baseline data. If the test / reference drug is studied on both forearms, randomly selected sites on one arm can be designated to measure drug uptake / steady state. Sites on the opposite arm can then be designated to measure drug disappearance. During drug uptake, both the time for removal of excess drug and stratum corneum stripping are the same, and stratum corneum stripping follows immediately after removal of excess drug. In the disappearance phase, excess drug is removed from the site at the steady state time point, and the stratum corneum is collected at consecutive time intervals over 24 hours to obtain an estimate of the disappearance phase.

[0126] Sample Collection: Skin stripping is initially performed using commercially available products (e.g., D-Squame, Transpore) to remove the first 1 - 2 layers of the stratum corneum in two adhesive tape strip / disk applications. These first two tape strips contain drug that is usually not absorbed, as opposed to that which has permeated or been absorbed, and are thus analyzed separately from the remaining tape strips. The remaining stratum corneum from each site is stripped at designated time intervals. This is achieved by stripping the site with an additional 10 adhesive tape strips. All 10 tape strips obtained from a given time point are combined and extracted, and the drug content is determined using a valid analytical method. The value is generally quantity / area (e.g., ng / cm 2) It is represented as such. For the test product and the reference product, data can be calculated to obtain the entire drug concentration-time profile, Cmax-ss, Tmax-ss, and AUC.

[0127] Procedure for skin stripping: Evaluation of drug uptake: The test and / or reference drug is applied simultaneously at multiple sites. After an appropriate interval, excess drug from a specific site is removed by gently wiping it three times with a tissue or cotton swab. Using information from preliminary studies, the appropriate timing for sample collection to evaluate drug uptake is determined. The application of the adhesive tape is repeated twice with uniform pressure after discarding the first two tape strips. Continue stripping at the same site to collect an additional 10 stratum corneum samples. Take care to avoid contamination at other sites. This procedure is repeated for each site at other specified time points. The drug is extracted from the combined 10 stripped skins, and the concentration is determined using a valid analytical method. The results are expressed as the amount of drug per square centimeter of the treatment area of the adhesive tape.

[0128] Evaluation of drug disappearance: The test and reference drugs are applied simultaneously to multiple sites selected based on the results of preliminary tests. An exposure period sufficient to reach the apparent steady-state level is given. Excess drug from the skin surface is removed as described above, including the first two skin strippings. Skin stripping samples are collected using a series of 10 tape strips at time intervals based on preliminary tests, and the drug content is analyzed.

[0129] Measurement Criteria and Statistical Analysis: Construct a plot of the stratum corneum drug concentration versus time profile to obtain the stratum corneum measurement criteria for Cmax, Tmax, and AUC. Two one-sided hypotheses at a significance level of α = 0.05 are tested for AUC and Cmax by constructing a 90% confidence interval (CI) for the ratio of the test mean to the reference mean. The parameters for individual subjects and summary statistics (mean, standard deviation, coefficient of variation, 90% CI) are reported. For the test product to be BE, the 90% CI for the ratio of the means (population geometric mean based on log-transformed data) of the test and reference treatments should fall within 80 - 125% for AUC and 70 - 143% for Cmax.

[0130] In vivo skin open flow microperfusion In skin open flow microperfusion (dOFM), a thin hollow tube is inserted just under the skin surface and exits externally through a portion of the skin several inches wide. A liquid similar to body fluid is injected into the tube. Since a portion of the tube under the skin is porous, any drug applied and absorbed through the outer layer of the skin enters the flowing liquid, which is subsequently collected for analysis. dOFM can reliably measure the changing amount of drug in the skin after topical application of a skin pharmaceutical.

Claims

1. 1. A topical anhydrous gel composition for treating a venous malformation in a subject in need thereof, the topical anhydrous gel composition comprising: 2.5% to about 4.5% by weight of rapamycin or a pharma- ceutically acceptable salt thereof, based on the total weight of the composition; about 80% to about 97% by weight of a solvent based on the total weight of the composition, the solvent being about 1% to about 30% by weight of diisopropyl adipate based on the total weight of the composition, about 1% to about 30% by weight of glycerol based on the total weight of the composition, about 40% to about 60% by weight of polyethylene glycol based on the total weight of the composition, and about 1% to about 30% by weight of isopropyl alcohol based on the total weight of the composition; From about 0.1% to about 5% by weight of a gelling agent, based on the total weight of the composition; From about 0.001% to about 1% by weight of an antioxidant, based on the total weight of the composition; optionally additional pharma- ceutically acceptable excipients; Including, The total weight of the composition is 100% by weight, A topical anhydrous gel composition, wherein said anhydrous gel composition has a pH of about 4 to about 8.

2. 2. The topical anhydrous gel composition of claim 1, wherein the gelling agent is selected from the group consisting of hydroxypropylcellulose, carbomer 981, carbomer 934P, glyceryl tris 12-hydroxystearate, hydroxystearin, propylene carbonate, polyvinylpyrrolidine, and combinations thereof.

3. 10. The topical anhydrous gel composition of claim 1, wherein the antioxidant is selected from the group consisting of ascorbyl palmitate, propyl gallate, α-tocopherol, and combinations thereof.

4. 10. The topical anhydrous gel composition of claim 1, further comprising a polymeric surfactant, a humectant, a cooling agent, a rheology modifier, a preservative, and combinations thereof.

5. 10. The topical anhydrous gel composition of claim 1, further comprising a skin care agent selected from the group consisting of cis-retinoic acid, trans-retinoic acid, retinol, retinyl esters, and combinations thereof.

6. 2. The topical anhydrous gel composition of claim 1, comprising: about 3% to about 4.5% rapamycin by weight of the composition; From about 40% to about 60% polyethylene glycol, by weight of the composition; About 15% isopropyl alcohol by weight of the composition; About 15% by weight of the composition of diisopropyl adipate; About 10% glycerol by weight of the composition; From about 0.1% to about 1%, by weight of the composition, of a gelling agent; from about 0.001% to about 0.1% by weight of the composition of an antioxidant; Including, A topical anhydrous gel composition, wherein said additional pharma- ceutically acceptable excipient is a buffering agent.

7. 7. The topical anhydrous gel composition of claim 6, wherein the composition comprises: About 3.9% rapamycin by weight of the composition; About 15% isopropyl alcohol by weight of the composition; About 55.3% by weight of the composition of polyethylene glycol; About 15% by weight of the composition of diisopropyl adipate; About 10% glycerol by weight of the composition; the gelling agent is hydroxypropyl cellulose; the antioxidant is selected from propyl gallate, ascorbyl palmitate, and α-tocopherol; A buffering agent; 1. A topical anhydrous gel composition comprising:

8. 8. The topical anhydrous gel composition of claim 7, wherein the anhydrous gel composition comprises: About 3.9% rapamycin by weight of the composition; About 15% isopropyl alcohol by weight of the composition; About 55.3% by weight of the composition of polyethylene glycol; About 15% by weight of the composition of diisopropyl adipate; About 10% glycerol by weight of the composition; About 0.75% by weight of the composition of hydroxypropyl cellulose; About 0.05% by weight of the composition of propyl gallate; About 0.02% by weight of the composition of ascorbyl palmitate; About 0.002% α-tocopherol by weight of the composition; A buffering agent; 1. A topical anhydrous gel composition comprising:

9. 10. The topical anhydrous gel composition of claim 1, wherein said composition has a pH of about 4.5 to about 6.

10. 10. The topical anhydrous gel composition of claim 1, wherein said composition has a viscosity of about 5000 cP to about 20,000 cP.

11. 10. The topical anhydrous gel composition of claim 1, wherein the rapamycin or a pharma- ceutically acceptable salt thereof is stable in the composition at a temperature of about 4°C to about 40°C for 12 to 36 months.

12. 1. A topical anhydrous gel composition for treating basal cell carcinoma in a subject in need thereof, comprising: 2.5% to about 4.5% by weight of rapamycin or a pharma- ceutically acceptable salt thereof, based on the total weight of the composition; about 80% to about 97% by weight of a solvent based on the total weight of the composition, the solvent being about 1% to about 30% by weight of diisopropyl adipate based on the total weight of the composition, about 1% to about 30% by weight of glycerol based on the total weight of the composition, about 40% to about 60% by weight of polyethylene glycol based on the total weight of the composition, and about 1% to about 30% by weight of isopropyl alcohol based on the total weight of the composition; From about 0.1% to about 5% by weight of a gelling agent, based on the total weight of the composition; From about 0.001% to about 1% by weight of an antioxidant, based on the total weight of the composition; optionally additional pharma- ceutically acceptable excipients; Including, The total weight of the composition is 100% by weight, A topical anhydrous gel composition, wherein said anhydrous gel composition has a pH of about 4 to about 8.

13. 13. The topical anhydrous gel composition of claim 12, wherein the gelling agent is selected from the group consisting of hydroxypropylcellulose, carbomer 981, carbomer 934P, glyceryl tris 12-hydroxystearate, hydroxystearin, propylene carbonate, polyvinylpyrrolidine, and combinations thereof.

14. 13. The topical anhydrous gel composition of claim 12, wherein the antioxidant is selected from the group consisting of ascorbyl palmitate, propyl gallate, α-tocopherol, and combinations thereof.

15. 13. The topical anhydrous gel composition of claim 12, further comprising a polymeric surfactant, a humectant, a cooling agent, a rheology modifier, a preservative, and combinations thereof.

16. 13. The topical anhydrous gel composition of claim 12, further comprising a skin care agent selected from the group consisting of cis-retinoic acid, trans-retinoic acid, retinol, retinyl esters, and combinations thereof.

17. 13. The topical anhydrous gel composition of claim 12, wherein the composition comprises: about 3% to about 4.5% rapamycin by weight of the composition; From about 40% to about 60% polyethylene glycol, by weight of the composition; About 15% isopropyl alcohol by weight of the composition; About 15% by weight of the composition of diisopropyl adipate; About 10% glycerol by weight of the composition; From about 0.1% to about 1%, by weight of the composition, of a gelling agent; from about 0.001% to about 0.1% by weight of the composition of an antioxidant; Including, A topical anhydrous gel composition, wherein said additional pharma- ceutically acceptable excipient is a buffering agent.

18. 18. The topical anhydrous gel composition of claim 17, comprising: About 3.9% rapamycin by weight of the composition; About 15% isopropyl alcohol by weight of the composition; About 55.3% by weight of the composition of polyethylene glycol; About 15% by weight of the composition of diisopropyl adipate; About 10% glycerol by weight of the composition; the gelling agent is hydroxypropyl cellulose; the antioxidant is selected from propyl gallate, ascorbyl palmitate, and α-tocopherol; A buffering agent; 1. A topical anhydrous gel composition comprising:

19. 20. The topical anhydrous gel composition of claim 18, wherein the anhydrous gel composition comprises: About 3.9% rapamycin by weight of the composition; About 15% isopropyl alcohol by weight of the composition; About 55.3% by weight of the composition of polyethylene glycol; About 15% by weight of the composition of diisopropyl adipate; About 10% glycerol by weight of the composition; About 0.75% by weight of the composition of hydroxypropyl cellulose; About 0.05% by weight of the composition of propyl gallate; About 0.02% by weight of the composition of ascorbyl palmitate; About 0.002% α-tocopherol by weight of the composition; A buffering agent; 1. A topical anhydrous gel composition comprising:

20. 13. The topical anhydrous gel composition of claim 12, wherein said composition has a pH of about 4.5 to about 6.

21. 13. The topical anhydrous gel composition of claim 12, wherein the composition has a viscosity of about 5000 cP to about 20,000 cP.

22. 13. The topical anhydrous gel composition of claim 12, wherein the rapamycin or a pharma- ceutically acceptable salt thereof is stable in the composition at a temperature of about 4°C to about 40°C for 12 to 36 months.

23. 13. The topical anhydrous gel composition of claim 12, wherein the composition is for treating basal cell nevus syndrome in a subject in need thereof.

24. 24. The topical anhydrous gel composition of claim 23, wherein the gelling agent is selected from the group consisting of hydroxypropylcellulose, carbomer 981, carbomer 934P, glyceryl tris 12-hydroxystearate, hydroxystearin, propylene carbonate, polyvinylpyrrolidine, and combinations thereof.

25. 24. The topical anhydrous gel composition of claim 23, wherein the antioxidant is selected from the group consisting of ascorbyl palmitate, propyl gallate, α-tocopherol, and combinations thereof.

26. 24. The topical anhydrous gel composition of claim 23, further comprising a polymeric surfactant, a humectant, a cooling agent, a rheology modifier, a preservative, and combinations thereof.

27. 24. The topical anhydrous gel composition of claim 23, further comprising a skin care agent selected from the group consisting of cis-retinoic acid, trans-retinoic acid, retinol, retinyl esters, and combinations thereof.

28. 24. The topical anhydrous gel composition of claim 23, comprising: about 3% to about 4.5% rapamycin by weight of the composition; From about 40% to about 60% polyethylene glycol, by weight of the composition; About 15% isopropyl alcohol by weight of the composition; About 15% by weight of the composition of diisopropyl adipate; About 10% glycerol by weight of the composition; From about 0.1% to about 1%, by weight of the composition, of a gelling agent; from about 0.001% to about 0.1% by weight of the composition of an antioxidant; Including, A topical anhydrous gel composition, wherein said additional pharma- ceutically acceptable excipient is a buffering agent.

29. 29. The topical anhydrous gel composition of claim 28, wherein the composition comprises: About 3.9% rapamycin by weight of the composition; About 15% isopropyl alcohol by weight of the composition; About 55.3% by weight of the composition of polyethylene glycol; About 15% by weight of the composition of diisopropyl adipate; About 10% glycerol by weight of the composition; the gelling agent is hydroxypropyl cellulose; the antioxidant is selected from propyl gallate, ascorbyl palmitate, and α-tocopherol; A buffering agent; 1. A topical anhydrous gel composition comprising:

30. 30. The topical anhydrous gel composition of claim 29, wherein the anhydrous gel composition comprises: About 3.9% rapamycin by weight of the composition; About 15% isopropyl alcohol by weight of the composition; About 55.3% by weight of the composition of polyethylene glycol; About 15% by weight of the composition of diisopropyl adipate; About 10% glycerol by weight of the composition; About 0.75% by weight of the composition of hydroxypropyl cellulose; About 0.05% by weight of the composition of propyl gallate; About 0.02% by weight of the composition of ascorbyl palmitate; About 0.002% α-tocopherol by weight of the composition; A buffering agent; 1. A topical anhydrous gel composition comprising:

31. 24. The topical anhydrous gel composition of claim 23, wherein said composition has a pH of about 4.5 to about 6.

32. 24. The topical anhydrous gel composition of claim 23, wherein the composition has a viscosity of about 5000 cP to about 20,000 cP.

33. 24. The topical anhydrous gel composition of claim 23, wherein the rapamycin or a pharma- ceutically acceptable salt thereof is stable in the composition at a temperature of about 4°C to about 40°C for 12 to 36 months.

Images