Roflumilast topical foam preparation

Abstract

The invention relates to a topical preparation comprising roflumilast or its pharmaceutical salt. Furthermore, the invention relates to a process for preparing the preparation and a method for using it to treat a skin disorder. The invention specifically relates to a topical foam preparation comprising roflumilast or its pharmaceutical salt.

Description

[0001] TOPICAL FOAM COMPOSITION OF ROFLUMILAST

[0002] RELATED APPLICATION

[0003] This application claims the benefit of Indian Provisional Application No. 202321073408 filed on October 27, 2023; which is hereby incorporated by reference in its entirety.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to a topical composition comprising roflumilast or a pharmaceutically acceptable salts thereof. Further the invention relates to a process of preparing the composition and its method of use for treating skin disorder. The present invention particularly relates to a topical foam composition comprising roflumilast or a pharmaceutically acceptable salts thereof.

[0006] BACKGROUND

[0007] Phosphodiesterase-4 (PDE4) inhibitors are a class of medications that play a significant role in the treatment of various inflammatory skin disorders, particularly psoriasis. Psoriasis is a chronic autoimmune skin condition characterized by the rapid turnover of skin cells, leading to the development of plaques, redness, and scaling. PDE4 inhibitors have been shown to be effective in managing psoriasis and other skin disorders. PDE4 inhibitors, by modulating inflammatory responses and immune system activity, play a valuable role in the management of psoriasis and other inflammatory skin disorders. These medications offer an additional treatment option for individuals affected by these conditions and can provide relief from the symptoms associated with chronic skin inflammation. However, like any medication, their use should be carefully monitored by healthcare professionals.

[0008] Roflumilast is a PDE4 inhibitor, and this is approved as topical cream as well as topical foam compositions for the treatment of plaque psoriasis and seborrheic dermatitis (ZORVYE®; Roflumilast 0.3% w / w). The topical foam composition of ZORVYE contains roflumilast at the concentration of 0.3%w / w, and excipients such as hexylene glycol, diethylene glycol monoethyl ether, and phosphate emulsifier.

[0009] The topical foam composition of ZORVYE is disclosed in US Patent Application No. 2023 / 0201177 wherein the formulation comprises excipients like cetearyl alcohol, dicetyl phosphate, ceteareth-10 phosphate in an oil in water emulsion and a propane / isobutane / butane propellant blend. Topical foam composition is challenging to develop due to the formulation complexity like precipitations, crystal formation, adequate foam density, foam stability, foam quality, content uniformity, inter-can variability, intra-can variability, compatibility of inactive ingredients with active substance and the like.

[0010] There is still a need to develop a stable foam composition of roflumilast. Inventors of the present invention have developed a stable foam composition of roflumilast with a foam base and a propellant that provides stable and uniform composition having good foam quality attributes. Specially the foam formulation of the present invention doesn’t contain any phosphate emulsifier and the solvent like hexylene glycol and diethylene glycol monoethyl ether.

[0011] SUMMARY OF THE INVENTION

[0012] The present invention relates to a topical foamable composition and / or topical foam comprising roflumilast or a pharmaceutically acceptable salts thereof.

[0013] The present invention relates to a topical foam composition comprising roflumilast or a pharmaceutically acceptable salts thereof, and it further comprises one or more pharmaceutically acceptable excipients thereof.

[0014] The present invention relates to a topical foamable composition comprising roflumilast or a pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the composition comprises at least about 50% of total amount of roflumilast in non-solubilized form.

[0015] In an embodiment, the present invention relates to a topical foamable composition comprising: i) roflumilast or a pharmaceutically acceptable salts thereof; ii) a foam base composition comprises a) a penetration enhancer, b) an aqueous component, c) one or more oil component(s) and one or more pharmaceutically acceptable excipients, wherein the composition comprises at least about 50% of total amount of roflumilast in non-solubilized form.

[0016] In some embodiments, the present invention relates to a topical foamable composition comprising roflumilast or a pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients, wherein the composition comprises between about 50% to about 100% of total amount of roflumilast in non-solubilized form.

[0017] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component and aqueous component.

[0018] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s).

[0019] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, an aqueous component and optionally a gelling agent(s); wherein the aqueous component is present in more than about 50% by weight of the total composition.

[0020] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, an aqueous component and optionally a gelling agent(s); wherein the aqueous component is present from about 50% to about 90% by weight of the total composition.

[0021] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, an aqueous component and optionally a gelling agent(s); wherein the aqueous component comprises at least about 50% of water by weight of the total composition.

[0022] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, an aqueous component and optionally a gelling agent(s); wherein the aqueous component comprises about 50% to about 90% of water by weight of the total composition.

[0023] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, an aqueous component and optionally a gelling agent(s); wherein at least about 50% of the total roflumilast or a pharmaceutically acceptable salts thereof is dispersed in the aqueous component.

[0024] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein at least about 70% of the total roflumilast or a pharmaceutically acceptable salts thereof is dispersed in the aqueous component.

[0025] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein at least about 90% of the total roflumilast or a pharmaceutically acceptable salts thereof is dispersed in the aqueous component.

[0026] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein at least about 99% of the total roflumilast or a pharmaceutically acceptable salts thereof is dispersed in the aqueous component.

[0027] In one embodiment, the topical composition of the present invention comprises one or more solvent(s). The solvent system according to the present invention comprises at least one solvent, and at least one co-solvent. The present invention particularly relates to a solvent system that is suitable for preparing topical composition of roflumilast. The solvent system comprises solvent and co-solvent in the weight ratio of from about 1 :0.05 to about 5: 1.

[0028] In some embodiments, the solvent and co-solvent are hydrophilic in nature.

[0029] In some embodiments, the solvent and co-solvent are lipophilic in nature.

[0030] In an embodiment, the topical foamable composition of the present invention comprises: i) roflumilast; ii) a solvent system comprising: solvent and co-solvent; and iii) one or more pharmaceutically acceptable excipient(s) thereof; wherein weight ratio between solvent and cosolvent is from about 1 :0.05 to about 5: 1.

[0031] In an embodiment, the topical foamable composition of the present invention comprises: i) roflumilast; ii) a solvent system comprising: from about 1% w / w to about 50% w / w polyethylene glycol and from about 0.05% w / w to about 10% w / w propylene glycol; and iii) one or more pharmaceutically acceptable excipient(s) thereof; wherein weight ratio between solvent and co-solvent is from about 1 :0.05 to about 5: 1.

[0032] In an embodiment, the topical foam composition of the present invention comprises: i) roflumilast; ii) a solvent system comprising: solvent and co-solvent; iii) one or more pharmaceutically acceptable excipient(s) thereof and a propellant; wherein weight ratio between solvent and co-solvent is from about 1 :0.05 to about 5: 1.

[0033] In one embodiment, the topical foamable composition of the present invention is physically and / or chemically stable at room temperature at least for 7 days.

[0034] In another embodiment, the topical foamable composition of the present invention comprises at least one excipient selected from emulsifying agent, stabilizing agent, pH modifying agent, solvent, co-solvent, penetration enhancer, gelling agent, thickening agent, preservative and any combination of any of the foregoing.

[0035] In an embodiment, the present invention related to a method of treating a skin disorder in a subject, the said method comprises topically administering a foamable composition comprising from about 0.01%w / w to about 2% w / w of roflumilast or a pharmaceutically acceptable salts thereof; wherein the method involves administering the topical composition once or twice daily, and the composition further comprises a solvent and co-solvent in a ratio of from about 1 :0.05 to about 5: 1.

[0036] In some embodiments, the skin disorder is any skin disorder that are treatable by Phosphodiesterase 4 inhibitor(s) otherwise known as PDE4 inhibitors. The skin disorder is selected from psoriasis, acne, rosacea, eczema, atopic dermatitis, seborrheic dermatitis and the like.

[0037] In a specific embodiment, the skin disorder is psoriasis.

[0038] In a specific embodiment, the skin disorder is plaque psoriasis.

[0039] In a specific embodiment, the skin disorder is atopic dermatitis.

[0040] In a specific embodiment, the skin disorder is seborrheic dermatitis.

[0041] DETAILED DESCRIPTION

[0042] Disclosed herein are detailed descriptions of specific aspects of the present invention of a topical composition in the form of a cream, ointment, gel, lotion, emulgel, emulsion, aerosol foam, solution, spray, suspension, swab, sponge, powder or paste. It will be understood that the disclosed embodiments are merely examples of the way in which certain aspects of the application can be implemented and do not represent an exhaustive list of all of the ways the application may be embodied.

[0043] Definitions:

[0044] The terms “active” and “active agent” as used herein refers to a therapeutically active agent used in the treatment of a disease or disorder. For example, an active agent may be roflumilast or its pharmaceutically acceptable salts. The term “subject” as used herein refers to human subject or an animal including mammals (such as monkeys, guinea pig, domestic pets, for instance cats and dogs).

[0045] As used herein, the term “about” when used to refer to weight % in a composition or other numeral amounts means plus or minus up to 20% (alternatively, up to 10% or 5%) of the reported value.

[0046] The term “aqueous component” as used herein refers an aqueous portion of the biphasic emulsion composition that comprises water and / or one or more excipients that are hydrophilic in nature, and the aqueous component can be a continuous phase or discontinuous phase. For example, the aqueous phase comprises water in an amount of more than 50% w / w based on total weight of the composition and particularly in an amount of more than 60% w / w based on total weight of the composition.

[0047] The term “solvent system” as used herein refers to one or more pharmaceutically acceptable solvents that can solubilize roflumilast completely in the room temperature. In some embodiments, the solvent system comprises more than one solvents that is selected from acetone, ethanol, butyl alcohol, ethyl acetate, isopropyl alcohol, isopropyl isostearate, glycerol, polyethylene glycol, diethylene glycol monoethyl ether, benzyl alcohol, dimethyl isosorbide, oleyl alcohol, oleic acid, stearic acid, isostearic acid, propylene glycol monolaurate, propylene glycol monocaprylate, capryl ocaproyl macrogol-8 glyceride, octyldodecanol, diethyl sebacate, diisopropyl adipate, phenoxyethanol, lauroglycol, benzyl alcohol, PPG 11 sterayl ether, polyethylene glycol, propylene glycol, isopropyl alcohol, C1-C5 lower alcohol (linear or branched), sodium cetostearyl sulfate.

[0048] In some embodiments, the solvent system comprises co-solvent. The term “co-solvent” as used herein refers to a chemical substance that provides enhanced solubility to the active together with solvent. Co-solvents can significantly increase the solubility of a solute in a solvent, allowing for the dissolution of substances that might be sparingly soluble or insoluble in the pure solvent. Further, co-solvent(s) are chosen to be compatible with the active and solvent.

[0049] The term “emulsifier” as used herein refers to an amphiphilic substance and is a substance or compound that is added to a mixture of immiscible substances, such as oil and water, to facilitate the formation and stabilization of an emulsion. Emulsions are colloidal systems in which tiny droplets of one liquid (the dispersed phase) are dispersed within another liquid (the continuous phase), and they are typically immiscible or do not readily mix on their own. Emulsifying agents play a crucial role in preventing the separation of these immiscible phases and maintaining the stability of the emulsion. The term “emulsifier” can be interchangeably used with “emulsifying agent” and / or “surfactant”. The emulsifying agent that can be referred as a foaming agent. If an emulsifier or surfactant acts as a foaming agent, that will have higher HLB value. For example, sodium lauryl sulfate is a surfactant that have HLB i.e., ~40.

[0050] The term “pharmaceutically acceptable excipient(s)” as used herein refers to one or more excipients are selected from, but not limited to, solvent, emulsifying agent, coemulsifying agent, gelling agent, polymer, foaming agent, foam adjuvants, thickening agent, viscosity-enhancing agent, cosolvent, emollient, pH adjusting agent, penetration enhancing agent, antioxidant, preservative, water-miscible substance(s), water-immiscible substance(s), and any combination of any of the foregoing thereof.

[0051] The term “skin disorder” as used herein refers to any skin disorder selected from, but not limited to, acne vulgaris, psoriasis, atopic dermatitis, facial mottle, hyperpigmentation, hypopigmentation, photoaging, papule, pustule, nodulocystic acne lesion (both inflamed and non-inflamed), sebaceous gland disorder(s), hair follicle disorder(s), hirsutism, and androgenetic alopecia and lentigo. In some embodiments, the skin disorder is plaque psoriasis.

[0052] The term “Roflumilast” as used herein refers to "N-(3,5-dichloropyridin-4-yl)-3- cyclopropylmethoxy-4-difluoromethoxybenzamide, and The term “Roflumilast” encompasses active metabolite of roflumilast such as roflumilast N-oxide (chemically known as "N-(3,5- dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzamide”) and / or roflumilast and its pharmaceutically acceptable salts. The term “Roflumilast” should be interpreted broadly to cover any salts of roflumilast, physiologically active related substance of roflumilast and / or active metabolites.

[0053] The term “solubilized” as used herein refers to roflumilast is in completely solubilized state in the composition.

[0054] The term “non-solubilized” as used herein refers to roflumilast is in completely suspended state in the composition, and the suspended form of roflumilast in crystal form. The non-solubilized form of roflumilast refers to the crystalline state of roflumilast within a pharmaceutical composition during its shelf life. In its non-solubilized form, it exists as solid crystalline particles within the composition, rather than being fully dissolved or solubilized in the liquid or matrix of the formulation.

[0055] The term “substantially in non-solubilized state” as used herein refers to a composition that contains more than 70% of total amount of the roflumilast particles are in non-solubilized state, i.e., suspended. The substantially non-solubilized can be defined 7:3 i.e., 70% of total amount of roflumilast are in suspended state, and the rest of the amount of roflumilast may be in solubilized state.

[0056] The “weight ratio” or “percentage weight ratio” between non-solubilized fraction to solubilized fraction of total amount of roflumilast is starting from 50% fraction is nonsolubilized and 50% fraction is solubilized, 60% fraction is non-solubilized and 40% fraction is solubilized, 70% fraction is non-solubilized and 30% fraction is solubilized, 80% fraction is non-solubilized and 20% fraction is solubilized, 90% fraction is non-solubilized and 10% fraction is solubilized, 95% fraction is non-solubilized and 5% fraction is solubilized, 100% fraction is non-solubilized and 0% fraction is solubilized. This ratio can be expressed as following: 1 : 1, 3:2, 2: 1, 3: 1, 4: 1, 9: 1, 1 :0.

[0057] For example, the non-solubilized fraction to solubilized fraction in the foamable composition containing 3mg roflumilast in each 1000 mg of composition can be expressed as follows: 1 : 1 to 100:0. The ratio of 1 : 1 to 100:0 covers non-solubilized fraction to solubilized fraction ratio of 50% non-solubilized fraction to 50% solubilized fraction and 100% non- solubilized fraction to 0% solubilized fraction. The ratio of non-solubilized to solubilized fractions, ranging from 1 : 1 (50%: 50%) to 100:0 (100%: 0%), which are individually selected from about 1 : 1, about 2: l, about 3: l, about 4: l, about 5: 1, about 6: l, about 7: 1, about 8: 1, about 9: 1, and about 10: 1, about 11 : 1, about 12: 1, about 13: 1, about 14: 1, about 15: 1, about 20: 1, about 25: 1, about 30: 1, about 35: 1, about 50: 1, about 60: 1, about 70: 1, about 80: 1, about 90: 1, about 95: 1, about 100: 1, marking a non-solubilized fraction nearing about 99% or higher. The percentage weight ratio can further be in a ratio like about 120: 1, about 150: 1, about 200: 1, about 300: 1, about 400: 1, about 500: 1, about 750:1, about 900: 1. The ratio of non-solubilized to solubilized is 100:0, where the non-solubilized fraction is 100% and solubilized is completely absent. The various ratio in which the particles of roflumilast is present in non-solubilized state. It should be understood that particles of roflumilast is substantially in non-solubilized state.

[0058] The particles of roflumilast is present in the composition is partially solubilized or fully non-solubilized state. The non-solubilized roflumilast particles are having irregular shape.

[0059] The term “foamable” as used herein refers to a topically administrable composition that is not in the form of a foam and these compositions can be administered to a subject as a regular topical product such as cream. Particularly, the foamable composition is used herein to denote topical composition, ointment and the like that are dispensed without propellant, however, if added to propellant and dispensed using suitable actuator, these foamable compositions will form a foam. The term “foam” as used herein refers to a composition which is in the form of a foam and / or foamable composition that is dispensed with suitable propellant. The topical composition according to the present invention can either be a foamable composition, foamable cream composition (i.e., oil-in-water emulsion), and / or aerosol foam composition which is dispensed with propellant.

[0060] The “foam base” as used herein refers to a carrier composition in which active is solubilized or dispersed or suspended. The foam base composition has a tendency of forming a foam when expelled using a propellant. The foam base composition can be alternatively called as a carrier composition, foamable carrier. The foam base composition comprises at least two component s) such as an aqueous component and an oil component. The foam base composition additionally comprises an excipient that have tendency of forming body to the composition such as a gelling agent.

[0061] The term “solvent” or “co-solvent” as used herein refers to an inactive excipient that can solubilize the roflumilast and / or can aid in permeation of roflumilast in the skin layers. The solvent, co-solvent, permeation enhancer, or penetration enhancer can be used interchangeably in the description of the present invention.

[0062] Topical Foamable / Foam composition:

[0063] The present invention relates to a topical foamable composition comprising roflumilast or a pharmaceutically acceptable salts thereof. Particularly, topical compositions of present invention are foamable composition.

[0064] The present invention relates to a topical foam composition comprising roflumilast or a pharmaceutically acceptable salts thereof, and it further comprises one or more pharmaceutically acceptable excipients thereof.

[0065] The present invention relates to a topical foamable composition comprising roflumilast or a pharmaceutically acceptable salts thereof, wherein the composition comprises at least about 50% of total amount of roflumilast in non-solubilized form.

[0066] In some embodiments, the present invention relates to a topical foamable composition comprising roflumilast or a pharmaceutically acceptable salts thereof, wherein the composition comprises between about 50% to 99% of total amount of roflumilast in non-solubilized form.

[0067] In some embodiments, the present invention relates to a topical foamable composition comprising roflumilast or a pharmaceutically acceptable salts thereof, wherein the composition comprises between about 99% of total amount of roflumilast in non-solubilized form. In some embodiments, the present invention relates to a topical foamable composition comprising roflumilast or a pharmaceutically acceptable salts thereof, wherein the composition comprises about 99.9% of total amount of roflumilast in non-solubilized form.

[0068] In some embodiments, the present invention relates to a topical foamable composition comprising roflumilast or a pharmaceutically acceptable salts thereof, wherein the composition comprises 100% of total amount of roflumilast in non-solubilized form.

[0069] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component and aqueous component.

[0070] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s).

[0071] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein the aqueous component comprises more than about 50% by weight of the total composition.

[0072] In some embodiments, the aqueous component comprises water more than about 55% by weight of the total composition and one or more hydrophilic excipient(s). In some embodiment, water is present in the aqueous component is more than 50% by weight of the total composition, 55% by weight of the total composition, 60% by weight of the total composition, 65% by weight of the total composition, 70% by weight of the total composition, 75% by weight of the total composition, 80% by weight of the total composition, 85% by weight of the total composition, 90% by weight of the total composition.

[0073] In a specific embodiment, the water concentration in the final composition is selected from about 51.35% by weight of the total composition or about 52% by weight of the total composition or about 54.6% by weight of the total composition or about 55% by weight of the total composition or about 62% by weight of the total composition or about 70% by weight of the total composition or about 74.5% by weight of the total composition or about 75% by weight of the total composition or about 85% by weight of the total composition or about 85.5% by weight of the total composition or about 90% by weight of the total composition. In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein the aqueous component is present from about 50% to about 99.5% by weight of the total composition.

[0074] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein the aqueous component comprises at least about 50% of water.

[0075] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein the aqueous component comprises about 50% to about 99.5% of water.

[0076] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein at least about 50% of the total amount of roflumilast or a pharmaceutically acceptable salts thereof is in nonsolubilized form in the aqueous component.

[0077] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein at least about 70% of the total amount of roflumilast or a pharmaceutically acceptable salts thereof is in nonsolubilized form in the aqueous component.

[0078] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein at least about 90% of the total amount of roflumilast or a pharmaceutically acceptable salts thereof is in nonsolubilized form in the aqueous component. In one embodiment, the topical foamable composition of the present invention comprises one or more solvent(s). The solvent system according to the present invention comprises at least one solvent, and at least one co-solvent. The present invention particularly relates to a solvent system that is suitable for preparing topical composition of roflumilast. The solvent system comprises solvent and co-solvent in the weight ratio of from about 1 :0.05 to about 5: 1.

[0079] In one embodiment, the solvent and co-solvents interchangeably termed as permeation enhancer or penetration enhancer. The penetration or permeation enhancers are lipophilic in nature.

[0080] In an embodiment, the topical foamable composition of the present invention comprises: i) roflumilast; ii) a solvent system comprising: solvent and co-solvent; and iii) one or more pharmaceutically acceptable excipient(s) thereof; wherein weight ratio between solvent and cosolvent is from about 1 :0.05 to about 5: 1.

[0081] In an embodiment, the topical foamable composition of the present invention comprises: i) roflumilast; ii) a solvent system comprising: from about 1% w / w to about 50% w / w polyethylene glycol and from about 0.05% w / w to about 10% w / w propylene glycol; and iii) one or more pharmaceutically acceptable excipient(s) thereof; wherein weight ratio between solvent and co-solvent is from about 1 :0.05 to about 5: 1.

[0082] In some embodiments, the topical foamable composition of the present invention is dispensed in a pump. The topical foamable composition is expelled from the aerosol valve as a foam.

[0083] In some pharmaceutical formulations, especially suspensions or emulsions, active pharmaceutical ingredients like roflumilast can exist as crystalline particles that are not fully dissolved. These particles may remain in a suspended or dispersed state within the composition. This crystalline form can impact the stability, release rate, and bioavailability of the drug, which is an important consideration in the development and formulation of pharmaceutical products.

[0084] Understanding the non-solubilized form of a drug like roflumilast is essential for ensuring that the drug maintains its desired properties and effectiveness throughout its shelf life. The composition of the present invention is formulated in such a way that crystalline particles of roflumilast is suspended in the composition without causing physical instability. In other words, physical stability herein means the crystalline particles of the roflumilast may exist in the composition without changing the size of the particle during shelf life, without causing agglomeration during shelflife, without causing precipitation during shelf life, without change in color of the composition, without phase separation during shelf life and the like. The particle size as used herein generally expressed as D90 value which is generally 90% of the particles or crystals in the suspension are less than X microns the D90 is X microns. In other words, the great majority of particles are smaller than Y microns.

[0085] In one or more embodiments, the D90 of the particles is in the range of about 1 micron to about 50 microns.

[0086] In some embodiments, the D90 particle size of roflumilast or its pharmaceutically acceptable salts from about 10 microns to about 40 microns.

[0087] In a preferred embodiment, the D90 particle size of roflumilast or its pharmaceutically acceptable salts from about 20 microns to about 40 microns.

[0088] In a preferred embodiment, the D90 particle size of roflumilast or its pharmaceutically acceptable salts from about 1 micron to about 10 microns.

[0089] In a preferred embodiment, the D90 particle size of roflumilast or its pharmaceutically acceptable salts is about 3 microns.

[0090] In a preferred embodiment, the D90 particle size of roflumilast or its pharmaceutically acceptable salts is about 5 microns.

[0091] In a preferred embodiment, the D90 particle size of roflumilast or its pharmaceutically acceptable salts is about 7 microns.

[0092] In a preferred embodiment, the D90 particle size of roflumilast or its pharmaceutically acceptable salts is about 9 microns. The D90 particle size of the roflumilast can be selected from about 1.0 microns, about 1.5 microns, about 2.0 microns, about 2.5 microns, about 3.0 microns, about 3.5 microns, about 4.0 microns, about 4.5 microns, about 5.0 microns, about 5.5 microns, about 6.0 microns, about 6.5 microns, about 7.0 microns, about 7.5 microns, about 8.0 microns, about 8.5 microns, about 9.0 microns, about 9.5 microns, about 10.0 microns.

[0093] In some embodiments, morphology of the particle of roflumilast suspended in the composition can be measured using optical microscopy or scanning electron microscopy by the method that are well known. The particle of roflumilast are irregular shape. The particles of the roflumilast have an average length from about 1 micron to 60 microns and an average breath from about 1 micron to about 60 microns. The particles of roflumilast in the composition have a surface area of from about 1 pm2to about 7000 pm2. The average surface area of the particles of roflumilast is from about 10 pm2to 5000 pm2or from about 20 pm2to about 500 pm2.

[0094] In some embodiments, the topical foamable composition comprises i) from about 0.001% w / w to about 3% w / w of roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foamable base; wherein the foamable base is biphasic system comprises one or more oil component, aqueous component and optionally a gelling agent(s); wherein the average surface area of particles of roflumilast is from about 20 pm2to 500 pm2.

[0095] In a preferred embodiment, the topical foamable composition comprising: i) roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foam base; wherein the composition comprises: a) one or more oil components less than about 20% w / w; b) at least one emulsifying agent less than about 10% w / w; c) an aqueous component of at least about 40% w / w; and d) optionally comprises a solvent and / or a co-solvent is present up to 15% w / w; wherein the foamable composition is free of hexylene glycol and di ethylene glycol monoethyl ether and the average surface area of particles of roflumilast in the range of from about 20pm2to about 500 pm2and D90 particle size of the roflumilast particle is less than about 20pm2.

[0096] In a preferred embodiment, the average surface area of particles of roflumilast is selected from about 20 pm2, about 30 pm2, about 40 pm2, about 50 pm2, about 60 pm2, about 70 pm2, about 80 pm2, about 90 pm2, about 100 pm2, about 110 pm2, about 120 pm2, about 130 pm2, about 140 pm2, about 150 pm2, about 160 pm2, about 170 pm2, about 180 pm2, about 190 pm2, about 200 pm2, about 210 pm2, about 220 pm2, about 230 pm2, about 240 pm2, about 250 pm2, about 260 pm2, about 270 pm2, about 280 pm2, about 290 pm2, about 300 pm2, about 310 pm2, about 320 pm2, about 330 pm2, about 340 pm2, about 350 pm2, about 360 pm2, about 370 pm2, about 380 pm2, about 390 pm2, about 400 pm2, about 410 pm2, about 420 pm2, about 430 pm2, about 440 pm2, about 450 pm2, about 460 pm2, about 470 pm2, about 480 pm2, about 490 pm2, about 500 pm2.

[0097] The term “HLB” as used herein refers to Hydrophilic-Lipophilic Balance (HLB). These values are usually greater than 10 and can range up to 20 or even higher. Emulsifying agents with higher HLB values are more hydrophilic, meaning they have a stronger affinity for water. Lipophilic emulsifying agents typically have low HLB (Hydrophilic-Lipophilic Balance) values. These values are generally less than 10 and often closer to 1 or 2. Emulsifying agents with low HLB values have a stronger affinity for oils and lipids.

[0098] The present invention relates to a topical foamable composition comprising roflumilast or a pharmaceutically acceptable salts thereof.

[0099] The present invention relates to a topical foamable composition comprising roflumilast or a pharmaceutically acceptable salts thereof, and it further comprises one or more pharmaceutically acceptable excipients thereof.

[0100] In one embodiment, the topical foamable composition of the present invention comprises one or more solvent(s). In another embodiment, the topical foamable composition of the present invention comprises at least one solvent and at least one co-solvent.

[0101] In one embodiment, the topical foamable composition of the present invention is physically and / or chemically stable at room temperature at least for 7 days, at least for 30 days, at least for 3 months, at least for 6 months or at least for 12 months.

[0102] In another embodiment, the topical foamable composition of the present invention comprises at least one excipient selected from emulsifying agent, stabilizing agent, pH modifying agent, solvent, co-solvent, penetration enhancer, gelling agent, thickening agent, preservative and any combination of any of the foregoing.

[0103] In one embodiment, the present invention relates to a topical foamable composition comprising i) roflumilast or a pharmaceutically acceptable salts thereof, and ii) an emulsion composition; wherein the emulsion composition comprises at least one aqueous phase, at least one oil phase, at least one emulsifying agent, and at least one solvent.

[0104] In some embodiments, the topical foamable composition comprises oil-in-water emulsion, water-in-oil emulsion, water-in-oil-in-water any combination of any of the foregoing.

[0105] In some embodiments, the roflumilast or a pharmaceutically acceptable salts thereof may be in solubilized form, or in partially solubilized form, or in insoluble form.

[0106] In some embodiments, the roflumilast or a pharmaceutically acceptable salts thereof is solubilized at least 90% of total roflumilast concentration.

[0107] In some embodiments, the roflumilast or a pharmaceutically acceptable salts thereof is solubilized at least 95% of total roflumilast concentration.

[0108] In some embodiments, the roflumilast or a pharmaceutically acceptable salts thereof is fully solubilized in the composition.

[0109] In some embodiments, the roflumilast or a pharmaceutically acceptable salts thereof is partially solubilized in the composition.

[0110] In some embodiments, the roflumilast or a pharmaceutically acceptable salts thereof is solubilized in the composition from about 1% to about 50% of total roflumilast concentration.

[0111] In some embodiments, the roflumilast or a pharmaceutically acceptable salts thereof is solubilized in the composition from about 1% to about 50% of total roflumilast concentration and remaining concentration of roflumilast is in suspended form.

[0112] In some embodiments, the roflumilast or a pharmaceutically acceptable salts thereof is in completely non-solubilized form.

[0113] In some embodiments, the roflumilast or a pharmaceutically acceptable salts thereof may be present in aqueous phase or in oil phase or dispersed in both aqueous and oil phase. In one embodiment, the present invention relates to a topical foamable composition comprising: i) roflumilast or a pharmaceutically acceptable salts thereof; ii) a solvent system comprising at least one solvent and a co-solvent; iii) an emulsion composition comprising a) aqueous phase; b) an oil phase; and c) an emulsifying agent; wherein the roflumilast or a pharmaceutically acceptable salts thereof is present in solubilized form in the composition.

[0114] In some embodiments, the topical foamable composition comprises a solvent and a cosolvent in the weight ratio of from about 1 :0.05 to about 5:1. Preferably the weight ratio between solvent and co-solvent in the composition is selected from 1:0.05, 1:0.06, 1:0.07, 1:0.08.1:0.09, 1:0.1, 1:0.25, 1:0.5, 1:1, 1.5:0.5, 1.5:1, 2:0.5, 2:1, 2.5:0.5, 2.5:1, 3:0.5, 3:1, 3.5:0.5, 3.5:1, 4:0.5, 4:1, 4.5:0.5, 4.5:1, 5:0.5, 5:1.

[0115] In some embodiments, the topical foamable composition comprising: i) roflumilast or a pharmaceutically acceptable salts thereof; ii) a solvent system comprising at least one solvent and a co-solvent; iii) an emulsion composition comprising a) aqueous phase; b) an oil phase; and c) an emulsifying agent; wherein the roflumilast or a pharmaceutically acceptable salts thereof is present in partially solubilized form in the composition and the topical composition comprises a solvent and a co-solvent in the weight ratio of from about 1 :0.05 to about 5:1.

[0116] In some embodiments, the topical foamable composition comprises roflumilast or a pharmaceutically acceptable salts thereof and a solvent system. The solvent system is essential to keep the roflumilast in solubilized form or suitably suspended without any change during the shelflife. The weight ratio between roflumilast and solvent system is 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:95, 1:100, 1:105, 1:110, 1:115, 1:120, 1:125, 1:130, 1:135, 1:140, 1:145, 1:150, 1:155, 1:160, 1:165, 1:170, 1:175, 1:180, 1:185, 1:190, 1:195, 1:200, 1:205, 1:210, 1:215, 1:220, 1:225, 1:230, 1:235, 1:240, 1:245, 1:250.

[0117] In some embodiments, the solvent system of the present invention is substantially free of hexylene glycol.

[0118] In some embodiments, the solvent system of the present invention is free of hexylene glycol.

[0119] In some embodiments, the solvent system of the present invention is substantially free of diethylene glycol monoethyl ether.

[0120] In some embodiments, the solvent system of the present invention is free of diethylene glycol monoethyl ether.

[0121] In some embodiments, the topical foamable composition comprises additionally one or more excipients that are assisting in formation of foam. The carrier, i.e., foam base composition of the present invention is prepared in order to suit for foam composition as well as cream composition. The carrier composition containing one or more emulsifying agent(s), and along with foam adjuvant(s) makes the composition as foamable composition.

[0122] The foamable composition can be administered topically on the subject’s skin as foam composition.

[0123] In one embodiment, the present invention relates to a topical foamable composition comprising: i) roflumilast or a pharmaceutically acceptable salts thereof; ii) a solvent system comprising at least one solvent and a co-solvent; iii) an emulsion composition comprising a) aqueous phase; b) an oil phase; and c) an emulsifying agent; wherein the composition comprises at least about 95% of the total roflumilast in solubilized form.

[0124] In one embodiment, the topical foamable composition comprising: i) from about 0.01%w / w to about 2% w / w of roflumilast or a pharmaceutically acceptable salts thereof; ii) a solvent system comprising at least two agents selected from polyethylene glycol, diethylene glycol monoethyl ether, dimethyl isosorbide, oleyl alcohol, oleic acid, propylene glycol monolaurate, propylene glycol monocaprylate, caprylocaproyl macrogol-8 glyceride, octyl dodecanol, diethyl sebacate, diisopropyl adipate, phenoxyethanol, lauroglycol, diethyl sebacate, capryl ocacroyl caprate, isosteric acid, phenoxyethanol, benzyl alcohol, propylele carbonate, dimethyl sulfoxide, benzyl alcohol, PPG 11 sterayl ether, polyethylene glycol, propylene glycol, isopropyl alcohol, C1-C5 lower alcohol (linear or branched), sodium cetostearyl sulfate; iii) an emulsion composition comprising a) aqueous phase; b) an oil phase; and c) an emulsifying agent; wherein the roflumilast or a pharmaceutically acceptable salts thereof is present in partially solubilized form in the composition.

[0125] In one embodiment, the present invention relates to a topical foamable composition comprising: i) from about 0.01%w / w to about 2% w / w of roflumilast or a pharmaceutically acceptable salts thereof; ii) a solvent system comprising at least two agents selected from polyethylene glycol, diethylene glycol monoethyl ether, dimethyl isosorbide, oleyl alcohol, oleic acid, propylene glycol monolaurate, propylene glycol monocaprylate, caprylocaproyl macrogol-8 glyceride, octyl dodecanol, diethyl sebacate, diisopropyl adipate, phenoxyethanol, lauroglycol, diethyl sebacate, capryl ocacroyl caprate, isosteric acid, phenoxyethanol, benzyl alcohol, propylele carbonate, dimethyl sulfoxide, benzyl alcohol, PPG 11 sterayl ether, polyethylene glycol, propylene glycol, isopropyl alcohol, C1-C5 lower alcohol (linear or branched), sodium cetostearyl sulfate; iii) an emulsion composition comprising a) aqueous phase; b) an oil phase; and c) an emulsifying agent; wherein the composition comprises at least about 99% of the total roflumilast in solubilized form. In one embodiment, the present invention relates to a topical foamable composition comprising: i) from about 0.01%w / w to about 2% w / w of roflumilast or a pharmaceutically acceptable salts thereof; ii) a solvent system comprising polyethylene glycol and at least one co-solvent selected from the group comprising a) diethylene glycol monoethyl ether, dimethyl isosorbide, oleyl alcohol, oleic acid, propylene glycol monolaurate, propylene glycol monocaprylate, caprylocaproyl macrogol-8 glyceride, octyldodecanol, diisopropyl adipate, phenoxyethanol, lauroglycol, diethyl sebacate, caprylocacroyl caprate, isosteric acid, phenoxyethanol, benzyl alcohol, propylele carbonate, dimethyl sulfoxide, benzyl alcohol, PPG 11 sterayl ether, polyethylene glycol, propylene glycol, isopropyl alcohol, C1-C5 lower alcohol (linear or branched), sodium cetostearyl sulfate; iii) an emulsion composition comprising a) aqueous phase; b) an oil phase; and c) an emulsifying agent; wherein the composition comprises at least about 99% of the total roflumilast in solubilized form.

[0126] In one of the preferred embodiments, the solvent according to the present invention have low vapor pressure that is vapor pressure below 1 mmHg (about 0.133 kPa).

[0127] In some embodiments, the topical foamable composition comprising a solvent system which includes a combination of hydrophilic solvent as well as lipophilic solvent.

[0128] In some embodiment, the topical composition comprising a solvent system from about 10% w / w to about 99% w / w.

[0129] In a specific embodiment, the topical foamable composition of the present invention is topical foam.

[0130] In a specific embodiment, the topical foamable composition of the present invention is oil-in-water emulsion.

[0131] In a specific embodiment, the topical foamable composition of the present invention provides spreadable foam at the time of application.

[0132] In an embodiment, the topical foamable composition of the present invention comprises i) from about 0.01%w / w to about 2% w / w of roflumilast or a pharmaceutically acceptable salts thereof; ii) an emulsifying agent; and iii) a solvent system; wherein the composition is substantially free of phosphate emulsifier(s).

[0133] In some embodiments, the emulsifying agent comprises combination of hydrophilic and lipophilic emulsifying agent.

[0134] In some embodiments, the emulsifying agent comprises a combination of hydrophilic emulsifying agent, lipophilic emulsifying agent, and one or more adjuvant.

[0135] In some embodiments, the emulsifying agent according to the present invention does not comprise phosphate ester emulsifiers. These phosphate emulsifiers are less preferable due to the cost of development, compatibility and other factors, as compared to other emulsifying agent(s).

[0136] In some embodiments, the emulsifying agent(s) is selected based on RHLB based on other excipients in the composition. For example, RHLB of the present invention is between 5 to 20. The emulsifying agent is a combination of hydrophilic emulsifying agent and lipophilic emulsifying agent.

[0137] The emulsifying agent is selected from, but not limited to, 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, choleth-24, cocamide ether sulfate, cocamine oxide, coco betaine, coco di ethanol ami de, coco monoethanolamide, coco-caprylate / caprate, disodium cocoamphodi acetate, disodium laureth sulfosuccinate, disodium lauryl sulfoacetate, disodium lauryl sulfosuccinate, disodium oleamido monoethanolamine sulfosuccinate, docusate sodium, laureth-2, laureth-23, laureth-4, lauric di ethanol ami de, lecithin, mehoxy PEG-16, methyl gluceth-10, methyl gluceth-20, methyl glucose sesqui stearate, 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 sesqustearate, 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, pentaerythritol cocoate, pol oxamer 124, pol oxamer 181, pol oxamer 182, poloxamer 188, poloxamer 237 poloxamer 407, polyglyceryl-3 oleate, polyoxyethylene alcohols, polyoxyethylene fatty acid esters, polyoxyl 20 cetostearyl ether, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polyoxyl 6 and polyoxyl 32, polyoxyl glyceryl stearate, polyoxyl stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, PPG-26 oleate, PROMULGEN™ 12, propylene glycol diacetate, propylene glycol dicaprylate, glyceryl monostearate, propylene glycol monostearate, sodium xylene sulfonate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, steareth-2, steareth-20, steareth-21, steareth-40, tallow glycerides, and emulsifying wax.

[0138] In some embodiments, the emulsifying agent is in the range of from about 0% w / w to about 25% w / w.

[0139] In some embodiments, the emulsifying agent is in the range of from about 0.1% w / w to about 25% w / w. In some embodiments, the emulsifying agent is in the range of from about 0.5% w / w to about 22% w / w.

[0140] In some embodiments, the emulsifying agent is in the range of from about 1% w / w to about 20% w / w.

[0141] In some embodiments, the emulsifying agent is less than 10% w / w based on the total weight of the composition.

[0142] The topical composition of the present invention further contains one or more excipients selected from, but not limited to, co-emulsifying agent, gelling agent, polymer, thickening agent, viscosity-enhancing agent, cosolvent, emollient, pH adjusting agent, penetration enhancing agent, antioxidant, preservative, water-miscible substance(s), water-immiscible substance(s), and any combination of any of the foregoing thereof.

[0143] The topical composition of the present invention comprises one or more oil component.

[0144] In some embodiments, the oil component present in the topical foamable composition is from about 1% w / w to about 45% w / w.

[0145] In some embodiments, the oil component present in the topical foamable composition is from about 1% w / w to about 40% w / w.

[0146] In some embodiments, the oil component present in the topical foamable composition is from about 1% w / w to about 35% w / w.

[0147] In some embodiments, the oil component present in the topical foamable composition is from about 1% w / w to about 30% w / w.

[0148] In some embodiments, the oil component is selected from one or more excipient(s) selected from mineral oil, fatty acid, fatty alcohol, esters of fatty acid(s), PEG esters / ethers of fatty alcohol, vegetable oil, hydrocarbons and any combinations thereof.

[0149] In some embodiments, the oil component is selected from one or more excipient(s) selected from mineral oil, hydrocarbon oil, an ester oil, an ester of a dicarboxylic acid, a triglyceride oil, an oil of plant origin, an oil from animal origin, an unsaturated or polyunsaturated oil, a diglyceride, a PPG alkyl ether, an essential oil, a silicone oil, a liquid paraffin, an isoparaffin, a polyalphaolefin, a polyolefin, a polyisobutylene, a synthetic isoalkane, isohexadecane, isododecane, alkyl benzoate, alkyl octanoate, C12-C15 alkyl benzoate, C12-C15 alkyl octanoate, arachidyl behenate, arachidyl propionate, benzyl laurate, benzyl myristate, benzyl palmitate, bis(octyldodecyl stearoyl) dimer dilinoleate, butyl myristate, butyl stearate, cetearyl ethylhexanoate, cetearyl isononanoate, cetyl acetate, cetyl ethylhexanoate, cetyl lactate, cetyl myristate, cetyl octanoate, cetyl palmitate, cetyl ricinoleate, decyl oleate, diethyleneglycol diethylhexanoate, diethyleneglycol dioctanoate, diethyleneglycol diisononanoate, di ethyleneglycol diisononanoate, diethylhexanoate, diethylhexyl adipate, diethylhexyl malate, diethylhexyl succinate, diisopropyl adipate, diisopropyl dimerate, diisopropyl sebacate, diisosteary dimer dilinoleate, diisostearyl fumerate, dioctyl malate, dioctyl sebacate, dodecyl oleate, ethylhexyl palmitate, ester derivatives of lanolic acid, ethylhexyl cocoate, ethylhexyl ethylhexanoate, ethylhexyl hydroxystarate, ethylhexyl isononanoate, ethylhexyl palmytate, ethylhexyl pelargonate, ethylhexyl stearate, hexadecyl stearate, hexyl laurate, isoamyl laurate, isocetyl behenate, isocetyl lanolate, isocetyl palmitate, isocetyl stearate, isocetyl salicylate, isocetyl stearate, isocetyl stearoyl stearate, isocetearyl octanoate, isodecyl ethylhexanoate, isodecyl isononanoate, isodecyl oleate, isononyl isononanoate, isodecyl oleate, isohexyl decanoate, isononyl octanoate, isopropyl isostearate, isopropyl lanolate, isopropyl laurate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, isostearyl behenate, isosteary citrate, isostearyl erucate, isostearyl glycolate, isostearyl isononanoate, isostearyl isostearate, isostearyl lactate, isostearyl linoleate, isostearyl linolenate, isostearyl malate, isostearyl neopentanoate, isostearyl palmitate, isosteary salicylate, isosteary tartarate, isotridecyl isononanoate, isotridecyl isononanoate, lauryl lactate, myristyl lactate, myristyl myristate, myristyl neopentanoate, myristyl propionate, octyldodecyl myristate, neopentylglycol dicaprate, octyl dodecanol, octyl stearate, octyl palmitate, octyldodecyl behenate, octyldodecyl hydroxystearate, octyldodecyl myristate, octyldodecyl stearoyl stearate, oleyl erucate, oleyl lactate, oleyl oleate, propyl myristate, propylene glycol myristyl ether acetate, propylene glycol dicaprate, propylene glycol dicaprylate, propylene glycol dicaprylate, maleated soybean oil, stearyl caprate, stearyl heptanoate, stearyl propionate, tocopheryl acetate, tocopheryl linoleate, glyceryl oleate, tridecyl ethyl hexanoate, tridecyl isononanoate, triisocetyl citrate, fatty acid such as stearic acid, isostearic acid, oleic acid, alexandria laurel tree oil, an avocado oil, an apricot stone oil, a barley oil, a borage seed oil, a calendula oil, a canelle nut tree oil, a canola oil, a caprylic / capric a triglyceride castor oil, a coconut oil, a com oil, a cotton oil, a cottonseed oil, an evening primrose oil, a flaxseed oil, a groundnut oil, a hazelnut oil, glycereth triacetate, glycerol triheptanoate, glyceryl trioctanoate, glyceryl triundecanoate, a hempseed oil, a jojoba oil, a lucerne oil, a maize germ oil, a marrow oil, a millet oil, a neopentylglycol di capryl ate / di caprate, an olive oil, a palm oil, a passionflower oil, pentaerythrityl tetrastearate, a poppy oil, propylene glycol ricinoleate, a rapeseed oil, a rye oil, a safflower oil, a sesame oil, a shea butter, a soya oil, a soybean oil, a sweet almond oil, a sunflower oil, a sysymbrium oil, a syzigium aromaticum oil, a tea tree oil, a walnut oil, wheat germ glycerides, a wheat germ oil, PPG-2 butyl ether, PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG- 12 butyl ether, PPG- 14 butyl ether, PPG- 15 butyl ether, PPG- 15 stearyl ether, PPG- 16 butyl ether, PPG- 17 butyl ether, PPG- 18 butyl ether, PPG-20 butyl ether, PPG- 22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether, PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether, PPG- 10 cetyl ether, PPG- 28 cetyl ether, PPG-30 cetyl ether, PPG-50 cetyl ether, PPG-30 isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 methyl ether, PPG-3 myristyl ether, PPG- 4 myristyl ether, PPG-10 oleyl ether, PPG-20 oleyl ether, PPG-23 oleyl ether, PPG-30 oleyl ether, PPG-37 oleyl ether, PPG-40 butyl ether, PPG-50 oleyl ether, PPG-11 stearyl ether, a herring oil, a cod-liver oil, a salmon oil, a cyclomethicone, a dimethyl polysiloxane, a dimethicone, an epoxy-modified silicone oil, a fatty acid-modified silicone oil, a fluoro group- modified silicone oil, a methylphenylpolysiloxane, phenyl trimethicone, a polyether group- modified silicone oil and mixtures of any two or more thereof.

[0150] The oil component(s) is selected from, but not limited to, fatty alcohol, fatty acid, fatty acid ester, silicone substance(s), vegetable oil(s) and any combination of any of the foregoing thereof. The fatty acid ester(s) is selected from, but not limited to, ethyl laurate, isopropyl laurate, ethyl myristate, n-propyl myristate, isopropyl myristate, ethyl palmitate, isopropyl palmitate, methyl palmitate, methyl stearate, ethyl stearate, isopropyl stearate, butyl stearate, isobutyl stearate, amyl stearate, isoamyl stearate and diethyl sebacate. The fatty alcohol is selected from, but not limited to, elaidyl alcohol, linoleyl alcohol, linolenyl alcohol, caproic alcohol, lauryl alcohol, stearyl alcohol, cetostearyl alcohol, behenyl alcohol, oleyl alcohol, oleic acid, octyl dodecanol, 2-heptyl-l-undecanol, 1,17-hepatadecanediol and any combinations any of the foregoing.

[0151] In some embodiments, topical foamable composition of the present invention comprises fatty alcohols and / or emulsifier(s) as foam adjuvant.

[0152] In some embodiments, topical foamable composition of the present invention comprises one or more foam adjuvant selected from fatty alcohol, emulsifier(s), and a gelling agent.

[0153] In some embodiments, the foam adjuvant may be selected from one or more pharmaceutically acceptable excipient that provide support to form foam when ejected from container.

[0154] In some embodiments, the foam adjuvant may be selected from one or more pharmaceutically acceptable excipient that aids in stabilization of foam. For example, a gelling agent might help to form quality and stable foam. Hence, foam adjuvant should be interpreted without any restriction.

[0155] In some aspects, the topical foamable composition of the present invention comprises one or more emollient(s) selected from, but not limited to, oils of natural origin such as almond oil, coconut oil, olive oil, palm oil, peanut oil and the like, fatty acids such as lauric acid, myristic acid, palmitic acid, and stearic acid, monohydric alcohol esters of the fatty acids such as ethyl laurate, isopropyl laurate, ethyl myristate, n-propyl myristate, isopropyl myristate, ethyl palmitate, isopropyl palmitate, methyl palmitate, methyl stearate, ethyl stearate, isopropyl stearate, butyl stearate, isobutyl stearate, amyl stearate, isoamyl stearate, diethyl sebacate, medium chain triglyceride, octyldodecanol, silicones such as cyclomethicone, dimethicone, mineral oil, paraffin, waxes, and any combination of any of the foregoing. In other words, the oil phase of the emulsion comprising one or more substance selected from paraffins, petrolatum, waxes, silicone substance(s), hydrocarbon ointment bases and any combination of any of the foregoing.

[0156] The gelling agent(s) are selected from, but not limited to, but are not limited to, a cellulose ether, such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethyl cellulose, carboxymethylcellulose, carboxymethylhydroxyethylcellulose, and cationic celluloses, dextrin, carbomer (homopolymer of acrylic acid is crosslinked with an allyl ether pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene), such as Carbopol® 934, Carbopol® 940, Carbopol® 941, Carbopol® 980 and Carbopol® 981, acrylamide / sodium acryloyl dimethyltaurate copolymer / isohexadecane / polysorbate 80 (available as Sepineo P 600 from SEPPIC Inc. of Fairfield, N.J.), Pemulen, Klucel, and aluminum starch octenyl succinate (AS OS) or other derivatized polymers, polyethylene glycol, having molecular weight of 1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG 10,000), polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer (available as SOLUPLUS®), pol oxamer, aluminium starch octenyl succinate, locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guar gum, cationic guars, hydroxypropyl guar gum, starch, amine -bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid and hyaluronic acid or their salts such as sodium alginate and sodium hyaluronate; chemically modified starches, carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride.

[0157] In some aspects, the gelling agent is carbomer (homopolymer of acrylic acid is crosslinked with an allyl ether pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene), such as Carbopol® 934, Carbopol® 940, Carbopol® 941, Carbopol® 980 and Carbopol® 981, acrylamide / sodium acryloyl dimethyltaurate copolymer / isohexadecane / polysorbate 80 (available as Sepineo P 600 from SEPPIC Inc. of Fairfield, N.J.), Pemulen, Klucel, and aluminum starch octenyl succinate (AS OS).

[0158] In some aspects, the gelling agent is xanthan gum.

[0159] In some aspects, the gelling agent is acrylamide / sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80.

[0160] According to the present invention, the gelling agent plays essential role in the compositions of topical dosage forms, particularly in the composition of the present invention, as the composition of the present invention comprises non-solubilized fraction higher than solubilized fraction. The gelling agent enhances physical stability and prevent change in particle size during the shelflife. In some aspects, the gelling agent is selected from acrylamide / sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80 (available as Sepineo P 600 from SEPPIC Inc. of Fairfield, N.J.), xanthan gum, polyvinyl caprolactam-polyvinyl acetatepolyethylene glycol graft copolymer (available as SOLUPLUS®), and pol oxamer.

[0161] In some embodiments, the gelling agent is in the range of from about 0.01% w / w to about 5% w / w.

[0162] In some embodiments, the gelling agent is in the range of from about 0.01% w / w to about 2% w / w.In some embodiments, the gelling agent is in the range of from about 0.01% w / w to about 1% w / w

[0163] Suitable chelating agents include, but are not limited to, ethylenediamine tetracetic acid (EDTA), commercially available both as the free acid and as various salts, for example, disodium EDTA, tetrasodium EDTA, dipotassium EDTA, and calcium disodium EDTA. Other suitable chelators include the naturally occurring amino acid L-cysteine, HSCFE CHINEE) CO2 H, and its acetylated derivative N-acetyl-L-cysteine, HSCH2-CH(NHCOCH3)C02 H, commonly referred to as NAC.

[0164] Suitable humectant(s) and moisturizers are selected from, but not limited to, urea, glycerin, polyhydroxy acids, and ammonium lactate.

[0165] Suitable buffering agents include, but are not limited to, citrate / citric acid, acetate / acetic acid, phosphate / phosphoric acid, formate / formic acid, propionate / propionic acid, lactate / lactic acid, carbonate / carbonic acid, ammonium / ammonia, edentate / edetic acid, and derivatives thereof, sodium hydroxide, sodium chloride, aluminum sulphate, calcium acetate, potassium chloride, potassium carbonate and mixtures thereof. Suitable antioxidants include, for example, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, tocopherols and tocotrienols (e.g. vitamin E), carotenes, flavonoids (e.g. quercetin) or mixtures, tertiary butyl hydroquinone, propyl gallate, alphatocopherol, sodium metabisulfite, glutathione, N-acetylcysteine, thioproline, taurine, sodium selenite, sulfurous acid salts and organic esters such as bisulfites, pyrosulfites, metabisulfites (such as sodium metabisulfite), and sulfites, and any combination of any of the foregoing.

[0166] In some embodiments, the foamable carrier of the topical composition comprising a solvent system, emulsifying agent, and a pharmaceutically acceptable excipient; and a propellant.

[0167] In some embodiments, the weight ratio between topical compositions to propellant is 1 : 1 to 10: 1, preferably 2: 1 to 8: 1.

[0168] In some embodiments, the weight ratio between topical compositions to propellant is 1 :0.03 to 1 :0.25, preferably 1 :0.05 to 1 :0.17.

[0169] In some embodiments, the foamable carrier of the topical composition comprising a solvent system, emulsifying agent, and a pharmaceutically acceptable excipient; and a dimethyl ether as a propellant, wherein the propellant solubilizes crystals of roflumilast formed in the composition during shelf life.

[0170] In some embodiments, the weight ratio between a solvent component to water is selected from 1 : 10 to 10: 1.

[0171] Suitable propellants include volatile hydrocarbons such as butane, propane, isobutene or mixtures thereof. In one or more embodiments a hydrocarbon mixture AP-70 is used. Hydrofluorocarbon (HFC) propellants are also suitable as propellants in the context disclosed herein. Exemplary HFC propellants include 1,1, 1,2 tetrafluorethane (Dymel 134), and 1,1, 1,2, 3, 3, 3 heptafluoropropane (Dymel 227). Dimethyl ether is also useful. In one or more embodiments use of compressed gases (e.g., air, carbon dioxide, nitrous oxide, and nitrogen) is also possible. Chloro fluorocarbon propellants on the other hand are no longer considered suitable for use in cosmetic, pharmaceutical and other formulations due to inter alia the potential environmental damage that they can do.

[0172] In one or more embodiments at least one propellant or a combination of at least two or more propellants, selected from HFC, hydrocarbon propellants, dimethyl ether and compressed gases is contemplated.

[0173] In a specific embodiment, the propellant for the foamable composition of the present invention dimethyl ether. In some embodiments, the aerosol foam composition of the present invention comprises one or more emulsifying agent(s) For example, the emulsifying agent is a non-ionic emulsifying agent with a HLB between about 9-16 provides a better foam quality and stability than a nonionic emulsifying agent with a HLB value lower than about 9 or higher than about 16.

[0174] In some embodiments, the aerosol foam composition of the present invention comprises one or more non-ionic emulsifying agent(s) with HLB of 9- 16; and one or more foam stabilizing agent and foam adjuvant.

[0175] In some embodiments, topical foam composition of the present invention comprises i) a foamable carrier comprising one or more emulsifying agent, foam adjuvant, and one or more pharmaceutically acceptable excipient(s); and ii) a propellant.

[0176] In some embodiments, topical foam composition of the present invention comprises i) a foamable carrier comprising one or more emulsifying agent, foam adjuvant, and one or more pharmaceutically acceptable excipient(s); and ii) a propellant; wherein the propellant is selected from dimethyl ether, butane, propane, isobutene, hydrofluorocarbon (HFC) propellants, compressed gases or mixtures thereof.

[0177] The foam dispenser having a pump assembly which includes a liquid pump, an air pump and a common actuation part to simultaneously actuate the liquid pump and the air pump) or by using a pressurized container and a propellant.

[0178] In some embodiments, the propellant may be introduced into the composition at the time of filling, utilizing a pressurized container such as a standard aerosol dispenser.

[0179] In some embodiments, the composition may be expelled from its container by mechanical means, such as by a pump action or a squeezing action on the container.

[0180] In some embodiments, suitable pressurized containers for use herein include aluminum, tin-plate and glass containers.

[0181] In some embodiments, the pressurized container may be a one-piece aluminum container; wherein the container is coated with coating material selected from polyamide-imide (PAM), epoxy phenolic coatings, microflex coating, modified polyester coatings and acrylic coatings.

[0182] In a preferred embodiment, the pressurized container is coated internally with epoxy phenolic coating.

[0183] In some embodiments, topical foam composition of the present invention comprises i) a foamable carrier comprising one or more emulsifying agent, foam adjuvant, and one or more pharmaceutically acceptable excipient(s); and ii) a propellant; wherein the propellant is selected from hydrocarbon propellant(s). In some embodiments, topical foam composition of the present invention comprises i) a foamable carrier comprising one or more emulsifying agent, foam adjuvant, and one or more pharmaceutically acceptable excipient(s); and ii) a propellant; wherein the propellant is dimethyl ether.

[0184] In an embodiment, the topical foam composition of the present invention comprises: i) roflumilast or a pharmaceutically acceptable salts thereof, and ii) a foamable carrier.

[0185] In an embodiment, the topical foamable composition of the present invention comprises: i) roflumilast or a pharmaceutically acceptable salts thereof, ii) a foam carrier and iii) a propellant.

[0186] In some embodiments, the topical foamable composition of the present invention comprises: i) roflumilast or a pharmaceutically acceptable salts thereof, ii) a foam baseand iii) a propellant, wherein the roflumilast is present in non-solubilized state in the composition.

[0187] In some embodiments, the topical foamable composition of the present invention comprises: i) roflumilast or a pharmaceutically acceptable salts thereof, and ii) a foamable carrier; and a propellant, characterized in that weight ratio between topical compositions to propellant is from about 1 :0.03 to about 1 :0.25 and the roflumilast is present in non-solubilized state from about 1% to about 50% of total roflumilast concentration in the composition and wherein the roflumilast is present in non-solubilized state from about 1% to about 50% of total roflumilast concentration in the composition

[0188] In some embodiments, the topical foamable composition of the present invention comprises: i) roflumilast or a pharmaceutically acceptable salts thereof, ii) a foam base and iii) a propellant, characterized in that weight ratio between topical compositions to propellant is from about 1 :0.03 to about 1:0.25.

[0189] In some embodiments, the topical foamable composition of the present invention comprises: i) roflumilast or a pharmaceutically acceptable salts thereof, ii) a foam base and iii) a propellant, characterized in that weight ratio between topical compositions to propellant is about 1 :0.03 to about 1 :0.25.

[0190] In some embodiments, the topical foamable composition of the present invention comprises: i) roflumilast or a pharmaceutically acceptable salts thereof, ii) a foam base and iii) a propellant, characterized in that weight ratio between topical compositions to propellant is about 15:0.5 to about 5: 1.

[0191] In some embodiments, the topical foamable composition of the present invention has pH from about 3 to about 8. In a preferred embodiment, the pH of the topical foam composition is from about 4 to about 7 or from about 4 to about 6.

[0192] T1 In some embodiments, the topical foamable composition of the present invention comprises: i) roflumilast or a pharmaceutically acceptable salts thereof, ii) a foam base and iii) a propellant, characterized in that weight ratio between topical compositions to propellant is about 2: 1 to about 8: 1.

[0193] In an embodiment, the present invention relates to a process for preparing topical foamable composition comprising roflumilast.

[0194] In an embodiment, the present invention relates to a process for preparing topical foamble composition comprising roflumilast; the process comprising steps of: i) preparing roflumilast phase comprising mixing roflumilast with a solvent system; ii) preparation of base composition; and iii) addition of roflumilast phase to the base composition; wherein the base composition can be selected from emulsion base, emulgel, gel base or foamable base; and wherein the step iii) may be occurring during preparation of base composition and / or after preparation of base composition.

[0195] In an embodiment, the present invention relates to a process for preparing topical foamble composition comprising roflumilast; the process comprising steps of: i) preparing roflumilast phase comprising mixing roflumilast with a solvent system; ii) preparation of base composition; and iii) addition of roflumilast phase to the base composition; wherein the base composition can be selected from emulsion base, emulgel, gel base or foamable base; and wherein the step iii) occurs after preparation of base composition.

[0196] In some embodiments, the roflumilast phase is prepared by dissolving roflumilast in the solvent system; or either in a solvent or in a co-solvent.

[0197] In an embodiment, the present invention relates to a method of treating a skin disorder in a subject in need thereof, wherein the said method comprises topically administering a foamble composition comprising roflumilast or a pharmaceutically acceptable salts thereof; wherein the composition is free of hexylene glycol.

[0198] In an embodiment, the present invention related to a method of treating a skin disorder in a subject, the said method comprises topically administering a foamble composition comprising from about 0.01%w / w to about 2% w / w of roflumilast or a pharmaceutically acceptable salts thereof; wherein the method involves administering the topical composition once or twice daily, and the composition further comprises a solvent and co-solvent in a ratio of from about 1 :0.05 to about 5: 1.

[0199] The foamable composition of the present invention provides following foam parameter after expelling from pump. The drying rate of the foam is to be understood as percentage of weight loss post expelling from pump. The drying rate of the foam is depending on the amount of water loss from the foam. The drying rate of the foam is generally expressed in terms of percentage of weight lost in given time period. The drying time indicates the quality of the foam.

[0200] The drying time of the foam composition of the present invention is at least 30% weight loss in 30 minutes or at least 40% weight loss in 30 minutes or at least 50% weight loss in 30 minutes or at least 60% weight loss in 30 minutes.

[0201] Following are preferred embodiments of the present invention:

[0202] A topical foamable composition comprising: i) roflumilast or a pharmaceutically acceptable salts thereof; ii) a foam base and iii) a propellant; wherein the foam base comprises a) from about 50% w / w to about 97% w / w of an aqueous component, b) from about 1% w / w to about 45% w / w of an oil component, c) from about 0.01% w / w to about 10% w / w an emulsifying agent and d) from about 0.01% w / w to about 1% w / w of a gelling agent; and wherein the weight ratio between non-solubilized fraction to solubilized fraction of the roflumilast in the composition is from about 1 : 1 to about 100:0 in other words, from about 50% : 50% to about 100% : 0%.

[0203] The topical foamable composition of present invention comprises the roflumilast is present from about 0.01% w / w to about 1% w / w.

[0204] The topical foamable composition of present invention comprises the roflumilast concentration is selected from 0.05 %w / w, 0.1% w / w, 0.15% w / w, 0.2% w / w, 0.25% w / w, 0.3% w / w, and 0.35% w / w.

[0205] The topical foamable composition of present invention comprises the oil component is present from about 1% w / w to about 30% w / w.

[0206] The topical foamable composition of present invention comprises the oil component comprises one or more excipient(s) selected from fatty acid, fatty acid ester, fatty alcohol, vegetable oil, medium chain triglyceride, silicones, mineral oil, paraffin, waxes, petrolatum and any combinations thereof.

[0207] The topical foamable composition of present invention comprises the emulsifying agent is selected from anionic, cationic and non-ionic emulsifying agents and any combinations thereof.

[0208] The topical foamable composition of present invention comprises the composition comprises one or more excipients selected from preservative, penetration enhancer, solvent, cosolvent, pH adjusting agent, a gelling agent and any combinations thereof. The topical foamable composition of present invention comprises the composition has pH of from about 4 to about 8.

[0209] The topical foamable composition of present invention comprises the composition has pH of from about 4 to about 7.

[0210] The topical foamable composition of present invention comprises the weight ratio between non-solubilized to solubilized fraction of total roflumilast in the composition is relative weight ratio.

[0211] The topical foamable composition of present invention comprises the weight ratio between non-solubilized to solubilized fraction of total roflumilast in the composition is selected from 4: 1 to 29: 1.

[0212] The topical foamable composition of present invention comprises the weight ratio between non-solubilized to solubilized fraction of total roflumilast in the composition is selected from 14: 1 to 30:0.

[0213] A topical foamable composition comprising: i) roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foam base; wherein the composition comprises: a) one or more oil components less than about 20% w / w; b) at least one emulsifying agent less than about 10% w / w; c) an aqueous component of at least about 40% w / w; and d) optionally comprises a solvent and / or a co-solvent is present up to 15% w / w; wherein the foamable composition is free of hexylene glycol and diethylene glycol monoethyl ether and the average surface area of particles of roflumilast in the range of from about 20 um2 to about 500 um2 and D90 particle size of the roflumilast particle is less than about 20um.

[0214] The topical foamable composition of present invention comprises the D90 particle size of the roflumilast particle is less than about lOum.

[0215] The topical foamable composition of present invention comprises the aqueous component is present at least about 50%.

[0216] The topical foamable composition of present invention comprises the aqueous component is present at least about 60%.

[0217] In a specific embodiment, the skin disorder is psoriasis. In a specific embodiment, the skin disorder is plaque psoriasis. In a specific embodiment, the skin disorder is atopic dermatitis. In a specific embodiment, the skin disorder is seborrheic dermatitis.

[0218] The following examples are provided to illustrate certain specific aspects and embodiments of the application, and are not to be construed as limiting the scope of the application in any manner. EXAMPLES

[0219] Example-1 : Topical composition containing roflumilast

[0220] Manufacturing process: The roflumilast phase was prepared by mixing propylene glycol, and polyethylene glycol with roflumilast and methyl paraben propyl paraben. This steps optionally involves heating around 50-60°C. The base composition according to the F1-F7 is emulsion. Hence, the base composition preparation involves preparing oil phase and water phase.

[0221] The oil phase was prepared by melting petrolatum, glyceryl monostearate, polyethylene 100 stearate, mineral oil and cetostearyl alcohol at 65-75°C or till melting. The water phase was prepared by heating water at 70°C and preparation of aqueous phase; heat purified water to 65- 75°C and disperse acrylamide / sodium acryloyldimethyltaurate copolymer / isohexadecane / polysorbate 80, Xanthan gum & / pol oxamer 188 under stirring till uniform dispersion. The emulsification was done under homogenization of oil to water phase at 70°C to prepare base composition i.e., emulsion. The roflumilast phase was added to the emulsion. Roflumilast phase can be added during emulsification. The emulsion was cooled to 25°C.

[0222] Example-2: Roflumilast Foamable composition

[0223] The manufacturing process was same to that of the process of Example- 1. The modification required if any may be modified according to the present ingredients.

[0224] The compositions of Example-2 were expelled using standard nostril, and the foam quality was assessed in two stages prefoam and post expel.

[0225] Example-3: Topical foamable composition

[0226] The cumulative drug release from the composition F13 was measured and the results are provided below: The drying rate of the foam composition was measured for F14, F15 and F16.

[0227] Microscopic analysis was performed for compositions F14, F15 and F16. The microscopic analysis of the formulations Fl 4, F15, and F16 showed that the surface area of the single crystal of roflumilast in the range of from 10.1 pm2 to 500 pm2.

[0228] The foam expelled formed from the foam compositions of F14, F15, and F16 were expandable foam composition. The collapse time of the foam formed by F14 was more than 6 hours whereas the collapse time for foam formed by F15 and F16 were less than 6 hours.

[0229] Example-4: Roflumilast solubility trials

[0230] Procedure for study: Roflumilast is suspended in the equimolar mixture of solvent system (Polyethylene glycol and propylene glycol) with a gelling agent(s) were subjected to solubility trial and water was added post solubilization of roflumilast in the mixture. The results were analyzed for precipitation.

[0231] Soluble and In-soluble fraction analysis of Formulation 13 (F 13):

[0232] The sample for analysis was prepared by transfering about 5gm of sample in 50mL Centrifuge tube, added to it 1.5mL of 10% Calcium Chloride Solution (Prepared in Water to break the emulsion) and was mixed it with tapping the centrifuge tube. The mass was found loosen. Then centrifuge at 11000RPM for 15 minutes, two layers are separated. The aqueous layer was taken for estimation.

[0233] Conclusion from the study showed that the solubilized portion of roflumilast was always more than 70% of total amount of roflumilast present in the composition.

Claims

We Claim:

1. A topical foamable composition comprising: i) roflumilast or a pharmaceutically acceptable salts thereof; ii) a foam base and iii) a propellant; wherein the foam base comprises, a) from about 50% w / w to about 97% w / w of an aqueous component, b) from about 1% w / w to about 45% w / w of an oil component, c) from about 0.01% w / w to about 10% w / w an emulsifying agent and d) from about 0.01% w / w to about 1% w / w of a gelling agent; and wherein the percentage weight ratio between non-solubilized fraction to solubilized fraction of the roflumilast in the composition is from about 50%: 50% to about 100%: 0%.

2. The topical composition of claim 1, wherein the roflumilast is present from about 0.01% w / w to about 1% w / w.

3. The topical composition of claim 1, wherein the roflumilast concentration is selected from 0.05 %w / w, 0.1% w / w, 0.15% w / w, 0.2% w / w, 0.25% w / w, 0.3% w / w, and 0.35% w / w.

4. The topical composition of claim 1, wherein the aqueous component is present from about 60% to 95% w / w.

5. The topical composition of claim 1, wherein the oil component is present from about 1% w / w to about 30% w / w.

6. The topical composition of claim 1, wherein the oil component comprises one or more excipient(s) selected from fatty acid, fatty acid ester, fatty alcohol, vegetable oil, medium chain triglyceride, silicones, mineral oil, paraffin, waxes, petrolatum and any combinations thereof.

7. The topical composition of claim 1, wherein the emulsifying agent is selected from anionic, cationic and non-ionic emulsifying agents and any combinations thereof.

8. The topical composition of claim 1, wherein the composition comprises one or more excipients selected from preservative, penetration enhancer, solvent, co-solvent, pH adjusting agent, a gelling agent and any combinations thereof.

9. The topical composition of claim 1, wherein the composition has pH of from about 4 to about 8.

10. The topical composition of claim 1, wherein the composition has pH of from about 4 to about 7.

11. The topical composition of claim 1, wherein at least about 50% of the total amount of roflumilast or a pharmaceutically acceptable salts thereof is dispersed in the aqueous component.

12. The topical composition of claim 1, wherein the percentage weight ratio between nonsolubilized to solubilized fraction of total roflumilast in the composition is selected from about 80%: 20% to about 97%: 3%.

13. The topical composition of claim 1, wherein the percentage weight ratio between nonsolubilized to solubilized fraction of total roflumilast in the composition is selected from about 94%: 6% to about 100%: 0%.

14. A topical foamable composition comprising: i) roflumilast or a pharmaceutically acceptable salts thereof; and ii) a foam base; wherein the composition comprises: a) one or more oil components less than about 20% w / w; b) at least one emulsifying agent less than about 10% w / w; c) an aqueous component of at least about 40% w / w; and d) optionally comprises a solvent and / or a co-solvent is present up to 15% w / w; wherein the foamable composition is free of hexylene glycol and diethylene glycol monoethyl ether and the average surface area of particles of roflumilast in the range of from about 20 pm2to about 500 pm2and D90 particle size of the roflumilast particle is less than about 20pm.

15. The topical composition of claim 14, wherein the D90 particle size of the roflumilast particle is less than about 10pm.

16. The topical composition of claim 14, wherein the aqueous component is present at least about 50% w / w.

17. The topical composition of claim 14, wherein the aqueous component is present at least about 60% w / w.

18. A topical foamable composition comprising: i) roflumilast or a pharmaceutically acceptable salts thereof; ii) from about 50% w / w to about 90% w / w of an aqueous component; iii) from about 1% w / w to about 45% w / w of an oil component; iv) from about 0.01% w / w to about 10% w / w an emulsifying agent; and v) from about 0.01% w / w to about 2 % w / w of a gelling agent; wherein the gelling agent is selected from xanthan gum, guar gum, a mixture of acrylamide and sodium acryloyldimethyltaurate copolymer, carbomer homopolymer type A, carbomer homopolymer type B, carbomer homopolymer type C, polyvinyl alcohol polyacrylic acid polymers, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, and hydroxy propylmethyl cellulose; wherein the composition comprises at least about 90% of total roflumilast is present in the aqueous component in non-solubilized state.

19. The topical composition of claim 18, wherein the gelling agent is present from about 0.01% w / w to about 1% w / w of the total weight of the composition.