DESC:FIELD OF THE APPLICATION
[0001] The present application relates to a topical pharmaceutical composition of apremilast. It also relates to method of treating skin disorders by using said topical pharmaceutical composition of apremilast.
BACKGROUND
[0002] Inflammatory diseases, such as psoriasis, dermatitis (e.g. atopic dermatitis, contact dermatitis), pruritus, arthritis or related arthritic conditions (e.g., ankylosing spondylitis, osteoarthritisor rheumatoid arthritis), are prevalent and problematic worldwide.
[0003] Phosphodiesterase type 4 (PDE4) belongs to a family of isoenzymes referred to as cyclic nucleotide phosphodiesterases (PDE). It is believed that the primary cellular mechanism for the inactivation of cAMP is the breakdown of adenosine 3',5'-cyclic monophosphate (cAMP) by phosphodiesterases. Inhibition of PDE4 has been shown to be particularly effective in the inhibition of inflammatory mediator releases. Thus, compounds that inhibit PDE4 specifically may be beneficial therapeutics in inflammatory conditions. In particular, inflammatory conditions or diseases includes inflammatory skin disorder such as dermatitis (e.g. atopic dermatitis, contact dermatitis), pruritus, psoriasis, keratosis, eczema, rosacea, acne, inflammation, and any other skin related disorders. Apremilast is a small-molecule inhibitor of phosphodiesterase 4 (PDE4) enzyme.
[0004] US patent nos. 6,020,358, 6,962,940, 7,208,516, 7,427,638, 7,659,302 cover the apremilast compound and its use in various ailments. All references cited herein are incorporated in its entirety.
[0005] Apremilast is chemically designated as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetyl-aminoisoindoline-1,3-dione. The empirical formula is C22H24N2O7S and the molecular weight is 460.5; the chemical structure is as follows:
.
[0006] Apremilast is available as an oral tablet dosage form and marketed under the trade name of OTEZLA by Celegene Corp. It is available in 10mg, 20mg, and 30mg strengths and indicated for the treatment of psoriasis or psoriatic arthritis.
[0007] The therapeutic use of apremilast is limited by its systemic side effects, and there remains an unmet need for a topical pharmaceutical compositions of apremilast, which can offer minimal or no systemic side effects, and also with minimum or no irritancy to the skin.
[0008] For any topical composition, the solubilization and release of the drug from composition remains essential and important factor to ensure effective treatment. As apremilast is poorly soluble in water, it remains a great challenge to develop a topical pharmaceutical composition in which apremilast is maximally solubilized and readily released from the composition into the skin.
[0009] There is no approved dosage form of apremilast available for treating inflammatory skin conditions/ diseases. Thus, a need exists for topical dosage forms comprising apremilast with advantageous physical and pharmaceutical properties to reduce the conditions/symptoms associated with the inflammatory skin diseases, such as dermatitis (e.g. atopic dermatitis, contact dermatitis), pruritus, psoriasis, acne, keratosis, eczema, rosacea, skin cancers, inflammation, or other skin related disorders. In an attempt to develop a novel composition of apremilast, the present inventors have developed a stable pharmaceutical composition which would be suitable for topical application.

DESCRIPTION OF THE EMBODIMENTS
[00010] The details of one or more embodiments of the present invention are set forth in this document. Modifications to embodiments described in this document, and other embodiments, will be evident to those of ordinary skill in the art after a study of the information provided in this document. The information provided in this document, and particularly the specific details of the described exemplary embodiments, is provided primarily for clearness of understanding and no unnecessary limitations are to be understood therefrom. In case of conflict, the specification of this document, including definitions, will control.
[00011] Definitions: The terms as used herein have the following meanings:
[00012] The term "comprising" (and its grammatical variations) as used herein is meant to be open ended and used in the inclusive sense of "having" or "including" and not in the exclusive sense of "consisting only of." The term "consists essentially of," as used herein means the claimed elements and others, but is meant to exclude things that are inconsistent with the basic and novel characteristics of the inventions.
[00013] The terms "a" “an” "the" and “(s)” as used herein are understood to encompass the plural as well as the singular or otherwise clearly mentioned wherever needed. For example, reference to "base(s)" includes reference to one or more of such bases, and reference to "the solvent" includes reference to one or more of such solvents.
[00014] The terms such as “about,” “up to,” “generally,” and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances, and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technical error and instrumental error for a given experiment, technique or an instrument used to measure a value. The term "about" is used to provide flexibility to a numerical range endpoint by providing that a given value may be "a little above" or "a little below" the endpoint. As used herein, the term "about" means a slight variation of the value specified, preferably within 10 percent of the value specified. Nevertheless, the term "about" can mean a higher tolerance of variation depending on for instance the experimental technique used. Said variations of a specified value are understood by the skilled person and are within the context of the present application. As an illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3 from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4.1, and 5.4, individually. This same principle applies to ranges reciting only one numerical value as a minimum or a maximum.
[00015] The term "topical composition" as used herein, refers to a composition suitably applied directly to the skin, nail, or mucosal tissue, either by hand or through suitable applicator. Also, the "topical composition" described herein are either solid or semi-solid at room temperature and are easily spreadable over the skin in the form of a cream, ointment, salve, gel, jelly, stick, or other commercially acceptable form. As used herein, the "topical composition" has a rheology typical of pseudoplastic or plastic fluids, and when applied to the skin the composition imparts a soft, lubricious, lotion-like feel to the touch.
[00016] As used herein, the terms "composition" and "formulation" are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. Also the terms "formulation" and "composition" may be used to refer to a mixture of one or more active agents with a carrier or other excipients. Furthermore, the term "dosage form" can include one or more formulation(s) or composition(s) provided in a format for administration to the patient in need thereof like ointment, emulsion, cream, gels, suspensions, foams, lotions, sprays and the like. In certain embodiments, the composition of the present application may be a monophasic ointment or biphasic ointment, emulsion or cream.
[00017] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance does or does not occur or exist and that the description includes instances where said event or circumstance occurs or exists and instances where it does not.
[00018] As used herein, the term "mammal" shall refer to the mammalia class of higher vertebrates. The term "mammal" includes, but is not limited to, a human.
[00019] As used herein, the terms “treatment” or “treating” relate to curing or substantially curing a condition, as well as ameliorating at least one symptom of the condition, and are inclusive of prophylactic treatment and therapeutic treatment. As would be recognized by one or ordinary skill in the art, treatment that is administered prior to clinical manifestation of a condition then the treatment is prophylactic (i.e., it protects the subject against developing the condition). If the treatment is administered after manifestation of the condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, control, or maintain the existing condition and/or side effects associated with the condition). The terms relate to medical management of a subject with the intent to substantially cure, ameliorate, stabilize, or substantially prevent a condition, including but not limited to prophylactic treatment to preclude, avert, obviate, forestall, stop, or hinder something from happening, or reduce the severity of something happening, especially by advance action. As such, the terms treatment or treating include, but are not limited to: inhibiting the progression of a condition of interest; arresting or preventing the development of a condition of interest; reducing the severity of a condition of interest; ameliorating or relieving symptoms associated with a condition of interest; causing a regression of the condition of interest or one or more of the symptoms associated with the condition of interest; and preventing a condition of interest or the development of a condition of interest.
[00020] The term “dermatitis” or “atopic dermatitis” as used herein includes a skin condition caused due to inflammation of the skin that may result in itchy, red, swollen, rash and cracked skin. The area of skin involved can vary from small to the entire body. Dermatitis includes atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis, and stasis dermatitis.
[00021] The term “psoriasis” as used herein includes a skin condition characterized by patches of abnormal skin, which are typically red, itchy, and scaly. Psoriasis includes plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis erythrodermic psoriasis or psoriatic arthritis.
[00022] As used herein, an "effective amount" or a "therapeutically effective amount" of a drug refers to a non-toxic, but sufficient to achieve therapeutic results in treating a condition for which the drug is known to be effective. In this instance, an effective amount is an amount of apremilast which is sufficient to treat inflammatory diseases or reduce the conditions/symptoms associated with the inflammatory skin diseases, such as dermatitis (e.g. atopic dermatitis, contact dermatitis), pruritus, psoriasis, acne, keratosis, eczema, rosacea, skin cancers, inflammation, or other skin related disorders, in a patient in need thereof.
[00023] The term "apremilast," as used herein, is intended to include, but not limited to, apremilast and pharmaceutically acceptable, pharmacologically active derivatives of apremilast, including both individual enantiomers of apremilast (dextrogyral and levogyral enantiomers) in their substantially pure form and their pharmaceutically acceptable salts, mixtures (in any ratio) of apremilast enantiomers and their pharmaceutically acceptable salts, and active metabolites of apremilast and their pharmaceutically acceptable salts. The chemical name of apremilast is N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide or (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetyl-aminoisoindoline-1,3-dione. The solid state form of apremilast used in the composition is not critical. For example, apremilast can be amorphous or crystalline. It further includes its salts, stereoisomers, polymorphs, pseudo-polymorphs, hydrates, solvates, prodrugs, chelates, or complexes.
[00024] The term “pharmaceutically acceptable salts” as used herein, includes those salts 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, allergic response and the like, which are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the pharmaceutically active substance having a free base function with a suitable organic acid or inorganic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, any of the salts or co-crystals of apremilast selected from hydrochloride, hydrobromide, sulphate, citrate, phosphate, maleate, formate, acetate, nitrate, mesylate, succinate, benzoate and the like. The salts may be in the form of solvate, hydrate, hemihydrates, or anhydrous forms.
[00025] In an embodiment, the present application relates to a method of treating inflammatory skin conditions or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said administration results in an effective concentration of apremilast in the dermal layers of said subject.
[00026] In another embodiment, the present application relates to a method of treating psoriasis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said administration results in an effective concentration of apremilast in the dermal layers of said subject.
[00027] In another embodiment, the present application relates to a method of treating dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said administration results in an effective concentration of apremilast in the dermal layers of said subject.
[00028] In another embodiment, the present application relates to a method of treating atopic dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said administration results in an effective concentration of apremilast in the dermal layers of said subject.
[00029] In an aspect of the above embodiments, the pharmaceutical composition of apremilast of present application upon topical administration does not show significant plasma concentration.
[00030] In an embodiment, the present application relates to a method of treating inflammatory skin conditions or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition upon topical administration does not show significant plasma concentration.
[00031] In another embodiment, the present application relates to a method of treating psoriasis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition upon topical administration does not show significant plasma concentration.
[00032] In another embodiment, the present application relates to a method of treating dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition upon topical administration does not show significant plasma concentration.
[00033] In another embodiment, the present application relates to a method of treating atopic dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition upon topical administration does not show significant plasma concentration.
[00034] In another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises apremilast in an amount from about 0.005% w/w to about 30% w/w, in an amount from about 0.01% w/w to about 20% w/w, in an amount from about 0.1% w/w to about 5% w/w, in an amount from about 0.2% w/w to about 3.0% w/w, in an amount of about 0.5% w/w, about 0.4% w/w, about 0.3% w/w, about 0.2% w/w, about 1% w/w, about 1.1% w/w, about 1.15% w/w, about 1.2% w/w, about 1.25% w/w, about 1.3% w/w, about 1.35% w/w, about 1.4% w/w, about 1.45% w/w, about 1.5 % w/w, about 1.55% w/w, about 1.6% w/w, about 1.65% w/w, about 1.7% w/w, about 1.75% w/w, about 2% w/w, about 2.25 % w/w, about 2.5% w/w, about 2.75 % w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5 % w/w based on total weight of the composition.
[00035] In another aspect of the above embodiments, the topical pharmaceutical composition of apremilast is formulated into topically applicable dosage form such as a cream, an ointment, a paste, an unguent, a salve, an emulsion, a suspension, a solution, a lotion, a gel, a jelly, a stick, a foam, a spray, a mist, an aerosol, or any other commercially acceptable form.
[00036] In yet another aspect of the above embodiments, the topical pharmaceutical composition of apremilast is stable for at least three months.
[00037] In an embodiment, the present application relates to a method of treating inflammatory skin conditions or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition is stable for at least three months.
[00038] In another embodiment, the present application relates to a method of treating psoriasis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition is stable for at least three months.
[00039] In another embodiment, the present application relates to a method of treating dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition is stable for at least three months.
[00040] In another embodiment, the present application relates to a method of treating atopic dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition is stable for at least three months.
[00041] In one aspect of the above embodiments, the topical pharmaceutical composition of apremilast comprises a pharmaceutically acceptable carrier or excipients. The carriers are useful for topical delivery of the apremilast and according to embodiments of the present application can be any carrier known in the art for topically administering pharmaceuticals, including, but not limited to, pharmaceutically acceptable solvents, such as a polyalcohol or water; emulsions (either oil-in-water or water-in-oil emulsions), such as creams or lotions; micro emulsions; gels; ointments; and aqueous solutions or suspensions. The pharmaceutically acceptable carrier need to be an inert pharmaceutical excipient and does not have any pharmacological effect or cause irritation to the skin.
[00042] In an embodiment, the present application relates to a method of treating inflammatory skin conditions or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition comprises:
a) apremilast or a pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable carrier comprising at least one solubilizer and at least one base or a vehicle.
[00043] In an embodiment, the present application relates to a method of treating psoriasis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition comprises:
a) apremilast or a pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable carrier comprising at least one solubilizer and at least one base or a vehicle.
[00044] In an embodiment, the present application relates to a method of treating dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition comprises:
a) apremilast or a pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable carrier comprising at least one solubilizer and at least one base or a vehicle.
[00045] In an embodiment, the present application relates to a method of treating atopic dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition comprises:
a) apremilast or a pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable carrier comprising at least one solubilizer and at least one base or a vehicle.
[00046] In one aspect of the above embodiments, the topical pharmaceutical composition of the present application may be formulated as ointment or cream or gel or lotion or spray.
[00047] In one embodiments, the present application relates to a topical pharmaceutical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition comprises:
a) apremilast or a pharmaceutically acceptable salt thereof;
b) a pharmaceutically acceptable carrier comprising at least one solubilizer and at least one base or a vehicle.
[00048] In one embodiments, the present application relates to a topical ointment composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition comprises:
a) apremilast or a pharmaceutically acceptable salt thereof;
b) a pharmaceutically acceptable carrier comprising at least one solubilizer and at least one base or a vehicle;
c) at least one permeation enhancer; and
d) at least one stiffening agent.
[00049] In another embodiments, the present application relates to a topical ointment composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition comprises:
a) apremilast or a pharmaceutically acceptable salt thereof;
b) a pharmaceutically acceptable carrier comprising at least one solubilizer and at least one base or a vehicle;
c) at least one emulsifying agent; and
d) at least one viscofying agent.
[00050] In an aspect of the above embodiments, the present application relates to a method of treating inflammatory skin conditions or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical ointment comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof.
[00051] In another aspect of the above embodiments, the present application relates to a method of treating psoriasis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical ointment comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof.
[00052] In another aspect of the above embodiments, the present application relates to a method of treating dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical ointment comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof.
[00053] In another aspect of the above embodiments, the present application relates to a method of treating atopic dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical ointment comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof.
[00054] In another embodiments, the present application relates to a topical cream composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition comprises:
a) apremilast or a pharmaceutically acceptable salt thereof;
b) a pharmaceutically acceptable carrier comprising at least one solubilizer and at least one base or a vehicle;
c) at least one emulsifying agent; and
d) at least one viscofying agent.
[00055] In an aspect of the above embodiments, the present application relates to a method of treating inflammatory skin conditions or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical cream comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof.
[00056] In another aspect of the above embodiments, the present application relates to a method of treating psoriasis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical cream comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof.
[00057] In another aspect of the above embodiments, the present application relates to a method of treating dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical cream comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof.
[00058] In another aspect of the above embodiments, the present application relates to a method of treating atopic dermatitis or a symptom associated therewith in a subject in need thereof, the method comprising topically administering to the affected skin area of the subject a topical cream comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof.
[00059] In another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more solubilizer(s). Apremilast is poorly soluble in water. Thus one or more solubilizer(s) may be used in the preparation of said topical composition. Thus solubilizer(s) used herein, refers to an agent or organic solvent which is used to disperse, solubilize or dissolve apremilast.
[00060] In an aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more solubilizer(s) in an amount from about 0.1% w/w to about 50% w/w, in an amount from about 0.5% w/w to about 40% w/w, in an amount from about 1% w/w to about 30% w/w, in an amount of about 1% w/w, about 2.5% w/w, about 5% w/w, about 7.5% w/w, about 10% w/w, about 12.5% w/w, about 15% w/w, about 17.5% w/w, about 20% w/w, about 22.5% w/w, about 25% w/w, about 27.5% w/w or about 30% w/w, based on total weight of the composition.
[00061] Suitable examples of solubilizer(s) that may be used in the present application include, but are not limited to, solubilizer(s) with group comprising ethers, e.g., diethylene glycol monoethyl ether or Transcutol P.; glycols, such as propylene glycol, polyethylene glycol, or glycerin; dimethyl isosorbide; fatty acid esters, such as isopropyl myristate, isopropyl palmitate, isopropyl stearate, or ethyl oleate; di(lower)alkyl esters of diacids such as diisopropyl adipate or diethyl sebacate; fatty acids, such as capric acid, lauric acid, myristic acid, oleic acid, or linoleic acid; polyoxyethylene sorbitan ester, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80; propylene carbonate, propylene glycol esters such as Capryol 90, propylene glycol diacetate, polyvinyl alcohol, benzyl alcohol or any combination thereof. Propylene glycol esters are mixtures of mono- and diesters of propylene glycol with acids. The acids could be carboxylic acids or saturated and unsaturated fatty acids derived from edible oils and fats. The fatty acid could be long chain or medium chain or small chain. Examples of propylene glycol esters include but are not limited to propylene glycol diacetate, propylene glycol monocaprylate (Caproyl 90), propylene glycol dicaprylate, propylene glycol oleate, propylene glycol isostearate, propylene glycol laurate, propylene glycol myristate any combination thereof.
[00062] In an aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more solubilizer(s), wherein said solubilizer is selected from diisopropyl adipate, propylene carbonate, Capryol 90, dimethyl isosorbide, propylene glycol diacetate, diethyl sebacate, Transcutol P, benzyl alcohol or any combination thereof.
[00063] In another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more base(s) or vehicle to prepare pharmaceutically acceptable topical dosage form.
[00064] In an aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more base(s) or vehicle in an amount from about 2% w/w to about 98% w/w, in an amount from about 5% w/w to about 95% w/w, in an amount from about 10% w/w to about 90% w/w, in an amount from about 15% w/w to about 90% w/w, in an amount from about 20% w/w to about 90% w/w, in an amount from about 30% w/w to about 90% w/w, in an amount from about 40% w/w to about 90% w/w, in an amount from about 50% w/w to about 90% w/w, in an amount of about 50% w/w, about 55% w/w, about 60% w/w, about 65% w/w, about 70% w/w, about 75% w/w, about 80% w/w, about 85% w/w or about 90% w/w, or about 95% w/w based on total weight of the composition.
[00065] Suitable examples of base(s) that may be used in the present application include, but are not limited to, petrolatum, vegetable oil, mineral oil or polyethylene glycol. Suitable petrolatum includes, but are not limited to, mineral jelly, petroleum jelly, white petrolatum, yellow petrolatum, yellow soft paraffin, yellow petroleum or white soft paraffin or any combination thereof. Suitable vegetable oil includes, oils of plant origin such as ojoba oil, sesame oil, rapeseed oil, soyabean oil, medium chain triglycerides (MCT oil) or any combination thereof. Suitable mineral oil includes, but are not limited to, light mineral oil, paraffin oil or lanolin alcohol or any combination thereof. Suitable polyethylene glycol include, but are not limited to, PEG-100, PEG-200, PEG-300, PEG-400, PEG-600 or PEG-800 or any combination thereof.
[00066] In one aspect, the topical pharmaceutical composition of the present application comprises mixture of base materials comprising white petrolatum and mineral oil.
[00067] In another aspect, the topical pharmaceutical composition of the present application comprises mixture of base materials comprising PEG-400 and PEG-3350.
[00068] In yet another aspect, the topical pharmaceutical composition of the present application comprises one or more materials used as vehicle. The vehicle includes, but are not limited to, water or water-miscible solvents such as glycerin or propylene glycol and the like thereof.
[00069] In an aspect of the above embodiments, the topical pharmaceutical composition of the present application optionally further comprises one or more pharmaceutically acceptable excipients, selected from the group comprising of permeation enhancer(s); stiffening agent(s); emulsifying agent(s); viscofying agent(s), preservative(s); chelating agent(s); pH-adjusting agent(s) or neutralizer(s); crystalization inhibitor(s); humectants; fragrances; and any combination thereof.
[00070] Permeation enhancer(s) or penetration enhancer(s) are generally used in topical compositions for promoting the percutaneous absorption of the drug. In one aspect, the topical pharmaceutical composition of the present application may comprise at least one permeation enhancer.
[00071] In aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more permeation enhancer(s) in an amount from about 0.1% w/w to about 30% w/w, in an amount from about 0.5% w/w to about 20% w/w, in an amount from about 1% w/w to about 10% w/w, in an amount of about 1% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w or about 7% w/w, or about 8% w/w, or about 9% w/w, or about 10% w/w, based on total weight of the composition.
[00072] Suitable examples of penetration enhancer(s) that may be used in the present application include, but are not limited to, 2-(2-ethoxyethoxy) ethanol, dimethyl isosorbide, isostearic acid, octanoic acid, oleic acid, oleyl alcohol, lauryl alcohol, ethyl oleate, isopropyl myristate, butyl stearate, methyl laurate, diisopropyl adipate, glyceryl monolaurate, tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethylene glycol, propylene glycol, glycerol and the like or any combinations thereof.
[00073] In another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more penetration enhancer(s), wherein said penetration enhancer is selected from oleyl alcohol, isopropyl myristate, glycerin or any combination thereof.
[00074] In one aspect, the topical pharmaceutical composition of the present application may comprise at least one stiffening agent.
[00075] In aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more stiffening agent(s) in an amount from about 0.5% w/w to about 30% w/w, in an amount from about 1% w/w to about 20% w/w, in an amount from about 2% w/w to about 10% w/w, in an amount of about 2% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 7% w/w or about 8% w/w, based on total weight of the composition.
[00076] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more stiffening agent(s), wherein said stiffening agent(s) includes but are not limited to wax. Suitable wax includes, but are not limited to, white wax, beeswax, paraffin wax, spermaceti wax or any combination thereof.
[00077] In one aspect, the topical pharmaceutical composition of the present application may comprise at least one emulsifying agent.
[00078] In an aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more emulsifying agent(s) or emulsifier in an amount from about 0.1% w/w to about 30% w/w, in an amount from about 0.5% w/w to about 20% w/w, in an amount from about 1% w/w to about 10% w/w, in an amount of about 1% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, about 5% w/w, about 5.5% w/w, about 6% w/w, about 6.5% w/w or about 7% w/w, based on total weight of the composition.
[00079] In another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more emulsifying agent(s) or emulsifier, wherein said emulsifying agent(s) include, but are not limited to, sodium lauryl sulfate, sorbitan sesquioleate, polyglyceryl-2-sesquioleate, polyethylene glycol cetyl/stearyl ethers, polyoxyl 20 cetostearyl ether, sorbitan monostearate, cetostearyl alcohol, cetyl alcohol, stearyl alcohol, glyceryl monostearate, polysorbate 80, Vitamin E TPGS or any combinations thereof.
[00080] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises emulsifying agent, wherein said emulsifying agent is selected from sorbitan sesquioleate, sorbitan monooleate, polyoxyl 20 cetostearyl ether, sorbitan monostearate, cetostearyl alcohol or any combination thereof.
[00081] In another aspect, the topical pharmaceutical composition of the present application may comprise at least one viscofying agent or gelling agent.
[00082] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more viscofying agent(s) or gelling agent(s), in an amount from about 0.01% w/w to about 20% w/w, in an amount from about 0.05% w/w to about 10% w/w, in an amount from about 0.1% w/w to about 5% w/w, in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w, based on total weight of the composition.
[00083] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more viscofying agent(s) or gelling agent(s), wherein said viscofying agent(s) or gelling agent(s), include but are not limited to, carbopol, carbopol 980, acrylamide/sodium acryloyldimethyltaurate copolymer (Sepineo P600), xanthan gum, arabic gum, tragacanth gum, agar, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, carbomer copolymer type B, polyvinyl pyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, or any combination thereof.
[00084] In another aspect, the topical pharmaceutical composition of the present application may comprise at least one preservative.
[00085] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more preservative(s) in an amount from about 0.01% w/w to about 20% w/w, in an amount from about 0.02% w/w to about 10% w/w, in an amount from about 0.03% w/w to about 5% w/w, in an amount of about 0.03% w/w, about 0.05% w/w, about 0.07% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w, based on total weight of the composition.
[00086] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more preservative(s), wherein said preservative(s) include, but are not limited to, benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, sorbic acid or any combination thereof.
[00087] In another aspect, the topical pharmaceutical composition of the present application may comprise at least one pH-adjusting or neutralizer agent.
[00088] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more pH-adjusting agent(s) or neutralizer(s) in an amount from about 0.01% w/w to about 20% w/w, in an amount from about 0.02% w/w to about 10% w/w, in an amount from about 0.05% w/w to about 5% w/w, in an amount of about 0.05% w/w, about 0.075% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w, based on total weight of the composition.
[00089] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more pH-adjusting or neutralizer agent(s), wherein said pH-adjusting or neutralizer agent(s) include, but are not limited to, organic or inorganic acids, such as citric acid, acetic acid, fumaric acid, tartaric acid, phosphoric acid, or hydrochloric acid; organic or inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, triethanolamine, trolamine or any combination thereof.
[00090] In another aspect, the topical pharmaceutical composition of the present application may comprise at least one chelating agent.
[00091] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more chelating agent(s) in an amount from about 0.01% w/w to about 20% w/w, in an amount from about 0.02% w/w to about 10% w/w, in an amount from about 0.05% w/w to about 5% w/w, in an amount of about 0.05% w/w, about 0.075% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w, based on total weight of the composition.
[00092] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more chelating agent(s), wherein said chelating agent(s) include, but are not limited to, disodium edetate, dihydroxyethyl glycine, glucamine or gluconic acid or any combination thereof.
[00093] In another aspect, the topical pharmaceutical composition of the present application may comprise at least one crystalization inhibitor.
[00094] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more crystalization inhibitor(s) in an amount from about 0.01% w/w to about 20% w/w, in an amount from about 0.05% w/w to about 10% w/w, in an amount from about 0.1% w/w to about 5% w/w, in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.5% w/w, about 2% w/w, about 2.5% w/w, about 3% w/w, about 3.5% w/w, about 4% w/w, about 4.5% w/w, or about 5% w/w, based on total weight of the composition.
[00095] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more crystalization inhibitor(s), wherein said crystalization inhibitor(s) include, but are not limited to, polyethylene oxides or polyvinyl alcohol.
[00096] In another aspect, the topical pharmaceutical composition of the present application may comprise at least one humectant.
[00097] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more humectant(s) in an amount from about 0.1% w/w to about 30% w/w, in an amount from about 0.5% w/w to about 20% w/w, in an amount from about 1% w/w to about 10% w/w, in an amount of about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, or about 10% w/w, based on total weight of the composition.
[00098] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more humectant(s), wherein said humectant(s) include, but are not limited to, propylene glycol, glycerin, butylene glycol, sorbitol, triacetin or any combination thereof.
[00099] In another aspect, the topical pharmaceutical composition of the present application may comprise at least one fragrance.
[000100] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more fragrances in an amount from about 0.01% w/w to about 10% w/w, in an amount from about 0.05% w/w to about 5% w/w, in an amount from about 0.1% w/w to about 2% w/w, in an amount of about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 0.6% w/w, about 0.7% w/w, about 0.8% w/w, about 0.9% w/w, about 1% w/w, about 1.5% w/w or about 2% w/w, based on total weight of the composition.
[000101] In yet another aspect of the above embodiments, the topical pharmaceutical composition of the present application comprises one or more fragrance, wherein said fragrance include, but are not limited to, lavender oil, rose oil, lemon oil, almond oil, other FDA approved fragrances or any combination thereof.
[000102] In one aspect of the above embodiments, the topical pharmaceutical composition of apremilast of present application can be used in combination with any other agents for the treatment of psoriasis or atopic dermatitis.
[000103] The topical pharmaceutical composition of apremilast of present application can be manufactured using a method comprising:
a) preparing an oil phase by combining the oil soluble ingredients;
b) preparing a drug phase by dissolving Apremilast in the solubilizers; and adding the drug phase in the oil phase with continuous stirring.
c) optionally, preparing an aqueous phase by combining water soluble ingredients in warm water or vehicle, and optionally adding a preservative
d) adding the aqueous phase of step c) into the step b), followed by homogenization.
[000104] The topical pharmaceutical composition of apremilast of the present application can be part of a kit or device and may be filled into laminated tubes, jars, bottles, pumps, aerosol containers, and any other forms of packaging that facilitate application topically. The compositions are meant to be applied topically, either manually or by using a convenient applicator, for patient compliance and ease of application. The dose, number, and frequency of applications can be determined by a person skilled in the art of treating conditions, such as a physician, a dermatologist, and the like.
[000105] Laminated tubes may be used for packaging. The features and advantages of laminated tubes include ability to retain smoothness, flexibility and softness, increase in product shelf life, excellent barrier properties, excellent seal ability, resistance to print bleeding, tamper evident closures with nozzle seals available, and hot foil stamping. HDPE tubes may also be used for packaging. Examples are pre-printed monolayer plastic tubes made of LDPE/LLDPE blends by extrusion processes and fitted with snap-on flip caps made up of polypropylene.

[000106] The present application is further illustrated by the examples which are provided merely to be exemplary of the pharmaceutical composition described above and do not limit the scope of the application. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.
[000107] The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the present invention, and not to be construed as limiting the application. The following examples may include compilations of data that are representative of data gathered at various times during the course of development and experimentation related to the present invention.

EXAMPLES
[000108] Examples 1 : The composition is tabulated in table below
Ingredients % w/w
Apremilast 2
White petrolatum 66.25
White wax 6.75
Mineral oil 5
Oleyl alcohol 5
Diisopropyl adipate 15

[000109] Procedure:
1. White petrolatum and white wax were melted and mineral oil, oleyl alcohol were added in the mixture.
2. Apremilast was added in diisopropyl adipate and mixed.
3. Mixture of step 2 was added in the mixture of step 1 under stirring and continued stirring to cool the product.

[000110] Examples-2: The composition is tabulated in table below
Ingredients % w/w
Apremilast 2
White petrolatum 70
Sorbitan Sesquioleate 2
Silicon dioxide 1
Diisopropyl adipate 20
Propylene Carbonate 5

[000111] Procedure:
1. White petrolatum and sorbitan sesquioleate were melted.
2. Apremilast was added in the mixture of diisopropyl adipate and propylene carbonate and mixed.
3. Silicon dioxide was added in step 2 mixture and stirred.
4. Mixture of step 3 was added in the mixture of step 1 under stirring and continued stirring to cool the product.

[000112] Examples-3: The composition is tabulated in table below:
Ingredients % w/w
Apremilast 2
PEG 400 51.7
PEG 3350 36
Oleyl alcohol 5
Methyl paraben 0.2
Propyl paraben 0.1
Propylene Carbonate 5

[000113] Procedure:
1. PEG 3350 was melted, and PEG 400 and oleyl alcohol were added in the mixture.
2. Apremilast was added in propylene carbonate and mixed.
3. Methyl paraben and propyl paraben were added in step 2 mixture and stirred.
4. Mixture of step 3 was added in the mixture of step 1 under stirring and continued stirring to cool the product.

[000114] Examples-4: The composition is tabulated in table below:
Ingredients % w/w
Apremilast 2
Diisopropyl adipate 15
Propylene carbonate 5
Carbomer copolymer type B 0.25
Cetostearyl alcohol 5
Polyoxyl 20 cetostearyl ether 3
Sorbitan monostearate 2
Polyvinyl alcohol 2
Glycerin 5
Disodium edetate 0.1
Propyl paraben 0.03
Methyl paraben 0.2
Trolamine 0.4
Purified water 60.020

[000115] Procedure:
1. Cetostearyl alcohol, polyoxyl 20 cetostearyl ether, and sorbitan monostearate were melted, and propyl paraben were added and mixed.
2. Methyl paraben and disodium edetate were added in hot water, and mixed, carbomer copolymer type B and polyvinyl alcohol were added and stirred, followed by addition of glycerin and stirred the mixture.
3. Apremilast was added in the mixture of diisopropyl adipate and propylene carbonate and mixed together. The mixture was added in step 1.
4. Mixture of step 3 was added in the mixture of step 2 under homogenization to obtain emulsion/cream.
5. Trolamine was added in the mixture of step 4 to neutralize carbomer under stirring and continued stirring to cool the product.

[000116] Examples-5: The composition is tabulated in table below:
Ingredients % w/w
Apremilast 3
PEG 400 40.7
PEG 3350 31
Dimethyl isosorbide 15
Propylene glycol diacetate 10
Methyl Paraben 0.2
Propyl Paraben 0.1

[000117] Procedure:
1. PEG 3350 was melted, and PEG 400 were added in the mixture. Methyl paraben and propyl paraben were added subsequently and stirred well.
2. Apremilast was added in propylene glycol diacetate and mixed. Dimethyl isosorbide was added subsequently and stirred.
3. Mixture of step 2 was added in the mixture of step 1 under continued stirring and cool the product till mass congeals.

[000118] Examples- (6a-6c): The compositions are tabulated in table below:
Ingredients 6a (% w/w) 6b (% w/w) 6c (% w/w)
Apremilast 3 2.5 2.5
Propylene Carbonate 40 15 15
Caproyl 90 - 10 10
MCT Oil 10 20 20
Steareth-2 6 5.5 -
Steareth 21 4 4 -
TPGS 0.05 - -
Glyceryl monostearate - - 6
Polysorbate 80 - - 4
Stearyl alcohol 2 2 2
Sepineo P 600 0.5 1 2.5
Purified Water 34.5 40 38

Procedure:
1. Drug phase was prepared by adding apremilast in to propylene carbonate & caproyl 90 mixture as presented in table 6a-6c and dissolved it.
2. Oil Phase was prepared by melting (65-75 °C) oil soluble excipients like MCT oil, steareth-2, steareth-21, stearyl alcohol in a SS vessel and mixed it well.
3. Mixture of Step 1 was added to step 2 and with stirring.
4. Aqueous phase was prepared by adding TPGS or polysorbate 80 in water in a beaker and heated it at 65-75 °C until it dissolves completely.
5. The aqueous phase prepared in step 4 was added to the oil phase prepared in step 3 and homogenized at 6000-7000 rpm for 15 min.

[000119] Stability study
The stability of the topical compositions of present specification were evaluated through accelerated stability studies. Composition was prepared according to the formula and process of example 5, and the composition was subjected to stability study at various temperature and humidity conditions. The composition was found to be stable at accelerated conditions. Table 1 represents the study result data.

Table 1: Stability data of the topical Apremilast composition
Storage
Condition ? Description
Assay Related Substances
Viscosity pH
Single Max Unknown impurity Total Impurities
Initial White colored uniform 100.6 0.042 0.10 7.99 2.68
1 M 40°C/75% RH White colored uniform 96.3 0.546 0.645 7.71 4.46
2 M 40°C/75% RH White colored uniform 98.3 0.065 0.244 6.88 4.41
3 M 40°C/75% RH White colored uniform 97.30 0.09 0.40 6.28 4.48
3 M 25°C/60% RH White colored uniform 97.31 0.06 0.30 7.95 4.52
6 M 25°C/60% RH White colored 96.5 0.12 0.71 6.75 4.42

,CLAIMS:1. A topical composition comprising a therapeutically effective amount of apremilast or its pharmaceutically acceptable salt thereof, wherein said composition comprises:
(i) apremilast or a pharmaceutically acceptable salt thereof, and
(ii) one or more solubilizers.

2. The topical composition as claimed in claim 1, wherein apremilast and the solubilizers are present in ratio of about 1:1 to 1: 40.

3. The topical composition as claimed in claim 1, wherein the solubilizer is selected from one or more of diisopropyl adipate, propylene carbonate, Capryol 90, dimethyl isosorbide, propylene glycol diacetate, diethyl sebacate, benzyl alcohol or mixtures thereof.

4. The topical composition as claimed in claim 3, wherein the solubilizer is propylene carbonate.

5. The topical composition as claimed in claim 3, wherein the solubilizer is mixture of propylene carbonate and propylene glycol diacetate.

6. The topical composition as claimed in claim 1, wherein the composition further comprises one or more bases or a vehicles.

7. The topical composition as claimed in claim 6, wherein the bases are selected from petrolatum, vegetable oil, mineral oil, polyethylene glycol or mixtures thereof.

8. The topical composition as claimed in claim 6, wherein the vehicle is water.

9. The topical composition as claimed in claim 1, wherein the composition further comprises one or more emulsifying agents selected from sodium lauryl sulfate, sorbitan sesquioleate, polyglyceryl-2-sesquioleate, polyethylene glycol cetyl/stearyl ethers, polyoxyl 20 cetostearyl ether, sorbitan monostearate, cetostearyl alcohol, cetyl alcohol, stearyl alcohol, glyceryl monostearate, polysorbate 80, Vitamin E TPGS or mixtures thereof.

10. The topical composition as claimed in claim 1, wherein the composition further comprises one or more viscofying agents or gelling agent selected from, carbopol, carbopol 980, acrylamide/sodium acryloyldimethyltaurate copolymer, xanthan gum, arabic gum, tragacanth gum, agar, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, sodium carboxymethylcellulose, carbomer copolymer type B, polyvinyl pyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, or any mixtures thereof.