Acne topical formulations

Abstract

Disclosed herein, in part, is a topical formulation comprising a drug substance (S)- (-)-3-(4'-acetamidophenyl)-2-methoxypropionic acid, or a pharmaceutically acceptable salt thereof, in an amount from about 1 % to about 7 % by weight of the drug substance in its free base form; and an antioxidant, wherein the % weights are based on the total weight of the topical formulation. The topical formulation can also include a thickening agent; a co-solvent; and water. In certain embodiments, the antioxidant is sodium thiosulfate. In various embodiments, the topical formulation is in the form of a gel.

Description

ACNE TOPICAL FORMULATIONSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 612,486 filed on December 20, 2023, the content of which is hereby incorporated by reference herein in its entirety.BACKGROUND

[0002] Acne is the most common skin disorder globally and in the United States of America, affecting 40 to 50 million Americans each year. In 2015, acne was estimated to affect 633 million people globally or almost 10% of the global population, making it the eighth most common disease worldwide. Generally, the prevalence of acne continues to grow globally in all regions except Sub-Saharan Africa, although a higher disease prevalence and rate of growth is observed in wealthier regions such as Western Europe, high-income Asian Pacific regions, the United States of America, and Canada.

[0003] Acne commonly occurs in adolescence and affects an estimated 80-90% of teenagers in the Western world, including 85% of individuals between the ages of 12 and 25. Children and adults may also be affected before and after puberty. Although acne becomes less common in adulthood, it persists in nearly half of affected people into their twenties (64% of individuals) and thirties (43% of individuals) and a smaller group continue to have difficulties into their forties. Acne also has a significant public health cost. For instance, in the United States of America, over $3 billion dollars per year is lost to the cost of treatment and loss of productivity.

[0004] Acne is a multifactorial pathology of the sebaceous gland, characterized by the presence of a number of physical skin features, including blackheads, whiteheads, papules, pustules (also known as pimples), cysts, and nodules. Acne can result in permanent dark spots and scars if not treated.

[0005] Aside from its physical effects, acne can have severe psychological, social, and emotional effects, especially in teenagers. For instance, acne can cause decreased self-esteem and confidence, resulting in decreased social interaction and decreased work and school attendance (with negative effects on employment and academic performance, respectively). Distress caused by acne can also result in depression, as well as suicidal ideation in individuals suffering from severe acne.

[0006] In general, acne results from alterations in oil production, clogging of hair follicles sebum and dead skin cells, bacterial growth, and / or increased androgen levels. Acne development also appears to be linked, in part, to the Western diet, which includes high levels of hyperglycemic carbohydrates and insulinotropic dairy products. Notably, insulin / IGF-1 signaling are also reported to play a role in inducing sebogenesis and inflammation. Stress also appears to worsen symptoms of acne. There also appears to be a significant genetic component to acne.SUMMARY

[0007] The disclosure is directed, at least in part, to novel formulations that can be useful for treating or preventing a skin disease or disorder such as acne. The present disclosure should be understood to include the formulations as described herein as well as methods of using the formulations for treatment or prevention of a skin disease or disorder, e.g., acne. Each of these different aspects is described more particularly by the various embodiments described herein, which embodiments can be equally applicable to the different aspects.

[0008] In one aspect, provided herein is a topical formulation comprising: a drug substance (S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid, or a pharmaceutically acceptable salt thereof, in an amount from about 1 % to about 7 % by weight of the drug substance in its free base form; and an antioxidant; whereby the topical formulation remains substantially clear in colour when stored at 25 °C for at least one year from the time of manufacture.

[0009] In another aspect, provided herein is a topical formulation, comprising: a drug substance (S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid, or a pharmaceutically acceptable salt thereof, in an amount from about 1 % to about 7 % by weight of the drug substance in its free base form; a thickening agent, in an amount from about 1 % to about 5 % by weight; an antioxidant, in an amount from about 0.3 % to about 1 % by weight; a co-solvent, in an amount from about 3 % to about 45 % by weight; and water in an amount from about 50 % to about 95%; by weight;wherein the % weights are based on the total weight of the topical formulation.

[0010] In another aspect, provided herein is a topical formulation, comprising:(S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid in an amount of about 2 % by weight; a thickening agent, in an amount of about 1.9 % by weight; sodium thiosulfate, in an amount of about 0.5 % by weight, a preservative, in an amount of about 0.22 % by weight; a chelating agent, in an amount of about 0.05 % by weight; a co-solvent, in an amount of about 10 % by weight; and water in an amount of about 85% by weight; wherein the % weights are based on the total weight of the topical formulation.

[0011] In another aspect, provided herein is a topical formulation, comprising:(S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid in an amount of about 5 % by weight; a thickening agent, in an amount of about 3 % by weight; sodium thiosulfate, in an amount of about 0.5 % by weight; a preservative, in an amount of about 0.22 % by weight; a chelating agent, in an amount of about 0.05% by weight; a co-solvent, in an amount of about 10 % by weight; and water in an amount of about 81% by weight; wherein the % weights are based on the total weight of the topical formulation.

[0012] In another aspect, provided herein is a topical formulation comprising: a drug substance (S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid, or a pharmaceutically acceptable salt thereof, in an amount from about 1 % to about 7 % by weight of the drug substance in its free base form; and an antioxidant. The topical formulation may comprise the antioxidant in an amount of about 0.3 to about 1 % by weight, based on the total weight of the topical formulation. The antioxidant may be sodium thiosulfate.

[0013] In various embodiments, the topical formulation is in the form of a gel.BRIEF DESCRIPTION OF THE FIGURE

[0014] FIG. 1 illustrates the efficacy results comparison, obtained in patients affected by acne vulgaris, following a 12-week topical treatment with Formulation A: Vehicle (matching placebo) and 2% (S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic topical formulation, and Formulation B): Vehicle (matching placebo), 2% (S)-(-)-3-(4’-acetamidophenyl)-2- methoxypropionic topical formulation, and 5% (S)-(-)-3-(4’-acetamidophenyl)-2- methoxypropionic topical formulation. Efficacy was evaluated as the proportion of patients with an IGA success upon the 12-week treatment, defined as score of “clear” (IGA score = 0) or “almost clear” (IGA score = 1) and at least a 2-score point reduction in IGA at week 12. Formulation A and B differ in the presence of sodium thiosulfate (0.8% sodium thiosulfate present in Formulation B and absent in Formulation A).DETAILED DESCRIPTION

[0015] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Definitions

[0016] “Preventing” includes delaying the onset of clinical symptoms, complications, or biochemical indicia of the state, disorder, disease, or condition developing in a subject that may be afflicted with or predisposed to the state, disorder, disease, or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder, disease, or condition. “Preventing” includes prophylactically treating a state, disorder, disease, or condition in or developing in a subject, including prophylactically treating clinical symptoms, complications, or biochemical indicia of the state, disorder, disease, or condition in or developing in a subject.

[0017] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein interchangeably refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically activesubstances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.

[0018] “Individual,” “patient,” or “subject” are used interchangeably and include to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds of the invention can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In some embodiments, the mammal treated in the methods of the invention is desirably a mammal in whom modulation of PPAR receptor activity, for example, a PPARy receptor, is desired.

[0019] In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor, for example, a dermatologist, or other clinician. The compounds of the invention are administered in therapeutically effective amounts to treat and / or prevent a disease, condition, disorder, or state. Alternatively, a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and / or prophylactic effect, such as an amount which results in the prevention of or a decrease in the symptoms associated with a disease associated with modulation of PPAR receptor activation (e.g., PPARy).

[0020] The term “pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in compounds used in the present compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including but not limited to malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, -toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that include an amino moiety may form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Pharmaceutically acceptable salts of the disclosure include, for example, pharmaceutically acceptable salts ofN-acetyl-3-(4’-aminophenyl)-2-methoxypropionic acid, or a stereoisomer thereof, for example, pharmaceutically acceptable salts of N-acetyl-(S)-3- (4’-aminophenyl)-2-methoxypropionic acid.

[0021] The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present invention encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.

[0022] Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0023] The compounds disclosed herein can exist in solvated as well as unsolvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.

[0024] The invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,170,31P,32P,35S,18F, and36C1, respectively.

[0025] Certain isotopically-labeled disclosed compounds (e.g., those labeled with3H and14C) are useful in compound and / or substrate tissue distribution assays. Tritiated (i.e.,3H) and carbon- 14 (i.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labeled compounds of the invention can generally be prepared by following procedures analogous to those disclosed in the e.g., Examples herein by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0027] Throughout the description, where compositions or formulations are described as having, including, or comprising specific components, or where methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and formulations of the present disclosure that consist essentially of, or consist of, the recited components, and that there are methods according to the present disclosure that consist essentially of, or consist of, the recited steps.

[0028] In the application, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0029] Further, it should be understood that elements and / or features of a composition, formulation, or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions and formulations of the present disclosure and / or in methods of the present disclosure, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments can be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the disclosure(s) described and depicted herein.

[0030] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, “an element” means one element or more than one element.

[0031] The term “and / or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0032] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0033] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remain operable. Moreover, two or more steps or actions can be conducted simultaneously.

[0034] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present disclosure and does not pose a limitation on the scope of the disclosure unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present disclosure.

[0035] Where the use of the term “about” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. Further, unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

[0036] Where a molecular weight is provided and not an absolute value, for example, of a polymer, then the molecular weight should be understood to be an average molecule weight, unless otherwise stated or understood from the context.

[0037] At various places in the present specification, variables are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual sub-combination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0038] As a general matter, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0039] Various aspects of the disclosure are set forth herein under headings and / or in sections for clarity; however, it is understood that all aspects, embodiments, or features of the disclosure described in one particular section are not to be limited to that particular section but rather can apply to any aspect, embodiment, or feature of the present disclosure.

[0040] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.Formulations

[0041] The disclosure provides, in part, novel formulations useful for preventing or treating a skin disease or disorder, e.g., acne, in a subject in need thereof. In some embodiments, the contemplated formulations include a PPARy modulator. In certainembodiments, the formulations include a compound represented by formula I (i.e., N-acetyl- 3-(4’-aminophenyl)-2-methoxypropionic acid); and a pharmaceutically or cosmetically acceptable excipient.

[0042] In various embodiments, the formulations can include at least one compound selected from N-acetyl-(R)-3-(4’-aminophenyl)-2 -methoxypropionic acid, and N-acetyl-(S)- 3-(4’-aminophenyl)-2-methoxypropionic acid. In some embodiments, the compound is N- acetyl-(S)-3-(4’-aminophenyl)-2-methoxypropionic acid, which is also known as (S)-(-)-3- (4’-acetamidophenyl)-2-methoxypropionic acid.

[0043] The compounds disclosed herein can be prepared in a number of ways well known to one skilled in the art of organic synthesis. Methods for making the compounds of formula I can be found, for example, in International Publication Nos. WO 2007 / 010516, WO 2007 / 010514, and WO 2020 / 161362, each of which is incorporated by reference herein in its entirety.

[0044] In one aspect, provided herein is a topical formulation, comprising: a drug substance (S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid, or a pharmaceutically acceptable salt thereof, in an amount from about 1 % to about 7 % by weight of the drug substance in its free base form; a thickening agent, in an amount from about 1 % to about 5 % by weight; an antioxidant, in an amount from about 0.3 % to about 1 % by weight; a co-solvent, in an amount from about 3 % to about 45 % by weight; and water in an amount from about 50 % to about 95% by weight; wherein the % weights are based on the total weight of the topical formulation.

[0045] In some embodiments, the topical formulation comprises a preservative.

[0046] In certain embodiments, the preservative is present in an amount from about 0.02 % to about 1 % by weight, from about 0.01% to about 2% by weight, from about 0.02% to about 0.5% by weight, from about 0.05% to about 0.5 % by weight, from about 0.05% to about 0.4% by weight, or from about 0.1% to about 0.3% by weight, about 0.1% by weight, about 0.11% by weight, about 0.12% by weight, about 0.13% by weight, about 0.14% by weight, about 0 15% by weight, about 0.16% by weight, about 0.17% by weight, about 0.18% by weight, about 0.19% by weight, about 2% by weight, about 2.1% by weight, about 2.2% by weight, about 2.3% by weight, about 2.4% by weight, about 2.5% by weight, about 2.6% by weight, about 2.7% by weight, about 2.8% by weight, about 2.9% by weight, or about 3% by weight.

[0047] In some embodiments, the preservative is selected from the group consisting of sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, and combinations thereof.

[0048] In certain embodiments, the topical formulation comprises a chelating agent.

[0049] In some embodiments, the chelating agent is present in an amount from about 0.01 % to about 0.2 % by weight, from about 0.01% to about 0.1% by weight, from about 0.02% to about 0.08% by weight, from about 0.03% to about 0.07% by weight, about 0.01% by weight, about 0.02% by weight, about 0.03% by weight, about 0.04% by weight, about 0.05% by weight, about 0.06% by weight, about 0.07% by weight, about 0.08% by weight, about 0.09% by weight, about 0.1% by weight, or about 0.2% by weight.

[0050] In certain embodiments, the chelating agent is disodium edetate.

[0051] In some embodiments, the drug substance is present in an amount from about 2 % to about 5 % by weight, from about 1% to about 10% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight.

[0052] In certain embodiments, the thickening agent is carboxypolymethylene.

[0053] In some embodiments, the thickening agent is present in an amount from about 1.5 % to about 5 % by weight, from about 1% to about 4% by weight, or from about 1% to about 3% by weight, about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, about 2% by weight, about 2.1% by weight, about 2.2% by weight, about 2.3% by weight, about 2.4% by weight, about 2.5% by weight,about 2.6% by weight, about 2.7% by weight, about 2.8% by weight, about 2.9% by weight, about 3% by weight, about 3.1% by weight, about 3.2% by weight, about 3.3% by weight, about 3.4% by weight, about 3.5% by weight, about 3.6% by weight, about 3.7% by weight, about 3.8% by weight, about 3.9% by weight, about 4% by weight, or about 5% by weight.

[0054] In certain embodiments, antioxidant is present in an amount from about 0.5 % to about 1 % by weight, about 0.3% by weight, about 0.4% by weight, about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, or about 1% by weight.

[0055] In certain embodiments, the antioxidant is sodium thiosulfate.

[0056] In certain embodiments, the co-solvent is propylene glycol.

[0057] In some embodiments, the co-solvent is present in an amount from about 5 % to about 45% by weight, from about 5% to about 20% by weight, from about 7% to about 12% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, or about 45% by weight.

[0058] In certain embodiments, the water is present in an amount from about 80 % to about 95 % by weight, from about 70% to 90% by weight, about 50% by weight, about 60% by weight, about 70% by weight, about 80% by weight, about 81% by weight, about 82% by weight, about 83% by weight, about 84% by weight, about 85% by weight, about 86% by weight, about 87% by weight, about 88% by weight, about 89% by weight, about 90% by weight, or about 95% by weight.

[0059] In some embodiments, the topical formulation further comprises a pH adjusting agent in an amount sufficient to adjust the pH of the topical formulation to from about 4.5 to about 6, about 4,5, about 4.6, about 4.7, about 4.8, about 4.9, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6.

[0060] In certain embodiments, the pH adjusting agent is present in an amount sufficient to adjust the pH of the topical formulation to from about 4.8 to about 5.8, from about 5 to about 5.8, or from about 5.2 to about 5.8.

[0061] In some embodiments, the pH adjusting agent is sodium hydroxide, potassium hydroxide, and combinations thereof.

[0062] In certain embodiments, the topical formulation is in the form of a gel.

[0063] In some embodiments, the topical formulation is substantially clear in colour. In certain embodiments, the topical formulation is substantially clear in colour when stored at 25 °C for at least 3 months, for at least 6 months, for at least 9 months, or for at least 12 months (1 year) from the time of manufacture.

[0064] In another aspect, provided herein is a topical formulation, comprising:(S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid in an amount of about 2 % by weight; a thickening agent, in an amount of about 1.9 % by weight; sodium thiosulfate, in an amount of about 0.5 % by weight; a preservative, in an amount of about 0.22 % by weight; a chelating agent, in an amount of about 0.05 % by weight; a co-solvent, in an amount of about 10 % by weight; and water in an amount of about 85% by weight; wherein the % weights are based on the total weight of the topical formulation.

[0065] In another aspect, provided herein is topical formulation, comprising:(S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid in an amount of about 5 % by weight; a thickening agent, in an amount of about 3 % by weight; sodium thiosulfate, in an amount of about 0.5 % by weight; a preservative, in an amount of about 0.22 % by weight; a chelating agent, in an amount of about 0.05% by weight; a co-solvent, in an amount of about 10 % by weight; and water in an amount of about 81% by weight; wherein the % weights are based on the total weight of the topical formulation.

[0066] In some embodiments, the pH of the topical formulation is between about 5 to about 5.8.

[0067] In certain embodiments, the thickening agent is carboxypolymethylene.

[0068] In some embodiments, the preservative is sodium methyl parahydroxybenzoate.

[0069] In certain embodiments, the preservative is sodium propyl parahydroxybenzoate.

[0070] In some embodiments, the chelating agent is disodium edetate.

[0071] In certain embodiments, the co-solvent is propylene glycol.

[0072] In various embodiments, the topical formulation is in the form of a gel.

[0073] The formulations described herein can further comprise at least one compound selected from the group consisting of pioglitazone, rosiglitazone, doxycycline, hydroxychloroquine, mycophenolate mofetil, rifampin, clindamycin, spermidine, azelaic acid, adapalene, isotretinoin, trifarotene and benzoyl peroxide

[0074] The contemplated pharmaceutically acceptable excipients include buffers, carriers, solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration, e.g., suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. The use of such media and agents for pharmaceutically active substances is known in the art. The excipient(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient.

[0075] The formulations of the present disclosure may be administered topically. In various embodiments, the topical formulations are in the form of a gel. Suitable carriers / excipients that may be used in the topical formulations discussed herein are known in the art and include, but are not limited to, solubilizers such as C2 to Cs straight and branched chain alcohols, diols and triols, moisturizers and humectants such as glycerin, amino acids and amino acid derivatives, polyamino acids and derivatives, pyrrolidone carboxylic acids and its salts and derivatives, surfactants such as sodium laureth sulfate, sorbitan monolaurate, emulsifiers such as cetyl alcohol, stearyl alcohol, thickeners such as methyl cellulose, ethyl cellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and acrylic polymers.

[0076] The formulations described herein can be presented in a dosage unit form and can be prepared by any suitable method, for example, by methods well known in the pharmaceutical art. For example, ee Remington's Pharmaceutical Sciences, 18th ed (Mack Publishing Company, 1990).

[0077] Daily topical administration of the formulation described herein may be once per day in the morning, and / or once per day in the evening during a treatment period which may be between one week, two weeks, one month, two months, or three months and one year may be effective to prevent and / or ameliorate acne or a disease, a condition, or a disorder characterized by alteration of sebocyte differentiation. The topical formulation can be administered in an amount of, for example, between about 1.0 mL / 5 cm2and 1.0 mL / 50 cm2, or between about 1.0 mL / 5 cm2and 50 mL / 50 cm2, or between about 1.0 mL / 5 cm2and 100 mL / 50 cm2.

[0078] Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also contains an alcohol and, optionally, an oil. In embodiments, “organic macromolecules,” i.e., gelling agents, are crosslinked acrylic acid polymers such as the “carbomer” family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the CARBOPOL™ trademark. Hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxy ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methyl cellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin may also be included. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, or stirring, or combinations thereof.

[0079] Formulations may also be prepared with liposomes, micelles, and microspheres. Liposomes are microscopic vesicles having a lipid wall including a lipid bilayer, and can be used as drug delivery systems herein as well. Generally, liposome formulations are poorly soluble or insoluble pharmaceutical agents. Liposomal preparations for use in the instant disclosure may include cationic (positively charged), anionic (negatively charged), and neutral preparations. Cationic liposomes are readily available. For example, N[l-2,3- dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA) liposomes are available under the trade name LIPOFECTIN™. (ThermoFisher). Similarly, anionic and neutral liposomes arereadily available as well, e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can be easily prepared using readily available materials. Such materials include phosphatidyl choline, cholesterol, phosphatidyl ethanolamine, dioleoylphosphatidyl choline (DOPC), dioleoylphosphatidyl glycerol (DOPG), and dioleoylphosphatidyl ethanolamine (DOPE), among others. These materials can also be mixed with DOTMA in appropriate ratios. Methods for making liposomes using these materials are well known in the art.

[0080] Micelles are known in the art as included of surfactant molecules arranged so that their polar head groups form an outer spherical shell, while their hydrophobic, hydrocarbon chains are oriented towards the center of the sphere, forming a core. Micelles form in an aqueous solution containing surfactant at a high enough concentration so that micelles naturally result. Surfactants useful for forming micelles include, but are not limited to, potassium laurate, sodium octane sulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodium lauryl sulfate, docusate sodium, decyltrimethylammonium bromide, dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide, tetradecyltrimethylammonium chloride, dodecyl ammonium chloride, polyoxyl 8 dodecyl ether, polyoxyl 12 dodecyl ether, nonoxynol 10, and nonoxynol 30. Micelle formulations can be used in conjunction with the present disclosure either by incorporation into the reservoir of a topical or transdermal delivery system, or into a formulation to be applied to the body surface.

[0081] Microspheres, similarly, may be incorporated into the present formulations and drug delivery systems. Like liposomes and micelles, microspheres essentially encapsulate a drug or drug-containing formulation. Microspheres are generally, although not necessarily, formed from synthetic or naturally occurring biocompatible polymers, but may also be included of charged lipids such as phospholipids. Preparation of microspheres is well known in the art and described in the pertinent texts and literature.

[0082] Various additives, known to those skilled in the art, may be included in the topical formulations. For example, solvents, including relatively small amounts of alcohol, may be used to solubilize certain formulation components. In embodiment, the formulation includes a suitable enhancer, e.g., but are not limited to, ethers such as di ethylene glycol monoethyl ether (available commercially as TRANSCUTOL™) and di ethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), Tween (20, 40, 60, 80), and lecithin (U.S. Patent No. 4,783,450); alcohols such as ethanol, propanol, octanol, benzylalcohol, and the like; polyethylene glycol and esters thereof such as polyethylene glycol monolaurate (PEGML); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, l-methyl-2- pyrrolidone, ethanolamine, diethanolamine, and triethanolamine; terpenes; alkanones; and organic acids, particularly citric acid and succinic acid. AZONE™ and sulfoxides such as DMSO and Cio MSO may also be used.

[0083] The present formulations may also include conventional additives such as opacifiers, antioxidants, fragrance, colorant, gelling agents, thickening agents, stabilizers, surfactants, and the like. Other agents may also be added, such as antimicrobial agents, to prevent spoilage upon storage, i.e., to inhibit growth of microbes such as yeasts and molds. Suitable antimicrobial agents are typically selected from the group consisting of the methyl and propyl esters of / 9-hydroxybenzoic acid (i.e., methyl and propyl paraben), sodium benzoate, sorbic acid, imidurea, and combinations thereof.

[0084] The formulations may also contain irritation-mitigating additives to minimize or eliminate the possibility of skin irritation or skin damage resulting from the pharmacologically active base or other components of the composition. Suitable irritationmitigating additives include, for example: a-tocopherol; monoamine oxidase inhibitors, particularly phenyl alcohols such as 2-phenyl-l -ethanol; glycerin; salicylic acids and salicylates; ascorbic acids and ascorbates; ionophores such as monensin; amphiphilic amines; ammonium chloride; N-acetylcysteine; cis-urocanic acid; capsaicin; and chloroquine. The irritant-mitigating additive, if present, may be incorporated into the present formulations at a concentration effective to mitigate irritation or skin damage, typically representing not more than about 20 wt. %, more typically not more than about 5 wt. %, of the composition.Therapeutic Applications

[0085] Also provided herein are methods of using the formulations described herein. In some embodiments, provided herein are methods for preventing or treating a skin disease or disorder, e g., acne, by acting on the main pathogenetic factors of acne, for example, reduced sebum secretion (both in terms of quantity and quality of sebum), inhibition of inflammation (in both sebocytes and keratinocytes), and inhibition of hyperkeratinization (e.g., keratinocytes altered proliferation and differentiation induced by inflammatory cytokines). The methods can also include preventing a disease or a disorder characterized by alteration of sebocyte differentiation by administering the formulations disclosed herein, for example,topically to the skin (e.g., the epidermis) or other body surface, for example to a specific region or regions of the skin (e.g., the back, the face, the cheeks, the forehead, the chin, the nose, the head, the neck, the shoulders, the arms, the legs, and / or the chest) via topical administration.

[0086] In some embodiments, methods of treating or preventing acne or a disease, a condition, or a disorder characterized by alteration of sebocyte differentiation include administering the formulation disclosed herein to a patient in need thereof in combination with a therapy for treating or preventing acne or a disease, a condition, or a disorder characterized by alteration of sebocyte differentiation. Therapies for treating or preventing acne or a disease, a condition, or a disorder characterized by alteration of sebocyte differentiation include, but are not limited to, light-based therapies, laser therapies, photodynamic therapy, chemical peels e.g., chemical peels that include one or more applications of a chemical solution, such as salicylic acid, glycolic acid, or retinoic acid), direct extraction of whiteheads and blackheads, and steroid injection.

[0087] In some embodiments, the contemplated disease or the disorder to be treated with the formulation described herein is selected from non-inflammatory acne, inflammatory acne, acne vulgaris, acne fulminans, acne mechanica, acne conglobata, gram-negative folliculitis, pyoderma faciale, sebaceous hyperplasia, sebaceous adenitis, comedones (including whiteheads, blackheads, papules), pustules, nodules, cysts, cystic lesions, mild acne, moderate acne, severe nodulocystic acne. In some embodiments, the amount of the compound or composition administered is an amount that is effective to induce sebocyte differentiation and / or an amount that is effective to reduce insulin-induced LOX activity and / or inflammation.

[0088] The disclosed formulations may be administered to subjects (e.g., animals and / or humans) in need of prevention or treatment in dosages that will provide optimal pharmaceutical efficacy.

[0089] Generally, a therapeutically effective amount of active component will be in the range of from about 0.1 mg / kg to about 100 mg / kg, from about 0.1 mg / kg to about 1 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 1000 mg / kg, from about 1 mg / kg to about 1000 mg / kg, from about 1 mg / kg to about 100 mg / kg, from about 1 mg / kg to 10 mg / kg, from about 10 mg / kg to about 20 mg / kg, from about 20 mg / kg to about 30 mg / kg, from about 30 mg / kg to about 40 mg / kg, from about 40 mg / kg to about 50 mg / kg,from about 50 mg / kg to about 60 mg / kg, from about 60 mg / kg to about 70 mg / kg, from about 70 mg / kg to about 80 mg / kg, from about 80 mg / kg to about 90 mg / kg, from about 90 mg / kg to about 100 mg / kg, from about 100 mg / kg to about 500 mg / kg, from about 500 mg / kg to about 1000 mg / kg, or from about 1000 mg / kg to about 2000 mg / kg. A therapeutically effective amount of active component can be in the range of about 0.5 mg / kg to about 50 mg / kg or about 0.5 mg / kg to about 25 mg / kg, or about 0.5 mg / kg to about 20 mg / kg, or about 0.5 mg / kg to about 15 mg / kg, or about 0.5 mg / kg to about 10 mg / kg.

[0090] For example, a therapeutically effective amount of active component can be about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg about 10 mg / kg, about 20 mg / kg, about 30 mg / kg, about 40 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, or about 1000 mg / kg. The amount administered will depend on variables such as the type and extent of disease or indication to be treated, the overall health status of the particular patient, the relative biological efficacy of the compounds, formulations of compounds, the presence and types of excipients in the formulation, and the route of administration.

[0091] The initial dosage administered may be increased beyond the upper level in order to rapidly achieve the desired blood-level or tissue level, or the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. Human dosage can be optimized, e.g., in a conventional Phase I dose escalation study designed to run from 0.5 mg / kg to 20 mg / kg.

[0092] Dosing frequency can vary, depending on factors such as route of administration, dosage amount, and the disease condition being treated. Exemplary dosing frequencies are once per day, twice per day, three times per day, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, once every other day, once every three days, once every four days, once every five days, once every six days, once every eight days, once every nine days, once every ten days, once every eleven days, once every twelve days, once every thirteen days, and once every two weeks.

[0093] The method of delivery of the formulations disclosed herein, may vary, but may involve application of a formulation of the disclosure to an area of body surface affected with or at risk of being affected with acne or a disease, a condition, or a disorder characterized by alteration of sebocyte differentiation.

[0094] The dose regimen of the formulations described herein will depend on a number of factors that may readily be determined, such as severity or likely severity of the acne, or the disease, the condition, or the disorder characterized by alteration of sebocyte differentiation being treated, prevented, and / or ameliorated, and the responsiveness or likely responsiveness of the condition being treated, prevented, and / or ameliorated, but will normally be one or more doses per day, with a course of administration lasting from several days to several months. In general, the formulation can be applied one to four times daily.Sebocyte biology

[0095] The sebaceous gland and hair follicles together form the pilosebaceous unit of the skin. Sebocytes are the main cellular units of the sebaceous gland, which produces sebum - a mixture of cell debris, lipids, antimicrobial substances, free fatty acids, and matrix metalloproteinases. Sebum is a composed mainly of lipids, including: triglycerides, free fatty acids, wax esters, squalene, cholesterol esters, and cholesterol. Sebum functions to prevent excess water from entering the skin, while trapping and preventing necessary moisture from getting out. Additionally, sebum has antimicrobial and antioxidant delivery properties.While too little sebum can result in dry skin, excessive amounts of sebum results in clogging of the sebaceous gland and bacterial growth. The body reacts to bacterial growth caused by sebum blockage by mobilizing white blood cells. White blood cell mobilization in turn causes skin inflammation. Sebum synthesis is strongly regulated by hormone levels, in particular by androgens, which stimulate lipid production in sebocytes and sebocyte differentiation.Acne pathology

[0096] The formulations and methods described herein are useful for preventing or treating a skin disease or disorder, e.g., acne, or a disease, a condition, or a disorder characterized by alteration of sebocyte differentiation in a patient. Acne and related conditions include, but are not limited to, non-inflammatory acne, inflammatory acne, acne vulgaris, acne fulminans, acne mechanica, acne conglobata, gram-negative folliculitis, pyoderma faciale, sebaceous hyperplasia, sebaceous adenitis, comedones (including whiteheads, blackheads, papules), pustules, nodules, cysts, cystic lesions, mild acne, moderate acne, and severe nodulocystic acne.

[0097] In general, acne occurs when hair follicles become clogged with dead skin cells and sebum, and / or as a result of excessive growth of the skin bacterium Propionib acteriumacnes. Causes of acne include genetic predisposition, hormonal activity associated with puberty and female menstrual cycles (e.g., increased levels of androgens, testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), growth hormone (GH), and insulin-like growth factor 1 (IGF-1)), bacterial overgrowth or infection, diet, stress, and environmental factors. Characteristics of acne include blackheads or whiteheads, pimples, oily skin, and scarring. Acne can present on areas of the skin, for example, the face, arms, shoulders, chest, head, and back.

[0098] Major pathogenic factors associated with acne are hyperkeratinization, obstruction of sebaceous follicles resulting from abnormal keratinization of the infundibular epithelium, stimulation of sebaceous gland secretion by androgens, and microbial colonization of pilosebaceous units by Propionibacterium acnes. In general, acne develops when a mixture of sebum and desquamated cells obstructs sebaceous follicles. The accumulation of sebum and cells distends the sebaceous follicle, forming a microcomedo, which expands to form an open or closed comedo. Without being bound by theory, P. acnes is believed to colonize and proliferate in the comedo, releasing inflammatory cytokines and chemotactic factors. This release of inflammatory cytokines and chemotactic factors weakens the follicular wall, causing it to rupture, and allowing the keratin-sebum mixture to leak into the dermis. This series of events results in the inflammatory lesions e.g., papules, pustules, nodules, and cysts) associated with acne.

[0099] The body’s inflammatory response is believed to play an important role in the pathogenesis of acne. For instance, early stage acne lesions are associated with lymphoid perivascular infiltrate, and accumulation of polymorphonuclear leukocytes continues in later stages of acne, causing distension, pustule formation, and, ultimately, lesion rupture. Additionally, P. acnes is believed to activate TLR2 in monocytes, resulting in proinflammatory cytokine release (including IL-12 and IL-8) and expression of antimicrobial peptides (including defensin-1, defensin-2, and defensin-3). Protease release by P. acnes also activates protease-activated receptor-2 (PAR-2) on keratinocytes, which enhances transcription of proinflammatory cytokines IL- la, IL-8, and tumor necrosis factor-a (TNF-a), matrix metalloproteinases, and the cathelicidin LL-37.

[0100] Diet may play an important role in acne development as well. For instance, hyperglycemic carbohydrates, milk and dairy products, and saturated fats are increased in the Western diet and contribute to acne development. Insulin / insulin-like growth factor (IGF-1) signaling, along with branched-chain amino acids (BCAAs), glutamine, and palmitate, all ofwhich are also generally increased in individuals who partake in a Western diet and increase mammalian target of rapamycin complex 1 (mTORCl) signaling. Furthermore, increased mTORCl activity in keratinocytes stimulates keratinocyte proliferation, pro-inflammatory NFKB signaling, increased transcription of pro-inflammatory cytokines (e.g., TNFa, IL-6, IL- 8 IL-17, IL-20, IL-22 and IL-23), lipid biosynthesis, comedone development, and acne. Increased mTORCl activity also promotes T cell activation and generation of CD4+and CD8+effector T cells. IGF-1 signaling also stimulates sterol response element binding protein-1 (SREBP-1) expression and lipogenesis in sebocytes via activation of the PI3K / AKT pathway, and IGF-1 suppresses nuclear FoxOl in sebocytes, which also contributes to increased lipogenesis.Acne evaluation

[0101] Severity of acne and related disorders can be evaluated using different methods, including counting lesions and grading based on different observational criteria. Multiple grading systems exist, including the global acne grading system (GAGS), in which the face, chest, and back are divided into six areas and each area is assigned a factor based on its size. (See Doshi et al., (1997) Int J Dermatol 36:416-8.) Each type of lesion is given a value depending (e.g., no lesions = 0, comedones = 1, papules = 2, pustules = 3 and nodules = 4), and the score for each area is calculated by multiplying the factor for each area by a severity grade of 0-4. The global score is the sum of each area’s score. A score of 1-18 is considered mild, a score of 19-30 is considered moderate, a score of 31-38 is considered severe, and a score of greater than 39 is considered very severe. In the Investigator’s Global Assessment (IGA) of acne severity grading system, a patient is assigned a score of 0-4 based on established criteria. In particular, a score of 0 (clear) indicates residual hyperpigmentation and potentially the presence of erythema; a score of 1 (almost clear) indicates a few scattered comedones and a few small papules; a score of 2 (mild) indicates that less than half the face is involved but that some comedones, papules, and pustules are observed; a score of 3 (moderate) indi cates that more than half the face is involved, many comedones, papules, and pustules are present, and one nodule may be present; and a score of 4 (severe) indicates that the subject’s entire face is involved, and is covered with comedones, numerous papules and pustules, and a few nodules and cysts. Methods of counting lesions generally require recording the number of each type of acne lesion and determining the overall severity of the lesions. Counting lesions or evaluating acne severity using, for example, the GAGS or IGA scoring systems, can be performed in connection with the methods described herein. Apatient or patients without acne can be characterized as having a score of zero with either the GAGS or IGA scoring systems.EXAMPLES

[0102] The embodiments described herein are further illustrated by the following examples. The examples are provided for illustrative purposes only and are not to be construed as limiting the scope or content of the embodiments in any way.Example 1 Topical formulations and clinical study

[0103] Formulations without sodium thiosulfate are provided in Table 1 for comparison purposes. Table 1. Topical gel formulations without sodium thiosulfate: FORMULATION A*pH adjustment as needed to achieve a final pH of 4.8-5.8

[0104] Topical formulations containing (S)-(-)-3-(4’-acetamidophenyl)-2- methoxypropionic acid are provided in Table 2.Table 2. Topical gel formulations: FORMULATION B*pH adjustment as needed to achieve a final pH of 4.8-5.8

[0105] Sodium thiosulfate is an antioxidant excipient and is used to avoid discoloration of the topical formulation from transparent to slightly yellow / brown.

[0106] Two different formulations (Formulations A and B) were used during Phase II clinical studies. During the Phase II clinical studies to test the efficacy of a topical formulation comprising the drug substance (S)-(-)-3-(4’-acetamidophenyl)-2- methoxypropionic acid, the initial Formulation A was updated to Formulation B, to include the addition of the antioxidant sodium thiosulfate in order to prevent the yellow / brown topical formulation discolouration that was noted in the Formulation A during stabilitystudies. The prevention of potential topical formulation discolouration was necessary to ensure appropriate clinical study blinding. Aside from not containing sodium thiosulfate (and therefore displaying a yellow / brown discolouration during stability studies), Formulation A previously used during Phase II clinical studies was otherwise identical and all parameters were within specifications.

[0107] As can be seen in FIG. 1, the comparison of the efficacy results in acne patients (expressed as IGA success, i.e., % of patients Clear / Almost Clear & IGA Reduction > 2) upon 12 weeks of treatment, for Formulation B Vehicle compared to Formulation A Vehicle, show a large increase in efficacy (24% IGA - Clear / Almost Clear & Reduction > 2 versus 0% Clear / Almost Clear & Reduction > 2 respectively). An unexpected increase in efficacy was also seen for Formulation B: 2% (S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic topical formulation compared to Formulation A: 2% (S)-(-)-3-(4’-acetamidophenyl)-2- methoxypropionic topical formulation (33.3% IGA - Clear / Almost Clear & Reduction > 2 verses 14.3% Clear / Almost Clear & Reduction > 2, respectively).

[0108] The marked increase in the efficacy of the both the vehicle and 2% drug ‘Formulation B’ topical formulations in the clinical treatment of acne was highly unexpected considering that the formulations were identical apart from the addition of a minimal amount of the antioxidant sodium thiosulfate in Formulation B which was used for the prevention / avoidance of discolouration that could affect study blinding.Example 2. Stability Data

[0109] To avoid the yellowish discolouration observed in Formulation A, addition of sodium thiosulfate pentahydrate at two different concentrations (0.4 % and 0.8%, corresponding to approximately 0.25% and 0.5% of sodium thiosulfate) was attempted and the evaluation of the stability of the three formulations was performed up to 36 months. Appearance was monitored and recorded for the three formulations.

[0110] The formulations of the tested products are as shown in Table 3.Table 3. Formulations of tested products*pH adjustment as needed to achieve a final pH to approximately 5.0

[0111] The Carbopol concentration was adapted to reach the same viscosity of the formulations. Formulations A and A + 0.4% sodium thiosulfate were stored at 25 °C / 60% RH for 36 months. Formulation B was stored at 30 °C / 65% RH for 36 months. The samples were analyzed visually, and appearance was recorded. The results are shown in Table 4.

[0112] Table 4.

[0113] All the products were colourless after manufacturing (at time = 0 M).Formulation A (without sodium thiosulfate) turned from colourless to slightly yellow after 3 months and yellow after 9 months storage at 25°C. Formulation A + 0.4% sodium thiosulfate turned slightly yellow after 18 months storage at 25°C and appearance did not change up to 36 months storage. On the contrary, discolouration did not occur in Formulation B, which appeared as a colourless homogeneous gel up to 36 months of storage at a higher temperature / humidity (30 °C / 65% RH). Equivalents

[0114] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

Claims

CLAIMS1. A topical formulation comprising: a drug substance (S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid, or a pharmaceutically acceptable salt thereof, in an amount from about 1 % to about 7 % by weight of the drug substance in its free base form; and an antioxidant; whereby the topical formulation remains substantially clear in colour when stored at 30°C for at least one year from the time of manufacture2. The topical formulation of claim 1, wherein the antioxidant is sodium thiosulfate.

3. The topical formulation of claim 1 or 2, wherein the topical formulation is in the form of a gel.

4. A topical formulation, comprising: a drug substance (S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid, or a pharmaceutically acceptable salt thereof, in an amount from about 1 % to about 7 % by weight of the drug substance in its free base form; a thickening agent, in an amount from about 1 % to about 5 % by weight; an antioxidant, in an amount from about 0.3 % to about 1 % by weight; a co-solvent, in an amount from about 3 % to about 45 % by weight; and water in an amount from about 50 % to about 95% by weight; wherein the % weights are based on the total weight of the gel formulation.

5. The topical formulation of claim 4, wherein the antioxidant is sodium thiosulfate.

6. The topical formulation of claim 4 or 5, wherein the topical formulation is in the form of a gel.

7. The topical formulation of any one of claims 4-6, comprising a preservative.

8. The topical formulation of claim 7, wherein the preservative is present in an amount from about 0.02 % to about 1 %.

9. The topical formulation of claim 7 or 8, wherein the preservative is selected from the group consisting of sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate, and combinations thereof.

10. The topical formulation of any one of claims 4-9, comprising a chelating agent.

11. The topical formulation of claim 10, wherein the chelating agent is present in an amount from about 0.01 % to about 0.2 % by weight.

12. The topical formulation of claim 10 or 11, wherein the chelating agent is disodium edetate.

13. The topical formulation of any one of claims 1-12, wherein the drug substance is present in an amount from about 2 % to about 5 % by weight.

14. The topical formulation of any one of claims 4-13, wherein the thickening agent is carboxypolymethylene.

15. The topical formulation of any one of claims 4-14 wherein the thickening agent is present in an amount from about 1.5 % to about 3 % by weight.

16. The topical formulation of any one of claims 4-15, wherein the co-solvent is propylene glycol.

17. The topical formulation of any one of claims 4-16, wherein the co-solvent is present in an amount from about 5 % to about 15% by weight.

18. The topical formulation of any one of claims 4-17, wherein the water is present in an amount from about 80 % to about 90 % by weight.

19. The topical formulation of any one of claims 4-18, further comprising a pH adjusting agent in an amount sufficient to adjust the pH of the topical formulation from about 4.5 to about 6.

20. The topical formulation of claim 19, wherein the pH adjusting agent is present in an amount sufficient to adjust the pH of the gel formulation to about 5 to about 5.5.

21. The topical formulation of claim 19 or 20, wherein the pH adjusting agent is sodium hydroxide, potassium hydroxide, and combinations thereof.

22. The topical formulation of any one of claims 4-21, wherein the topical formulation is substantially clear.

23. A topical formulation, comprising:(S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid in an amount of about 2 % by weight; a thickening agent, in an amount of about 1.9 % by weight; sodium thiosulfate, in an amount of about 0.5 % by weight; a preservative, in an amount of about 0.22 % by weight; a chelating agent, in an amount of about 0.05 % by weight; a co-solvent, in an amount of about 10 % by weight; and water in an amount of about 85% by weight; wherein the % weights are based on the total weight of the topical formulation.

24. A topical formulation, comprising:(S)-(-)-3-(4’-acetamidophenyl)-2-methoxypropionic acid in an amount of about 5 % by weight; a thickening agent, in an amount of about 3 % by weight; sodium thiosulfate, in an amount of about 0.5 % by weight; a preservative, in an amount of about 0.22 % by weight; a chelating agent, in an amount of about 0.05% by weight; a co-solvent, in an amount of about 10 % by weight; and water in an amount of about 81% by weight; wherein the % weights are based on the total weight of the topical formulation.

25. The topical formulation of claim 23 or 24, wherein the topical formulation is in the form of a gel.

26. The topical formulation of any one of claims 23-25, wherein the pH of the topical formulation is between about 5 to about 5.8.

27. The topical formulation of any one of claims 23-26, wherein the thickening agent is carboxypolymethylene.

28. The topical formulation of any one of claims 23-27, wherein the preservative is sodium methyl parahydroxybenzoate.

29. The topical formulation of any one of claims 23-28, wherein the preservative is sodium propyl parahydroxybenzoate.

30. The topical formulation of any one of claims 23-29, wherein the chelating agent is di sodium edetate.

31. The topical formulation of any one of claims 23-30, wherein the co-solvent is propylene glycol.

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