Ophthalmic topical cream preparation and its use

Abstract

In this specification, C 7-20 A topical cream formulation comprising an alkane, a metal chelating agent and a buffer is described.

Description

Technical Field

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 392,266, filed Jul. 26, 2022. The entire content of the application is hereby incorporated by reference herein.

Background Art

[0002] Background The skin provides many functions, including a barrier or protective function that prevents excessive water loss from internal organs or tissues and limits the entry of toxic, pathogenic, or foreign substances into the body. Due to this function, there is a major challenge in locally delivering an active pharmaceutical ingredient (API) at a therapeutically appropriate level via formulations such as gels, lotions, creams, ointments, solutions, etc., which are necessary and beneficial for the subject. Therefore, there is a continuing need for topical formulations that are physically and chemically stable, at least for commercial reasons, and capable of delivering one or more APIs in a therapeutically appropriate amount to the subject in need thereof.

Summary of the Invention

Means for Solving the Problems

[0003] Summary Described herein are topical cream formulations that may be ophthalmic topical cream formulations containing C 7-20 alkanes, metal chelating agents, and / or buffers. According to the formulations described herein, a plurality of problems arising from addressing diseases with topical therapeutic formulations are overcome. For example, the formulations are chemically and physically stable (e.g., under accelerated storage conditions of 40° C. / relative humidity (RH) 75%), and the formulations achieve therapeutically appropriate bioavailability of the active pharmaceutical ingredient in target tissues (e.g., aqueous humor and iris / ciliary body tissue), as observed in preclinical studies.

Brief Description of the Drawings

[0004]

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[0005] DETAILED DESCRIPTION Topical formulations that may contain at least one API have been found to remain physically and chemically stable over a commercially appropriate period (which may include a shelf life of at least 6 months or at least 1 year). It has been discovered that with such formulations, it is possible to penetrate one or more APIs through the skin and then deliver the APIs to target tissues beneath the skin. It has also been discovered that by topical application of the formulations provided herein, APIs can be delivered through the surface of the eyelid to underlying eye tissues or locations. More specifically, it has been found that a combination of isocetadecane, ethylenediaminetetraacetic acid (EDTA) or its salts, and citric acid or its salts in a single topical formulation can significantly improve the bioavailability of one or more APIs or their delivery to the target site. The formulations are useful for delivering one or more APIs to the target site of interest and, thus, for reducing or treating one or more eye diseases that the subject may have or be susceptible to.

[0006] Definitions Certain terms are defined below, whether used alone or as part of a phrase or another term.

[0007] The articles “a” and “an” refer to one or more than one of the grammatical object of this article.

[0008] Numerical values regarding measurements are subject to the influence of measurement errors that impose limits on their accuracy. For this reason, all numerical values provided herein are understood to be modified by the term “about” unless otherwise specified. Accordingly, the last decimal place of the numerical values provided herein indicates the degree of their accuracy. In the absence of other given errors, the maximum error is confirmed by applying the rounding convention to the last decimal place or, if there is no decimal in the given numerical value, to the last significant digit.

[0009] The terms "alkane", "alkyl", or "alkylene" refer to saturated hydrocarbons or fragments thereof that are branched, cyclic, or straight-chain, or combinations thereof.

[0010] The term "ameliorate" means a reduction in the severity of at least one indicator of a condition or disease, e.g., a delay or retardation in the progression of one or more indicators of a condition or disease. The severity of the indicator can be determined by subjective or objective measures known to those of ordinary skill in the art.

[0011] "C n-m " refers to a moiety containing from n to m carbon atoms, where n and m are integers.

[0012] The terms "formulation" and "pharmaceutical formulation" refer to a mixture of at least one compound described herein and a pharmaceutically acceptable carrier. The pharmaceutical formulation facilitates administration of the compound to a patient or subject.

[0013] The terms "effective amount" and "therapeutically effective amount" refer to an amount of an active ingredient, e.g., a compound described herein, administered to a subject either as a single dose or as part of a series of doses, which produces a desired effect. Generally, an effective amount can first be estimated in cell culture assays or mammalian models, e.g., any of non-human primates, mice, rabbits, dogs, or pigs. Also, appropriate concentration ranges and routes of administration can be determined using animal models. Then, such information can be used to determine useful dosages and routes of administration for non-human and human subjects.

[0014] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier involved in the carriage or transport within or to a patient, such as a liquid filler, solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickening agent, solvent, or encapsulating material, so that at least one compound described in the present specification can exert its intended function. A given carrier must be "acceptable" in the sense that it is compatible with the other ingredients of a particular formulation containing the compounds described in the present specification and is not harmful to the patient. Other ingredients that may be included in the pharmaceutical formulations described in the present specification are known in the art and are described, for example, in "Remington’s Pharmaceutical Sciences" (Genaro (Ed.), Mack Publishing Co., 1985). The entire content of this reference is incorporated herein by reference.

[0015] The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, where the parent compound is modified by converting any existing acidic or basic moieties into their salt form. Pharmaceutically acceptable salts can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds in water, an organic solvent, or a mixture of these two solvents with a stoichiometric amount of the appropriate base or acid. A list of suitable salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (P. Henrich Stahl & Camille G. Wermuth (Eds.), VHCA & Wiley-VCH, 2002). The entire content of this reference is incorporated herein by reference.

[0016] The term "refractory disease" refers to a disease that continues to progress during treatment with pharmaceutical ingredients other than the compounds provided in this specification, a disease that partially responds to other treatments, or a disease that transiently responds to other treatments. This term can be applied to each of the diseases mentioned in this specification.

[0017] The term "treatment" or "treating" refers to the application of one or more specific procedures used for the improvement of a disease. "Preventive" treatment refers to reducing the rate of progression of the disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset.

[0018] The description of a range of values herein is intended to serve merely as a shorthand reference for referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or unless clearly inconsistent with the context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein is intended merely to better illuminate the described subject matter and is not otherwise limiting of the claimed subject matter. No language in this specification should be construed as indicating any non-claimed component as essential to the practice of the described subject matter.

[0019] The use of the terms "composition" and "formulation" herein may be interchangeable in some cases.

[0020] The grouping of alternative components or embodiments of the present disclosure is not to be construed as limiting. The members of each group can be referred to and claimed individually or in any combination with other members of that group or other components found herein. Further, the recited members of a group may, for convenience or reasons of patentability, be included in or excluded from another recited group.

[0021] In this specification, when reference is made to a patent document or other publication, the entire content of such document or publication is hereby incorporated by reference into this specification.

[0022] Embodiments of the present disclosure are illustrative. Accordingly, the present disclosure is not precisely limited as shown and described.

[0023] Formulation In some embodiments, a composition is described that comprises at least one active pharmaceutical ingredient and at least one C 7-20 alkane.

[0024] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one metal chelating agent.

[0025] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one buffer.

[0026] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one antioxidant.

[0027] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one base.

[0028] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one methylxanthine.

[0029] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one diol.

[0030] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one emulsifier.

[0031] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one Lewis acid.

[0032] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one oil.

[0033] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one preservative.

[0034] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one thickening agent.

[0035] In other embodiments, the composition may comprise at least one active pharmaceutical ingredient and at least one isotonic agent.

[0036] In some embodiments, a composition is described that comprises at least one active pharmaceutical ingredient, at least one C 7-20 alkane, and at least one metal chelating agent.

[0037] In some embodiments, a composition is described that comprises at least one active pharmaceutical ingredient, at least one C 7-20 alkane, and at least one buffer.

[0038] In some embodiments, a composition is described that comprises at least one active pharmaceutical ingredient, at least one C 7-20 alkane, and at least one antioxidant.

[0039] In some embodiments, a composition is described that comprises at least one active pharmaceutical ingredient, at least one C 7-20 alkane, and at least one base.

[0040] In some embodiments, a composition is described that comprises at least one active pharmaceutical ingredient, at least one C 7-20A composition comprising an alkane and at least one methylxanthine is described.

[0041] In some embodiments, a composition comprising at least one active pharmaceutical ingredient, at least one C 7-20 A composition comprising an alkane and at least one diol is described.

[0042] In some embodiments, a composition comprising at least one active pharmaceutical ingredient, at least one C 7-20 A composition comprising an alkane and at least one emulsifier is described.

[0043] In some embodiments, a composition comprising at least one active pharmaceutical ingredient, at least one C 7-20 A composition comprising an alkane and at least one Lewis acid is described.

[0044] In some embodiments, a composition comprising at least one active pharmaceutical ingredient, at least one C 7-20 A composition comprising an alkane and at least one oil is described.

[0045] In some embodiments, a composition comprising at least one active pharmaceutical ingredient, at least one C 7-20 A composition comprising an alkane and at least one preservative is described.

[0046] In some embodiments, a composition comprising at least one active pharmaceutical ingredient, at least one C 7-20 A composition comprising an alkane and at least one thickening agent is described.

[0047] In some embodiments, a composition comprising at least one active pharmaceutical ingredient, at least one C 7-20 A composition comprising an alkane and at least one isotonic agent is described.

[0048] In some embodiments, a composition comprising at least one active pharmaceutical ingredient, at least one C 7-20 A composition comprising an alkane, at least one metal chelating agent and at least one buffer is described.

[0049] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, and at least one antioxidant.

[0050] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, and at least one base.

[0051] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, and at least one methylxanthine.

[0052] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, and at least one diol.

[0053] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, and at least one emulsifier.

[0054] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, and at least one Lewis acid.

[0055] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, and at least one oil.

[0056] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, and at least one preservative.

[0057] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, and at least one thickening agent.

[0058] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, and at least one isotonic agent.

[0059] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, and at least one antioxidant.

[0060] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, and at least one base.

[0061] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, and at least one methylxanthine.

[0062] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, and at least one diol.

[0063] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, and at least one emulsifier.

[0064] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, and at least one Lewis acid.

[0065] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, and at least one oil.

[0066] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, and at least one preservative.

[0067] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, and at least one thickening agent.

[0068] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, and at least one isotonic agent.

[0069] In some embodiments, a composition is provided that includes at least one active pharmaceutical ingredient, at least one C 7-20A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one base.

[0070] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one methylxanthine.

[0071] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one diol.

[0072] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one emulsifier.

[0073] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one Lewis acid.

[0074] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one oil.

[0075] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one preservative.

[0076] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one thickening agent.

[0077] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one isotonic agent.

[0078] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one methylxanthine.

[0079] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one diol.

[0080] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one emulsifier.

[0081] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one Lewis acid.

[0082] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one oil.

[0083] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one preservative.

[0084] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one thickening agent.

[0085] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one isotonic agent.

[0086] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one diol.

[0087] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one emulsifier are included in a composition.

[0088] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one Lewis acid are included in a composition.

[0089] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one oil are included in a composition.

[0090] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one preservative are included in a composition.

[0091] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one thickening agent are included in a composition.

[0092] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one isotonic agent.

[0093] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one emulsifier.

[0094] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one Lewis acid.

[0095] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one oil.

[0096] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one preservative.

[0097] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one thickening agent.

[0098] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one isotonic agent.

[0099] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one Lewis acid.

[0100] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one oil.

[0101] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one preservative.

[0102] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one thickening agent are included in the composition.

[0103] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one isotonic agent are included in the composition.

[0104] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, and at least one oil are included in the composition.

[0105] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, and at least one preservative are included in the composition.

[0106] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, and at least one thickening agent.

[0107] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, and at least one isotonic agent.

[0108] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, and at least one preservative.

[0109] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, and at least one thickening agent.

[0110] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, and at least one isotonic agent.

[0111] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, at least one preservative, and at least one thickening agent.

[0112] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, at least one preservative, and at least one isotonic agent.

[0113] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, at least one preservative, at least one thickening agent, and at least one isotonic agent.

[0114] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one metal chelating agent.

[0115] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one buffer.

[0116] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one antioxidant.

[0117] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one base.

[0118] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one methylxanthine.

[0119] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one diol.

[0120] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one emulsifier.

[0121] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one Lewis acid.

[0122] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one oil.

[0123] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one preservative.

[0124] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one thickening agent.

[0125] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient and at least one isotonic agent.

[0126] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one buffer.

[0127] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one antioxidant.

[0128] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one base.

[0129] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one methylxanthine.

[0130] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one diol.

[0131] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one emulsifier.

[0132] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one Lewis acid.

[0133] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one oil.

[0134] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one preservative.

[0135] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one thickening agent.

[0136] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, and at least one isotonic agent.

[0137] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, and at least one antioxidant.

[0138] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, and at least one base.

[0139] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, and at least one methylxanthine.

[0140] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, and at least one diol.

[0141] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, and at least one emulsifier.

[0142] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, and at least one Lewis acid.

[0143] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, and at least one oil.

[0144] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, and at least one preservative.

[0145] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, and at least one thickening agent.

[0146] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, and at least one isotonic agent.

[0147] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one base.

[0148] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one methylxanthine.

[0149] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one diol.

[0150] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one emulsifier.

[0151] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one Lewis acid.

[0152] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one oil.

[0153] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one preservative.

[0154] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one thickening agent.

[0155] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, and at least one isotonic agent.

[0156] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one methylxanthine.

[0157] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one diol.

[0158] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one emulsifier.

[0159] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one Lewis acid.

[0160] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one oil.

[0161] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one preservative.

[0162] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one thickening agent.

[0163] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, and at least one isotonic agent.

[0164] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one diol.

[0165] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one emulsifier.

[0166] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one Lewis acid.

[0167] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one oil.

[0168] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one preservative.

[0169] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one thickening agent.

[0170] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, and at least one isotonic agent.

[0171] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one emulsifier.

[0172] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one Lewis acid.

[0173] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one oil.

[0174] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one preservative.

[0175] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one thickening agent.

[0176] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, and at least one isotonic agent.

[0177] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one Lewis acid.

[0178] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one oil.

[0179] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one preservative.

[0180] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one thickening agent.

[0181] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one isotonic agent.

[0182] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, and at least one oil.

[0183] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, and at least one preservative.

[0184] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, and at least one thickening agent.

[0185] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, and at least one isotonic agent.

[0186] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, and at least one preservative.

[0187] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, and at least one thickening agent.

[0188] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, and at least one isotonic agent.

[0189] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, at least one preservative, and at least one thickening agent.

[0190] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, at least one preservative, and at least one isotonic agent.

[0191] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one Lewis acid, at least one oil, at least one preservative, at least one thickening agent, and at least one isotonic agent.

[0192] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one oil are included in a composition.

[0193] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one preservative are included in a composition.

[0194] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one thickening agent.

[0195] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one isotonic agent.

[0196] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, and at least one preservative.

[0197] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, and at least one thickening agent.

[0198] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, and at least one isotonic agent.

[0199] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, at least one preservative, and at least one thickening agent.

[0200] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, at least one preservative, and at least one isotonic agent.

[0201] In some embodiments, at least one active pharmaceutical ingredient, at least one C 7-20 A composition is described that includes an alkane, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, at least one preservative, at least one thickening agent, and at least one isotonic agent.

[0202] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one oil.

[0203] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one preservative.

[0204] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one thickening agent.

[0205] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, and at least one isotonic agent.

[0206] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, and at least one preservative.

[0207] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, and at least one thickening agent.

[0208] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, and at least one isotonic agent.

[0209] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, at least one preservative, and at least one thickening agent.

[0210] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, at least one preservative, and at least one isotonic agent.

[0211] In some embodiments, a composition is described that includes at least one active pharmaceutical ingredient, at least one metal chelating agent, at least one buffer, at least one antioxidant, at least one base, at least one methylxanthine, at least one diol, at least one emulsifier, at least one oil, at least one preservative, at least one thickening agent, and at least one isotonic agent.

[0212] In some embodiments, herein, C 7-20 or C 10-20 An alkane (e.g., isocetadecane), a metal chelating agent (e.g., EDTA or its salts), and a buffer (e.g., acetic acid, ascorbic acid, azelaic acid, boric acid, carbonic acid, citric acid, glycolic acid, lactic acid, phosphoric acid or their salts) are included in a topical formulation. The formulation may contain about 0.05% to about 3% w / w C 7-20 or C 10-20 alkane, about 0.005% to about 0.5% w / w metal chelating agent, and about 1 mM to about 500 mM buffer. In some embodiments, the formulation may contain about 0.1% to about 2%, e.g., about 0.3% to about 1% C 7-20 or C 10-20 alkane. In some embodiments, the formulation may contain about 0.05% to about 0.3% w / w, e.g., about 0.1% to about 0.25% metal chelating agent. In some embodiments, the formulation may contain about 5 mM to about 100 mM, e.g., about 5 mM to about 25 mM buffer. The formulation may further contain one or more of the following.

[0213] a. At least one antioxidant (e.g., butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B9, vitamin B 12 , vitamin C, vitamin D, vitamin E or vitamin K). In some embodiments, this may be about 0.01 to about 0.5% w / w of the formulation.

[0214] b. At least one base (e.g., KOH, NaOH or NH4OH). This may be used to adjust the pH as needed.

[0215] c. At least one methylxanthine (e.g., aminophylline, caffeine, 3-isobutyl-1-methylxanthine (IBMX), paraxanthine, pentoxifylline, theobromine, or theophylline). In some embodiments, this may be from about 0.05% to about 0.5% w / w of the formulation.

[0216] d. At least one diol (e.g., a polyalkylene diol (e.g., polyethylene glycol, propylene glycol, or both)). In some embodiments, this may be from about 0.1% to about 10% w / w of the formulation.

[0217] e. At least one emulsifier (e.g., cetyl alcohol, lecithin, polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80). In some embodiments, this may be from about 0.02% to about 5% w / w of the formulation.

[0218] f. At least one Lewis acid (e.g., MgCl2 or CaCl2). In some embodiments, this may be from about 0.01% to about 3% w / w of the formulation.

[0219] g. At least one oil (e.g., castor oil or mineral oil). In some embodiments, this may be from about 0.1% to about 25% w / w of the formulation.

[0220] h. At least one preservative (e.g., benzalkonium chloride (BAK), benzododecinium bromide, biguanide compounds (e.g., bisbiguanide (e.g., alexidine), buformin, chlorproguanil, metformin, phenformin, polyhexamethylene biguanide (PHMB), polyhydroxymethyl biguanide or proguanil), chlorobutanol, polyquaternium (e.g., polyquaternium-1), parabens (e.g., butylparaben, ethylparaben, methylparaben or propylparaben), phenoxyethanol, sodium hypochlorite, sodium hypochlorite in combination with zinc chloride, SOFZIA (e.g., an ionic buffer containing borate, sorbitol, propylene glycol and zinc) or thimerosal). In some embodiments, this may be from about 0.00001 to about 0.3% w / w of the formulation.

[0221] i. At least one thickening agent (e.g., carbomer, carboxymethyl cellulose (CMC), carrageenan, crosslinked CMC, crosslinked hyaluronic acid, hyaluronic acid, polyvinylpyrrolidone (PVP), acrylamide / sodium acryloyldimethyltaurate copolymer or xanthan gum). In some embodiments, this may be from about 0.01 to about 10% w / w of the formulation.

[0222] j. At least one isotonic agent (e.g., sorbitol). In some embodiments, this may be from about 0.5 to about 10% w / w of the formulation.

[0223] Or, k. Water. In some embodiments, this may be from about 1 to about 90% w / w of the formulation.

[0224] In some embodiments, the API in the formulation may have antimicrobial properties and thus a separate preservative may be optional. Thus, in some embodiments, the formulations provided herein include a preservative that is not an API. In other embodiments, the formulations provided herein do not include a preservative. In some embodiments, the formulation does not include benzalkonium chloride.

[0225] In some embodiments, the formulations provided herein include methylxanthines (e.g., caffeine). In other embodiments, the formulations provided herein do not include methylxanthines (e.g., caffeine).

[0226] In some embodiments, the formulations provided herein include acrylamide / sodium acryloyldimethyltaurate copolymer, citric acid or its salts, EDTA or its salts, isododecane, and polysorbate 80. In some embodiments, the formulations provided herein include acrylamide / sodium acryloyldimethyltaurate copolymer, caffeine, citric acid or its salts, EDTA or its salts, isododecane, and polysorbate 80.

[0227] The formulations provided herein can include at least one API. The API may have a molar mass of about 1,500 g / mol or less, such as about 1,000 g / mol or less, such as about 500 g / mol or less. In some embodiments, the API is amphiphilic, hydrophilic, or hydrophobic. In some embodiments, the API is aflibercept, apraclonidine, atropine, betaxolol, brimonidine, brinzolamide, carbachol, dexamethasone, dipivefrin, donepezil, dorzolamide, levobunolol, metipranolol, pilocarpine, physostigmine, prostaglandin (e.g., bimatoprost, latanoprost, prostaglandin F2α as an isopropyl ester, tafluprost or travoprost or their corresponding free acids), steroid (e.g., androgen, corticosteroid (e.g., glucocorticoid or mineralocorticoid (e.g., loteprednol (loteprednol etabonate))), estrogen or progestogen) or timolol or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, a formulation is described that contains zero or up to about 0.16% w / w caffeine, about 0.5 to about 4% w / w carbomer homopolymer type C, about 0.5% w / w cetyl alcohol, about 0.02 to about 0.2% w / w disodium EDTA, about 0.05 to about 0.18 methylparaben, about 10% w / w mineral oil, about 2% PEG8000, about 5% w / w polyoxyl 35 castor oil, about 2% w / w polysorbate 80, about 0.01 to about 0.02 propylparaben, about 4.4% w / w propylene glycol, zero or up to about 4% w / w Sepineo P600 (Sepineo P600 contains about 30 to 40% w / w acrylamide / sodium acryloyldimethyltaurate copolymer (e.g., having a ultra-high molecular weight of at least 10 MDa), about 5 to 10% w / w polysorbate 80 (in addition to other polysorbate 80 present) and about 20 to 25% w / w isohexadecane), about 6% w / w sorbitol and / or about 0.004 to about 4% w / w active pharmaceutical ingredient.

[0229] In some embodiments, the formulations described herein do not contain caffeine.

[0230] In some embodiments, the formulations described herein do not contain Sepineo P600, but may contain one or more components of Sepineo P600.

[0231] In some embodiments, herein, a composition is described that contains about 0.05% to about 3% w / w C 7-20 alkane, about 0.005% to about 0.5% w / w metal chelating agent and about 1 mM to about 500 mM buffer. In some embodiments, the composition is as follows: a. At least one antioxidant; b. At least one base; c. At least one methylxanthine; d. At least one diol; e. At least one emulsifier; f. At least one Lewis acid; g. At least one oil; h. at least one preservative; i. at least one thickening agent; j. at least one isotonic agent; k. water; or l. at least one active pharmaceutical ingredient may include one or more of them.

[0232] In some embodiments, herein, zero or up to about 0.16% w / w caffeine; about 0.5 to about 4% w / w carbomer homopolymer type C; about 0.5% w / w cetyl alcohol; about 0.02 to about 0.2% w / w disodium EDTA; about 0.05 to about 0.18 methylparaben; about 10% w / w mineral oil; about 2% PEG8000; about 5% w / w polyoxyl 35 castor oil; about 2% w / w first polysorbate 80; about 0.01 to about 0.02 propylparaben; about 4.4% w / w propylene glycol; zero or up to about 4% w / w component (the component includes about 30 - 40% w / w acrylamide / sodium acryloyldimethyltaurate copolymer, about 5 - 10% w / w second polysorbate 80 and about 20 - 25% w / w isohexadecane); about 6% w / w sorbitol; about 0.004 to about 4% w / w at least one active pharmaceutical ingredient comprising, the pH is about 3.5 ± 0.5 or about 5.5 ± 0.5, wherein, optionally, a composition comprising about 0.025% w / w butylated hydroxyanisole and about 6 mM to about 7 mM potassium citrate is described.

[0233] In some embodiments, herein, Zero or up to about 0.16% w / w caffeine; About 0.5 to about 4% w / w Carbomer homopolymer type C; About 0.5% w / w Cetyl alcohol; About 0.02 to about 0.2% w / w EDTA disodium; About 0.05 to about 0.18 Methylparaben; About 10% w / w Mineral oil; About 2% PEG8000; About 5% w / w Polyoxyl 35 castor oil; About 2% w / w First polysorbate 80; About 0.01 to about 0.02 Propylparaben; About 4.4% w / w Propylene glycol; Zero or up to about 4% w / w component (the component contains about 30 - 40% w / w acrylamide / sodium acryloyldimethyltaurate copolymer, about 5 - 10% w / w second polysorbate 80 and about 20 - 25% w / w isohexadecane); About 6% w / w Sorbitol; About 0.004 to about 4% w / w at least one active pharmaceutical ingredient comprising, the pH is about 3.5 ± 0.5 or about 5.5 ± 0.5, wherein a composition is described that contains about 0.025% w / w butylated hydroxyanisole and about 6 mM to about 7 mM potassium citrate.

[0234] In some embodiments, herein, Zero or up to about 0.16% w / w caffeine; About 0.5 to about 4% w / w Carbomer homopolymer type C; About 0.5% w / w Cetyl alcohol; About 0.02 to about 0.2% w / w EDTA disodium; About 0.05 to about 0.18 Methylparaben; About 10% w / w Mineral oil; About 2% PEG8000; About 5% w / w Polyoxyl 35 castor oil; About 2% w / w of first polysorbate 80; About 0.01 to about 0.02 propylparaben; About 4.4% w / w propylene glycol; Zero or up to about 4% w / w of a component (the component comprising about 30 to 40% w / w acrylamide / sodium acryloyldimethyltaurate copolymer, about 5 to 10% w / w of second polysorbate 80 and about 20 to 25% w / w isocetadecane); About 6% w / w sorbitol; About 0.004 to about 4% w / w of at least one active pharmaceutical ingredient comprising, the pH is about 3.5 ± 0.5 or about 5.5 ± 0.5, wherein a composition is described which does not contain butylated hydroxyanisole and does not contain potassium citrate.

[0235] In some embodiments herein, zero or up to about 0.16% w / w caffeine; About 0.5 to about 4% w / w carbomer homopolymer type C; About 0.5% w / w cetyl alcohol; About 0.02 to about 0.2% w / w disodium EDTA; About 0.05 to about 0.18 methylparaben; About 10% w / w mineral oil; About 2% PEG8000; About 5% w / w polyoxyl 35 castor oil; About 2% w / w of first polysorbate 80; About 0.01 to about 0.02 propylparaben; About 4.4% w / w propylene glycol; Zero or up to about 4% w / w of a component (the component comprising about 30 to 40% w / w acrylamide / sodium acryloyldimethyltaurate copolymer, about 5 to 10% w / w of second polysorbate 80 and about 20 to 25% w / w isocetadecane); About 6% w / w sorbitol; From about 0.004% w / w to about 4% w / w of at least one active pharmaceutical ingredient comprising wherein the pH is about 3.5 ± 0.5 or about 5.5 ± 0.5, and a composition is described which does not contain butylated hydroxyanisole.

[0236] In some embodiments herein, zero or up to about 0.16% w / w caffeine; from about 0.5% w / w to about 4% w / w carbomer homopolymer type C; about 0.5% w / w cetyl alcohol; from about 0.02% w / w to about 0.2% w / w disodium EDTA; from about 0.05 to about 0.18 methylparaben; about 10% w / w mineral oil; about 2% PEG8000; about 5% w / w polyoxyl 35 castor oil; about 2% w / w first polysorbate 80; from about 0.01 to about 0.02 propylparaben; about 4.4% w / w propylene glycol; zero or up to about 4% w / w of a component which comprises about 30 - 40% w / w acrylamide / sodium acryloyldimethyltaurate copolymer, about 5 - 10% w / w second polysorbate 80 and about 20 - 25% w / w isohexadecane; about 6% w / w sorbitol; From about 0.004% w / w to about 4% w / w of at least one active pharmaceutical ingredient comprising wherein the pH is about 3.5 ± 0.5 or about 5.5 ± 0.5, and a composition is described which does not contain potassium citrate.

[0237] In some embodiments herein, a composition is described which is a cream formulation.

[0238] In some embodiments herein, a composition is described which is an oil-in-water cream formulation.

[0239] In some embodiments, as used herein, a composition is described wherein C 7-20 alkane is a softening agent.

[0240] In some embodiments, as used herein, a composition is described wherein C 7-20 alkane is isohexadecane.

[0241] In some embodiments, as used herein, a composition is described that comprises at least one active pharmaceutical ingredient, and the ingredient is travoprost.

[0242] In some embodiments, as used herein, a composition is described wherein the metal chelating agent is ethylenediaminetetraacetic acid or a salt thereof.

[0243] In some embodiments, as used herein, a composition is described wherein the buffer is citric acid or a salt thereof.

[0244] In some embodiments, as used herein, a composition is described that comprises at least one active pharmaceutical ingredient, and the ingredient is selected from aflibercept, apraclonidine, atropine, betaxolol, brimonidine, brinzolamide, carbachol, dexamethasone, dipivefrin, donepezil, dorzolamide, levobunolol, metipranolol, pilocarpine, physostigmine, prostaglandin, steroid or timolol or pharmaceutically acceptable salts thereof.

[0245] In some embodiments, as used herein, a composition is described that comprises at least one active pharmaceutical ingredient, and the ingredient is selected from: a. prostaglandins selected from bimatoprost, latanoprost, prostaglandin F2α as an isopropyl ester, tafluprost or travoprost or their corresponding free acids; or b. steroids selected from androgens, corticosteroids, estrogens or progesterones.

[0246] In some embodiments, described herein is a composition comprising at least one active pharmaceutical ingredient selected from a glucocorticoid or a mineralocorticoid.

[0247] In some embodiments, described herein is a composition comprising at least one active pharmaceutical ingredient, which is loteprednol etabonate.

[0248] In some embodiments, described herein is a composition comprising C 7-20 wherein the alkane is isohexadecane, the metal chelating agent is disodium ethylenediaminetetraacetate, and the buffer is potassium citrate.

[0249] In some embodiments, described herein is a composition comprising about 0.4 - 0.5% w / w isohexadecane and about 0.012% w / w travoprost.

[0250] In some embodiments, described herein is a composition comprising about 1%, about 1.25%, about 1.5%, about 2%, about 3% or about 4% w / w pilocarpine (as the neutral free base), pilocarpine nitrate or pilocarpine hydrochloride.

[0251] In some embodiments, described herein is a composition comprising about 6 - 7 mM potassium citrate, about 0.2% w / w disodium ethylenediaminetetraacetate, about 0.4 - 0.5% w / w isohexadecane and about 0.012% w / w travoprost.

[0252] The formulations herein can be applied topically to a portion of the subject's skin. In some embodiments, the topical application is to the eyelids (e.g., the upper eyelid or lower eyelid of one or both eyes of the subject, combinations thereof). The formulations provided herein allow the API contained therein to penetrate the skin, thereby enabling delivery of the API to the subject's tissue, including the subject's organs or internal tissues or regions. In some embodiments, with the formulations herein, after applying the formulation to the subject's skin, the API therein is delivered to the subject's eye.

[0253] When developing topical formulations, it is necessary to balance many factors, including suppression of the formation of API by-products (impurities), the physical appearance of the formulation, e.g., homogeneity and viscosity, and the subject's somatic sensations when using the formulation (e.g., mechanical and thermal sensations).

[0254] APIs can decompose at various rates as a result of various factors related to their immediate chemical environment. For example, pilocarpine contains a lactone ring that can undergo hydrolysis. The hydrolysis of the lactone ring of pilocarpine can be catalyzed by both acids and bases and can be pH-controlled. Acid-catalyzed hydrolysis is slower. Without being bound by theory, acids catalyze reactions that protonate the carbonyl oxygen, making the carbonyl carbon somewhat more positive and thus more susceptible to nucleophilic attack. Base-catalyzed hydrolysis is faster and generally not reversible. For example, without being bound by theory, a strong base such as NaOH can hydrolyze the lactone ring of pilocarpine, resulting in saponification to pilocarpinate. Once saponification occurs, this reaction is generally not reversible. To minimize this chemical decomposition, the pH needs to be maintained below the pKa of pilocarpine (about pH 6.5), preferably below pH 5.0 or even further below pH 4.0. To facilitate the reclosure of the hydrolyzed lactone ring, the use of a Lewis acid (electron pair acceptor) such as MgCl2 or CaCl2 can stabilize the electrophilic carbonyl carbon and thus minimize the formation of by-products due to nucleophilic attack on the carbonyl bond. For example, MgCl2 is used to facilitate the reclosure of the lactone ring and prevent pilocarpine from hydrolyzing to pilocarpic acid. Surprisingly, a pilocarpine-containing formulation having a pH of about 3.5 has been discovered that does not contain a Lewis acid such as MgCl2 or CaCl2 or a buffer (e.g., a buffer having a pKa in the range associated with a formulation having a pH of about 3.5), yet this pilocarpine formulation remains chemically stable for at least about 6 months under accelerated storage conditions of 40 °C corresponding to commercially appropriate storage conditions.

[0255] The physical appearance of the topical formulation, such as homogeneity and viscosity, are two factors to be considered during formulation development. When a thickening agent for the formulation, such as CARBOPOL®, is included in the formulation, in some cases, when the carboxylic acid groups of its acrylate are protonated under acidic conditions, the desired physical appearance or viscosity cannot be achieved. To achieve the desired formulation viscosity, the pH is controlled to be above about pH 3, preferably above about pH 4.0, or more preferably above about pH 5.0. In some embodiments, the formulations provided herein may have a pH of about 3.5 ± 0.5, about 4.5 ± 0.5 or about 5.5 ± 0.5. For example, Formulations 1 and 9 have a pH of about 3.5, while Formulations 3, 4, 5, 6, 7 and 8 have a pH of about 5.5.

[0256] In some embodiments, the formulation is Formulation 3 shown in Table 1, which may contain an API. In some embodiments, the formulation comprises Formulation 3, 1 - 500 mM potassium citrate buffer and an API. In some embodiments, the formulation comprises Formulation 3, about 1 - 500 mM potassium citrate buffer and travoprost. In some embodiments, the formulation comprises Formulation 3, about 10 mM potassium citrate buffer and about 0.004 - about 0.012% w / w travoprost (e.g., about 0.004, about 0.008 or about 0.012% w / w travoprost).

[0257] Table 1. Formulation 3 and Comparative Formulation 4

Table 1

[0258] In some embodiments, the formulations provided herein comprise isododecane and travoprost. In some embodiments, the formulation comprises isododecane, travoprost, ethylenediaminetetraacetic acid (e.g., disodium EDTA) and a citrate buffer (e.g., potassium citrate buffer). In some embodiments, the formulation is Formulation 5, Formulation 7 or Formulation 8 shown in Table 2.

[0259] Table 2. Formulation 5, Formulation 7, Formulation 8, and Comparative Formulation 6 [Table 2]

[0260] Sepineo P600 contains approximately 30 - 40% w / w acrylamide / sodium acryloyldimethyltaurate copolymer (e.g., having a ultra-high molecular weight of at least 10 MDa, e.g., for use as a thickener), approximately 5 - 10% w / w polysorbate 80, and approximately 20 - 25% w / w isohexadecane (C 16 alkane, i.e., 2-methylpentadecane, e.g., for use as a penetration enhancing solvent). Thus, certain formulations herein may contain Sepineo P600, and as a result, the formulation contains approximately 0.6 - 0.8% w / w acrylamide / sodium acryloyldimethyltaurate copolymer, approximately 0.1 - 0.2% w / w polysorbate 80 (which will be added in addition to any polysorbate 80 already contained in a particular example of the formulations herein, e.g., Formulation 5), and approximately 0.4 - 0.5% w / w isohexadecane. In some embodiments, certain formulations herein may contain Sepineo P600, and as a result, the formulation contains approximately 1.2 - 1.6% w / w acrylamide / sodium acryloyldimethyltaurate copolymer, approximately 0.2 - 0.4% w / w polysorbate 80 (which will be added in addition to any polysorbate 80 already contained in a particular example of the formulations herein), and approximately 0.8 - 1.0% w / w isohexadecane. Without being bound by theory, since the acrylamide / sodium acryloyldimethyltaurate copolymer has an MW of about 10 MDa or more, it is unlikely to promote permeation. Further, adding polysorbate 80 from Sepineo P600 in addition to what is already contained in a particular formulation is also unlikely to contribute to the penetration enhancing effect. Thus, without being bound by theory, isohexadecane may be an important component in the formulations herein.

[0261] Method The formulations described herein are useful for delivering a therapeutically appropriate amount of one or more APIs through the skin of a subject to underlying tissue, structure, or organ in the subject. Accordingly, provided herein is a method of delivering one or more APIs to a subject in need of API delivery, the method comprising topically administering to the subject an effective amount of a formulation described herein. In some embodiments, the topical administration is not direct to a mucosa, such as in the case of a particular pilocarpine gel formulation, but to the skin surface of the eyelid. In some embodiments, the topical administration is to the skin surface located between the eyelashes of the upper eyelid of the subject and the corresponding eyebrow of the eye. In some embodiments, the topical administration is to the skin surface in the upper eyelid sulcus, the skin surface in the lower eyelid sulcus, or both. In some embodiments, the topical administration is to the skin surface in the wrinkles of the upper eyelid, the wrinkles of the lower eyelid, the nasolabial fold, the nasojugal fold, the skin surface adjacent to the outer canthus of the eye, or a combination thereof.

[0262] Also provided herein is a method of treating one or more eye diseases by delivering a therapeutically appropriate amount of one or more active agents through the skin of a subject having one or more eye diseases, e.g., the eyelid. Thus, in some embodiments, provided herein is a method of treating an eye disease in a subject in need of treatment for an eye disease, the method comprising topically administering to the subject a therapeutically effective amount of a formulation provided herein. In some embodiments, the eye diseases to be treated include one or more of age-related macular degeneration, allergic conjunctivitis, blepharitis, retinitis, diabetic macular edema, diabetic retinopathy, dry eye disease, episcleritis, geographic atrophy, glaucoma, graft-versus-host disease, inflammation by gene therapy vectors, injury-related ocular inflammation or dry eye syndrome, iritis, keratitis, dry keratoconjunctivitis, macular degeneration (exudative or atrophic), meibomian gland dysfunction, myopia, non-infectious uveitis, ocular hyperemia, presbyopia, primary or secondary Sjogren's syndrome, hyperemia, retinal inflammation, retinal vein occlusion, aseptic conjunctivitis, Thygeson superficial punctate keratitis, or uveitis.

[0263] In some embodiments, described herein is a method comprising administering to a subject the compositions described herein.

[0264] In some embodiments, described herein is a method of treating a disease in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of the compositions described herein, wherein the composition comprises at least one active pharmaceutical ingredient.

[0265] In some embodiments, described herein is a method comprising administering to a subject Formulations 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 described herein.

[0266] In some embodiments, described herein is a method of treating a disease in a subject in need thereof, the method comprising topically administering to the subject a therapeutically effective amount of Formulations 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 described herein, wherein the composition comprises at least one active pharmaceutical ingredient.

[0267] In some embodiments of the methods described herein, the disease is an eye disease.

[0268] In some embodiments of the methods described herein, the active pharmaceutical ingredient is delivered to the subject's skin or through the subject's skin to internal tissues of the subject. In some embodiments of the methods described herein, the active pharmaceutical ingredient is travoprost, pilocarpine (as the free base), pilocarpine nitrate or pilocarpine hydrochloride.

[0269] In some embodiments of the methods described herein, the formulation is Formulation 3 and comprises at least one API. In some embodiments of the methods described herein, the formulation is Formulation 3 and comprises travoprost.

[0270] Kit In some embodiments, provided herein is a packaged formulation comprising a container holding a therapeutically effective amount of at least one formulation described herein, and instructions for using the at least one formulation according to one or more of the methods provided herein.

[0271] The formulations and related materials can be finished as commercial products by conventional processes performed in the art, such as appropriate sterilization and packaging processes. For example, the materials can be treated by UV / vis irradiation (200 - 500 nm) using, for example, photoinitiators having different absorption wavelengths (e.g., Irgacure 184, 2959, e.g., 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propan-1-one), preferably water-soluble initiators (e.g., Irgacure 2959). Such irradiation is typically carried out for an irradiation time of 1 - 60 minutes, although longer irradiation times may be applicable depending on the specific method. The materials of the present disclosure are finally aseptically packaged and may be packaged in suitable containers (such as boxes, etc.) (e.g., with a specific product information leaflet attached) so as to maintain sterility until use.

[0272] According to a further embodiment, the formulation can also be provided in the form of a kit combined with other components necessary for the administration of the formulation to a patient. For example, the disclosed kits for use in the treatment of cancer may further include administration materials such as spatulas, rulers, etc.

[0273] The kit is designed in various forms based on specific deficiencies when designed for treatment.

[0274] The formulations provided herein can be prepared and placed in a container for storage at ambient temperature or elevated temperature. When the formulation is stored in a plastic container made of polyolefin as compared to a plastic container made of polyvinyl chloride, discoloration of the formulation may be reduced. Without being bound by theory, the container may reduce exposure of the contents of the container to electromagnetic radiation, whether it is visible light (e.g., having a wavelength of about 380 - 780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190 - 320 nm (UV B light) or about 320 - 380 nm (UV A light)). Also, some containers include the ability to reduce the attachment or adsorption of the active agent to the surface of the container. Additionally, some containers include the ability to reduce exposure of the contents of the container to infrared light or a second component having such ability. Containers that can be used include those made of polyolefin, such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly those made of polyethylene, polypropylene, or combinations thereof. In some embodiments, the container is a glass container and the user scoops out the contents from the container using a measured spatula, spoon, etc. In some embodiments, the container is malleable, thereby allowing the user to squeeze out the contents from the container. The container may be further disposed within a second container, such as a container made of paper, cardboard, paperboard, metal film or foil, or combinations thereof, to further reduce exposure of the contents of the container to UV light, visible light, or infrared light. The formulations provided herein have the advantage that discoloration, degradation, or both are reduced during storage in such containers. The formulations provided herein may require storage for up to 3 months or longer, and in some cases, up to 1 year or longer. The container may be in any form suitable for containing the contents, such as a bag, bottle, tube, or box.

[0275] The following examples further illustrate aspects of the present disclosure. However, these do not in any way limit the teachings or disclosure described herein.

Examples

[0276] Example 1: Influence of pH on Chemical / Physical Stability

[0277] An oil-in-water formulation containing Formulation 1 (pH 3.5) and Formulation 2 (pH 5) was prepared and pilocarpine was added (see Tables 3 and 4 below). This formulation was compounded with the same composition, apparatus / process and stored under control at room temperature or 40 °C. Oil-in-water formulations 3 to 14 were prepared in the same manner. Samples were evaluated for decomposition impurities by liquid chromatography over several weeks. Triplicate samples were used at each sampling time point. The results are shown in Figures 1 and 7.

[0278] Table 3. Formulation 1, Formulation 2, Formulation 9 and Formulation 10

Table 3

[0279] Table 4. Formulation 11, Formulation 12, Formulation 13 and Formulation 14

Table 4

[0280] Figure 1 illustrates the variation in the chemical stability of pilocarpine in formulations having different pH levels. At controlled room temperature (about 20 to about 25 °C), the total impurity level of the formulation at pH 5 was about 50% higher than that of the formulation at pH 3.5. At 40 °C, the total impurity level of the formulation at pH 5 was more than 100% higher than that of the formulation at pH 3.5. In particular, at the 2-month time point, the total impurity level of the formulation at pH 5 stored under controlled room temperature exceeded the level of the formulation at pH 3.5 stored at 40 °C. Further, the total impurity level of the formulation at pH 3.5 stored at 40 °C surprisingly remained stable with respect to the decomposition of pilocarpine for at least 3 to 6 months. That is, further decomposition of pilocarpine was not observed after about 3 months; about 95% of the original pilocarpine remained intact after accelerated storage conditions at 40 °C for about 6 months (e.g., about 200 days). This suggests that the storage of this formulation achieved the effect of commercially appropriate storage stability. Also, the comparison between formulation 9 and formulation 10 showed that the pH 3.5 pilocarpine formulation provided herein is more beneficial than the pH 5 pilocarpine formulation.

[0281] Example 2: pH Stability Assay Formulation 5 (containing Formulation 3 and 0.004% w / w travoprost) was subjected to storage conditions of 40 °C / 75% RH and an eBeam dose of 40 kGy. The results are shown in Figure 2. As can be seen, the pH of the formulation was stable for at least about 8 months.

[0282] Example 3: Viscosity Stability Assay Formulation 5 was subjected to storage conditions of 40 °C / 75% RH and an eBeam dose of 40 kGy. The results are shown in Figure 3. As can be seen, the viscosity of the formulation was stable for at least about 7 months.

[0283] Example 4: Sterilization Stability Assay Individual excipients or active pharmaceutical ingredients exhibit different responses to electron beam irradiation. Therefore, it is important to confirm that the maximum applicable dose irradiated during the sterilization of the packaged product will not have a harmful effect on the product's function or the patient's safety over the intended shelf life of the product. The experimental samples of the product should be irradiated at least up to the maximum dose to which they will be subjected during normal processing. For example, a product that is to receive an electron beam sterilization dose of 25 - 40 kilograys (kGy) should be tested by irradiating the samples up to at least 40 kGy. A conservative approach is to irradiate the samples at a dose up to twice the expected maximum dose.

[0284] Therefore, formulation 5 was subjected to storage conditions of 40°C / 75% RH and an eBeam dose of 40 kGy. The travoprost concentration and impurities were measured to determine the stability profile before and after sterilization. The results are shown in Figure 4. As can be seen, this formulation was physically stable for at least about 5 months and was predicted to be stable for at least 1 year.

[0285] Example 5: Preclinical Trials of Formulation Use The formulations described herein are provided to the subject in a flexible plastic tube with a cap for use in the treatment of the subject's eye disease.

[0286] The length of the tip of the tube is used as a reference for the dose size for extruding the cream in a strip shape. The cream is applied to the upper eyelid, lower eyelid, or both of the subject's one or both eyes. The subject is careful to ensure that the tip of the tube does not come into contact with the eye, hand, or any other surface so that the tip of the tube is not contaminated. The subject refrains from wearing contact lenses or using artificial tears / eye lubricants during the test, and refrains from using eye cosmetics including, but not limited to, eyeshadow, eye cream / lotion / gel / cosmetic liquid, eyelash extensions, false eyelashes, or other eye-related products. Also, the subject avoids direct sunlight for 30 minutes after cream application. After formulation application, it is recommended to wear sunglasses that cut ultraviolet A and B (UVA and UVB) light outdoors where direct sunlight hits.

[0287] Application sequence: 1. Before applying the product around the eyes, wash hands. 2. Break the unsealing label and remove the cap from the tube. Do not use if the seal has been broken before use. 3. Squeeze out 1 / 4 inch (about the same size as the length of the tip of the tube) of the ophthalmic topical cream from the tube directly onto the fingertip. 4. To apply this cream to the upper eyelid and / or lower eyelid, gently move the lower side of the upper eyelid back and forth (without pulling or rubbing) until the cream is fully applied. Do not apply the cream directly from the tube to the eyelid, too close to the eyelashes, or into the eye. 5. If applicable, repeat steps 3 and 4 for the other eye. 6. Put the cap back on the tube tightly and store at room temperature. 7. After applying the product to both eyes, wash hands. 8. Apply the ophthalmic topical cream to the upper eyelids of both eyes every 12 hours (e.g., BID at morning (8 am ± 2 hours) and evening (8 pm ± 2 hours)). By following this application sequence, appropriate therapeutic bioavailability is achieved with the formulation. That is, the subject's eye disease is treated until a statistically significant degree or until subjective observation of the reduction of one or more symptoms of the eye disease is seen in the subject.

[0288] Example 6:

[0054] In vivo Pharmacokinetic Skin Topical Eyelid Administration Test Apply formulation 5 (containing formulation 3 and 0.012% w / w travoprost) or formulation 6 (containing formulation 4 and 0.012% w / w travoprost) to the eyelids of the minipig model. Collect aqueous humor (AH) and iris / ciliary body (ICB), and analyze by liquid chromatography / tandem mass spectrometry (LC / MS-MS) method to quantitatively measure the concentration of the model drug travoprost. The concentrations of the model drug travoprost in AH and ICB after a single topical application of formulation 5 and formulation 6 are shown in Figures 5 and 6.

[0289] From these test results, it is shown that the concentrations of the model drug in AH and ICB are significantly and surprisingly higher when using a formulation based on Formulation 3 (e.g., Formulation 5) than when using a formulation based on Formulation 4 (e.g., Formulation 6). Calculationally, the average drug concentration in AH when using Formulation 5 is approximately 48 times higher than that when using Formulation 6 at the 2-hour time point after application, while in ICB when using Formulation 5, it is approximately 20 times higher than that when using Formulation 6 at the 8-hour time point after application.

[0290] Fick's first law relates the diffusion flux to the concentration gradient. It assumes that the flux, which is proportional to the concentration gradient (spatial derivative), moves from the high-concentration region to the low-concentration region. Briefly, it is the concept that the solute will move from the high-concentration region to the low-concentration region across the concentration gradient. The diffusion process according to Fick's law is called normal diffusion or Fickian diffusion. Just adding 0.4 - 0.5% of isocetadecane to the formulations described herein would computationally add an additional 0.3-fold (or 30%) permeability (assuming a linear correlation between concentration and permeability from Fick's diffusion law). However, this factor alone cannot explain the more than 20-fold improvement in the permeability of travoprost achieved with Formulation 5 compared to Formulation 6. Here, in topical formulations, a specific combination of elements that cause the delivery of the API in the formulation not to follow Fick's law has been discovered. That is, a formulation that does not follow Fick's law has been discovered. This formulation exhibits non-Fickian diffusion or anomalous diffusion. Without being bound by theory, this can be explained by an unexpected or surprising synergistic effect between isocetadecane, which is a chemical penetration enhancer, and excipients including EDTA and citrate, which are excipients.

[0291] Although the present disclosure has been described in detail with reference to its specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present disclosure.

[0292] The alternative components or groupings of embodiments disclosed herein may be referred to and claimed individually or in any combination with other members of that group or other components found herein.

[0293] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0294] One of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. Approximately 0.05% to approximately 3% w / w C ７－２０ The mixture contains alkanes, approximately 0.005% to 0.5% w / w of metal chelating agents, and approximately 1 mM to 500 mM buffer, optionally including the following: a. At least one antioxidant; b. At least one type of base; c. At least one type of methylxanthine; d. At least one type of diol; e. At least one emulsifier; f. At least one Lewis acid; g. At least one type of oil; h. At least one type of preservative; i. At least one thickening agent; j. At least one isotonic agent; k. Water; or l. At least one active pharmaceutical ingredient A composition containing one or more of the following.

2. Zero or up to approximately 0.16% w / w caffeine; Approximately 0.5 to 4% w / w carbomer homopolymer type C; Approximately 0.5% w / w cetyl alcohol; Approximately 0.02 to 0.2% w / w EDTA disodium; Approximately 0.05 to 0.18% w / w methylparaben; Approximately 10% w / w mineral oil; Approximately 2% w / w PEG8000; Approximately 5% w / w polyoxyl 35 castor oil; Approximately 2% w / w of the first polysorbate 80; Approximately 0.01 to 0.02% w / w propylparaben; Approximately 4.4% w / w propylene glycol; A component comprising zero or up to approximately 4% w / w, wherein the component comprises approximately 30-40% w / w acrylamide / sodium acryloyldimethyltaurate copolymer, approximately 5-10% w / w second polysorbate 80, and approximately 20-25% w / w isohexadecane; Approximately 6% w / w sorbitol; Approximately 0.004 to approximately 4% w / w of at least one active pharmaceutical ingredient Includes, The pH is approximately 3.5 ± 0.5 or approximately 5.5 ± 0.

5. Herein, optionally, a composition comprising approximately 0.025% w / w butylated hydroxyanisole and approximately 6 mM to approximately 7 mM potassium citrate.

3. The composition according to claim 1 or 2, which is a cream formulation.

4. The composition according to claim 1 or 2, which is an oil-in-water cream.

5. C ７－２０ The composition according to claim 1, wherein the alkane is a softening agent.

6. C ７－２０ The composition according to claim 1, wherein the alkane is isohexadecane.

7. The composition according to claim 1 or 2, comprising at least one active pharmaceutical ingredient, wherein the ingredient is travoprost.

8. The composition according to claim 1, wherein the metal chelating agent is ethylenediaminetetraacetic acid or a salt thereof.

9. The composition according to claim 1, wherein the buffer is citric acid or a salt thereof.

10. The composition according to claim 1 or 2, comprising at least one active pharmaceutical ingredient, wherein the ingredient is selected from aflibercept, apraclonidine, atropine, betaxolol, brimonidine, brinzolamide, carbachol, dexamethasone, dipivefrin, donepezil, dorzolamide, levobunarol, metipranolol, pilocarpine, physostigmine, prostaglandin, steroid or timolol or pharmaceutically acceptable salts thereof.

11. The composition according to claim 1 or 2, comprising at least one active pharmaceutical ingredient, wherein the ingredient is a prostaglandin selected from bimatoprost, latanoprost, prostaglandin F2α as an isopropyl ester, tafluprost, or travoprost, or their corresponding free acids; or a steroid selected from androgens, corticosteroids, estrogens, or progestogens.

12. The composition according to claim 1 or 2, comprising at least one active pharmaceutical ingredient, wherein the ingredient is loteprednol etabonate.

13. C ７－２０ The composition according to claim 1, wherein the alkane is isohexadecane, the metal chelating agent is ethylenediaminetetraacetate disodium salt, and the buffer is potassium citrate.

14. The composition according to claim 13, comprising at least one active pharmaceutical ingredient, wherein the ingredient is travoprost.

15. The composition according to claim 14, comprising approximately 6-7 mM potassium citrate, approximately 0.2% w / w disodium ethylenediaminetetraacetate, approximately 0.4-0.5% w / w isohexadecane, and approximately 0.012% w / w travoprost.

16. The composition according to claim 1 or 2, wherein the pH of the composition is approximately 3.5 ± 0.

5.

17. The composition according to claim 16, wherein at least one active pharmaceutical ingredient comprises pilocarpine or a pharmaceutically acceptable salt thereof.

18. The composition according to claim 1 or 2, wherein the pH of the composition is approximately 5.5 ± 0.

5.

19. The composition according to claim 18, wherein at least one active pharmaceutical ingredient comprises travoprost.

20. A composition according to claim 1 or 2 for use in a method of treating an eye disease in a subject requiring treatment for an eye disease, The method includes administering a therapeutically effective amount of the composition topically to the target, Here, the composition comprises at least one active pharmaceutical ingredient.

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