DESC:Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

The term "Tofacitinib" as used herein includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof, the term "pharmaceutically acceptable salt"
15 means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

20 The term, "pharmaceutically acceptable excipients" as used herein refers to Solubiliser, solvents, co-solvents, preservatives, wetting agents, thickening agents, rheology modifiers or thickening agent, antifoaming agents, stabilizers, an antioxidant, a chelating agent, an oil phase, an emulsifier, a penetration enhancer, a pH adjusting agent, a preservative, an antimicrobial agent, an opacifier, a fragrance, a colorant, a gelling agent, a moisturizer, a
25 surfactant and the like. The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.

The term “Solubiliser” as used herein refers to any one of the solvents selected from the group comprising of dimethyl sulfoxide, propylene glycol, glycerin, poly ethylene glycol, isopropyl alcohol, methanol, sodium pyrrolidone carboxylate, 2-hydroxypropyl-?-cyclodextrin, acetone, purified water, ethanol, 1-propanol, butanediol, 2-(2-ethoxyethoxy)ethanol (transcutol), or a combination thereof. Preferably, tofacitinib is freely soluble in the solvent. More preferably, the solvent is dimethyl sulfoxide.

The term "Co-solvent" as used herein refers to any one of the solvents selected from the group comprising, but are not limited to propylene glycol, glycerin, poly ethylene glycol, isopropyl
10 alcohol, methanol, sodium pyrrolidone carboxylate, 2-hydroxypropyl-?-cyclodextrin, acetone, purified water, ethanol, 1-propanol, butanediol, 2-(2-ethoxyethoxy)ethanol (transcutol), or a combination thereof.
The term "Rheology Modifier or Thickening Agent" as used herein refers to any one of the
15 agent selected from the group comprising, but are not limited to cellulose derivative, Hydroxy Propyl Cellulose, polyvinylpyrrolidone, carbomer polymer, carbomer derivative, maltodextrin, polydextrose, dextrates, carboxypolymethylene, polyvinyl alcohol, poloxamers, polyethylene glycols, or a combination thereof. More preferably, the thickening agent is hydroxypropyl cellulose.
20
The term " antioxidant " as used herein refers to any one of the agent. Preferably, the antioxidant selected from the group comprising, but are not limited to butylated hydroxyanisole, butylated hydroxytoluene, vitamin C, vitamin E, vitamin A, lutein, lycopene, retinyl palmitate, potassium metabisulfite, sodium metabisulfite, sodium thiosulfate pentahydrate, 3,4-dihydroxybenzoic
25 acid, propyl gallate, alpha-lipoic acid, ascorbyl palmitate, sodium pyrosulfite, ubiquinone, selenium, or a combination thereof. More preferably, the antioxidant is butylated hydroxyanisole.

The term "chelating agent" as used herein refers to any one of the agent. Preferably, the chelating agent selected from the group comprising, but are not limited to ethylenediaminetetraacetic acid (EDTA), a salt of EDTA, desferrioxamine B, deferoxamine, dithiocarb sodium, penicillamine, pentetate calcium, a sodium salt of pentetic acid, succimer, trientine, nitrilotriacetic acid, trans-diaminocyclohexanetetraacetic acid (DCTA), diethylenetriaminepentaacetic acid, bis(aminoetliyl) glycolether-N,N,N',N'-tetraacetic acid, iminodiacetic acid, citric acid, tartaric acid, fumaric acid, or a combination thereof. More preferably, the chelating agent is ethylenediaminetetraacetic acid (EDTA).

The term "emulsifier" as used herein refers to any one of the agent preferably the emulsifier selected from the group comprising, but are not limited to cetearyl alcohol, sorbitan isostearate,
10 glyceryl stearate, PEG-100 stearate, potassium olivate, polysorbate, sorbitan ester, decyl glucoside, hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, or a combination thereof. More preferably, the emulsifier is hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer.

15 The term "Oil phase" as used herein refers to any one of the agent. Preferably, the Oil phase selected from the group comprising, but are not limited to vegetable oil, mineral oil, petrolatum, medium chain triglyceride (MCT) oil, soybean oil, sesame-seed oil, peanut oil, sunflower oil, cotton-seed oil, castor oil, olive oil, animal oils, fatty acids, synthetic oils, natural and synthetic glycerides, sterol esters, fatty alcohols, silicone oil, or a combination thereof. More preferably,
20 the oily material is mineral oil, medium chain triglyceride (MCT) oil, or castor oil. Most preferably, the oily material is castor oil.

The term "Topical composition" or "pharmaceutical composition" or “dosage form” as used herein synonymously include Topical dosage forms such as a solution, a suspension, a cream,
25 an ointment, a lotion and a gel. Preferably, the topical formulation is a solution or a gel. More preferably, the topical formulation is a gel.

The term "stable" as used herein refers to formulations that substantially retain the label amount of the therapeutically active ingredient during storage for commercially relevant times, and the
30 drug-related impurity contents in the formulations remain within acceptable limits.

In certain exemplary embodiments, the pharmaceutical composition comprises, Tofacitinib or its pharmaceutically acceptable salt thereof, as generally described below. Some preferred, but non-limiting examples of suitable pharmaceutically acceptable organic and/or inorganic acids
5 are hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, acetic acid and citric acid, as well as other pharmaceutically acceptable acids

The terms “prevent” and “preventing” as used herein refers the prevention of the recurrence, spread or onset. It is not intended that the present disclosure be limited to complete prevention.
10 In some embodiments, the onset is delayed, or the severity of the disease is reduced.

The articles "a" and "an" are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "a solvent" means one solvent or more than one solvent.
15
Throughout this specification and the appended claims, it is to be understood that the words "comprise", “have”, “contain” and "include" and variations such a "comprises", "comprising", "having", "containing" "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an
20 element or elements not specifically recited.

According to one embodiment, the present invention relates to a stable topical compositions comprising tofacitinib or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
25
In another embodiment, the present invention relates to a stable topical composition, wherein the topical composition is in the form selected from the group consisting of a solution, a suspension, a cream, an ointment, a lotion and a gel.

In another embodiment, the present invention relates to a stable topical composition, wherein the topical formulation is in the form selected from a solution, a gel and a cream.

According to one embodiment, the present invention relates to a stable topical composition
5 comprising:
(a) about 0.1 % w/w to about 10 % w/w tofacitinib or pharmaceutically acceptable salt thereof;
(b) about 1 % w/w to about 95 % w/w of a Solubiliser;
(c) about 10 % w/w to about 70% w/w of a Co-Solvent;
(d) about 0.01 % w/w to about 5% w/w of a Rheology Modifier or thickening agent;
10 (e) about 0 % to about 5 % of antioxidant; and
(f) optionally, one or more other pharmaceutically acceptable excipients.

According to one embodiment, the present invention relates to a stable topical composition comprising:
15 (a) about 0.1 % w/w to about 10 % w/w tofacitinib or pharmaceutically acceptable salt thereof;
(b) about 1% w/w to about 95 % w/w of a Dimethyl Sulfoxide;
(c) about 10% w/w to about 70% w/w of a Iso Propyl Alcohol;
(d) about 0.01% w/w to about 5% w/w of a Hydroxy Propyl Cellulose;
(e) about 0 % to about 5 % of butylated hydroxyanisole; and
20 (f) optionally, one or more other pharmaceutically acceptable excipients.

In another embodiment, the present invention relates to a stable topical composition comprising:
(a) about 0.1 % w/w to about 10 % w/w tofacitinib citrate;
25 (b) about 1% w/w to about 95 % w/w of a Dimethyl Sulfoxide;
(c) about 10% w/w to about 70% w/w of a Iso Propyl Alcohol;
(d) about 0.01% w/w to about 5% w/w of a Hydroxy Propyl Cellulose;
(e) about 0 % to about 5 % of butylated hydroxyanisole; and
(f) optionally, one or more other pharmaceutically acceptable excipients.
30
In another embodiment, the present invention relates to the process of preparation of an stable topical composition of tofacitinib, which is prepared by mixing Dimethyl Sulfoxide and tofacitinib until clear solution is obtained. To the above mixture Iso Propyl Alcohol followed by Hydroxy Propyl Cellulose is added and stirred well until uniform gel is obetained. The above
5 composition is allowed to stand under vacuum blended for 60- 120 minutes with intermittent stirring at low speed till a clear gel free of entrapped air is obtained.

In another embodiment, the present invention composition relates to the stable topical composition comprising tofacitinib or its pharmaceutical salt thereof having good stability,
10 excellent skin penetration capacity and better bioavailability.

In another embodiment, tofacitinib is administered to the skin at a daily therapeutically effective dose of about 0.5 mg/cm2 to about 60 mg/cm2. The topical composition is meant for once daily, twice daily or thrice daily administration.
15
According embodiment, the present invention relates to the stable topical composition comprising tofacitinib or its pharmaceutical salt thereof for the treatment JAK mediated diseases selected from rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Ulcerative Colitis in adults and Polyarticular Course Juvenile Idiopathic Arthritis
20
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

25 Example 1: Tofacitinib Citrate topical composition:

S. No. Ingredients Functional
Category Quantity per unit
(mg) % w/w
1. Tofacitinib Citrate API 32.30 3.23
2. Dimethyl Sulfoxide Solubiliser 350.00 35.00
3. Iso Propyl Alcohol Co-Solvent 597.70 59.77
4. Hydroxy Propyl
Cellulose Rheology Modifier 20.00 20.00
Total 1000.00 100.00

MANUFACTURING PROCESS:
i. Tofacitinib Citrate was dissolved in Solubiliser until clear solution is obtained.
ii. To the above obtained clear solution Iso Propyl Alcohol was added and stirred to obtain
5 a clear solution.
iii. To the above obtained clear solution Hydroxy Propyl Cellulose was added and stirred at medium speed until uniform gel is obtained.
iv. The above obtained gel was allowed to stand under vacuum, for about 60 – 120 minutes with intermittent stirring at low speed till a clear gel free of entrapped air is obtained.
10 v. Transfer the gel from manufacturing vessel to suitable container for storage until packing.
,CLAIMS:1) A topical composition comprising Tofacitinib or pharmaceutically acceptable salt and at least one solubiliser, a co-solvent, rheology modifier, one or more pharmaceutically acceptable excipients.

2) The topical composition as claimed in claim 1, where in the pharmaceutically acceptable excipients are dimethyl sulfoxide, iso-propyl alcohol, hydroxy propyl cellulose, butylated hydroxyanisole and one or more pharmaceutically acceptable excipients.

3) The topical composition as claimed in claim 1, where in the composition is a topical formulation of cream, ointment, lotion and gel.

4) The topical composition as claimed in claim 1, where in the composition is a topical formulation of gel.

5) The process of preparation of a topical composition as claimed in claim 1, comprising mixing dimethyl sulfoxide and Tofacitinib, followed by iso-propyl alcohol, to the above mixture, hydroxy propyl cellulose is added and stirred well until uniform gel is obtained, the uniform gel is allowed to stand under vacuum blended till a clear gel free of entrapped air is obtained.

6) The topical composition as claimed in claim 1, used for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis in adults and polyarticular course Juvenile Idiopathic Arthritis in patients 2 years of age and older.