DESC:
Field of invention:
The present invention relates to a topical composition comprising roflumilast, N-oxide of roflumilast or salts thereof and process of preparation of same. The invention also relates to a method of treatment of a dermal disease by topical administration of said topical composition.

Background of invention:
Roflumilast 3-(cyclopropylmethoxy)-n-(3,5-dichloropyridin-4-yl)-4-(difluoromethoxy)-benzamide is a PDE4 inhibitor having the following structure:

Roflumilast is having very low water solubility of 0.0062 mg/mL.
Roflumilast is approved by USFDA as tablet dosage form, under brand name of Daliresp®, for the treatment of COPD.
Topical roflumilast, as cream and foam dosage forms, are under clinical trial for the treatment of plaque psoriasis and atopic dermatitis.
Topical roflumilast is also known for the treatment of various diseases like psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus in the genitoanal region, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa. The acne is selected from acne vulgaris, papulopustular acne and nodular acne, and the rosacea is selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea.
PCT Publication No. 202244005 relates to a low permeable topical composition comprising roflumilast, N -oxide of roflumilast or salts thereof, and to a method of treatment of a dermal disease by topical administration of said composition.
US Publication No. 20210236432 discloses topical composition comprising roflumilast, roflumilast N-oxide or salts thereof as an active agent. The active agent in the composition of this invention is in encapsulated or non-encapsulated form, according to need. The composition is useful for the treatment, prevention or alleviation of a dermal disease selected from Hidradenitis suppurativa and Prurigo nodularis.
IN patent No. 211414 relates to the field of pharmaceutical technology and describes a topically applicable pharmaceutical preparation comprising as active ingredient a slightly soluble PDE 4 inhibitor. The invention additionally relates to processes for producing the topically applicable pharmaceutical preparation and to the use for the treatment of disorders of the skin, of the eyes and of the airways.
IN Publication No. 201717004287 discloses topical formulations that can be prepared at ambient temperature without the need for any heating step during preparation. Thus the formulations are particularly suitable for cosmetic and pharmaceutical active ingredients that are relatively heat sensitive. The invention also provides methods for preparing the same.
PCT Publication No. 2021155173 relates to methods for improving the therapeutic outcome of treatment with roflumilast. The therapeutic outcome is improved by consistent delivery and/or a longer plasma half-life of a topically administered roflumilast composition. The roflumilast composition preferably includes dicetyl phosphate, ceteth-10 phosphate, diethylene glycol monoethyl ether, and/or hexylene glycol.
PCT Publication No. 2018226584 relates to controlling crystal growth of roflumilast during the storage. The growth of roflumilast crystals can be inhibited during storage by including hexylene glycol in the composition. The resulting composition has improved bioavailability and efficacy and can be used to inhibit phosphodiesterase 4 in patient in need of such treatment.
PCT Publication No. 2019236374 relates to decreasing skin penetration lag times will improve the bioavailability of a topically administered roflumilast composition. A shorter skin penetration lag time provides quicker onset of disease relief and more consistent bioavailability as there is less transference to clothing or other people. The skin penetration lag time for roflumilast can be reduced by formulating a roflumilast composition to have a pH between 4.0 - 6.5 and/or combining roflumilast with an emulsifier blend comprising cetearyl alcohol, dicetyl phosphate and ceteth-10 phosphate.
PCT Publication No. 2021045804 relates to method for altering the PK profile of a pharmaceutical formulation containing a PDE-4 inhibitor, such as roflumilast, to reduce the spike in Cmax. The spike in Cmax is reduced by topically administering the PDE-4 inhibitor in combination with one or more phosphate ester surfactants. Reducing the spike in Cmax will reduce gastrointestinal side effects and result in better patient compliance.
PCT Publication No. 2019060379 discloses low aqueous solubility of roflumilast in parenteral preparations and topical emulsions, suspensions, gels or solutions can be improved by including a blend of water-miscible solvents in the pharmaceutical composition. The blend of water-miscible solvents can include diethylene glycol monoethyl ether (Tradename Transcutol®; abbreviated DEGEE) and water. The ratio of diethylene glycol monoethyl ether to water is from 1:10 to 20:1. The resulting composition has improved bioavailability and efficacy and can be used to inhibit phosphodiesterase 4 in a patient in need of such treatment.
Inventors have surprisingly found that composition of the present inventions exhibits enhanced permeability when compared with the marketed products such as ZoryveTM.

Summary of Invention
In one aspect, the invention provides a topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration.
In another aspect, the invention provides a topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration.
In another aspect, the invention provides a topical composition comprising about 0.1 mg to about 1000 mg of roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration.
In another aspect, the invention provides a topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof, wherein the topical composition can be formulated as a cream, a lotion, an ointment, an emulsion, a solution, a suspension, an elixir, a tincture, a paste, a foam, an aerosol, a spray, a patch, a transdermal patch or as a pre-filled applicator syringe.
In another aspect, the invention provides a topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof, wherein roflumilast, N-oxide of roflumilast, or salts thereof is not in encapsulated form or coated form.
In another aspect, the invention provides a topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration, wherein the carrier is selected from group comprising emollient, permeation enhancer, solvent, co-solvent, preservative, chelating agent, fragrance and pH adjusting agent or mixture thereof.
In another aspect, the invention provides topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof and polyethylene glycol hexadecyl ether.
In another aspect, the invention provides topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, cetosteryl alcohol and polyethylene glycol hexadecyl ether.
In another aspect, the invention provides a topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration, wherein the composition is free of hexylene glycol or diethylene glycol monoethyl ether or polyethylene glycol or dicetyl phosphate or polyethylene glycol ether of cetyl alcohol.
In another aspect, the invention provides a topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof and polyethylene glycol hexadecyl ether, wherein the composition is in the form of cream.
In another aspect, the invention provides a topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, cetosteryl alcohol and polyethylene glycol hexadecyl ether, wherein the composition is in the form of cream.
In another aspect, the invention provides a topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof and polyethylene glycol hexadecyl ether, wherein the composition is in the form of lotion.
In another aspect, the invention provides a topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, cetosteryl alcohol and polyethylene glycol hexadecyl ether, wherein the composition is in the form of lotion.
In another aspect, the invention provides a topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein the composition is not in the form of gel.
In another aspect, the invention provides a topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, polyethylene glycol hexadecyl ether and one or more additional carrier suitable for topical administration.
In another aspect, the invention provides a topical cream comprising roflumilast, cetosteryl alcohol, polyethylene glycol hexadecyl ether, light liquid paraffin, white liquid paraffin, propylene glycol, disodium edetate, methyl paraben, benzyl alcohol, fresh citrus flavour, sodium hydroxide and purified water.
In another aspect, the invention provides a topical cream comprising about 0.300 % w/w of roflumilast, about 6.000 % w/w of cetosteryl alcohol, about 1.500 % w/w of polyethylene glycol hexadecyl ether, about 4.000 % w/w of light liquid paraffin, about 4.000 % w/w of white liquid paraffin, about 20.000 % w/w of propylene glycol, about 0.010 % w/w of disodium edetate, about 0.140 % w/w of methyl paraben, about 1.000 % w/w of benzyl alcohol, about 0.029 % w/w of fresh citrus flavour, sodium hydroxide in an amount sufficient to adjust pH of about 4 to about 7 of the composition and purified water.
In another aspect, the invention provides a topical cream comprising about 0.300 % w/w of roflumilast, about 6.500 % w/w of cetosteryl alcohol, about 1.560 % w/w of polyethylene glycol hexadecyl ether, about 4.500 % w/w of light liquid paraffin, about 4.500 % w/w of white liquid paraffin, about 20.500 % w/w of propylene glycol, about 0.015 % w/w of disodium edetate, about 0.150 % w/w of methyl paraben, about 1.500 % w/w of benzyl alcohol, about 0.030 % w/w of fresh citrus flavour, sodium hydroxide in an amount sufficient to adjust pH of about 4 to about 7 of the composition and purified water.
In another aspect, the invention provides a topical lotion comprising roflumilast, cetosteryl alcohol, polyethylene glycol hexadecyl ether, medium chain triglycerides, stearic acid, emulsifying wax, glycerine, propylene glycol, methyl paraben, propyl paraben, fresh citrus flavour, sodium hydroxide and purified water.
In another aspect, the invention provides a topical lotion comprising about 0.300 % w/w of roflumilast, about 1.067 % w/w of cetosteryl alcohol, about 0.400 % w/w of polyethylene glycol hexadecyl ether, about 1.467 % w/w of medium chain triglycerides, about 0.713 % w/w of stearic acid, about 0.600 % w/w of emulsifying wax, about 4.000 % w/w of glycerine, about 10.000 % w/w of propylene glycol, about 0.150 % w/w of methyl paraben, about 0.015 % w/w of propyl paraben, about 0.029 % w/w of fresh citrus flavour, sodium hydroxide in an amount sufficient to adjust pH of about 4 to about 7 of the composition and purified water.
In another aspect, the invention provides a topical lotion comprising about 0.300 % w/w of roflumilast, about 1.072 % w/w of cetosteryl alcohol, about 0.500 % w/w of polyethylene glycol hexadecyl ether, about 1.490 % w/w of medium chain triglycerides, about 0.741 % w/w of stearic acid, about 0.900 % w/w of emulsifying wax, about 4.500 % w/w of glycerine, about 10.500 % w/w of propylene glycol, about 0.240 % w/w of methyl paraben, about 0.020 % w/w of propyl paraben, about 0.035 % w/w of fresh citrus flavour, sodium hydroxide in an amount sufficient to adjust pH of about 4 to about 7 of the composition and purified water.
In another aspect, the invention provides a topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein pH of the composition is in the range of about 4 to about 7.
In another aspect, the invention provides a topical cream comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein pH of the cream is 5.5.
In another aspect, the invention provides a topical lotion comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein pH of the lotion is 5.7.
In another aspect, the invention provides method of treating, preventing and/or managing dermal disease in humans in need thereof. The method comprises administering topical composition comprising therapeutically or prophylactically effective amount of roflumilast, N-oxide of roflumilast, or salts thereof to a patient in need of such treatment, prevention or management.
In another aspect, the invention provides method of treating dermal disease, which comprises administering topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof to a patient in need of such treatment, prevention or management.
In another aspect, the invention provides topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of dermal disease.
In another aspect, the invention provides topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of dermal disease, wherein the dermal disease is selected from psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus in the genitoanal region, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
In another aspect, the invention provides topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of dermal disease, wherein the composition is to be administered at least once a day.
In another aspect, the invention provides a process for preparing topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof.
In yet another aspect, the invention provides enhanced permeability as compared with the marketed products such as ZoryveTM.
These and other features of the present invention will be more fully understood from the detailed description, examples and tables that follow.

Detailed Description of the Invention
The present invention relates to a topical composition comprising roflumilast, N-oxide of roflumilast or salts thereof and process of preparation of same. The invention also relates to a method of treatment of a dermal disease by topical administration of said topical composition.
Roflumilast is approved by USFDA as tablet dosage form, under brand name of Daliresp®, for the treatment of COPD. Topical roflumilast as cream and foam dosage forms are under clinical trial for the treatment of plaque psoriasis and atopic dermatitis.
Topical roflumilast is also known for the treatment of various diseases like psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus in the genitoanal region, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa. The acne is selected from acne vulgaris, papulopustular acne and nodular acne, and the rosacea is selected from erythematotelangiectatic rosacea, papulopustular rosacea, rhinophyma rosacea and ocular rosacea.
Acne is a chronic inflammatory disease of the pilosebaceous unit resulting from androgen-induced increased sebum production, altered keratinization, inflammation, and bacterial colonisation of hair follicles on the face, neck, chest, and back by Propionib acterium acnes (P. acnes). Although early colonisation with P. acnes and family history might have important roles in the disease, exactly what triggers acne and how treatment affects the course of the disease remains unclear. There is no ideal treatment for acne. Good quality evidence on comparative effectiveness of common topical and systemic acne therapies is scarce. Topical therapies including benzoyl peroxide, retinoids, and antibiotics when used in combination usually improve control of mild to moderate acne, but suffer from side-effects. Treatment with combined oral contraceptives can help women with acne. Patients with more severe inflammatory acne usually need oral antibiotics combined with topical benzoyl peroxide to decrease antibiotic-resistant organisms. Oral isotretinoin is the most effective therapy and is used early in severe disease, but its use is limited by teratogenicity and other side-effects. The treatment of acne with the composition of this invention results in reduced side effects, due to long penetration lag time.
Rosacea is a chronic skin disease that affects more than 16 million Americans. The cause of rosacea is still unknown, and there is no cure. However, research has allowed doctors to find ways to treat the condition by minimizing its symptoms. There are four subtypes of rosacea. Each subtype has its own set of symptoms. It is possible to have more than one subtype of rosacea at a time. Rosacea’s typical symptom is small, red, pus-filled bumps on the skin that are present during flare-ups. Typically, rosacea affects only skin on the nose, cheeks, and forehead. Flare-ups often occur in cycles. This means that one will experience symptoms for weeks or months at a time, the symptoms will go away, and then return. The four types of rosacea are:
Subtype one, known as erythematotelangiectatic rosacea (ETR), is associated with facial redness, flushing, and visible blood vessels.
Subtype two, papulopustular (or acne) rosacea, is associated with acne-like breakouts, and often affects middle-aged women.
Subtype three, known as rhinophyma, is a rare form associated with thickening of the skin on your nose. It usually affects men and is often accompanied by another subtype of rosacea.
Subtype four is known as ocular rosacea, and its symptoms are centred on the eye area.
Dermatitis is a group of diseases resulting in skin inflammation, itchiness, red skin and rash. The dermatitis group of diseases includes atopic dermatitis (AD), allergic contact dermatitis, irritant contact dermatitis and stasis dermatitis. Atopic dermatitis is the most common type of dermatitis.
Definitions:
As used herein, unless otherwise specified, by "pharmaceutically acceptable excipients", it is meant any of the components of a pharmaceutical composition other than the active ingredients and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
As used herein, unless otherwise specified, the term “patient” or “subject” refers to a human patient unless indicated otherwise. The patient can be of any age, having dermal disease as described above.
As used herein, unless otherwise specified, the terms "treat," "treatment," and "treating" in the context of the administration of a therapy to a patient refers to the reduction or inhibition of the progression and/or duration of a disease or condition, the reduction or amelioration of the severity of a disease or condition, and/or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies.
As used herein, unless otherwise specified, the terms “prevent,” “preventing” and “prevention” contemplate an action that occurs before a patient begins to suffer from the specified disease or disorder, which inhibits or reduces the severity or symptoms of the disease or disorder.
As used herein, and unless otherwise indicated, the terms “manage,” “managing” and “management” encompass preventing the recurrence of the specified disease or disorder in a patient who has already suffered from the disease or disorder, and/or lengthening the time that a patient who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and/or duration of the disease or disorder, or changing the way that a patient respond to the disease or disorder.
As used herein, unless otherwise specified, an “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g. reduce one or more symptoms of a disease or condition). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, delay, inhibition, suppression, or reduction of a symptom or symptoms of a disease or disorder, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms (and grammatical equivalents of this phrase) means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). An “effective amount” of a drug can be an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present disclosure, should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose may also be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner.
As used herein, unless indicated otherwise, the term “stable” refers to a pharmaceutical composition of the present invention, which after 3 or 6 months’ storage at 25° C and 60% relative humidity or 30° C and 75% relative humidity or 40° C and 75% relative humidity has at least 90, 95, or 98% of the initial amount of active ingredient present and total impurity of not more than 2%.
As used herein, the term “salts” or “pharmaceutically acceptable salt”, it is meant those salts, solvate and esters which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use. Representative acid additions salts include hydrochloride, furoate, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts. Representative alkali or alkaline earth metal salts include sodium, calcium, potassium and magnesium salts.
As used herein, the term “topical composition” refers to pharmaceutical composition to be administered at outer skin surface of the patients affected by dermal disease as described above.
The term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or even ±0.1% of the specified amount.
The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. The specification will be understood to also include embodiments which have the transitional phrase “consisting of” or “consisting essentially of” in place of the transitional phrase “comprising.” The transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim, except for impurities associated therewith. The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention.
Methods of Treatment
In one general embodiment, the invention provides method of treating, preventing and/or managing dermal disease in humans in need thereof. The method comprises administering topical composition comprising therapeutically or prophylactically effective amount of roflumilast, N-oxide of roflumilast, or salts thereof to a patient in need of such treatment, prevention or management.
In another embodiment, method of treating dermal disease, which comprises administering topical composition comprising therapeutically or prophylactically effective amount of roflumilast, N-oxide of roflumilast, or salts thereof to a patient in need of such treatment, prevention or management.
In some embodiments, dermal disease is selected from psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex, sunburn, pruritus in the genitoanal region, alopecia areata, hypertrophic scars, discoid lupus erythematosus, follicular and extensive pyodermas, acne, rosacea, atopic dermatitis, prurigo nodularis and hidradenitis suppurativa.
In another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of acne.
In another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of atopic dermatitis.
In another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of psoriasis.
In another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of eczema.
In another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration.
In another embodiment, topical composition comprising about 0.1% w/w to about 2.0 % w/w roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration.
In some embodiments, the topical composition comprising about 0.1 % w/w to about 2.0 % w/w, more preferably about 0.2 % w/w to about 1.0 % w/w, even more preferably about 0.3 % w/w to about 0.5 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof based on total weight of composition.
In some embodiments, the topical composition comprising about 0.3 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof based on total weight of composition.
In another embodiment, topical composition comprising about 0.1 mg to about 1000 mg of roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration.
In another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of dermal disease, wherein the composition is to be administered as per the requirement i.e. severity of the disease, age of the patient, patient body response to the dose of roflumilast and adverse reaction to the patient after administration.
In yet another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of dermal disease, wherein the composition is to be administered at least once a day.
In yet another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of dermal disease, wherein the composition is to be administered once a day.
In yet another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of dermal disease, wherein the composition is to be administered twice a day.
In yet another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof for the treatment of dermal disease, wherein the composition is to be administered thrice a day.
Pharmaceutical Composition
Pharmaceutical composition of present invention is topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration.
In another embodiment, topical composition comprising about 0.1% w/w to about 2.0 % w/w roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration.
In some embodiments, the topical composition comprising about 0.1 % w/w to about 2.0 % w/w, more preferably about 0.2 % w/w to about 1.0 % w/w, even more preferably about 0.3 % w/w to about 0.5 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof based on total weight of composition.
In some embodiments, the topical composition comprising about 0.3 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof based on total weight of composition.
In another embodiment, topical composition comprising about 0.1 mg to about 1000 mg of roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration.
In another embodiment, topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof, wherein the topical composition can be formulated as a cream, a lotion, an ointment, an emulsion, a solution, a suspension, an elixir, a tincture, a paste, a foam, an aerosol, a spray, a patch, a transdermal patch or as a pre-filled applicator syringe.
In some embodiments, the topical composition is cream.
In some embodiments, the topical composition is lotion.
In another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein the topical composition is not in the form of gel.
In another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein roflumilast, N-oxide of roflumilast, or salts thereof is dissolved within the composition.
In another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein roflumilast, N-oxide of roflumilast, or salts thereof is dispersed within the composition.
In another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein roflumilast, N-oxide of roflumilast, or salts thereof is partially dissolved and partially dispersed within the composition.
In another embodiment, roflumilast, N-oxide of roflumilast, or salts thereof is dissolved by mixing roflumilast, N-oxide of roflumilast, or salts thereof with at least one solvent or co-solvent and heating the mixture at temperature above 50oC.
In another embodiment, roflumilast, N-oxide of roflumilast, or salts thereof is dissolved by mixing roflumilast, N-oxide of roflumilast, or salts thereof with propylene glycol and heating the mixture at temperature of about 80oC to about 100oC.
In another embodiment, the invention provides a topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof, wherein roflumilast, N-oxide of roflumilast, or salts thereof is not in encapsulated form or coated form.
Topical composition may include one or more pharmaceutically acceptable excipient(s)/carrier(s). Suitable excipient(s)/carrier(s) include, but are not limited to, emulsifying agent(s)/emollient(s), permeation enhancer(s), solvent(s), co-solvent(s), chelating agent(s), preservative(s), fragrance(s), and pH adjusting agent(s).
Suitable emollients include, but are not limited to emollient oils, emollient fatty acids, fatty alcohols and fatty acid esters containing a C8-C20 acyl or alkyl group, preferably a C12-C18 acyl or alkyl group; lanolin; cholesterol; hydrophilic lanolin derivatives; phospholipids; and biological extracts.
Emollient oils include, but are not limited to, animal oils, vegetable or plant derived oils, hydrocarbon oils and silicone oils. The oils may be low viscosity, e.g., up to 1000 centipoises (cps.) or high viscosity, e.g., 2000 cps to over 10,000 cps. Specific examples of animal and vegetable or plant derived oils include mink oil, turtle oil, coconut oil, jojoba oil, almond oil, peanut oil, wheat germ oil, rice bran oil, corn oil, soybean oil, olive oil, safflower seed oil, sunflower seed oil, cottonseed oil, apricot kernel oil, peach kernel oil, walnut oil, palm kernel oil, poppy seed oil, hazelnut oil, grapeseed oil, canola oil, avocado oil, macadamia seed oil, castor oil and mixtures thereof. Specific examples of hydrocarbon oils are mineral oil, paraffin oils i.e. light liquid paraffin, white soft paraffin; and squalene. Specific examples of silicone oils are polymethylsiloxanes, polymethylphenylsiloxanes, cyclic polysiloxanes, polysiloxanes modified by polyoxyalkylenes or fatty acids or fatty alcohols and mixtures of the foregoing.
Specific examples of emollient, hydrophobic compounds containing a fatty (C12-C18) acyl or alkyl group include esters such as isopropyl myristate, isopropyl palmitate, sucrose distearate, butyl stearate, hexyl laurate, capric/caprylic triglyceride (Medium chain triglyceride), 2-ethylhexyl palmitate, diisopropyl adipate, octyl isononanoate, isopropyl isostearate, isocetyl palmitate, distearyl maleate, diglyceryl diisostearate and mixtures thereof. Specific examples of higher C12-C18 fatty alcohols include cetyl alcohol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol and mixtures of the foregoing. Specific examples of C12-C18 fatty acids include myristic acid, palmitic acid, behenic acid, stearic acid, oleic acid, isostearic and mixtures of the foregoing. Specific examples of hydrophobic, emollient extracts include Shea Butter or Butyrospermum Parkii that is a fat derived from karite tree.
Other suitable emollient materials include polyethylene glycol hexadecyl ether, marketed as brand name of cetomacrogol-1000, wax esters, e.g., emulsifying wax; lanolin; cholesterol and lanolin alcohols; hydrophilic lanolin derivatives, e.g., ethoxylan; and phospholipids, e.g., lecithin and cephalin. The emollients may be used in an amount from about 0.01% w/w to about 60 % w/w based on total weight of the composition.
In some embodiments, topical composition is cream having emollients selected from group comprising cetosteryl alcohol, polyethylene glycol hexadecyl ether, light liquid paraffin, white soft paraffin and mixture thereof.
In some embodiments, topical composition is lotion having emollients selected from group comprising cetosteryl alcohol, polyethylene glycol hexadecyl ether, medium chain triglyceride, stearic acid, emulsifying wax and mixture thereof.
Suitable gelling agents include, but are not limited to, cellulose derivatives (such as hydroxypropylmethyl cellulose (HPMC), hydroxyethylcellulose, and carboxymethylcellulose sodium), povidone, chitosan, poloxamers (Pluronic®), carboxyvinylpolymers (carbomer®), non-ionic poly(ethylene oxide) (Polyox WSR) and natural gums (such as guar gum and xanthan gum). A preferred mucoadhesive agent is selected from HPMC, carboxymethylcellulose sodium, carboxyvinylpolymers (carbomer), non-ionic poly(ethylene oxide) (Polyox WSR) or mixture thereof. The gelling agents may be used in an amount from about 0.01% w/w to about 50 % w/w based on total weight of the composition.
Suitable chelating agents include, but are not limited to, edetate disodium, diethylene-triamine-pentaacetic acid (DTPA), iminodisuccinic acid, ethylenediamine disuccinic acid or mixtures thereof. The chelating agent may be used in an amount from about 0.005% w/w to about 2 % w/w based on total weight of the composition.
In some embodiments, preferred chelating agent is edetate disodium.
The permeation enhancer can enhance the permeation of roflumilast through the topical skin surface. The permeation enhancer can be a hydroxyl group-containing compound. Non-limiting examples of hydroxyl group-containing compounds that may be used as permeation enhancers include alcohols (such as ethanol), diols (such as propylene glycol (also known as 1,2-propanediol), 1,3-propanediol, butylene glycol (including 1,3-butanediol, 1,2-butanediol, 2,3-butanediol, and 1,4 butanediol), hexylene glycol, dipropylene glycol, 1,5-pentanediol, 1,2-pentanediol, 1,8-octanediol, etohexadiol, p-menthane-3,8 diol, and 2-methyl-2,4-pentanediol), triols (such as glycerine), diethylene glycol monoethyl ether (Transcutol®), polyols (such as suitable polymers containing multiple hydroxyl groups) (including polyethylene glycols (PEGs) i.e. PEG 400, polypropylene glycols, polysorbates, i.e. polysorbate 80, and sorbitan esters, and suitable sugar alcohols), cyclitols (such as pinitol, insoitol), cyclic diols (such as cyclohexane diol), aromatic diols (such as hydroquinone, bisphenol A, resorcinol and catechol) or any combination thereof. Other permeation enhancer includes, but are not limited to, bile salts, vitamin E TPGS, alkyl maltosides, non-ionic, anionic or amphoteric surfactants having HLB value 8-14 or combination thereof. The non-limiting examples of such permeation enhancers are sodium glycocholate, sodium taurocholate, dodecyl maltosides, tridecyl maltoside or tetradecyl maltosides, or any combination thereof.
In one embodiment, the permeation enhancer may be present in the topical composition in an amount from about 0.5 % w/w to about 50 % w/w based on total weight of the composition.
In one embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein the composition is free of hexylene glycol or diethylene glycol monoethyl ether or polyethylene glycol or dicetyl phosphate or polyethylene glycol ether of cetyl alcohol.
In some embodiments, topical composition is cream and free of hexylene glycol or diethylene glycol monoethyl ether or polyethylene glycol or dicetyl phosphate or polyethylene glycol ether of cetyl alcohol.
In some embodiments, topical composition is lotion and free of hexylene glycol or diethylene glycol monoethyl ether or polyethylene glycol or dicetyl phosphate or polyethylene glycol ether of cetyl alcohol.
Suitable preservatives include, but are not limited to, benzalkonium chloride, potassium sorbate, methyl paraben, propyl paraben, chlorbutol, chlorocresol, chlorhexidine, sodium benzoate, benzyl alcohol, propylene glycol or polyethylene glycol ether of cetyl alcohol or mixtures thereof.
In one embodiment, preservatives may be used in an amount from about 0.0025% w/w to about 2.5 % w/w based on total weight of the composition.
In some embodiments, preferred preservatives are selected from methyl paraben, propyl paraben, benzyl alcohol or mixture thereof.
Suitable solvents and co-solvents include, but are not limited to, purified water, absolute ethanol, glycols such as propylene glycol, polypropylene glycol, glycerol, polyoxyethylene alcohols, polyoxyethylene fatty acid esters or mixtures thereof. The vehicle or solubilizer may be present in the composition in an amount from about 5 % w/w to about 20 % w/w, based on total weight of the composition.
In some embodiments, solvents and co-solvents are selected from group comprising propylene glycol and purified water.
Suitable flavouring agents include, but are not limited to, orange sweet oil, spearmint oil, citronella oil, black pepper oil, pine apple, cherry, berry, butterscotch, vanilla, honey, lemon, strawberry guarana, raspberry, black current, caramel chocolate, mint cool, fantasy flavour, bubble gum, citrus, lemon, lime, apple, apricot, peppermint, spearmint peach, pear, plum flavour and or mixture thereof.
Sodium hydroxide and/or hydrochloric acid is used to adjust the pH of about 4 to about 7.
In some embodiments, topical composition is in the form of lotion or cream.
In some preferred embodiments, topical composition is in the form of cream.
In some preferred embodiments, topical composition is in the form of lotion.
In some embodiments, topical composition is not in the form of gel.
In some embodiments, pH of the composition is in the range of about 4 to about 7.
In some embodiments, topical cream comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein pH of the cream is 5.5.
In some embodiments, topical lotion comprising roflumilast, N-oxide of roflumilast, or salts thereof, wherein pH of the lotion is 5.7.
In some preferred embodiments, topical composition is free of hexylene glycol or diethylene glycol monoethyl ether or polyethylene glycol or dicetyl phosphate or polyethylene glycol ether of cetyl alcohol or mixture thereof.
In some embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof and polyethylene glycol hexadecyl ether.
In some embodiments, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, cetosteryl alcohol and polyethylene glycol hexadecyl ether.
In some embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof and polyethylene glycol hexadecyl ether, wherein the composition is in the form of cream.
In some embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, cetosteryl alcohol and polyethylene glycol hexadecyl ether, wherein the composition is in the form of cream.
In some embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof and polyethylene glycol hexadecyl ether, wherein the composition is in the form of lotion.
In some embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, cetosteryl alcohol and polyethylene glycol hexadecyl ether, wherein the composition is in the form of lotion.
In still another embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof, polyethylene glycol hexadecyl ether and one or more additional carrier suitable for topical administration.
In still another embodiment, topical cream comprising roflumilast, cetosteryl alcohol, polyethylene glycol hexadecyl ether, light liquid paraffin, white liquid paraffin, propylene glycol, disodium Edetate, methyl paraben, benzyl alcohol, fresh citrus flavour, sodium hydroxide and purified water.
In still another embodiment, topical cream comprising about 0.300 % w/w of roflumilast, about 6.000 % w/w of cetosteryl alcohol, about 1.500 % w/w of polyethylene glycol hexadecyl ether, about 4.000 % w/w of light liquid paraffin, about 4.000 % w/w of white liquid paraffin, about 20.000 % w/w of propylene glycol, about 0.010 % w/w of disodium edetate, about 0.140 % w/w of methyl paraben, about 1.000 % w/w of benzyl alcohol, about 0.029 % w/w of fresh citrus flavour, sodium hydroxide in an amount sufficient to adjust pH of about 4 to about 7 of the composition and purified water.
In still another embodiment, topical cream comprising about 0.300 % w/w of roflumilast, about 6.500 % w/w of cetosteryl alcohol, about 1.560 % w/w of polyethylene glycol hexadecyl ether, about 4.500 % w/w of light liquid paraffin, about 4.500 % w/w of white liquid paraffin, about 20.500 % w/w of propylene glycol, about 0.015 % w/w of disodium edetate, about 0.150 % w/w of methyl paraben, about 1.500 % w/w of benzyl alcohol, about 0.030 % w/w of fresh citrus flavour, sodium hydroxide in an amount sufficient to adjust pH of about 4 to about 7 of the composition and purified water.
In still another embodiment, topical lotion comprising roflumilast, cetosteryl alcohol, polyethylene glycol hexadecyl ether, medium chain triglycerides, stearic acid, emulsifying wax, glycerine, propylene glycol, methyl paraben, propyl paraben, fresh citrus flavour, sodium hydroxide and purified water.
In still another embodiment, topical lotion comprising about 0.300 % w/w of roflumilast, about 1.067 % w/w of cetosteryl alcohol, about 0.400 % w/w of polyethylene glycol hexadecyl ether, about 1.467 % w/w of medium chain triglycerides, about 0.713 % w/w of stearic acid, about 0.600 % w/w of emulsifying wax, about 4.000 % w/w of glycerine, about 10.000 % w/w of propylene glycol, about 0.150 % w/w of methyl paraben, about 0.015 % w/w of propyl paraben, about 0.029 % w/w of fresh citrus flavour, sodium hydroxide in an amount sufficient to adjust pH of about 4 to about 7 of the composition and purified water.
In still another embodiment, topical lotion comprising about 0.300 % w/w of roflumilast, about 1.072 % w/w of cetosteryl alcohol, about 0.500 % w/w of polyethylene glycol hexadecyl ether, about 1.490 % w/w of medium chain triglycerides, about 0.741 % w/w of stearic acid, about 0.900 % w/w of emulsifying wax, about 4.500 % w/w of glycerine, about 10.500 % w/w of propylene glycol, about 0.240 % w/w of methyl paraben, about 0.020 % w/w of propyl paraben, about 0.035 % w/w of fresh citrus flavour, sodium hydroxide in an amount sufficient to adjust pH of about 4 to about 7 of the composition and purified water.
In one embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof is packed in conventional packaging material i.e. tube, bottle.
In some embodiments, packaging material is made up of conventional material like plastic or glass.
Plastic material is selected from, but not limited to, polyethylene (PE) polypropylene (PP), low-density polyethylene (LDPE) or high-density polyethylene (HDPE).
In some embodiments, topical cream is packed in lami tube.
In some embodiments, topical lotion is packed in HDPE bottle.
In one general embodiment, topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof is prepared using process comprising steps of:
a) Mixing roflumilast with at least one co-solvent and heating the mixture to the temperature of about 80oC to about 100oC to dissolve roflumilast in co-solvent and optionally adding at least one preservative;
b) Separately, mixing all the emollients and optionally permeation enhancers in a vessel and heating the mixture to the temperature of about 70oC to about 80oC to make clear solution;
c) Separately, taking purified water in vessel and heating to the temperature of about 70oC to about 80oC. Optionally, dissolving chelating agent in the purified water;
d) Slowly mixing solution of step b) in the purified water of step c) with constant stirring and cooling the emulsion till the temperature not more than about 50oC to about 55oC;
e) Slowly mixing solution of step a) in the solution of step d) with constant stirring and cooling the emulsion till the temperature of about 37oC;
f) Optionally, adding fragrance in the emulsion of step e);
g) Adjusting the pH of about 4 to about 7 using sodium hydroxide;
h) Adding the purified water to maintain the desired viscosity.
In some embodiments, preservatives are added during the process of topical composition preparation i.e. in drug solution preparation step of step a), in purified water heating step of step c), in drug and emulsion mixing step of step e), etc.
In some embodiments, preservatives are separately dissolved in co-solvent, i.e. propylene glycol, and mixed with emulsion preparation step of step d).
In another embodiment, topical cream comprising roflumilast, N-oxide of roflumilast, or salts thereof is prepared using process comprising steps of:
a) Mixing roflumilast with at least one co-solvent and heating the mixture to the temperature of about 80oC to about 100oC to dissolve roflumilast in co-solvent and optionally adding at least one preservative;
b) Separately, mixing all the emollients in a vessel and heating the mixture to the temperature of about 70oC to about 80oC to make clear solution;
c) Separately, taking purified water in vessel and heating to the temperature of about 70oC to about 80oC, optionally, dissolving chelating agent in the purified water;
d) Slowly mixing solution of step b) in the purified water of step c) with constant stirring and cooling the emulsion till the temperature not more than about 50oC to about 55oC;
e) Slowly mixing solution of step a) in the solution of step d) with constant stirring and cooling the emulsion till the temperature of about 37oC. optionally, mixing the second preservative;
f) Optionally, adding fragrance in the emulsion of step e);
g) Adjusting the pH of about 4 to about 7 using sodium hydroxide;
h) Adding the purified water to maintain the desired viscosity.
In still another embodiment, topical cream comprising roflumilast, N-oxide of roflumilast, or salts thereof is prepared using process comprising steps of:
a) Mixing roflumilast with propylene glycol and heating the mixture to the temperature of about 80oC to about 100oC to dissolve roflumilast in propylene glycol and adding methyl paraben as preservative, then cooling the solution to a temperature of about 50oC to about 65oC;
b) Separately, mixing cetostearyl alcohol, cetomacrogol-1000, light liquid paraffin and white soft paraffin in a vessel and heating the mixture to the temperature of about 70oC to about 80oC to make clear solution;
c) Separately, taking purified water in vessel and heating to the temperature of about 70oC to about 80oC, followed by dissolving disodium edetate in the purified water;
d) Slowly mixing solution of step b) in the purified water of step c) with constant stirring and cooling the emulsion till the temperature not more than about 50oC to about 55oC;
e) Slowly mixing solution of step a) in the solution of step d) with constant stirring and cooling the emulsion till the temperature of about 37oC. Slowly mixing the benzyl alcohol;
f) Adding fragrance in the emulsion of step e);
g) Adjusting the pH of about 4 to about 7 using sodium hydroxide;
h) Adding the purified water to maintain the desired viscosity.
In another embodiment, topical lotion comprising roflumilast, N-oxide of roflumilast, or salts thereof is prepared using process comprising steps of:
a) Mixing roflumilast with at least one co-solvent and heating the mixture to the temperature of about 80oC to about 100oC to dissolve roflumilast in co-solvent;
b) Separately, mixing all the emollients and permeation enhancers in a vessel and heat the mixture to the temperature of about 70oC to about 80oC to make clear solution;
c) Separately, taking purified water in vessel and heat to the temperature of about 70oC to about 80oC;
d) Slowly mixing solution of step b) in the purified water of step c) with constant stirring and cooling the emulsion till the temperature not more than about 50oC to about 55oC;
e) Slowly mixing solution of step a) in the solution of step d) with constant stirring and cooling the emulsion till the temperature of about 37oC;
f) Dissolving preservatives in co-solvent and mixing this preservative solution in the emulsion prepared in step d);
g) Optionally, adding fragrance in the emulsion of step f);
h) Adjusting the pH of about 4 to about 7 using sodium hydroxide;
i) Adding the purified water to maintain the desired viscosity.
In still another embodiment, topical lotion comprising roflumilast, N-oxide of roflumilast, or salts thereof is prepared using process comprising steps of:
a) Mixing roflumilast with propylene glycol and heating the mixture to the temperature of about 80oC to about 100oC to dissolve roflumilast in co-solvent,. then cooling the solution to a temperature of about 55oC to about 65oC;
b) Separately, mixing of medium chain triglycerides, cetostearyl alcohol, cetomacrogol-1000, stearic acid, emulsifying wax and glycerine in a vessel and heat the mixture to the temperature of about 70oC to about 80oC to make clear solution;
c) Separately, taking purified water in vessel and heating to the temperature of about 70oC to about 80oC;
d) Slowly mixing solution of step b) in the purified water of step c) with constant stirring and cooling the emulsion till the temperature not more than about 50oC to about 55oC;
e) Slowly mixing solution of step a) in the solution of step d) with constant stirring and cooling the emulsion till the temperature of about 37oC;
f) Dissolving methyl Paraben and propyl paraben in propylene glycol by heating to a temperature of about 75oC to about 80oC, then cooling the solution to a temperature of about 60oC to about 65oC and then adding preservative solution in the emulsion prepared in step d);
g) Optionally, adding fragrance in the emulsion of step f),
h) Adjusting the pH of about 4 to about 7 using sodium hydroxide,
i) Adding the purified water to maintain the desired viscosity.
In another embodiment, various parameters are measured of topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof such parameters include, but not limited to, viscosity, appearance, pH, spread-ability, wettability, permeability, toxicology, stability, etc.
Viscosity can be measured using a Brookfield Viscometer (model-‘LV/DV-II +P’) with a ‘LV3 (63)’ spindle at 150 RPM and temperature of about 20oC to about 25oC., and 10 % - 100 % torque.
Permeability of the composition can be measured using in vitro permeation testing (IVPT) such as such as Franz diffusion cells or Phoenix RDS Robotic Diffusion Station.
The wettability of the composition can be measured by any means know to the person skilled in the art. The wettability can be determined by contact angle goniometry. Advantageously, the wettability is determined using sessile (or static) drop measurements. Alternatively, the wettability is determined using advancing and/or receding contact angle measurements optionally measured using a wilhelmy balance. Any comparative data should use the same time of wettability measurement.
Spreadability is measured using any conventional method. Spreadability is dependent of viscosity of the composition. Higher the viscosity, lower the spreadability and lower the viscosity, higher the spreadability.
pH of the topical composition can be measured using pH meter.
Topical composition of the present invention is found to be stable throughout the stability testing storage period. The present invention provides stable topical composition comprising pharmaceutically effective amount of roflumilast and a total impurity of not more than 2 % when the topical composition is kept at 40°C/75% RH and 30°C/75% RH for at least 1 month. Single impurity like 4-amino-3,5 dichloropyridine is found in an amount of not more than 0.5 %. Similarly, total aerobic microbial count and Total yeast and mold count are found in amount of not more than 102 CFU/g, while Staphylococcus aureus and Pseudomonas aeruginosa are absent when the topical composition is kept at 40°C/75% RH and 30°C/75% RH for at least 1 month.
Unless defined otherwise, technical, and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.
The present disclosure is further illustrated by reference to the following examples which is for illustrative purpose only and does not limit the scope of the disclosure in any way.
Example 1
Topical cream comprising roflumilast
Sr No. Ingredients Qty.(% w/w)
1 Roflumilast 0.300
2 Cetostearyl Alcohol 6.500
3 Cetomacrogol -1000 1.560
4 Light liquid paraffin 4.500
5 White soft paraffin 4.500
6 Propylene Glycol 20.500
7 Disodium Edetate 0.015
8 Methyl paraben 0.150
9 Benzyl alcohol 1.500
10 Fresh Citrus 79575 0.030
11 Sodium Hydroxide q.s.
12 Purified water q.s.

Process of preparation:
1) Drug and preservative phase preparation:
Required quantity of propylene glycol was taken in drug phase vessel and roflumilast was dissolved by heating the mixture to the temperature of about 80oC to about 100oC. Methyl paraben was added in the obtained mixture at temperature of about 75oC to about 80oC and then solution was cooled to a temperature of about 55oC to about 65oC.
2) Oil phase preparation:
Cetostearyl alcohol, cetomacrogol-1000, light liquid paraffin and white soft paraffin were taken in oil phase vessel which was heated to a temperature of about 70oC to about 80oC to make clear solution.
3) Aqueous phase preparation:
Required quantity of purified water was taken into the aqueous phase vessel and disodium edetate was dissolved in purified water and heated to a temperature of about 70oC to about 80oC to ensure complete dissolution of disodium edetate.
4) Emulsification:
Aqueous solution of step 3 was stirred and maintained at a temperature of about 75oC to about 80oC. Oil phase of step no 2 was transferred to the aqueous phase of step 3 slowly under stirring till formation of white colored liquid. The preparation was mixed at fast speed for about 20 minutes under stirring, cooling and mixed at slow speed for about 10 minutes. Mixing was continued till cream reached temperature NMT about 50oC to about 55oC.
5) Drug and preservative phase obtained from step 1 was added to step no. 4 under stirring for 30 minutes maintaining temperature NMT about 50oC to about 55oC. Then benzyl alcohol was added slowly under constant stirring till formation of smooth paste and temperature becomes 35°C and below.
6) Fragrance Fresh Citrus 579575 was added to step no. 5 under stirring for 10 minutes.
7) pH of the cream was checked and adjusted with 1N NaOH solution.
8) Remaining purified water was added to step-7 to make up the volume of cream under constant stirring. pH of final cream was checked by preparing 5% Dispersion (in water).
Example 2
Topical lotion comprising roflumilast
Sr No. Ingredients Qty.(% w/w)
1 Roflumilast 0.300
2 Ceto Steryl Alcohol 1.072
3 Cetomacrogol-1000 0.500
4 Medium Chain Triglycerides (MCT) 1.490
5 Stearic Acid 0.741
6 Emulsifying Wax 0.900
7 Glycerine 4.500
8 Propylene Glycol 10.500
9 Methyl paraben 0.240
10 Propyl Paraben 0.020
11 Fragrance: Fresh Citrus 579575 0.035
12 Sodium Hydroxide q.s.
13 Purified water q.s.

Process of preparation:
1) Drug phase preparation:
Required quantity of propylene glycol was taken in drug phase vessel and roflumilast was dissolved by heating the mixture to a temperature of about 80oC to about 100oC. Then the solution was cooled to the temperature of about 50oC to about 65oC.
2) Oil phase preparation:
Required quantity of medium chain triglycerides, cetostearyl alcohol, cetomacrogol-1000, stearic acid, emulsifying wax and glycerin were taken in oil phase vessel and heated the material to a temperature of about 70oC to about 80oC to make clear solution.
3) Aqueous phase preparation:
Required quantity of purified water was taken into the aqueous phase vessel and heated to a temperature of about 70oC to about 80oC.
4) Emulsification:
Aqueous phase of step 3 was kept under constant stirring and maintained the temperature of about 75oC to about 80oC. Oil phase of step no 2 was transferred to the aqueous phase slowly under stirring formation of white colored liquid. Above preparation was mixed at fast speed for 20 minutes under stirring, cooled and then mix at slow speed for 10 minutes. Mixing was continued till lotion reached temperature NMT about 50oC to about 55oC.
5) Drug phase of step-1 was added to step no. 4 under stirring for about 30 minutes till drug phase temperature reached NMT about 50oC to about 55oC. The emulsion was cooled below 37°C.
6) Preservative phase preparation:
Remaining quantity of propylene glycol was taken in preservative phase vessel. Methyl Paraben and propyl paraben were mixed and dissolved by heating to a temperature of about 75oC to about 80oC. The solution was cooled to the temperature of about 60oC to about 65oC and then preservative phase was added to step no. 5 under stirring for 20 minutes under continuous stirring.
7) Fragrance Fresh Citrus 579575 was added to step no.5 under stirring for 10 minutes.
8) pH was checked of the lotion and adjusted with 1N NaOH solution.
9) Remaining quantity of purified water was added to step-7 for make up the volume of lotion under constant stirring. pH of final lotion was checked by preparing 5% dispersion (in water).

Example 3
Stability study of topical cream composition of example 1
Topical cream composition of roflumilast of example 1 was packed in lami tube and placed under stability study at 40°C/75% RH for 6 months.
Condition
Assay (%)
pH
Related Substance (RS)
4-amino-3,5 dichloropyridine Single highest unknown impurity Total unknown impurities Total impurities

Initial 100.7 5.47 ND ND ND ND
1 Month 100.3 5.48 ND ND ND ND
2 Month 100.4 5.48 ND ND ND ND
3 Month 101.3 5.46 ND 0.128 ND 0.008
6 Month 98.7 5.46 0.015 0.128 ND 0.023

ND: Not detected
Example 4
Stability study of topical lotion composition of example 2
Topical lotion composition of roflumilast of example 2 was packed in HDPE bottle and placed under stability study at 40°C/75% RH for 6 months.

Condition
Assay (%)
pH
Related Substance (RS)
4-amino-3,5 dichloropyridine Single highest unknown impurity Total unknown impurities Total impurities

Initial 100.2 5.78 ND ND ND ND
1 Month 99.3 5.75 ND ND ND ND
2 Month 98.5 5.76 ND ND ND ND
3 Month 97.7 5.78 ND 0.018 ND 0.018
6 Month 98.4 5.76 ND 0.053 ND 0.065

ND: Not detected

Example 5
Permeability study of topical cream composition of example 1
The permeability of the roflumilast cream formulation (test sample as manufactured in example 1) was studied using the Phoenix RDS Robotic Diffusion Station and was compared with reference product (brand Zoryve®). Test sample and reference product was transferred in the sample holder and was mounted onto the top of each vertical diffusion cell. Separately 20µl of blank (diffusion medium), standard preparations and sample (test sample and reference sample) were injected in HPLC and peak area counts for Roflumilast was recorded.
Roflumilast amount was calculated as given below-
Amount in cell, µg/mL (Uncorrected):
AT WS 5 P
Amount in cell, µg/ml = ----- x ---- x --- x ---- 100 x F x CV
(Uncorrected) AS 50 50 100

Where,
AT = Peak area count of Roflumilast in sample solution.
AS = Average Peak area count of Roflumilast in standard solution.
WS = Weight of working standard / reference standard taken in mg.
F = Correction factor
CV = Cell volume of the Diffusion apparatus (mL).
P = %Potency of Roflumilast working standard/reference standard on as is basis in mcg/g

Correction factor:
RV
Correction factor (C) = ----- x Amount in cell, µg/mL (Uncorrected)
CV
Where,
RV = Replacement volume (mL)
CV = Total cell volume of the Diffusion apparatus (mL).

Cumulative amount in cell (µg/cell volume in mL):
Cumulative amount in cell (µg/cell volume in mL, corrected) = Amount in cell, µg/ cell volume in mL (uncorrected) + Sum of correction factor of all previous intervals.
Calculate the Cumulative amount (Corrected) for Roflumilast at each time point (µg/ cell volume in mL) as per below formula,
Cumulative amount for first time point in µg/ cell volume in mL P1) = A1
Cumulative amount for second time point in µg/ cell volume in mL (P2) = A1+A2
Cumulative amount for third time point in µg/ cell volume in mL (P1) (P3) = A1+A2+A3

For Further time points Cumulative amount calculated same like as above
Where,
A1 = Amount of Roflumilast of first time point (µg/ cell volume in mL)
A2 = Cumulative amount of Roflumilast of second time point (µg/ cell volume in mL)
A3 = Cumulative amount of Roflumilast of third time point (µg/ cell volume in mL)

Cumulative Diffusion (µg/cm2):
Cumulative Diffusion (µg/cm2) Cumulative amount in cell (µg/ cell volume in mL)
= -----------------------------------------------------------
Surface Area of the Cell

Cumulative amount in cell µg/ml
% Diffusion = ---------------------------------------------- ×100
Total sample concentration

Table 1: Results of permeability study
% Diffusion
Time (hour) Reference product Test sample (Example 1)
0.5 4.3 6.5
1.0 7.4 10.5
2.0 12.4 17.5
4.0 20.6 26.2
6.0 27.9 33.2

Based on the data shown in table 1, test sample provided enhanced permeability of roflumilast when compared with the reference product, thereby demonstrating superior permeabilty. .Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.
All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.
,CLAIMS:
1. A topical composition comprising about 0.1% w/w to about 2.0 % w/w of roflumilast, N-oxide of roflumilast, or salts thereof, and a carrier suitable for topical administration.

2. The topical composition as claimed in claim 1, wherein the carrier is selected from group comprising emollient, permeation enhancer, solvent, co-solvent, preservative, chelating agent, fragrance and pH adjusting agent or mixture thereof.

3. The topical composition as claimed in claim 1, wherein the carrier is polyethylene glycol hexadecyl ether.

4. The topical composition as claimed in claim 1, wherein the carrier is mixture of cetosteryl alcohol and polyethylene glycol hexadecyl ether.

5. The topical composition as claimed in claim 1, wherein the composition is free of hexylene glycol or diethylene glycol monoethyl ether or polyethylene glycol or dicetyl phosphate or polyethylene glycol ether of cetyl alcohol.

6. The topical composition as claimed in claim 1, wherein the composition is in the form of cream or lotion.

7. The topical composition as claimed in claim 1, wherein the composition provides enhanced permeability.

8. A topical cream comprising about 0.300 % w/w of roflumilast, about 6.500 % w/w of cetosteryl alcohol, about 1.560 % w/w of polyethylene glycol hexadecyl ether, about 4.500 % w/w of light liquid paraffin, about 4.500 % w/w of white liquid paraffin, about 20.500 % w/w of propylene glycol, about 0.015 % w/w of disodium edetate, about 0.150 % w/w of methyl paraben, about 1.500 % w/w of benzyl alcohol, about 0.030 % w/w of fresh citrus flavour, sodium hydroxide in an amount sufficient to adjust pH of about 4 to about 7 of the composition and purified water.

9. A topical lotion comprising about 0.300 % w/w of roflumilast, about 1.072 % w/w of cetosteryl alcohol, about 0.500 % w/w of polyethylene glycol hexadecyl ether, about 1.490 % w/w of medium chain triglycerides, about 0.741 % w/w of stearic acid, about 0.900 % w/w of emulsifying wax, about 4.500 % w/w of glycerine, about 10.500 % w/w of propylene glycol, about 0.240 % w/w of methyl paraben, about 0.020 % w/w of propyl paraben, about 0.035 % w/w of fresh citrus flavour, sodium hydroxide in an amount sufficient to adjust pH of about 4 to about 7 of the composition and purified water.

10. The topical composition as claimed in any of the preceding claims, wherein the composition remains stable for at least 1 month when stored at 30°C and 75% relative humidity or at 40°C and 75% relative humidity.

11. A process for preparing topical composition comprising roflumilast, N-oxide of roflumilast, or salts thereof comprising steps of:
a. mixing roflumilast with at least one co-solvent and heating the mixture to the temperature of about 80oC to about 100oC to dissolve roflumilast in co-solvent and optionally adding at least one preservative;
b. separately, mixing all the emollients and optionally permeation enhancers in a vessel and heating the mixture to the temperature of about 70oC to about 80oC to make clear solution;
c. separately, taking purified water in vessel and heating to the temperature of about 70oC to about 80oC, optionally, dissolving chelating agent in the purified water;
d. slowly mixing solution of step b) in the purified water of step c) with constant stirring and cooling the emulsion till the temperature not more than about 50oC to about 55oC;
e. slowly mixing solution of step a) in the solution of step d) with constant stirring and cooling the emulsion till the temperature of about 37oC;
f. optionally, adding fragrance in the emulsion of step e);
g. adjusting the pH of about 4 to about 7 using sodium hydroxide;
h. adding the purified water to maintain the desired viscosity.