Pharmaceutical composition of roflumilast and solvent capable of dissolving large amounts of roflumilast

Abstract

Topical pharmaceutical compositions comprising roflumilast and a solvent capable of dissolving substantial amounts of roflumilast. The pharmaceutical composition is capable of dissolving large amounts of roflumilast relative to other commonly used solvents in approved topical pharmaceutical compositions. The solvent is particularly useful when mixed with water to maintain a high level of dissolved roflumilast, which is highly insoluble in water.

Description

[0001] Cross - reference to related applications

[0002] This application claims the priority of U.S. Provisional Application No. 63 / 406,921, filed on September 15, 2022, the disclosure of which is incorporated herein by reference. Technical field

[0003] The present invention relates to topical pharmaceutical compositions comprising roflumilast and solvents that can surprisingly dissolve a large amount of roflumilast. The inventors of the present application have developed pharmaceutical compositions that can surprisingly dissolve a large amount of roflumilast relative to other commonly used solvents in approved topical pharmaceutical compositions. Background art

[0004] Roflumilast is known to be suitable as a bronchodilator and for the treatment of inflammatory diseases. Compositions containing roflumilast are used in human and veterinary medicine and have been proposed for the treatment and prevention of diseases including, but not limited to: inflammatory and allergen - induced airway diseases (e.g., bronchitis, asthma, COPD); skin diseases (e.g., proliferative, inflammatory and allergen - induced skin diseases), and generalized inflammation in the gastrointestinal region (Crohn's disease and ulcerative colitis).

[0005] Roflumilast and its synthesis are described in U.S. Patent No. 5,712,298 ("the '298 patent"), which is incorporated herein by reference. Although roflumilast oral tablets are commercialized, WO95 / 01338 (corresponding to the '298 patent and incorporated herein by reference) reports that the compound has low water solubility, only 0.53 mg / l at 21°C. This low water solubility is problematic for the development of parenteral formulations and topical emulsions, suspensions, gels or aqueous solutions. In U.S. Patent No. 9,205,044 (incorporated herein by reference), the low water solubility of roflumilast is overcome by using alkoxylated fats, specifically polyoxyethylated 12 - hydroxy stearic acid, as a co - solvent for parenteral administration. In EP 1511516B1 (corresponding to U.S. Patent Publication No. 2014 / 0303215, incorporated herein by reference), the low water solubility of roflumilast in topical emulsion (cream) formulations is overcome by formulating with polyethylene glycol 400 (PEG 400) at a concentration exceeding 62% (w / w) while keeping the water weight percentage below 10%.

[0006] Topical administration for the treatment of skin diseases can provide excellent delivery, lower systemic exposure and easier use for patients. The molecular structure of a compound ultimately determines the ability of the drug to cross the epithelium of the tissue of the applied product. For skin application, the choice of formulation components determines the maximum skin permeability that can be achieved by the formulation designer.

[0007] Several methods have been proposed for enhancing the solubility of active ingredients with low water solubility. These methods include reducing particle size, hydrotrophy, complexation with precipitation inhibitors (such as HPMC, PVP, PVA, PEG), solvent deposition, pH modification, lyophilization, surfactants, co-solvency, microemulsions, solid dispersions, and solvate formation.

[0008] WO 2013 / 030789 discloses a combination of a PDE-IV inhibitor with poor water solubility and a binder selected from sugars (such as sucrose, lactose, starch, microcrystalline cellulose, low-viscosity hydroxypropyl cellulose, and / or hydroxypropyl methylcellulose), proteins (such as gelatin), or synthetic polymers (such as polyethylene glycol, polyvinyl acetate, polyvinyl alcohol, and propylene glycol).

[0009] In U.S. Patent No. 9,205,044 (incorporated herein by reference), the low water solubility of roflumilast is addressed by using an alkoxylated fat, specifically polyoxyethylene 12-hydroxystearic acid, as a co-solvent.

[0010] In EP 1511516B1, the low water solubility of roflumilast in a topical emulsion formulation (cream) is addressed by formulating with polyethylene glycol 400 (PEG 400) at a concentration exceeding 62% (w / w) while maintaining the water weight percentage below 10%.

[0011] U.S. Patent No. 7,951,398 (incorporated herein by reference) discloses a solid dispersion of roflumilast (which is specified as a poorly soluble drug), wherein roflumilast is dispersed in a matrix comprising a fatty alcohol, a triglyceride, and a fatty acid ester at a high temperature and then cooled and granulated with a hydrophilic polymer.

[0012] U.S. Patent No. 6,074,670 discloses a composition of fenofibrate (which is a poorly soluble drug) having improved dissolution. The composition comprises a hydrophilic polymer and a surfactant, wherein fenofibrate is granulated with a solution of a hydrophilic polymer (such as polyvinylpyrrolidone), which results in an improved dissolution profile.

[0013] U.S. Patent No. 8,431,154 (incorporated herein by reference) discloses a roflumilast composition having improved release and improved pharmacokinetic properties, which is granulated with an aqueous solution of polyvinylpyrrolidone (PVP) for roflumilast by preparing a solid solution or a solid dispersion.

[0014] 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 their suitable derivatives or polymers containing polyethylene glycol) to improve their solubility, dissolution rate, taste masking, bioavailability, and / or stability.

[0015] WO 2015 / 132708 discloses the use of a multi-particle composition comprising roflumilast and an inert component. The inert component is prepared by granulation and then mixed with roflumilast to obtain a composition with improved dissolution. The composition preferably comprises polyvinyl alcohol as part of the inert component.

[0016] One technique for increasing the solubility of an active ingredient is to mix an alcohol or diol with water to produce a solvent mixture with a lower polarity than water. Since pharmaceutically acceptable alcohols (such as ethanol or isopropanol) are not ideal excipients for topical application to inflamed skin diseases (because of their tendency to further irritate the inflamed skin), propylene glycol is a commonly used co-solvent in topical creams and gels for treating psoriasis or atopic dermatitis. Propylene glycol (abbreviated as 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 volatiles and / or less than 50% hydrocarbons, waxes, or polyols (definition of USP <1151> topical emulsions).

[0017] Another solvent first used in an FDA-approved topical product in 2005 is diethylene glycol monoethyl ether (trade name ), and abbreviated as DEGEE. Diethylene glycol monoethyl ether is used as a carrier and as a solubilizer in the preparation of pharmaceutical compositions (for example, see U.S. Patent No. 9,827,315; U.S. Patent Publication Nos. 2011 / 0117182 and 2017 / 0087102, incorporated herein by reference). U.S. Patent Publication No. 2019 / 009133 describes a formulation comprising roflumilast and DEGEE. SUMMARY OF THE INVENTION

[0018] The present invention relates to a topical pharmaceutical composition comprising roflumilast and a solvent that can surprisingly dissolve a large amount of roflumilast. The inventors of the present application have developed a pharmaceutical composition that can surprisingly dissolve a large amount of roflumilast relative to other commonly used solvents in approved topical pharmaceutical compositions. Although some of the solvents disclosed herein have been topically applied in commercial cosmetics, many of the solvents disclosed herein have not been used in topical drug products approved for the U.S. market to dissolve high concentrations of active ingredients. The solvents of the present invention are particularly useful when mixed with water to maintain a high level of solubility of roflumilast, which is highly insoluble in water.

[0019] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, water, and a solvent selected from 1,3 - butanediol, 1,2 - hexanediol, 1,3 - propanediol, 1,2 - pentanediol, dipropylene glycol, 2-(2 - butoxy - ethoxy)ethanol, 1,6 - hexanediol, propylene glycol methyl ethylacetate, 5 - methyl - oxolane - 2 - one, pantolactone, and combinations thereof. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of from about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in a mixture of about equimolar amounts or in a mixture with a solvent - to - water ratio of about 1:2 (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, antifoaming agents, preservatives, antioxidants, sequestering agents, stabilizers, buffers, pH adjusters, transdermal absorption enhancers, film - forming agents, dyes, pigments, and fragrances. In certain embodiments, the amount of the solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of the solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months.

[0020] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, 1,3 - butanediol, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of from about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in a mixture of about equimolar amounts or in a mixture with a solvent - to - water ratio of about 1:2 (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, antifoaming agents, preservatives, antioxidants, sequestering agents, stabilizers, buffers, pH adjusters, transdermal absorption enhancers, film - forming agents, dyes, pigments, and fragrances. In certain embodiments, the amount of the solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of the solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months.

[0021] 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 from about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present as a mixture of approximately equimolar amounts or a mixture of solvent to water in a ratio of about 1:2 (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulators, transdermal absorption enhancers, film - forming agents, dyes, pigments, and fragrances. In certain embodiments, the amount of the solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of the solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months.

[0022] 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 from about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present as a mixture of approximately equimolar amounts or a mixture of solvent to water in a ratio of about 1:2 (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulators, transdermal absorption enhancers, film - forming agents, dyes, pigments, and fragrances. In certain embodiments, the amount of the solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of the solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months.

[0023] 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 from about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in a mixture of approximately equimolar amounts or in a mixture of approximately 1:2 solvent to water (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulators, transdermal absorption promoters, film formers, dyes, pigments, and fragrances. In certain embodiments, the amount of the solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of the solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months.

[0024] 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 from about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in a mixture of approximately equimolar amounts or in a mixture of approximately 1:2 solvent to water (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulators, transdermal absorption promoters, film formers, dyes, pigments, and fragrances. In certain embodiments, the amount of the solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of the solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months.

[0025] 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 from about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present as a mixture in approximately equimolar amounts or a mixture of solvent to water in a ratio of about 1:2 (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulators, transdermal absorption promoters, film formers, dyes, pigments, and fragrances. In certain embodiments, the amount of the solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of the solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months.

[0026] 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 from about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present as a mixture in approximately equimolar amounts or a mixture of solvent to water in a ratio of about 1:2 (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulators, transdermal absorption promoters, film formers, dyes, pigments, and fragrances. In certain embodiments, the amount of the solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of the solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months.

[0027] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, propylene glycol monomethyl ether acetate, 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 a mixture of approximately equimolar amounts or in a mixture of approximately 1:2 solvent to water (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulators, transdermal absorption promoters, film formers, dyes, pigments, and fragrances. In certain embodiments, the amount of solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months.

[0028] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, 5-methyloxolane-2-one, 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 a mixture of approximately equimolar amounts or in a mixture of approximately 1:2 solvent to water (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulators, transdermal absorption promoters, film formers, dyes, pigments, and fragrances. In certain embodiments, the amount of solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months.

[0029] In certain embodiments, the topical pharmaceutical composition comprises a pharmaceutically effective amount of roflumilast, pantolactone, and water. In certain embodiments, the pharmaceutically effective amount of roflumilast is in an amount of from about 0.005% to about 2% w / w. In certain embodiments, the solvent and water are present in a mixture of approximately equimolar amounts or in a mixture of about 1:2 solvent to water (weight:weight). In certain embodiments, the pharmaceutical composition is selected from emulsions, gels, and ointments. In certain embodiments, the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulators, transdermal absorption promoters, film formers, dyes, pigments, and fragrances. In certain embodiments, the amount of the solvent present is sufficient to maintain the stability of the pharmaceutical composition when stored at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the amount of the solvent is sufficient to maintain most of the roflumilast in solution after storage at controlled room temperature and 40 °C for 1, 2, 3, 6, or 12 months. Detailed Description

[0030] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods, assay protocols, and reagents described herein, as these may vary. It should also 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, the scope of which is defined 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.

[0031] All publications, patents, and patent applications cited herein are incorporated herein by reference in their entirety unless otherwise indicated. When the same term is defined in a publication, patent, or patent application incorporated herein by reference and in the present disclosure, the definition in the present disclosure shall control. For publications, patents, and patent applications cited for describing a particular type of compound, chemistry, etc., the portions of such publications, patents, or patent applications related to such compounds, chemistry, etc. are the portions of the documents incorporated herein by reference.

[0032] 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 a single ingredient and two or more different ingredients, and "solvent" refers to a single solvent and two or more different solvents or a complex mixture of solvents.

[0033] When used in conjunction with a numerical value, the term "about" encompasses a value in a range that is 5% less than the stated value and 5% greater than the stated value.

[0034] The term "effective" refers to an amount of a compound, agent, substance, preparation, or composition that is of sufficient quantity to result in a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, or the prevention of injury or disability due to affliction with a disease. The amount can be as a single dose or according to a multiple-dose regimen, alone or in combination with other compounds, agents, or substances. A person of ordinary skill in the art can determine such an amount based on factors such as the body size of the individual, the severity of the individual's symptoms, and the specific composition or route of administration selected.

[0035] "Pharmaceutically acceptable" means that it is generally safe when administered to a human or an animal. Preferably, a pharmaceutically acceptable component is one that is approved by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia (published by the United States Pharmacopeial Convention, Inc., Rockville, Md.) or other recognized pharmacopeias for use in animals, and more particularly in humans.

[0036] A "pharmaceutical composition" according to the present invention can exist in the form of a composition in which different active ingredients and diluents and / or carriers are mixed with each other, or can take the form of a combination preparation in which the active ingredients are present in a partially or completely different form. An example of such a combination or combination preparation is a kit.

[0037] A "pharmaceutically effective amount" or "therapeutically effective amount" is an amount of a medicament or therapeutic agent that is sufficient to achieve the 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 body size of the individual receiving the therapeutic agent, and the purpose of administration. The effective amount in each individual case can be determined empirically by a person skilled in the art according to methods established in the art.

[0038] As used herein, the term "individual" or "patient" most preferably refers to a human. The term "individual" or "patient" can include any mammal that can benefit from the compounds described herein.

[0039] The term "substantially" means greater than 90%.

[0040] The term "topical" with respect to the administration of a drug or composition means the administration of such a drug or composition to the epithelial surface external to the body, including the skin or the cornea. For the purposes of this application, administration to the interior of a body orifice (such as the mouth, nose, or ear) is not considered to be topical administration.

[0041] As used herein, "treatment" of a disease or disorder refers to achieving one or more of the following: (a) reducing the severity and / or duration of the disorder; (b) limiting or preventing the development of the characteristic symptoms of the disorder being treated; (c) inhibiting the worsening of the characteristic symptoms of the disorder being treated; (d) limiting or preventing the recurrence of the disorder in a patient previously suffering from the disorder; and (e) limiting or preventing the recurrence of symptoms in a patient previously suffering from the disorder.

[0042] The abbreviation "w / w" indicates that the relative concentration of the components in the composition is "weight:weight" (i.e., the percentages refer to percentages of the total weight), rather than being based on volume or other quantities.

[0043] The present invention relates to a topical pharmaceutical composition comprising roflumilast and a solvent capable of surprisingly dissolving a large amount of roflumilast. The inventors of the present application have developed a pharmaceutical composition capable of surprisingly dissolving a large amount of roflumilast relative to other commonly used solvents in approved topical pharmaceutical compositions. The solvent of the present invention is particularly useful when mixed with water to maintain a high level of dissolution of roflumilast, which is highly insoluble in water.

[0044] Roflumilast is a compound of formula (I):

[0045]

[0046] wherein R1 is difluoromethoxy, R2 is cyclopropylmethoxy and R3 is 3,5-dichloropyridin-4-yl.

[0047] The compound has the chemical name N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide (International Nonproprietary Name (INN): roflumilast). Roflumilast can be prepared by methods known in the art, for example, as described in the '298 patent and U.S. Patent Publication No. 2014 / 0303215.

[0048] In certain embodiments, the pharmaceutical composition comprises an amount of roflumilast or a salt thereof of from about 0.005% to about 2.0% w / w, from about 0.05% to about 1.0% w / w, from about 0.05% to about 0.5% w / w or from about 0.1% to about 0.5% w / w. In certain embodiments, the pharmaceutical composition comprises 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 mixture can dissolve an amount of roflumilast of from about 0.005% to about 2%. In certain embodiments, the pharmaceutical composition comprises the N-oxide of roflumilast or a salt thereof. The amount of the N-oxide of roflumilast or a salt thereof can be the same amount as described for roflumilast.

[0049] The present invention relates to a pharmaceutical composition of roflumilast dissolved in one or more solvents and water. In certain embodiments, the solvent is selected from 1,3-butanediol, 1,2-hexanediol, 1,3-propanediol, 1,2-pentanediol (also known as pentylene glycol), dipropylene glycol, 2-(2-butoxy-ethoxy)ethanol (also known as butoxydiglycol), 1,6-hexanediol, propylene glycol monomethyl ether acetate (also known as PGMEA or 1-methoxy-2-propanol acetate), 5-methyl-oxolane-2-one (also known as γ-valerolactone), pantolactone, 1,3-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1-heptanol, 1-hexanol, 2-(2-ethoxyethoxy)ethyl 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 1,3-butanediol, 1,2-hexanediol, 1,3-propanediol, 1,2-pentanediol, dipropylene glycol, 2-(2-butoxy-ethoxy)ethanol, 1,6-hexanediol, propylene glycol monomethyl ether acetate, 5-methyl-oxolane-2-one, pantolactone, and combinations thereof. In certain embodiments, the solvent is selected from 1,2-pentanediol, 5-methyl-oxolane-2-one, 2-(2-butoxy-ethoxy)ethanol, propylene glycol monomethyl ether acetate, and 1,6-hexanediol.

[0050] The pharmaceutical composition preferably contains an amount of solvent sufficient to obtain the desired level of solubility of the active ingredient in the formulation. In certain embodiments, the pharmaceutical composition contains from about 5% to about 50% w / w, from about 10% to about 30% w / w, from about 10% to about 30% w / w, from about 15% to about 30% w / w, from about 15% to about 25% w / w, from about 20% to about 30% w / w, from about 20% to about 25% w / w, or from about 22.5% to about 27.5% w / w of solvent. In certain embodiments, the ratio of solvent to water (weight:weight) is from about 1:50 to about 20:1, from about 1:40 to about 1:1, from about 1:30 to about 1:1, from about 1:20 to about 20:1, or from 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 from about 1:15 to about 1:1, from about 1:14 to about 1:1, from about 1:13 to about 1:1, from about 1:12 to about 1:1, or from about 1:12 to 1:2 weight to weight. In certain embodiments, the ratio of solvent to water is an equimolar mixture of solvent and water.

[0051] In certain embodiments, the amount of solvent present is sufficient to maintain the stability of the pharmaceutical composition upon storage at a controlled room temperature for 1, 2, 3, 6 or 12 months. In certain embodiments, the solvent is capable of maintaining roflumilast, or at least a majority of roflumilast, in solution after storage at a controlled room temperature for 1, 2, 3, 4, 5, 6 or 12 months. 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 roflumilast in solution after storage at a controlled room temperature for 1, 2, 3, 4, 5, 6 or 12 months.

[0052] In certain embodiments, the solvent is present in an amount sufficient to maintain the stability of the pharmaceutical composition upon storage at 40 °C for 1, 2, 3, 6, or 12 months. In certain embodiments, the solvent is capable of maintaining roflumilast (or at least substantially all of the roflumilast) in solution after storage at 40 °C for 1, 2, 3, 4, 5, 6, or 12 months. 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 roflumilast in solution after storage at 40 °C for 1, 2, 3, 4, 5, 6, or 12 months.

[0053] In certain embodiments, the pharmaceutical composition is a topical formulation. The topical roflumilast pharmaceutical formulations can include those defined in the United States Pharmacopeia USP<1151> and include aerosols, foams, sprays, emulsions (which may also be referred to as creams, lotions, or ointments), gels (two-phase or single-phase), liquids, ointments, pastes, shampoos, suspensions, and systems. These are typical dosage forms containing a pharmaceutically active ingredient for topical administration to mammals, including humans.

[0054] Topical administration refers to the administration of a drug product to the skin, hair, or nails of a patient who would benefit from treatment with the drug product. Topical can also mean administration to the epithelium of a patient for local delivery. This includes administration of roflumilast via the eye, ear, oral mucosa, vaginal mucosa, rectal mucosa, or urethra. In certain embodiments, the topical pharmaceutical composition can include using the epithelium of the patient as a route of administration to obtain a therapeutic systemic level of the active ingredient. This form of topical pharmaceutical composition is commonly referred to as transdermal delivery of the therapeutically active ingredient.

[0055] The finished product is preferably in one of the following forms:

[0056] Oil-in-water emulsion: The topical product can be an emulsion comprising a discontinuous hydrophobic phase and a continuous aqueous phase, the aqueous phase comprising a solvent and water mixture and optionally one or more polar hydrophilic excipients as well as salts, surfactants, emulsifiers, and other components. These emulsions can contain water-soluble or water-swellable polymers that contribute to the stability of the emulsion. In certain embodiments, the emulsifier is a self-emulsifying wax mixture of dicetyl phosphate and ceteth-10 phosphate.

[0057] Water-in-oil emulsion: The composition can be a formulation in which roflumilast is incorporated into an emulsion comprising a continuous hydrophobic phase and an aqueous phase, the aqueous phase comprising a solvent and optionally one or more polar hydrophilic carriers as well as salts or other components. These emulsions can contain oil-soluble or oil-swellable polymers and one or more emulsifiers that contribute to the stability of the emulsion. In certain embodiments, the emulsifier is a self-emulsifying wax mixture of dicetyl phosphate and ceteth-10 phosphate.

[0058] For oil-in-water and water-in-oil emulsions, the order of addition of excipients can be important. Roflumilast can be pre-dissolved in the continuous aqueous phase containing a mixture of solvent and water. Similarly, roflumilast can be pre-dissolved in the hydrophobic discontinuous phase of the emulsion and then mixed with the solvent-water mixture and an optional hydrophilic excipient that does not contain the active ingredient. Roflumilast can be pre-dissolved in both the oil and water phases of the emulsion, or roflumilast pre-dissolved in a solvent or solvent-water mixture can be added after the emulsion has been formed. Some emulsions undergo a phase inversion within a specific temperature range during cooling of the emulsion. Thus, roflumilast can be added to a water-in-oil emulsion above the phase inversion temperature and the final pharmaceutical product is an oil-in-water emulsion at a controlled room temperature, or vice versa.

[0059] Thickened aqueous gels: These systems include a solvent-water mixture having roflumilast dissolved therein and optionally one or more polar hydrophilic carriers (such as hexylene glycol), which are thickened by a suitable natural, modified natural, or synthetic thickening agent as described below. Alternatively, the thickened aqueous gels can be thickened using a suitable polyethoxylated alkyl chain surfactant or other nonionic, cationic, or anionic system.

[0060] Thickened hydroalcoholic gels: These systems include a solvent-water-alcohol mixture having roflumilast dissolved therein and optionally one or more polar hydrophilic carriers (such as hexylene glycol) as the polar phase, which are thickened by a suitable natural, modified natural, or synthetic polymer as described below. Alternatively, the thickened hydroalcoholic gels can be thickened using a suitable polyethoxylated alkyl chain surfactant or other nonionic, cationic, or anionic system. The alcohol can be ethanol, isopropanol, or other pharmaceutically acceptable alcohol.

[0061] Hydrophilic or hydrophobic ointments: The composition is formulated with a hydrophobic matrix (such as petrolatum, thickened or gelled water-insoluble oils, etc.) and optionally a small amount of a solvent-water mixture containing dissolved roflumilast. Hydrophilic ointments generally contain one or more surfactants or wetting agents.

[0062] Solvent

[0063] In addition to the above solvents, the composition may include one or more other co-solvents to achieve the desired level of solubility of the active ingredient in the topical product. The co-solvent may also alter the skin penetration or activity of other excipients included in the formulation. Other solvents include, but are not limited to, acetone, ethanol, benzyl alcohol, butanol, diethyl sebacate, diethylene glycol monoethyl ether (DEGEE), diisopropyl adipate, dimethyl sulfoxide, ethyl acetate, isopropanol, isopropyl isostearate, isopropyl myristate, N-methylpyrrolidone, ethylene glycol, polyethylene glycol, glycerol, propylene glycol, oleic acid, limonene, eugenol, labrosol, and SD alcohol.

[0064] Moisturizer

[0065] The composition of the present invention may contain a moisturizer to increase the level of hydration. For emulsions, the moisturizer is typically a component of the discontinuous or continuous hydrophobic phase. The moisturizer may be a hydrophilic material, including a humectant, or it may be a hydrophobic material, including an emollient. Suitable moisturizers include, but are not limited to: diethylene glycol monoethyl ether (DEGEE), 1,2,6-hexanetriol, 2-ethyl-1,6-hexanediol, butylene glycol, glycerol, polyethylene glycol 200 - 8000, butyl stearate, cetearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cocoa butter, coconut oil, cyclomethicone, dimethicone, behenyl alcohol, ethylhexyl hydroxystearate, fatty acids, glyceryl isostearate, glyceryl laurate, glyceryl monostearate, glyceryl oleate, glyceryl palmitate, ethylene glycol distearate, ethylene 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.

[0066] Surfactants and Emulsifiers

[0067] The composition of the present invention may optionally contain one or more surfactants to emulsify the composition and assist in wetting the surface of the active ingredient or excipient. As used herein, the term "surfactant" refers to an amphiphilic molecule (a molecule having both covalently bonded polar and nonpolar regions) that is capable of reducing the surface tension of water and / or the interfacial tension between water and an immiscible liquid.Surfactants include, but are not limited to, sodium alkylaryl sulfonate, Amerchol-CAB, ammonium lauryl sulfate, almond oil PEG-6 ester, Arlacel, benzalkonium chloride, ceteth-6, ceteth-12, ceteth-15, ceteth-30, cetearyl alcohol / ceteareth-20, cetearyl ethylhexanoate, ceteareth-10, ceteareth-2, ceteareth-20, ceteareth-23, cholesteryl ethoxylate-24, cocamide ether sulfate, cocamine oxide, cocamidopropyl betaine, cocodiethanolamide, coco monoethanolamide, coco caprylate / caprate, disodium cocoamphodiacetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, disodium oleamide MEA sulfosuccinate, dioctyl sodium sulfosuccinate, laureth-2, laureth-23, laureth-4, lauryl 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 cocoamine, PEG-150 distearate, PEG-2 stearate, PEG-20 methyl glucose sesquistearate, 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, polyethylene glycol 7 stearate, pentaerythrityl tetracocoate, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 188, poloxamer 237, poloxamer 407, polyglyceryl-3 oleate, polyoxyethylene alcohol, polyoxyethylene fatty acid ester, polyoxyethylene 20 cetylstearyl ether, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 40 stearate, polyoxyethylene 6 and polyoxyethylene 32, polyoxyethylene glyceryl stearate, polyoxyethylene stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, PPG-26 oleate, PROMULGEN. TM12. Propylene glycol diacetate, propylene glycol dioctanoate, propylene glycol monostearate, sodium xylene sulfonate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, steareth-2, steareth-20, steareth-21, steareth-40, glyceryl tallowate, and emulsifying wax. In certain embodiments, the emulsifier is a self-emulsifying wax mixture of dicetyl phosphate and ceteth-10 phosphate.

[0068] Polymers and thickeners

[0069] For certain applications, it may be necessary 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, carboxymethyl cellulose, carboxypolymethylene, carrageenan, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, microcrystalline wax, and methyl cellulose.

[0070] Other components

[0071] The compositions of the present invention can be formulated with other components, such as fillers, carriers, and excipients commonly found in cosmetic and pharmaceutical topical products. Other components can be added to the compositions, including but not limited to defoamers, preservatives (such as parabens, benzyl alcohol, phenylmercuric salts, chlorocresol), antioxidants, chelating agents, stabilizers, buffers, pH adjusting solutions, transdermal absorption promoters, film formers, dyes, pigments, diluents, bulking agents, fragrances, and other excipients to improve stability or aesthetics.

[0072] The compositions of the present invention can be formulated with other active agents depending on the condition being treated. Other active agents include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., Aspirin, Ibuprofen, Ketoprofen, Naproxen), Apremilast, JAK inhibitors (e.g., Tofacitinib, Ruxolitinib, Oclacit), leukotriene inhibitors (such as Zileuton, Zafirlukast, Montelukast), mast cell stabilizers (e.g., Nedocromil, Cromolyn sodium, Ketotifen, Pemirolast), anthralin (anthranol), azathioprine, Tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, Propylthouracil, 6-thioguanine, Sulfasalazine, mycophenolate mofetil, fumarates, corticosteroids (e.g., Aclometasone, Amcinonide, Betamethasone, Clobetasol, Clocotolone, Mometasone, Triamcinolone, Fluocinolone, Fluocinonide, Flurandrenolide, Diflorasone, Desonide, Desoximetasone, Dexamethasone, Halcinonide, Halobetasol, Hydrocortisone, Methylprednisolone, Prednicarbate, Prednisone), adrenocorticotropic hormone, vitamin D analogs (e.g., calcipotriol, calcitriol), acitretin, Tazarotene, cyclosporine, resorcinol, colchicine, bronchodilators (e.g., β-agonists, anticholinergics, theophylline) and antibiotics (e.g., erythromycin, ciprofloxacin, metronidazole).

[0073] Administration and Dosage

[0074] The compositions of the present invention can 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, spray, cutaneous (topical), transdermal, and mucosal (e.g., sublingual, oral, nasal). In a preferred embodiment, the composition is administered topically.

[0075] 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 solutions, oral solutions).

[0076] The topical preparation containing roflumilast is applied to the skin in an amount sufficient to obtain the desired pharmacological effect, which is generally to improve the signs and / or symptoms of a medical disorder. The amount of the preparation applied can vary depending on the amount of roflumilast contained in the preparation, the concentration of roflumilast in the preparation, and the frequency of application of the preparation. Generally, the frequency of application of the preparation is from once a week to several times a day, preferably from once every other day to three times a day, and most preferably once or twice a day.

[0077] The compositions can be used in veterinary and human medicine for the treatment and prevention of all diseases considered treatable or preventable by the use of roflumilast, including but not limited to acute and chronic airway disorders such as bronchitis, allergic bronchitis, asthma, and COPD; proliferative, inflammatory, and allergic skin diseases 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, pruritus in the genital or anal area, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, endogenous and exogenous acne, rosacea, conditions based on the over-release of TNF and leukotrienes, heart diseases treatable by PDE inhibitors, inflammation of the gastrointestinal or central nervous system, eye diseases, diseases treatable by the tissue relaxation effect of PDE inhibitors, and other proliferative, inflammatory, and allergic skin diseases; and immune-mediated diseases such as arthritis, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, and psoriatic arthritis. Preferably, the compositions are used for the treatment of proliferative, inflammatory, and allergic skin diseases such as psoriasis (vulgaris), eczema, acne, lichen simplex, sunburn, pruritus, alopecia areata, hypertrophic scars, discoid lupus erythematosus, and pyodermia.

[0078] The composition may include other active agents suitable for treating a patient's condition. For example, when treating proliferative, inflammatory, and allergic skin diseases, the composition may additionally include anthralin (anthranol), azathioprine, tacrolimus, coal tar, methotrexate, methoxsalen, salicylic acid, ammonium lactate, urea, hydroxyurea, 5-fluorouracil, propylthiouracil, 6-thioguanine, sulfasalazine, mycophenolate mofetil, fumarates, corticosteroids (such as alclometasone, amcinonide, betamethasone, clobetasol propionate, clocortolone pivalate, mometasone, triamcinolone, fluocinolone acetonide, fluocinonide, fluocinolone, diflorasone diacetate, desonide, desoximetasone, dexamethasone, halcinonide, halobetasol propionate, hydrocortisone, methylprednisolone, prednicarbate, prednisone), adrenocorticotropic hormone, vitamin D analogs (such as calcipotriol, calcitriol), acitretin, tazarotene, cyclosporine, resorcinol, colchicine, adalimumab, ustekinumab, infliximab, and / or antibiotics.

[0079] Formulations for topical administration comprising roflumilast can be prepared by methods commonly used in the art of preparing pharmaceutical formulations for topical administration. 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 multiphase formulation such as an emulsion, for example, the components of the aqueous and oil phases can be separately combined and mixed until homogeneous solutions are 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 pharmaceutically active ingredients can be dissolved (the molecules are dispersed), complexed, or bound to an excipient or other active ingredient, or can be 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, for example, at an elevated temperature of 50 - 90 °C or at room temperature, i.e., 20 - 30 °C, or at a temperature between room temperature and the elevated temperature.

[0080] Example

[0081] Although various embodiments have been described herein, it should be understood that they are presented by way of example only and not by way of limitation. Accordingly, the breadth and scope of the present disclosure should not be limited by any of the above-described exemplary embodiments. Additionally, unless otherwise indicated herein or clearly contradicted by the context, the present disclosure encompasses any combination of the above elements in all possible variations thereof.

[0082] Example 1

[0083] Determine the solubility of roflumilast in various solvents. Prepare compositions of roflumilast and the solvents identified in Table 1. To prepare the compositions, add 10 g of the solvent - water mixture to a 20 mL clear glass vial. Add 0.05 g of the active pharmaceutical ingredient (API), roflumilast, to the vial. Mix the vial at an appropriate speed in a jar roller at controlled room temperature. Conduct a visual evaluation after shaking. If all of the API has dissolved, add an additional 0.05 g of API to the vial and mix further. If any API remains undissolved, record the total amount of API added to the vial. Repeat the visual inspection as necessary until no more API dissolves. For each solvent, filter the solvent mixture through a syringe filter (0.2 micron filter) to remove undissolved roflumilast, and determine the amount of dissolved roflumilast using HPLC analysis to determine the solubility. The composition of the solvent mixture is an equimolar solvent - water mixture and a 1:2 (weight:weight) solvent - water mixture. The actual solvent weights used in this study are listed in Table 1. Transcutol P, described in U.S. Patent Publication No. 2019 / 009133 and used in conjunction with roflumilast, is used as a reference in Example 1. The solubility results (μg of roflumilast dissolved per mL of mixture) are listed in Table 1.

[0084] Table 1. Solvent weights and saturation concentrations of roflumilast (μg / mL) in solvent mixtures.

[0085]

[0086]

[0087] The results in Table 1 demonstrate that the solvents studied were able to surprisingly dissolve a large amount of roflumilast.

[0088] Example 2

[0089] Prepare a topical pharmaceutical composition as shown in Table 2.

[0090] Table 2. Formulation A: 2.0% gel of roflumilast containing 2-(2-butoxy-ethoxy)ethanol

[0091] Ingredient Concentration (% w / w) Roflumilast 2.00％ 2-(2-Butoxy-ethoxy)ethanol 40.00％ Benzyl alcohol 2.00％ Dimethyl sulfoxide 20.00％ Isosorbide dimethyl ether 10.00％ Oleth-2 2.00％ Propylene glycol diacetate 5.00％ Hydroxypropyl cellulose 2.00％ Purified water Q.S. to 100

[0092] Example 3

[0093] Prepare a topical pharmaceutical composition as shown in Table 2.

[0094] Table 3. Formulation B: 0.3% cream of roflumilast containing 2-(2-butoxy-ethoxy)ethanol

[0095]

[0096] Example 4

[0097] Prepare the topical pharmaceutical composition as shown in Table 2.

[0098] Table 4. Formulation C: 0.3% cream of roflumilast containing propylene glycol monomethyl ether acetate

[0099]

[0100] Example 5

[0101] Prepare the topical pharmaceutical composition as shown in Table 2.

[0102] Table 5. Formulation D: 0.1% cream of roflumilast containing pentylene glycol (1,2-pentanediol)

[0103]

[0104] Example 6

[0105] Prepare the topical pharmaceutical composition as shown in Table 2.

[0106] Table 6. Formulation E: 0.3% cream of roflumilast containing γ-valerolactone (5-methyloxolane-2-one)

[0107]

[0108]

[0109] Example 7

[0110] Prepare the topical pharmaceutical composition as shown in Table 2.

[0111] Table 7. Formulation F: 5.0% gel of roflumilast containing γ-valerolactone (5-methyloxolane-2-one)

[0112] Ingredient Concentration (% w / w) Roflumilast 5.00％ γ-Valerolactone 40.00％ Benzyl alcohol 2.00％ Dimethyl sulfoxide 20.00％ Isosorbide dimethyl ether 10.00％ Oleth-2 2.00％ Propylene glycol diacetate 5.00％ Hydroxypropyl cellulose 2.00％ Purified water Q.S. to 100

[0113] Example 8

[0114] Prepare the topical pharmaceutical composition as shown in Table 2.

[0115] Table 8. Formulation G: 0.3% w / w cream of roflumilast containing 1,6-hexanediol

[0116]

[0117] Example 9

[0118] Prepare two preparations (Prep1 and Prep2 in Tables 9 to 15) of each of Formulations A, B, C, D, E, F, and G (as described in Examples 2 - 8). Each formulation was stored for three months at controlled room temperature and at 40 °C. Appearance, % w / w, and % LC were evaluated at the time of initial preparation (T = 0), after one month (T = 1), and after three months (T = 3).

[0119] The assay tests were performed using an HPLC method. A single - point calibration standard was prepared using a concentration of 0.1 mg / mL of roflumilast in acetonitrile. Samples were prepared according to Table 9 below by transferring the specified amount of sample to a suitable volumetric flask. The syringe was backfilled with the sample material to dispense into the flask. The flask was diluted to approximately half volume with acetonitrile and vortex - mixed for approximately 30 seconds. The flask was placed in a 60 °C water bath for 20 minutes. Then the flask was vortex - mixed for approximately 30 seconds. The flask was cooled to room temperature, diluted to volume with acetonitrile, and mixed thoroughly by vortexing and inverting. Approximately 1.5 mL of each solution was transferred to an Eppendorf microcentrifuge tube and centrifuged at 16,000 g for 5 minutes. Using a plastic transfer pipette, the supernatant was removed and placed in an autosampler vial. The method was developed using an Agilent 1200 system with a Model G1312B binary high - pressure mixing pump having a dwell volume of approximately 1.2 mL. Chromatographic parameters are listed in Table 10 and the gradient is listed in Table 11. The test results are reported in Tables 12 - 18 below.

[0120] Table 9. Sample Preparation.

[0121]

[0122] Table 10. Chromatographic Parameters.

[0123]

[0124] Table 11. Gradient.

[0125] Time (min) ％B 0.00 10 12.85 50 13.00 51 22.15 60 26.65 90 31.65 90 33.00 10 38.00 10

[0126] Table 12. Stability Data for Formulation A.

[0127]

[0128] Table 13. Stability Data for Formulation B

[0129]

[0130] Table 14. Stability Data for Formulation C

[0131]

[0132]

[0133] Table 15. Stability data of Preparation D

[0134]

[0135] Table 16. Stability data of Preparation E

[0136]

[0137] Table 17. Stability data of Preparation F

[0138]

[0139] Table 18. Stability data of Preparation G

[0140]

[0141]

[0142] The above specification has been presented for purposes of illustration and description. The specification is not intended to limit the invention to the precise forms disclosed. Those of ordinary skill in the art will appreciate that modifications and substitutions can be made to the basic inventive description.

Claims

1. A topical pharmaceutical composition comprising a pharmaceutically effective amount of roflumilast, water, and a pharmaceutically acceptable solvent selected from 1,3 - butanediol, 1,2 - hexanediol, 1,3 - propanediol, 1,2 - pentanediol, dipropylene glycol, 2-(2 - butoxy - ethoxy)ethanol, 1,6 - hexanediol, propylene glycol monomethyl ether acetate, 5 - methyl - 2 - oxolane, pantolactone, and combinations thereof.

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

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

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

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

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

7. The pharmaceutical composition according to claim 2, wherein the solvent and water are present as an approximately equimolar mixture.

8. The pharmaceutical composition according to claim 2, wherein the solvent and water are present as a mixture with a solvent - to - water ratio of approximately 1:2 (weight:weight).

9. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is selected from emulsions, gels, and ointments.

10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition further comprises at least one other component selected from humectants, surfactants or emulsifiers, polymers or thickeners, defoamers, preservatives, antioxidants, chelating agents, stabilizers, buffers, pH regulators, transdermal absorption promoters, film - forming agents, dyes, pigments, and fragrances.

11. The pharmaceutical composition according to claim 3, wherein the solvent comprises 1,3 - butanediol.

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

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

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

15. The pharmaceutical composition according to claim 3, wherein the solvent comprises dipropylene glycol.

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

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

18. The pharmaceutical composition according to claim 3, wherein the solvent comprises propylene glycol monomethyl ether acetate.

19. The pharmaceutical composition according to claim 3, wherein the solvent comprises 5-methyloxolane-2-one.

20. The pharmaceutical composition according to claim 3, wherein the solvent comprises pantolactone.

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