Pharmaceutical composition of roflumilast and a solvent capable of dissolving a large amount of roflumilast

Abstract

A topical pharmaceutical composition comprising roflumilast and a solvent capable of dissolving a large amount of roflumilast. The pharmaceutical composition is capable of dissolving a large amount of roflumilast compared to other solvents commonly used in approved topical pharmaceutical compositions. The solvent is particularly useful for maintaining a high dissolution level of roflumilast, which is very poorly soluble in water, when combined with water.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 406,921, filed September 15, 2022, the disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a topical pharmaceutical composition comprising roflumilast and a solvent capable of dissolving a surprisingly large amount of roflumilast. The inventors of the subject application have developed a pharmaceutical composition capable of dissolving a surprisingly large amount of roflumilast compared to other solvents commonly used in approved topical pharmaceutical compositions. [Background technology]

[0003] It is known that roflumilast is suitable as a bronchotherapeutic agent and for the treatment of inflammatory disorders.Compositions containing roflumilast are used in human medicine and veterinary medicine and are proposed for the treatment and prevention of diseases including, but not limited to, inflammatory and allergen-induced airway disorders (e.g., bronchitis, asthma, COPD); skin diseases (e.g., proliferative, inflammatory, and allergen-induced skin disorders), and general inflammation in the gastrointestinal tract (Crohn's disease and ulcerative colitis).

[0004] Roflumilast and its synthesis were described in U.S. Pat. No. 5,712,298 (the '298 patent), which is incorporated herein by reference. Although roflumilast lozenges are commercially available, the compound's low aqueous solubility of only 0.53 mg / L at 21°C was reported in WO 95 / 01338 (corresponding to the '298 patent, which is incorporated herein by reference). This low aqueous solubility poses a problem when developing aqueous parenteral formulations and topical emulsions, suspensions, gels, or solutions. In U.S. Pat. No. 9,205,044 (which is incorporated herein by reference), the poor aqueous solubility of roflumilast was overcome by using alkoxylated fats, specifically polyoxyethylated 12-hydroxystearic acid, as cosolvents for parenteral administration. In EP1511516B1 (corresponding to U.S. Patent Application Publication No. 2014 / 0303215, which is incorporated herein by reference), the low aqueous solubility of roflumilast was overcome by formulating it in a topical emulsion (cream) formulation with polyethylene glycol 400 (PEG 400) at concentrations greater than 62% (w / w), while keeping the weight percentage of water below 10%.

[0005] Topical application for treating skin diseases can provide excellent delivery, lower systemic exposure, and better ease of use for patients.The molecular structure of a compound fundamentally determines the drug's ability to cross the epithelium of the tissue to which the product is applied.When applied to the skin, the selection of formulation components determines the maximum skin penetration that the formulation can achieve.

[0006] Several approaches have been proposed to increase the solubility of active ingredients with poor aqueous solubility, including particle size reduction, hydrotrophy, precipitation inhibitors (e.g., HPMC, PVP, PVA, PEG), complexation, solvent deposition, pH modification, lyophilization, surfactants, cosolvent power, microemulsions, solid dispersions, and solvate formation.

[0007] WO2013 / 030789 discloses PDE-IV inhibitors with poor aqueous solubility combined with a binder selected from sugars (e.g., sucrose, lactose, starch, microcrystalline cellulose, low-viscosity hydroxypropyl cellulose and / or hydroxypropyl methylcellulose), proteins (e.g., gelatin), or synthetic polymers (e.g., polyethylene glycol, polyvinyl acetate, polyvinyl alcohol, and propylene glycol).

[0008] In U.S. Pat. No. 9,205,044 (incorporated herein by reference), the poor aqueous solubility of roflumilast was addressed by using alkoxylated fats, particularly polyoxyethylated 12-hydroxystearic acid, as cosolvents.

[0009] In EP 1511516 B1, the low aqueous solubility of roflumilast was addressed by formulating it in a topical emulsion preparation (cream) with polyethylene glycol 400 (PEG 400) concentrations of greater than 62% (w / w), while keeping the weight percentage of water below 10%.

[0010] U.S. Patent No. 7,951,398 (incorporated herein by reference) discloses a solid dispersion of roflumilast, which is shown to be a poorly soluble drug, in which roflumilast is dispersed in a matrix containing a fatty alcohol, a triglyceride, and a fatty acid ester at an elevated temperature, then cooled and granulated with a hydrophilic polymer.

[0011] U.S. Patent No. 6,074,670 discloses a composition of the poorly soluble drug fenofibrate that improves dissolution. The composition includes a hydrophilic polymer and a surfactant, and fenofibrate is granulated with a solution of a hydrophilic polymer, such as polyvinylpyrrolidone, which results in an improved dissolution profile.

[0012] U.S. Pat. No. 8,431,154 (incorporated herein by reference) discloses a composition of roflumilast with improved release and improved pharmacokinetic profile by using an aqueous solution of polyvinylpyrrolidone (PVP) for granulating roflumilast by preparing a solid solution or solid dispersion.

[0013] U.S. Patent No. 9,340,547 (incorporated herein by reference) discloses that novel PI3K inhibitors can be combined with soluble macromolecular entities, such as cyclodextrins and suitable derivatives thereof, or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability, and / or stability.

[0014] WO2015 / 132708 discloses the use of a multiparticulate composition comprising roflumilast and an inactive ingredient. The inactive ingredient is prepared by granulation and then combined with roflumilast to provide a composition with improved dissolution. The composition preferably includes polyvinyl alcohol as one of the inactive ingredients.

[0015] One technique for increasing the solubility of an active ingredient is to blend an alcohol or glycol with water to create a solvent blend that is less polar than water. Because pharmaceutically acceptable alcohols such as ethanol or isopropyl alcohol are not desirable excipients for topical application to inflammatory skin diseases due to their tendency to further irritate inflamed skin, propylene glycol is a frequently used cosolvent in topical creams and gels for the treatment of psoriasis or atopic dermatitis. Propylene glycol (abbreviated PG) has been used to increase the solubility of corticosteroids in topical gels, lotions, and creams, which tend to contain more than 20% water and volatile materials and / or less than 50% hydrocarbons, waxes, or polyols (USP <1151> Definition of Topical Emulsion).

[0016] Another solvent, first used in FDA-approved topical products in 2005, is diethylene glycol monoethyl ether (trade name Transcutol®), abbreviated DEGEE. Diethylene glycol monoethyl ether is used as a vehicle and solubilizer to prepare pharmaceutical compositions (see, e.g., U.S. Pat. No. 9,827,315, U.S. Patent Application Publication Nos. 2011 / 0117182 and 2017 / 0087102, which are incorporated herein by reference). U.S. Patent Application Publication No. 2019 / 009133 describes a formulation containing roflumilast and DEGEE. Summary of the Invention [Means for solving the problem]

[0017] The present invention relates to a topical pharmaceutical composition comprising roflumilast and a solvent capable of dissolving a surprisingly large amount of roflumilast. The inventors of the subject application have developed a pharmaceutical composition capable of dissolving a surprisingly large amount of roflumilast compared to other solvents commonly used in approved topical pharmaceutical compositions. While some of the solvents disclosed herein have been used topically in commercial cosmetics, many of the solvents disclosed herein have not been used in topical drug products approved on the U.S. market to dissolve high concentrations of active ingredients. The solvents of the present invention are particularly useful for maintaining a high dissolution level of roflumilast, which is very poorly soluble in water, when combined with water.

[0018] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, water, and a solvent selected from the group consisting of 1,3-butylene glycol, 1,2-hexanediol, 1,3-propanediol, 1,2-pentanediol, dipropylene glycol, 2-(2-butoxyethoxy)ethanol, 1,6-hexanediol, propylene glycol methyl ethyl acetate, 5-methyloxolan-2-one, pantolactone, and combinations thereof. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40° C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40° C.

[0019] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, 1,3-butylene glycol, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C.

[0020] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, 1,2-hexanediol, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C.

[0021] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, 1,3-propanediol, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C.

[0022] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, 1,2-pentanediol, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C.

[0023] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, dipropylene glycol, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C.

[0024] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, 2-(2-butoxy-ethoxy)ethanol, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C.

[0025] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, 1,6-hexanediol, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C.

[0026] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, propylene glycol methyl ethyl acetate, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C.

[0027] In certain embodiments, the topical pharmaceutical composition comprises pharmaceutically effective amounts of roflumilast, 5-methyloxolan-2-one, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C.

[0028] In certain embodiments, the topical pharmaceutical composition comprises pharmaceutically effective amounts of roflumilast, pantolactone, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in an approximately equal molar blend or an approximately 1:2 solvent to water blend (weight:weight). In certain embodiments, the pharmaceutical composition is selected from the group consisting of an emulsion, a gel, and an ointment. In certain embodiments, the pharmaceutical composition further comprises at least one additional ingredient selected from the group consisting of a humectant, a surfactant or emulsifier, a polymer or thickener, an antifoaming agent, a preservative, an antioxidant, a sequestering agent, a stabilizer, a buffer, a pH adjuster, a skin penetration enhancer, a film former, a dye, a pigment, and a fragrance. In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. In certain embodiments, the solvent is in an amount sufficient to maintain a majority of the roflumilast dissolved after 1, 2, 3, 6, or 12 months of storage at controlled room temperature and 40°C. DETAILED DESCRIPTION OF THE INVENTION

[0029] Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols, and reagents described herein, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is limited only by the appended claims. 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 to which this invention belongs.

[0030] All publications, patents, and patent applications cited herein are incorporated by reference in their entirety unless otherwise stated. Where the same term is defined in a publication, patent, or patent application incorporated by reference herein and in this disclosure, the definition in this disclosure represents the controlling definition. With respect to publications, patents, and patent applications referenced to describe particular types of compounds, chemistry, etc., the portions relevant to such compounds, chemistry, etc. are the portions of the documents incorporated by reference herein.

[0031] It should be noted that, as used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, "active ingredient" includes both a single ingredient and two or more different ingredients, and "solvent" refers to both a single solvent and two or more different solvents or complex mixtures of solvents.

[0032] The term "about," when used in connection with a numerical value, is meant to encompass numerical values ​​within a range having a lower limit of 5% less than the stated numerical value and an upper limit of 5% greater than the stated numerical value.

[0033] The term "effective" refers to an amount of a compound, agent, substance, preparation, or composition sufficient to reduce the severity of disease symptoms, increase the frequency and duration of disease symptom-free periods, or prevent impairment or disability due to disease affliction. The amount can be a single dose, or can be according to a multiple dose regimen, alone or in combination with other compounds, agents, or substances. One of ordinary skill in the art would be able to determine such amounts based on factors such as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0034] "Pharmaceutically acceptable" means generally safe for administration to humans or animals. Preferably, a pharmaceutically acceptable ingredient is one that has been approved by a federal or state regulatory agency or is listed in the US Pharmacopeia, published by the United States Pharmacopeial Convention, Inc., Rockville, Md., or other generally recognized pharmacopeia, for use in animals, more particularly humans.

[0035] A "pharmaceutical composition" according to the present invention can be in the form of a composition in which different active ingredients and diluents and / or carriers are mixed with one another, or it can take the form of a combined preparation in which the active ingredients are present in partly or completely different forms. An example of such a combination or combined preparation is a kit of parts.

[0036] A "pharmaceutically effective amount" or "therapeutically effective amount" is an amount of a pharmaceutical or therapeutic agent sufficient to achieve its intended purpose. The effective amount of a given therapeutic agent will vary depending on factors such as the nature of the agent, the route of administration, the size of the subject receiving the therapeutic agent, and the purpose of the administration. The effective amount in each individual case can be determined empirically by one of ordinary skill in the art according to methods established in the art.

[0037] As used herein, the term "subject" or "patient" most preferably refers to a "human." The term "subject" or "patient" can include any mammal that may benefit from the compounds described herein.

[0038] The term "substantially" means greater than 90%. The term "topical" with respect to the administration of a drug or composition refers to the application of such drug or composition to an epithelial surface outside the body, including the skin or cornea. With respect to this application, application inside a body orifice, such as the mouth, nose, ear, etc., is not considered topical application.

[0039] As used herein, "treat," "treating," or "treatment" of a disease or disorder means achieving one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the onset of symptoms characteristic of the disorder being treated; (c) inhibiting the worsening of symptoms characteristic of the disorder being treated; (d) limiting or preventing the recurrence of the disorder in a patient who previously had the disorder; and (e) limiting or preventing the recurrence of symptoms in a patient who was previously symptomatic for the disorder.

[0040] The abbreviation "w / w" expresses the relative concentrations of ingredients in a composition as "weight to weight" (i.e., percentages refer to percentages of total weight) instead of on a volume or other amount basis.

[0041] The present invention relates to a topical pharmaceutical composition comprising roflumilast and a solvent capable of dissolving a surprisingly large amount of roflumilast. The inventors of the subject application have developed a pharmaceutical composition capable of dissolving a surprisingly large amount of roflumilast compared to other solvents commonly used in approved topical pharmaceutical compositions. The solvent of the present invention is particularly useful for maintaining a high dissolution level of roflumilast, which is very poorly soluble in water, when combined with water.

[0042] Roflumilast is a compound of formula (I):

[0043] [ka]

[0044] wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy, and R3 is 3,5-dichloropyrid-4-yl. The compound has the chemical name N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN: roflumilast). Roflumilast can be prepared by methods known in the art, for example, as described in the '298 patent and U.S. Patent Application Publication No. 2014 / 0303215.

[0045] In certain embodiments, the pharmaceutical composition comprises roflumilast or a salt thereof in an amount of about 0.005% to about 2.0% w / w, about 0.05% to about 1.0% w / w, about 0.05% to about 0.5% w / w, or about 0.1% to about 0.5% w / w. In certain embodiments, the pharmaceutical composition comprises about 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 0.55%, 0.60%, 0.65%, 0.70%, 0.75%, 0.80%, 0.85%, 0.90%, 0.95%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0% w / w of roflumilast or a salt thereof. In certain embodiments, the solvent-water blend can dissolve roflumilast in an amount from about 0.005% to about 2%. In certain embodiments, the pharmaceutical composition includes an N-oxide of roflumilast or a salt thereof. The amount of N-oxide of roflumilast or a salt thereof can be the same amounts as those described for roflumilast.

[0046] The present invention is directed to pharmaceutical compositions of roflumilast dissolved in one or more solvents and water. In certain embodiments, the solvents are 1,3-butylene glycol, 1,2-hexanediol, 1,3-propanediol, 1,2-pentanediol (also known as pentylene glycol), dipropylene glycol, 2-(2-butoxyethoxy)ethanol (also known as butoxydicol), 1,6-hexanediol, propylene glycol methyl ethyl acetate (also known as PGMEA or 1-methoxy-2-propanol acetate), 5-methyloxolan-2-one (also known as gamma-valerolactone), pantolactone, 1,3-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1-heptanol, 1-hexanol, 2-(2-ethoxyethoxyl)ethyl acetate, or 2-(2-ethoxyethoxyl)ethyl acetate. acetate), 2-(2-methoxyethoxy)ethanol, 2-butoxyethanol, 2-butoxyethyl acetate, 2-ethoxyethanol, 2-ethoxyethyl acetate, 2-methoxyethanol, diethylene glycol dimethyl ether (also known as bis(2-methoxyethyl)ether), diethylene glycol, propylene glycol methyl ether, and combinations thereof. In certain embodiments, the solvent is selected from the group consisting of 1,3-butylene glycol, 1,2-hexanediol, 1,3-propanediol, 1,2-pentanediol, dipropylene glycol, 2-(2-butoxyethoxy)ethanol, 1,6-hexanediol, propylene glycol methyl ethyl acetate, 5-methyloxolan-2-one, pantolactone, and combinations thereof. In certain embodiments, the solvent is selected from the group consisting of 1,2-pentanediol, 5-methyloxolan-2-one, 2-(2-butoxy-ethoxy)ethanol, propylene glycol methyl ethyl acetate, and 1,6-hexanediol.

[0047] The pharmaceutical composition preferably contains a sufficient amount of solvent to achieve the desired level of active ingredient solubility in the formulation. In certain embodiments, the pharmaceutical composition contains solvent in an amount of about 5% to about 50% w / w, about 10% to about 30% w / w, about 10% to about 30% w / w, about 15% to about 30% w / w, about 15% to about 25% w / w, about 20% to about 30% w / w, about 20% to about 25% w / w, or about 22.5% to about 27.5% w / w. In certain embodiments, the ratio of solvent to water (weight:weight) is about 1:50 to about 20:1, about 1:40 to about 1:1, about 1:30 to about 1:1, about 1:20 to about 20:1, or about 1:20 to about 1:1 weight to weight. The ratio of solvent to water (weight:weight) can be about 1:50, 1:45, 1:40, 1:35, 1:30, 1:25, 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, or 20:1. In certain embodiments, the ratio of solvent to water (weight:weight) is about 1:15 to about 1:1 weight to weight, about 1:14 to about 1:1, about 1:13 to about 1:1, about 1:12 to about 1:1, or about 1:12 to 1:2. In certain embodiments, the ratio of solvent to water is an equimolar blend of solvent to water.

[0048] In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at controlled room temperature. In certain embodiments, the solvent is capable of maintaining dissolved roflumilast, or at least a majority of dissolved roflumilast, after 1, 2, 3, 4, 5, 6, or 12 months of storage at controlled room temperature. In certain embodiments, the solvent is capable of maintaining at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of dissolved roflumilast after 1, 2, 3, 4, 5, 6, or 12 months of storage at controlled room temperature.

[0049] In certain embodiments, the solvent is present in an amount sufficient to maintain stability of the pharmaceutical composition for 1, 2, 3, 6, or 12 months of storage at 40° C. In certain embodiments, the solvent is capable of maintaining dissolved roflumilast (or at least substantially all of the roflumilast) after 1, 2, 3, 4, 5, 6, or 12 months of storage at 40° C. In certain embodiments, the solvent is capable of maintaining at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.5% of dissolved roflumilast after 1, 2, 3, 4, 5, 6, or 12 months of storage at 40° C.

[0050] In certain embodiments, the pharmaceutical composition is a topical formulation. Topical roflumilast pharmaceutical formulations are available from US Pharmacopeia USP <1151> and may include aerosols, foams, sprays, emulsions (which may also be called creams, lotions, or ointments), gels (two-phase or single-phase), liquids, ointments, pastes, washes, suspensions, and systems, which are typical dosage forms containing a pharmaceutically active ingredient for topical application to mammals, including humans.

[0051] Topical application refers to administering to the skin, hair, or nails of a patient who will benefit from treatment with a pharmaceutical product. Topical application can also refer to application to the epithelium of a patient for local delivery. This includes application of roflumilast to the eye, ear, oral mucosa, vaginal mucosa, rectal mucosa, or urethra. In certain embodiments, the topical pharmaceutical composition can include using the epithelium of a patient as a route of administration to achieve therapeutic systemic levels of the active ingredient. This form of topical pharmaceutical composition is often referred to as transdermal delivery of therapeutically active ingredients.

[0052] The final product is preferably in one of the following forms: Oil-in-water emulsions: The topical products can be emulsions that include a discontinuous hydrophobic phase and a continuous aqueous phase that includes a blend of solvent and water, and optionally one or more polar hydrophilic excipients, as well as salts, surfactants, emulsifiers, and other ingredients. These emulsions can include water-soluble or water-swellable polymers that help stabilize the emulsion. In certain embodiments, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

[0053] Water-in-oil emulsions: The compositions may be formulations in which roflumilast is incorporated into emulsions comprising a continuous hydrophobic phase and an aqueous phase containing a solvent and, optionally, one or more polar hydrophilic carriers, as well as salts or other ingredients. These emulsions may contain an oil-soluble or oil-swellable polymer and one or more emulsifiers that help stabilize the emulsion. In certain embodiments, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

[0054] In both oil-in-water emulsions and water-in-oil emulsions, the order of excipient addition can be important. Roflumilast can be predissolved and added to a continuous aqueous phase containing a solvent and water blend. Similarly, roflumilast can be predissolved in the hydrophobic discontinuous phase of the emulsion, which is then mixed with the solvent-water blend and optional hydrophilic excipients that do not contain the active ingredient. Roflumilast can be predissolved in both the oil and aqueous phases of the emulsion, or predissolved and added to a solvent or solvent-water blend after the emulsion is formed. Some emulsions undergo phase inversion over a certain temperature range during cooling. Therefore, roflumilast can be added to a water-in-oil emulsion at a temperature higher than the phase inversion temperature, and the final drug product can become an oil-in-water emulsion at controlled room temperature, or vice versa.

[0055] Thickened aqueous gels: These systems comprise a solvent-water blend containing dissolved roflumilast and optionally one or more polar hydrophilic carriers, such as hexylene glycol, thickened with a suitable natural, modified natural, or synthetic thickener, as described below. Alternatively, the thickened aqueous gels can be thickened using a suitable polyethoxylate alkyl chain surfactant or other nonionic, cationic, or anionic systems.

[0056] Thickened hydroalcoholic gels: These systems comprise a solvent-water-alcohol blend containing dissolved roflumilast and, optionally, one or more polar hydrophilic carriers, such as hexylene glycol, as the polar phase, which is thickened with a suitable natural, modified natural, or synthetic polymer as described herein. Alternatively, the thickened hydroalcoholic gel can be thickened using a suitable polyethoxylated alkyl chain surfactant or other nonionic, cationic, or anionic system. The alcohol can be ethanol, isopropyl alcohol, or another pharmaceutically acceptable alcohol.

[0057] Hydrophilic or hydrophobic ointments: The compositions are formulated with a hydrophobic base (e.g., petrolatum, thickened or gelled water-insoluble oils, etc.), optionally with a small amount of a solvent-water blend containing dissolved roflumilast. Hydrophilic ointments generally contain one or more surfactants or humectants.

[0058] solvent In addition to the solvents mentioned above, the compositions may contain one or more additional cosolvents to achieve the desired level of active ingredient solubility in topical products. This cosolvent may also alter the skin penetration or activity of other excipients included in the formulation. Additional solvents include, but are not limited to, acetone, ethanol, benzyl alcohol, butyl alcohol, diethyl sebacate, diethylene glycol monoethyl ether (DEGEE), diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropyl alcohol, isopropyl isostearate, isopropyl myristate, N-methylpyrrolidinone, ethylene glycol, polyethylene glycol, glycerol, propylene glycol, oleic acid, limonene, eugenol, labrosol, and SD alcohol.

[0059] moisturizer The compositions of the present invention may include a humectant to enhance hydration. In emulsions, this humectant is often a component of the discontinuous or continuous hydrophobic phase. The humectant can be a hydrophilic material, including humectants, or it can be a hydrophobic material, including emollients. Suitable humectants include diethylene glycol monoethyl ether (DEGEE), 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerin, polyethylene glycol 200-8000, butyl stearate, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, docosanol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, and lauric acid. Ingredients include, but are not limited to, glyceryl, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, glycol distearate, glycol stearate, isostearic acid, isostearyl alcohol, lanolin, mineral oil, limonene, medium chain triglycerides, menthol, myristyl alcohol, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, olive oil, paraffin, peanut oil, petrolatum, Plastibase-50W, and stearyl alcohol.

[0060] surfactants and emulsifiers Compositions according to the present invention can optionally contain one or more surfactants to help emulsify the composition and wet the surface of the active molecule or excipient. As used herein, the term "surfactant" refers to an amphiphile (a molecule having both covalently bonded polar and non-polar regions) that can reduce the surface tension of water and / or the interfacial tension between water and immiscible liquids. Surfactants include: alkyl aryl sodium sulfonate, Amerchol-CAB, ammonium lauryl sulfate, apricot kernel oil PEG-6 esters, Arlacel, benzalkonium chloride, ceteareth-6, ceteareth-12, ceteareth-15, ceteareth-30, cetearyl alcohol / ceteareth-20, cetearyl ethylhexanoate, ceteth-10, ceteth-2, ceteth-20, ceteth-23, cholestrol-24, cocamide ether sulfate, cocamine oxyde, cocobetaine, cocodiethanolamide, cocomonoethanolamide, coco-caprylate / caprate, disodium cocoamphodiacetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, disodium oleamide monoethanolamine sulfosuccinate Oleamido monoethanolamine sulfosuccinate, docusate sodium, laureth-2, laureth-23, laureth-4, lauric acid diethanolamide, lecithin, methoxy PEG-16, methyl gluceth-10, methyl gluceth-20, methyl glucose sesquistearate, oleth-2, oleth-20, PEG 6-32 stearate, PEG-100 stearate, PEG-12 glyceryl laurate, PEG-120 methyl glucose dioleate, PEG-15 cocamine, PEG-150 distearate, PEG-2 stearate, PEG-20 methyl glucose sesquistearatesesqustearate), PEG-22 methyl ether, PEG-25 propylene glycol stearate, PEG-4 dilaurate, PEG-4 laurate, PEG-45 / dodecyl glycol copolymer, PEG-5 oleate, PEG-50 stearate, PEG-54 hydrogenated castor oil, PEG-6 isostearate, PEG-60 hydrogenated castor oil, PEG-7 methyl ether, PEG-75 lanolin, PEG-8 laurate, PEG-8 stearate, Pegoxol 7 stearate (Pegoxol 7 stearate), pentaerythritol cocoate, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, polyglyceryl-3 oleate, polyoxyethylene alcohol, polyoxyethylene fatty acid esters, polyoxyl 20 cetostearyl ether, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polyoxyl 6 and polyoxyl 32, polyoxylglyceryl stearate, polyoxyl stearate, polysorbate 20, poly Examples of suitable emulsifiers include, but are not limited to, sorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, PPG-26 oleate, PROMULGEN™ 12, propylene glycol diacetate, propylene glycol dicaprylate, propylene glycol monostearate, sodium xylene sulfonate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, steareth-2, steareth-20, steareth-21, steareth-40, tallow fatty acid glycerides, and emulsifying wax. In certain embodiments, the emulsifier is a self-emulsifying wax blend of dicetyl phosphate and ceteth-10 phosphate.

[0061] Polymers and Thickeners For certain applications, it may be desirable to formulate topical products thickened with soluble, swellable, or insoluble organic polymeric thickeners, such as natural and synthetic polymers or inorganic thickeners, including, but not limited to, acrylate copolymers, carbomer 1382, carbomer copolymer type B, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, carboxyvinyl copolymer, carboxymethylcellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, microcrystalline wax, and methylcellulose.

[0062] Additional ingredients The compositions according to the present invention may be formulated with additional ingredients such as fillers, carriers, and excipients conventionally found in topical cosmetic and pharmaceutical products. Additional ingredients may be added to the compositions, including, but not limited to, antifoaming agents, preservatives (e.g., p-hydroxybenzoic acid esters, benzyl alcohol, phenylmercuric salts, chlorocresol), antioxidants, sequestering agents, stabilizers, buffers, pH adjusting solutions, skin penetration enhancers, film formers, dyes, pigments, diluents, bulking agents, fragrances, and other excipients to improve stability or aesthetics.

[0063] The compositions according to the invention may be formulated with additional active agents depending on the condition being treated, such as NSAIDs (e.g., aspirin, ibuprofen, ketoprofen, naproxen), apremilast, JAK inhibitors (e.g., tofacitinib, ruxolitinib, oclacit), leukotriene inhibitors (e.g., zileuton, zafirlukast, montelukast), mast cell stabilizers (e.g., nedocromil, cromolyn sodium, ketotifen, pemirolast), anthralin (dithranol), azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfasalazine, mycophenolate mofetil, fumarates, and corticosteroids. (e.g., alclometasone, amcinonide, betamethasone, clobetasol, clocotolone, mometasone, triamcinolone, fluocinolone, fluocinonide, flurandrenolide, diflorasone, desonide, desoximetasone, dexamethasone, halcinonide, halobetasol, hydrocortisone, methylprednisolone, prednicarbate, prednisone), corticotropin, vitamin D analogs (e.g., calcipotriene, calcitriol), acitretin, tazarotene, cyclosporine, resorcinol, colchicine, bronchodilators (e.g., beta-agonists, anticholinergics, theophylline), and antibiotics (e.g., erythromycin, ciprofloxacin, metronidazole).

[0064] Administration and Dosage Compositions according to the invention may be administered by any suitable route of administration, including, but not limited to, oral, rectal, parenteral (e.g., intradermal, subcutaneous, intramuscular, intravenous, intramedullary, intraarterial, intrathecal, epidural), ocular, inhalation, nebulization, dermal (topical), transdermal, and mucosal (e.g., sublingual, buccal, nasal). In a preferred embodiment, the compositions are administered topically.

[0065] Suitable pharmaceutical dosage forms include, but are not limited to, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels, foams, transdermal patches, and solutions (e.g., injectable, oral).

[0066] Topical formulations containing roflumilast are applied to the skin in an amount sufficient to achieve the desired pharmacological effect, which is typically the amelioration of signs and / or symptoms of a medical disorder. The amount of formulation applied can vary depending on the amount of roflumilast contained in the formulation, the concentration of roflumilast in the formulation, and the frequency with which the formulation is intended to be applied. Generally, the formulation is applied once a week to several times daily, preferably every other day to three times daily, and most preferably once or twice daily.

[0067] The compositions are useful in treating acute and chronic airway disorders such as bronchitis, allergic bronchitis, asthma, and COPD; proliferative, inflammatory, and allergic dermatitis such as psoriasis, scalp psoriasis, or inverse psoriasis, irritant and allergic contact eczema, hand eczema, atopic dermatitis, seborrheic dermatitis, lichen simplex, sunburn, aphthous ulcers, lichen planus, vitiligo, genital or anal pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and widespread pyoderma, intrinsic and extrinsic acne, acne rosacea, disorders based on excessive release of TNF and leukotrienes. The compositions may be used in veterinary and human medicine for the treatment and prevention of all diseases that are believed to be treatable or preventable using roflumilast, including, but not limited to, cardiac disorders treatable by PDE inhibitors, inflammation in the gastrointestinal system or central nervous system, eye disorders, disorders treatable by the tissue-relaxing effects of PDE inhibitors, and other proliferative, inflammatory, and allergic skin disorders; and immune-mediated diseases such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, and arthritis, including psoriatic arthritis. Preferably, the compositions are used to treat proliferative, inflammatory, and allergic dermatitis, such as psoriasis (vulgaris), eczema, acne, lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, and pyoderma.

[0068] The compositions may include additional active agents suitable for treating the patient's condition. For example, when proliferative, inflammatory, and allergic dermatitis are treated, the compositions may include anthralin (dithranol), azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfasalazine, mycophenolate mofetil, fumarate esters, corticosteroids (e.g., alclometasone, amcinonide, betamethasone, clobeta), benzodiazepines, benzocaine, benzoyl peroxide ... In some embodiments, the active ingredient(s) may additionally include an active ingredient(s) such as benzodiazepine, benzocaine, ...

[0069] Topical formulations containing roflumilast can be prepared by methods typically used in the field of manufacturing pharmaceutical formulations for topical application. To prepare a single-phase formulation, such as a liquid, the components of the formulation can be combined and mixed until a homogeneous solution or suspension of the active ingredient is obtained. To prepare a multi-phase formulation, such as an emulsion, for example, the aqueous phase components and the oil phase components can be separately combined and mixed until a homogeneous solution is obtained, and then the aqueous and oil solutions can be combined and mixed, for example, by shear mixing, to form the formulation. The one or more active drug molecules can be dissolved (molecularly dispersed), complexed, associated with excipients or other active molecules, or particulate (amorphous or crystalline). The oil phase can be added to the aqueous phase, or the aqueous phase can be added to the oil phase. These phases can be combined and mixed at an elevated temperature, for example, 50-90°C, or at room temperature, for example, 20-30°C, or at a temperature between room temperature and the elevated temperature. [Example]

[0070] While various embodiments have been described herein, it should be understood that they have been presented by way of example only, and not limitation. Thus, the breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments. Moreover, unless otherwise indicated herein or otherwise clearly contradicted by context, any combination of the above-described elements in all possible variations thereof is encompassed by the present disclosure.

[0071] Example 1 The solubility of roflumilast in various solvents was determined. Compositions of roflumilast and the solvents identified in Table 1 were prepared. To prepare the compositions, 10 g of the solvent-water blend was added to a 20 mL clear glass vial. 0.05 g of the active pharmaceutical ingredient (API), roflumilast, was added to the vial. The vial was mixed on a jar roller at a controlled room temperature and at an appropriate speed. Visual evaluation was performed after shaking. If all of the API dissolved, an additional 0.05 g of API was added to the vial and further mixing was performed. If any API remained undissolved, the total amount of API added to the vial was recorded. Visual inspection was repeated as necessary until no more API was dissolved. For each solvent, solubility was determined by syringe filtering the solvent blend (0.2 micron filter) to remove undissolved roflumilast and using HPLC analysis to determine the amount of dissolved roflumilast. The solvent blend compositions included an equimolar solvent-water mixture and a 1:2 (wt:wt) solvent-water blend. The actual solvent weights used in this study are listed in Table 1. Transcutol P, described in U.S. Patent Application Publication No. 2019 / 009133 for use with roflumilast, was used as a reference point in Example 1. Solubility results (μg roflumilast dissolved per mL of blend) are listed in Table 1.

[0072] [Table 1]

[0073] As is clear from the results in Table 1, the solvents investigated were capable of dissolving surprisingly large amounts of roflumilast. Example 2 Topical pharmaceutical compositions were prepared as described in Table 2.

[0074] [Table 2]

[0075] Example 3 Topical pharmaceutical compositions were prepared as described in Table 2.

[0076] [Table 3]

[0077] Example 4 Topical pharmaceutical compositions were prepared as described in Table 2.

[0078] [Table 4]

[0079] Example 5 Topical pharmaceutical compositions were prepared as described in Table 2.

[0080] [Table 5]

[0081] Example 6 Topical pharmaceutical compositions were prepared as described in Table 2.

[0082] [Table 6]

[0083] Example 7 Topical pharmaceutical compositions were prepared as described in Table 2.

[0084] [Table 7]

[0085] Example 8 Topical pharmaceutical compositions were prepared as described in Table 2.

[0086] [Table 8]

[0087] Example 9 Two formulations each of Formulations A, B, C, D, E, F, and G (described in Examples 2-8) were prepared (Formulation 1 and Formulation 2 in Tables 9-15). Each formulation was stored at controlled room temperature and 40°C for 3 months. Appearance, % w / w, and % LC were evaluated after the initial preparation (T=0), 1 month (T=1), and 3 months (T=3).

[0088] Assay testing was performed using an HPLC method. Single-point calibration standards were prepared at a concentration of 0.1 mg / mL roflumilast in acetonitrile. Samples were prepared by transferring the specified amount of sample to a flask of appropriate volume according to Table 9 below. The sample material was backfilled into a syringe and dispensed into the flask. The flask was diluted to approximately half volume with acetonitrile and mixed by vortexing for approximately 30 seconds. The flask was placed in a 60°C water bath for 20 minutes. The flask was then mixed by vortexing for approximately 30 seconds. The flask was cooled to room temperature, diluted to volume with acetonitrile, and thoroughly mixed by vortexing and inversion. Approximately 1.5 mL of each solution was transferred to an Eppendorf microcentrifuge tube and centrifuged at 16,000 g for 5 minutes. The supernatant was removed using a plastic transfer pipette and placed in an autosampler vial. This method was developed using an Agilent 1200 system equipped with a model G1312B binary high-pressure mixing pump with a dwell volume of approximately 1.2 mL. The chromatographic parameters are listed in Table 10 and the gradients are listed in Table 11. The results of the studies are reported below in Tables 12-18.

[0089] [Table 9]

[0090] [Table 10]

[0091] [Table 11]

[0092] [Table 12]

[0093] [Table 13]

[0094] [Table 14]

[0095] [Table 15]

[0096] [Table 16]

[0097] [Table 17]

[0098] [Table 18]

[0099] The foregoing description has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise form disclosed. Those skilled in the art will recognize that modifications and substitutions to the basic invention description may be made.

Claims

1. A topical pharmaceutical composition comprising a pharmaceutically effective amount of roflumilast, water, and a pharmaceutically acceptable solvent selected from the group consisting of 1,3-butylene glycol, 1,2-hexanediol, 1,3-propanediol, 1,2-pentanediol, dipropylene glycol, 2-(2-butoxy-ethoxy)ethanol, 1,6-hexanediol, propylene glycol methyl ethyl acetate, 5-methyloxolan-2-one, pantolactone, and combinations thereof.

2. 10. The pharmaceutical composition of claim 1, wherein the roflumilast is present in an amount of about 0.005% to about 2% w / w.

3. 3. The pharmaceutical composition of claim 2, wherein the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for three months after storage at controlled room temperature.

4. 3. The pharmaceutical composition of claim 2, wherein the solvent is in an amount sufficient to maintain at least 95% of the roflumilast dissolved after storage at controlled room temperature for three months.

5. 3. The pharmaceutical composition of claim 2, wherein the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition for 3 months after storage at 40°C.

6. 3. The pharmaceutical composition of claim 2, wherein the solvent is in an amount sufficient to keep at least 95% of the roflumilast dissolved after storage at 40°C for 3 months.

7. 3. The pharmaceutical composition of claim 2, wherein the solvent and water are present in an approximately equal molar blend.

8. 3. The pharmaceutical composition of claim 2, wherein the solvent and water are present in an approximately 1:2 solvent to water blend (weight:weight).

9. 4. The pharmaceutical composition of claim 3, which is selected from the group consisting of an emulsion, a gel, and an ointment.

10. 10. The pharmaceutical composition of claim 9, further comprising at least one additional ingredient selected from the group consisting of humectants, surfactants or emulsifiers, polymers or thickeners, antifoaming agents, preservatives, antioxidants, sequestering agents, stabilizers, buffers, pH adjusters, skin penetration enhancers, film formers, dyes, pigments, and fragrances.

11. The pharmaceutical composition of claim 3, wherein the solvent comprises 1,3-butylene glycol.

12. The pharmaceutical composition of claim 3, wherein the solvent comprises 1,2-hexanediol.

13. The pharmaceutical composition of claim 3, wherein the solvent comprises 1,3-propanediol.

14. The pharmaceutical composition of claim 3, wherein the solvent comprises 1,2-pentanediol.

15. 4. The pharmaceutical composition of claim 3, wherein the solvent comprises dipropylene glycol.

16. 4. The pharmaceutical composition of claim 3, wherein the solvent comprises 2-(2-butoxy-ethoxy)ethanol.

17. The pharmaceutical composition of claim 3, wherein the solvent comprises 1,6-hexanediol.

18. 4. The pharmaceutical composition of claim 3, wherein the solvent comprises propylene glycol methyl ethyl acetate.

19. 4. The pharmaceutical composition of claim 3, wherein the solvent comprises 5-methyloxolan-2-one.

20. 4. The pharmaceutical composition of claim 3, wherein the solvent comprises pantolactone.

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