DESC:FIELD OF THE INVENTION

This invention relates to a stable topical composition comprising Tofacitinib or a pharmaceutically acceptable salt thereof, wherein the topical composition is lotion or gel, wherein the topical composition is stable for at least 6 months when stored at 30 °C temperature and 75 % relative humidity. Further, the present invention provides a process for the preparation of the said topical composition.

BACKGROUND OF THE INVENTION

Topical dosage form is the preferred dosage form due to ease of application and topical dosage forms increase patient compliance. The major issue in developing the topical dosage form is to develop a stable topical dosage form.

Tofacitinib citrate is a white to off-white powder with the following chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-ß-oxo-1piperidinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate (1:1). Tofacitinib citrate has a molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) and a molecular formula of C16H20N6O•C6H8O7. The chemical structure of tofacitinib citrate is:

The brand name of Tofacitinib citrate is XELJANZ. The XELJANZ is supplied in various dosage forms like immediate-release tablets, extended-release tablets, and solutions.

The XELJANZ immediate-release tablet contains Tofacitinib, croscarmellose sodium, HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin.

XELJANZ XR extended-release tablet contains Tofacitinib, cellulose acetate, copovidone, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC 2910/Hypromellose, magnesium stearate, red or yellow iron oxide, sorbitol, titanium dioxide, and triacetin.

XELJANZ Oral Solution contains tofacitinib, grape flavor (natural), hydrochloric acid, lactic acid, purified water, sodium benzoate, sucralose, and xylitol.

Tofacitinib as a product is disclosed in the USRE41783.

US9937181 discloses a once-daily pharmaceutical dosage form comprising a core comprising 11 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, and an osmagen, and a semi-permeable membrane coating surrounding the core wherein said coating comprises a water-insoluble polymer.

US11253523 discloses a method of treating an immunological disorder in a subject comprising administering to the subject in need thereof a once-daily pharmaceutical dosage form comprising a core comprising 11 mg of tofacitinib, or an equivalent amount of tofacitinib in the form of a pharmaceutically acceptable salt thereof, and an osmagen, and a semi-permeable membrane coating surrounding the core wherein said coating comprises a water-insoluble polymer, wherein said dosage form is a sustained release dosage form.

WO2023143345 discloses a composition comprising 0.6 to 2.9% of tofacitinib tartrate; 5 to 30% of diethylene glycol monoethyl ether; 5 to 20% of an emulsifier; and 31.1 to 77.4% of purified water.

US2023037905 discloses a topical composition comprising tofacitinib or a pharmaceutically acceptable salt thereof, and fingolimod or a pharmaceutically acceptable salt thereof.

US2022401447 discloses a method of delivering tofacitinib to or through the skin. Further, the US2022401447 discloses a topical composition, comprising tofacitinib, and an ionic liquid.

WO2022039850 discloses topical formulations containing tofacitinib and fingolimod that are useful for treating dermatological conditions, such as atopic dermatitis, psoriasis, vitiligo, and eczema.

WO2019152232 discloses a topical formulation comprising tofacitinib, at least one solvent, and optionally one or more other excipients. There is no example of lotion given in this patent application and no mention of stability for the long duration.

Recently Intas Pharmaceutical has launched Tofacitinib Ointment for Atopic Dermatitis.

Tofacitinib undergoes degradation to due to its inherent characteristics or changes in light, temperature, pH, or humidity during manufacturing, transportation, and storage, and therefore Developing a stable topical composition of Tofacitinib is a major challenge.

From the above, it can be said that the available references disclose oral dosage form, oral solution, ointment, and gel dosage form. However, none of the references discloses the topical composition having characteristics as per the present invention.

Therefore, there is a need to have a stable topical composition, specifically stable lotion and gel composition which is stable for at least 24 months and overcomes the limitations of the currently marketed formulations.

OBJECT OF THE INVENTION

The principal object of this invention is to provide a stable topical composition comprising Tofacitinib.

Another object of this invention is to provide a topical composition comprising a therapeutically effective amount of tofacitinib, at least one or more penetration enhancers, at least one or more solvents or a combination thereof, at least one or more viscosity modifiers and optionally, one or more other pharmaceutically acceptable excipients, wherein the topical composition is stable for at least 6 months when stored at 30 °C temperature and 75 % relative humidity.

Another object of this invention is to provide a stable topical composition comprising Tofacitinib, wherein the topical composition is lotion or gel.

Another object of this invention is to provide a stable topical composition comprising Tofacitinib, wherein the topical composition is lotion.

Another object of this invention is to provide a stable topical composition comprising Tofacitinib, wherein the topical composition is gel.

Another object of this invention is to provide a stable lotion composition comprising a therapeutically effective amount of tofacitinib, at least one or more penetration enhancers, at least one or more solvents or combination thereof, at least one or more viscosity modifiers; and optionally, one or more other pharmaceutically acceptable excipients.

Another object of this invention is to provide a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof, penetration enhancer, one or more solvents or combination thereof, wherein the lotion is stable for at least 6 months when stored at 30 °C temperature and 75 % relative humidity.

Another object of the present invention is to provide a stable lotion composition comprising a therapeutically effective amount of tofacitinib citrate, dimethyl sulfoxide, propylene glycol, water, alcohol, a viscosity modifier, and optionally, one or more other pharmaceutically acceptable excipients.

Another object of the present invention is to provide a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof, Dimethyl sulfoxide, Isopropyl alcohol, and water, wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5.

Another object of the present invention is to provide a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof, Dimethyl sulfoxide, Isopropyl alcohol, and water, wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5, wherein pH of the Lotion is pH 4.0 to 6.0.

Another object of this invention is to provide a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof in a concentration of 1% w/v to about 3% w/v and Dimethyl sulfoxide in an amount of 30% w/v to about 50% w/v and Isopropyl alcohol in an amount of 10% w/v to about 30% w/v, and water in an amount of 5% w/v to about 15% w/v, wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5.

Another object of this invention is to provide a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof in a concentration of 1% w/v to about 3% w/v and Dimethyl sulfoxide in an amount of 30% w/v to about 50% w/v and Isopropyl alcohol in an amount of 10% w/v to about 30% w/v, and water in an amount of 5% w/v to about 15% w/v, wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5, wherein the lotion is stable for at least 6 months when stored at 30 °C temperature and 75 % relative humidity.

Another object of the present invention is to provide a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof, Dimethyl sulfoxide, Isopropyl alcohol, and water, wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5; wherein the total impurity in the composition is less than 2% and a single maximum impurity is less than 0.5% of tofacitinib after 6 months when stored at 30 °C temperature and 75 % relative humidity.

A further object of this invention is to provide a stable gel composition comprising a therapeutically effective amount of tofacitinib, at least one or more penetration enhancers, at least one or more solvents or combination thereof, at least one or more viscosity modifiers; and optionally, one or more other pharmaceutically acceptable excipients.

A further object of this invention is to provide a stable gel composition comprising a therapeutically effective amount of tofacitinib citrate, dimethyl sulfoxide, propylene glycol, a viscosity modifier, suitable PH adjusting agent, and optionally, one or more other pharmaceutically acceptable excipients.

A further object of this invention is to provide a stable gel composition comprising a therapeutically effective amount of tofacitinib citrate, dimethyl sulfoxide, propylene glycol, a viscosity modifier, suitable PH adjusting agent, and optionally, one or more other pharmaceutically acceptable excipients, wherein pH of the Gel is 4.5 to 7.5.

SUMMARY OF THE INVENTION

The present invention provides a stable topical composition comprising Tofacitinib or a pharmaceutically acceptable salt thereof, wherein the topical composition is lotion or gel, wherein the topical composition is stable for at least 6 months when stored at 30 °C temperature and 75 % relative humidity. Further, the present invention provides a process for the preparation of the said topical composition. The stable lotion and gel composition has a shelf life of at least 24 months and overcomes the limitations of the currently marketed formulations.

DETAILED DESCRIPTION OF THE INVENTION

The detailed description and the examples provided herein are exemplary and any modification or variation within the scope of the invention will be apparent to a person skilled in the art. Further, unless otherwise defined, all the technical and scientific terms used herein shall bear the meaning as understood by a person who is ordinarily skilled in the art.

According to the present invention, the term “topical” means the pharmaceutical composition for application to a body surface, more specifically to the skin, more specifically topical composition according to the present invention is lotion or gel.

According to the present invention, the term “lotion” refers to a liquid composition containing at least one insoluble substance applied externally to the affected skin.

According to the present invention, the term “stable lotion” refers to a lotion of the present invention that is physically and chemically stable at room temperature for at least 18 months. The room temperature has the same meaning as known to the person skilled in the art and as mentioned in the official compendium like USP or IP.

According to the present invention, the term “gel” refers to semisolid preparations that contain the active ingredient in a suitable base.

According to the present invention, the term “stable gel” refers to a gel of the present invention that is physically and chemically stable at room temperature for at least 18 months. The room temperature has the same meaning as known to the person skilled in the art and as mentioned in the official compendium like USP or IP.

According to the present invention, the term “room temperature stable lotion” or “lotion stable at room temperature” refers to a lotion of the present invention that, when stored at room temperature (25 °C) and 60 % relative humidity, remains physically and chemically stable. The total impurities of the lotion are not more than 2 % and the single maximum impurity is not more than 0.5 % after 6 months of storage at 30 °C temperature and 75 % relative humidity.

According to the present invention, the term “room temperature stable gel” or “gel stable at room temperature” refers to a gel of the present invention that, when stored at room temperature (25 °C) and 60 % relative humidity, remains physically and chemically stable. The total impurities of the gel are not more than 2 % and the single maximum impurity is not more than 0.5 % after 6 months of storage at 25 °C temperature and 60 % relative humidity.

According to the present invention, the term “tofacitinib” means a tofacitinib in the form of free base, pharmaceutically acceptable salts, racemates, diastereomers, isomers, analogs, and mixtures thereof.

According to the present invention, Tofacitinib is in the form of a pharmaceutically acceptable salt like citrate salt, hydrochloride salt, hydrobromide salt, oxalate salt, nitrate salt, sulfate salt, phosphate salt, fumarate salt, succinate salt, maleate salt, besylate salt, tosylate salt, palmitate salt, and tartrate salt or like or mixture hereof. Preferably, the pharmaceutically acceptable salt is citrate salt.

The present invention provides a stable topical composition comprising Tofacitinib.

In one of the embodiments, the present invention provides a stable topical composition comprising Tofacitinib, wherein the topical composition is lotion or gel.

In one of the embodiments, the present invention provides a stable topical composition comprising Tofacitinib, wherein the topical composition is lotion.

According to the present invention, the topical composition is lotion, wherein the pH of the lotion is 4 – 6, preferably at pH 4.5 to 5.5.

In one of the embodiments, the present invention provides a stable topical composition comprising Tofacitinib, wherein the topical composition is gel.

In another embodiment, the present invention provides a topical composition comprising a therapeutically effective amount of tofacitinib, at least one or more penetration enhancers, at least one or more solvents or a combination thereof, at least one or more viscosity modifiers and optionally, one or more other pharmaceutically acceptable excipients, wherein the topical composition is stable for at least 6 months when stored at 30 °C temperature and 75 % relative humidity.

According to the present invention, the penetration enhancers are selected from dimethyl sulfoxide, dimethyl formamide, dimethyl isosorbide, sodium lauryl sulphate, diethylene glycol monoethyl ether, or like or a mixture thereof. Preferably, the penetration enhancer is dimethyl sulfoxide. The amount of penetration enhancers is 30% w/v to about 80% w/v.

According to the present invention, when the topical composition is a lotion, the solvent is selected from propylene glycol, polyethylene glycol, hexylene glycol, glycerin, purified water, alcohol, and a combination thereof. The alcohol can be ethanol, methanol, or isopropyl alcohol. More preferable, alcohol is isopropyl alcohol.

According to the present invention, the viscosity modifier can be selected from xanthan gum, tragacanth, cellulose derivatives, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose sodium, carbomer polymer, carbomer derivative or a mixture thereof. Preferably, the viscosity modifier is hydroxypropyl cellulose. The amount of the viscosity modifier is 0.1% w/v to about 1.5% w/v.

In another embodiment, the present invention provides a stable lotion composition comprising a therapeutically effective amount of tofacitinib, at least one or more penetration enhancers, at least one or more solvents or combination thereof, at least one or more viscosity modifiers; and optionally, one or more other pharmaceutically acceptable excipients.

The topical formulation of the present invention may include additional pharmaceutically acceptable excipients selected from a stabilizer, an antioxidant, a chelating agent, a preservative, an antimicrobial agent, a fragrance, a colorant, etc.

In another embodiment, the present invention provides a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof, penetration enhancer, one or more solvents or combination thereof, wherein the lotion is stable for at least 6 months when stored at 30 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a stable lotion composition comprising a therapeutically effective amount of tofacitinib citrate, dimethyl sulfoxide, propylene glycol, water, alcohol, a viscosity modifier, and optionally, one or more other pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof, Dimethyl sulfoxide, Isopropyl alcohol, and water, wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5.

In another embodiment, the present invention provides a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof, Dimethyl sulfoxide, Isopropyl alcohol, and water, wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5, wherein pH of the Lotion is pH 4.0 to 6.0, more preferably at pH 4.5 to 5.5.

In another embodiment, the present invention provides a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof in a concentration of 1% w/v to about 3% w/v, Dimethyl sulfoxide in an amount of 30% w/v to about 50% w/v, isopropyl alcohol in an amount of 10% w/v to 30% w/v, and water in an amount of 5% w/v to about 15% w/v, wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5.

In another embodiment, the present invention provides a stable lotion composition comprising about 1.615% w/v to about 4.845% w/v of tofacitinib citrate; 10% w/v to about 50 % w/v of dimethyl sulfoxide; about 10 % w/v to about 60 % w/v of mixture of propylene glycol, water and alcohol; 0.1 % w/v to about 2% w/v of hydroxypropyl cellulose; and optionally, one or more other pharmaceutically acceptable excipients, based on the total volume of the topical formulation.

In another embodiment, the present invention provides a stable lotion composition comprising about 1.615% w/v to about 4.845% w/v of tofacitinib citrate; 10% w/v to about 50 % w/v of dimethyl sulfoxide; about 10 % w/v to about 60 % w/v of mixture of propylene glycol, water and alcohol; 0.1 % w/v to about 2% w/v of hydroxypropyl cellulose; and optionally, one or more other pharmaceutically acceptable excipients, based on the total volume of the topical formulation, wherein the lotion is stable for at least 6 months when stored at 30 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof in a concentration of 1% w/v to about 3% w/v and Dimethyl sulfoxide in an amount of 30% w/v to about 50% w/v and Isopropyl alcohol in an amount of 10% w/v to about 30% w/v, and water in an amount of 5% w/v to about 15% w/v, wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5, wherein the lotion is stable for at least 6 months when stored at 30 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a stable lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof, Dimethyl sulfoxide, Isopropyl alcohol, and water, wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5; wherein the total impurity in the composition is less than 2% and a single maximum impurity is less than 0.5% of tofacitinib after 6 months when stored at 30 °C temperature and 75 % relative humidity.

In another embodiment, the present invention provides a stable gel composition comprising a therapeutically effective amount of tofacitinib, at least one or more penetration enhancers, at least one or more solvents or combination thereof, at least one or more viscosity modifiers; and optionally, one or more other pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a stable gel composition comprising a therapeutically effective amount of tofacitinib citrate, dimethyl sulfoxide, propylene glycol, a viscosity modifier, suitable PH adjusting agent, and optionally, one or more other pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a stable gel composition comprising a therapeutically effective amount of tofacitinib citrate, dimethyl sulfoxide, propylene glycol, a viscosity modifier, suitable PH adjusting agent, and optionally, one or more other pharmaceutically acceptable excipients, wherein pH of the Gel is 4.5 to 7.5, more preferably at pH 5.5 to 6.5.

In another embodiment, the present invention provides a stable gel composition comprising about 1.615% w/w to about 4.845% w/w of tofacitinib citrate; 10% w/ w to 80 % w / w of dimethyl sulfoxide; about 10 % w / w to 60 % w / w of propylene glycol; 0.5 % w/w to 5 % w/w of hydroxypropyl cellulose; and optionally, one or more other pharmaceutically acceptable excipients, based on the total weight of the topical formulation.

EXAMPLES

The present invention has been described by way of example only, and it is to be recognized that modifications thereto filling within the scope and spirit of appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be within the scope of this invention.

Examples 1: Composition of Tofacitinib lotion

Sr. No. Ingredients % w/v
1 Tofacitinib citrate 1 - 5
2 Penetration enhancer 10 - 50
3 Isopropyl alcohol 10 - 30
4 Purified water 5 - 15
5 Viscosity modifier 0.1 – 2
6 Propylene Glycol Q.S. to 100.00

Process for preparation for example 1:

1. Tofacitinib citrate was dissolved in a penetration enhancer to prepare the API solution.
2. A viscosity modifier was added to the mixture of Isopropyl alcohol, Purified water, and Propylene Glycol to prepare the lotion base.
3. The API solution of step 1 was added to the lotion base of step 2.
4. The solution of step 3 was stirred till the homogeneous lotion was obtained.

Examples 2: Composition of Tofacitinib lotion

Sr. No. Ingredients % w/v
1 Tofacitinib citrate 1 - 5
2 Dimethyl sulfoxide 10 - 50
3 Isopropyl alcohol 10 - 30
4 Purified water 5 - 15
5 Hydroxypropyl cellulose 0.1 – 2
6 Propylene Glycol Q.S. to 100.00

Process for preparation for example 2:

1. Tofacitinib citrate was dissolved in Dimethyl sulfoxide to prepare API solution.
2. Hydroxypropyl cellulose was added to the mixture of Isopropyl alcohol, Purified water, and Propylene Glycol to prepare the lotion base.
3. The API solution of step 1 was added to the lotion base of step 2.
4. The solution of step 3 was stirred till the homogeneous lotion was obtained.

Examples 3: Composition of Tofacitinib lotion (2% w/v)

Sr. No. Ingredients % w/v
1 Tofacitinib citrate 3.23
2 Dimethyl sulfoxide 40.00
3 Isopropyl alcohol 20.00
4 Purified water 10.00
5 Hydroxypropyl cellulose 0.50
6 Propylene Glycol Q.S. to 100.00

Process for preparation for example 3:

1. Tofacitinib citrate was dissolved in Dimethyl sulfoxide to prepare API solution.
2. Hydroxypropyl cellulose was added to the mixture of Isopropyl alcohol, Purified water, and Propylene Glycol to prepare the lotion base.
3. The API solution of step 1 was added to the lotion base of step 2.
4. The solution of step 3 was stirred till the homogeneous lotion was obtained.

The lotion of Example 3 was subject to stability study at two different stability conditions. Following are the stability study results.

Accelerated stability study (of lotion obtained in Example 3):

Accelerated stability study: Stability study condition: 40 °C temperature and 75 % relative humidity
Initial 3 - Months 6 - Months
Test Parameters
Description A clear pale yellow color liquid A clear pale yellow color liquid A clear pale yellow color liquid
pH 4.59 4.63 4.69
Assay 102.20% 100.40% 99.50%
Related Substances
Individual unknown Impurity 0.059% 0.065% 0.312%
Total impurities 0.105% 0.097% 1.154%

Long-term stability study (of lotion obtained in Example 3):

Long-term stability study: Stability study condition: 30 °C temperature and 75 % relative humidity
Initial 3 - Months 6 - Months
Test Parameters
Description A clear pale yellow color liquid A clear pale yellow color liquid A clear pale yellow color liquid
pH 4.59 4.67 4.71
Assay 102.20% 100.10% 99.60%
Related Substances
Single maximum impurity 0.059% 0.064% 0.111%
Total impurities 0.105% 0.091% 0.415%

Examples 4: Composition of Tofacitinib gel

Sr. No. Ingredients % w/w
1 Tofacitinib citrate 1 - 5
2 Dimethyl sulfoxide 10 - 80
3 Propylene glycol 10 - 60
4 Hydroxypropyl cellulose 0.5 - 5
5 2% w/v Sodium Hydroxide Solution 5 - 20
Total Weight 100

Process for preparation for example 4:

1. Tofacitinib citrate was dissolved in Dimethyl sulfoxide to prepare API solution.
2. Hydroxypropyl cellulose was dissolved into propylene glycol to prepare a gel base.
3. The API solution of step 1 was added to the gel base step 2.
4. pH was adjusted by 2% w/v sodium hydroxide solution.
5. The material obtained in step 4 was stirred till the homogeneous gel was obtained.

Examples 5: Composition of Tofacitinib gel (2% w/w)

Sr. No. Ingredients % w/w
1 Tofacitinib citrate 3.23
2 Dimethyl sulfoxide 43.00
3 Propylene glycol 39.47
4 Hydroxypropyl cellulose 3.00
5 2% w/v Sodium Hydroxide Solution 11.30
Total Weight 100

Process for preparation for example 5:

1. Tofacitinib citrate was dissolved in Dimethyl sulfoxide to prepare API solution.
2. Hydroxypropyl cellulose was dissolved into propylene glycol to prepare a gel base.
3. The API solution of step 1 was added to the gel base step 2.
4. pH was adjusted by 2% w/v sodium hydroxide solution.
5. The material obtained in step 4 was stirred till the homogeneous gel was obtained.

The Gel of Example 5 was subject to stability study. Following are the stability study results.

Long-term stability study (of the gel obtained in Example 5):

Long-term stability study: Stability study condition: 30 °C temperature and 75 % relative humidity
Initial 3M 6M 9M 12M 18M
Test Parameters
Description A clear colourless transparent gel A clear colourless transparent gel A clear colourless transparent gel A clear colourless transparent gel A clear colourless transparent gel A clear light yellow transparent gel
pH 5.96 5.97 5.97 5.96 5.96 6.18
Assay 99.70% 100.70% 101.30% 100.60% 100.10% 98.20%
Related Substances
Single maximum impurity 0.066% 0.085% 0.108% 0.111% 0.095% 0.100%
Total impurities 0.214% 0.259% 0.299% 0.329% 0.366% 0.356%
M – Months

Examples 6: Composition of Tofacitinib lotion

Sr. No. Ingredients % w/v
1 Tofacitinib citrate equivalent to Tofacitinib 3.23
2 Dimethyl sulfoxide 40.00
3 Isopropyl alcohol 20.00
4 Purified water 10.00
5 Butylated hydroxyanisole 0.10
6 Hydroxypropyl cellulose - H 0.50
7 Propylene Glycol QS to 100

Process for preparation for example 6:

1. Tofacitinib citrate was dissolved in Dimethyl sulfoxide to prepare API solution.
2. Hydroxypropyl cellulose - H was added to the mixture of Isopropyl alcohol, Purified water, Butylated hydroxyanisole and Propylene Glycol to prepare the lotion base.
3. The API solution of step 1 was added to the lotion base of step 2.
4. The solution of step 3 was stirred till the homogeneous lotion was obtained.

The lotion obtained in Example 6 was subject to stability study. Following are the stability study results.

Stability study results (of the lotion obtained in Example 6):

Parameters Initial 40°C/75%RH 30°C/75%RH
3M 6M 3M 6M
Assay 99.80 98.10 96.00 96.90 96.00
pH 4.81 4.83 4.79 4.80 4.81
Related Substance
Single Maximum unknown impurity 0.065 0.233 0.183 0.061 0.176
Total Impurity 0.140 0.301 0.350 0.093 0.251
M – Months, RH – Relative humidity

Examples 7: Composition of Tofacitinib lotion

Sr. No. Ingredients % w/v
1 Tofacitinib citrate equivalent to Tofacitinib 3.23
2 Dimethyl sulfoxide 40.00
3 Isopropyl alcohol 20.00
4 Purified water 10.00
5 Butylated hydroxyanisole 0.10
6 Lactic acid 0.20
7 Hydroxypropyl cellulose - H 0.50
8 Propylene Glycol QS to 100

Process for preparation for example 7:

1. Tofacitinib citrate was dissolved in Dimethyl sulfoxide to prepare API solution.
2. Hydroxypropyl cellulose - H was added to the mixture of Isopropyl alcohol, Purified water, Butylated hydroxyanisole, Lactic acid and Propylene Glycol to prepare the lotion base.
3. The API solution of step 1 was added to the lotion base of step 2.
4. The solution of step 3 was stirred till the homogeneous lotion was obtained.

The lotion obtained in Example 7 was subject to stability study. Following are the stability study results.

Stability study results (of the lotion obtained in Example 7):

Parameters Initial 40°C/75%RH 30°C/75%RH
3M 6M 3M 6M
Assay 99.6 99.20 99.10 99.50 99.40
pH 4.92 4.89 4.90 4.93 4.91
Related Substance
Single Maximum unknown impurity 0.060 0.063 0.172 0.064 0.077
Total Impurity 0.131 0.128 0.382 0.105 0.175
M – Months, RH – Relative humidity ,CLAIMS:I / We claim:

1. A stable topical composition comprising:
a) a therapeutically effective amount of tofacitinib,
b) at least one or more penetration enhancer,
c) at least one solvent,
d) at least one viscosity modifier,
wherein the topical composition is stable for at least 6 months when stored at 30 °C temperature and 75 % relative humidity.

2. A stable topical composition as claimed in claim 1, wherein the penetration enhancer is selected from dimethyl sulfoxide, dimethyl formamide, dimethyl isosorbide, sodium lauryl sulphate, diethylene glycol monoethyl ether, or a mixture thereof, wherein the amount of penetration enhancers is 30% w/v to about 80% w/v.

3. A stable topical composition as claimed in claim 1, wherein the solvent is selected from propylene glycol, polyethylene glycol, hexylene glycol, glycerin, purified water, alcohol or a mixture thereof.

4. A stable topical composition as claimed in claim 1, wherein the viscosity modifier is selected from xanthan gum, tragacanth, cellulose derivatives, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxy methyl cellulose sodium, carbomer polymer, carbomer derivative or a mixture thereof, wherein the amount of the viscosity modifier is 0.1% w/v to about 1.5% w/v.

5. A stable topical composition as claimed in claim 1, wherein the composition is lotion.

6. A stable topical composition as claimed in claim 5, wherein the lotion composition comprising Tofacitinib or pharmaceutically acceptable salt thereof, Dimethyl sulfoxide, Isopropyl alcohol, and water;
wherein the ratio of Dimethyl sulfoxide: Isopropyl alcohol: Water is 2:1:0.5, and
wherein pH of the Lotion is pH 4.0 to 6.0.

7. A stable topical composition as claimed in claim 5, wherein the lotion composition comprising:
a) Tofacitinib citrate
b) Dimethyl sulfoxide
c) Isopropyl alcohol
d) Purified water
e) Butylated hydroxyanisole
f) Hydroxypropyl cellulose
g) Propylene Glycol.

8. A stable topical composition as claimed in claim 1, wherein the composition is gel.

9. A stable topical composition as claimed in claim 8, wherein the gel composition comprising:
a) Tofacitinib citrate
b) Dimethyl sulfoxide
c) Propylene glycol
d) Hydroxypropyl cellulose
e) Sodium Hydroxide
wherein pH of the Gel is 4.5 to 7.5.

10. Process for the preparation of a stable topical composition as claimed in claim 7, comprising the following steps:
a) Dissolving Tofacitinib citrate in Dimethyl sulfoxide to prepare API solution.
b) Adding hydroxypropyl cellulose to the mixture of Isopropyl alcohol, Purified water, Butylated hydroxyanisole, and Propylene Glycol to prepare the lotion base.
c) Adding the API solution of step a) to the lotion base of step b).
d) Stirring the solution of step c) till the homogeneous lotion is obtained.