DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006

COMPLETE SPECIFICATION

(SECTION 10; RULE 13)

TITLE OF THE INVENTION:
PHARMACEUTICAL COMPOSITION COMPRISING TOFACITINIB
APPLICANT:
(a) Name : ALKEM LABORATORIES LIMITED
(b) Nationality : India
(c) Address : ALKEM HOUSE,
SENAPATI BAPAT MARG, LOWER PAREL,
MUMBAI, MAHARASHTRA, INDIA, PIN CODE 400013
PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which is to be performed.

CROSS-REFERENCE TO RELATED APPLICATIONS:
This application claims priority to and the benefit of Indian Patent Application No. 202421015355, filed on Mar. 01, 2024.

FIELD OF THE INVENTION:
The present invention relates to extended release composition of Tofacitinib or salt thereof, and process of manufacture thereof. Specifically, the present invention relates to the extended release composition comprising Tofacitinib or salt thereof, cellulosic polymer and pharmaceutically acceptable excipients. The invention also relates to the use of treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA).

BACKGROUND OF THE INVENTION:
Tofacitinib is a reversible inhibitor of the Janus kinase family of kinases (JAKl, JAK2, JAK3 and Tyrosine Kinase 2 (TyK2)). The chemical name is (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino)-ß-oxo-1-piperidinepropanenitrile, citrate salt (1: 1 ), of the formula:

Tofacitinib citrate is a white to off-white powder. The solubility of tofacitinib citrate in water is 2.9 mg/mL. 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. Tofacitinib Citrate is characterized as a Biopharmaceutical Classification System (BCS) class III compound, which means that it has high aqueous solubility and moderate permeability. Solubility of tofacitinib citrate is pH dependent; it ranges from 3.48 to 28 mg/mL in aqueous solution of pH 1 to 3.9, and
from 0.20 to 0.59 mg/mL in aqueous solution of pH 4.53 to 8. The solubility of tofacitinib citrate at 25ºC in aqueous solutions decreases strongly with increasing pH.
Tofacitinib citrate is marketed in USA as film coated tablets and oral solution under the brand name XELJANZ and as an extended release tablet (11 mg & 22 mg) under the brand name XELJANZ XR for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA).
PCT publication No. WO2001042246 discloses Tofacitinib generically.
US Patent No. 9937181 discloses the extrudable osmotic tablet composition containing Tofacitinib citrate. It discloses a once daily pharmaceutical dosage form comprising a core Tofacitinib, or pharmaceutically acceptable salt thereof, and an osmogen, 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, wherein the water-insoluble polymer is a cellulose derivative that sustains release of the Tofacitinib or pharmaceutically acceptable salt thereof.
PCT patent application WO2014174073 disclose sustained release formulations for oral administration comprising Tofacitinib or a pharmaceutically acceptable salt thereof, an alkalizing agent and hydrophilic polymer, wherein hydrophilic polymer is polyethylene oxide.
PCT patent application WO 2012100949 discloses an oral dosage form for modified release comprising tofacitinib and a non-erodible material as monolithic tablet containing a non-erodible material and other components such as pore formers is claimed.
PCT patent application WO2014174073 discloses sustained release formulation of tofacitinib with hydrophilic polymers and alkalizing agent.
PCT patent application WO2017029587 discloses sustained release oral pharmaceutical compositions of Tofacitinib. It contains release-controlling polymer and pharmaceutically acceptable excipients, wherein the sustained release oral pharmaceutical compositions further comprise an outer modified release coating that includes a modified release polymer.
The commercially available product for Tofacitinib extended release tablet is in the form of osmotic delivery system. The said tablets having drilled hole at one end of the tablet. The tablets with osmotic drug delivery is costly, complex and also problems of Gastro intestinal obstruction, serious gastrointestinal reaction, Dose dumping, size of drilled hole is critical, Retrieval therapy is not possible in the case of unexpected adverse events. Also the product known in the prior art for Tofacitinib extended release tablet contain polyethylene oxide and they are in the form of osmotic drug delivery system and having drilled hole at one end of the tablet. Therefore, there is need in the art to provide simple, cost effective, commercial feasible non osmotic extended release tablet of Tofacitinib and which also avoids, minimizes problems associated with osmotic drug delivery system.

SUMMARY OF THE INVENTION:
The present invention provides an extended release pharmaceutical composition comprising tofacitinib or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
Another aspect of the invention, an extended release pharmaceutical composition comprises tofacitinib or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from but not limited to diluents, binders, release controlling polymers, surfactants, lubricants/glidants.
In another aspect of the invention, an oral extended release pharmaceutical composition comprising about 5 % to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
In one aspect of the invention, there is provided a stable extended release pharmaceutical composition comprising:
a) Tofacitinib or its pharmaceutically acceptable salt thereof;
b) one or more extended release polymers or mixtures thereof;
c) one or more pharmaceutically acceptable excipients; and
d) optionally coated with film coating agent.
In yet another aspect, there is provided an extended release pharmaceutical composition comprising:
a) about 5 % to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 80 % to about 95% w/w of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of extended release tablets.
wherein a coating in an amount of 1% to 10.0% w/w in relation to the total tablet weight comprising a water-insoluble polymer and a pore former in a weight ratio of 0.5:99.5 w/w respectively.
In yet another aspect of the present invention provides extended release pharmaceutical composition comprising:
a) about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 40 % w/w to about 70 % w/w of diluent;
c) about 4 % w/w to about 40 % w/w of release controlling polymer;
d) about 1 % w/w to about 10 % w/w of surfactant;
e) about 0.5 % w/w to about 5 % w/w of lubricant;
f) about 1 % w/w to about 10 % w/w of film coating; and
g) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides extended release pharmaceutical composition comprising:
a) about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 40 % w/w to about 70 % w/w of diluent;
c) about 4 % w/w to about 40 % w/w of release controlling polymer;
d) about 1 % w/w to about 10 % w/w of surfactant;
e) about 0.5 % w/w to about 5 % w/w of lubricant;
f) about 1 % w/w to about 10 % w/w of film coating; and
g) optionally other pharmaceutically acceptable excipients.
wherein said composition is stable for at least 3 months of storage at 40°C/75%RH.
In yet another aspect of the present invention provides extended release pharmaceutical composition comprising:
a) about 16.4 % w/w tofacitinib or pharmaceutically acceptable salt thereof;
b) about 48.06 % w/w of lactose;
c) about 25.76 % w/w of hydroxypropyl methylcellulose;
d) about 3.7 % w/w of sodium lauryl sulfate;
e) about 2.8 % w/w of magnesium stearate;
f) about 3.3 % w/w of film coating; and
g) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides extended release pharmaceutical composition comprising:
a) about 35.5 mg of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 100 mg to about 130 mg of lactose;
c) about 10 mg to about 60 mg of hydroxypropyl methylcellulose;
d) about 4 mg to about 12 mg of sodium lauryl sulfate;
e) about 1 mg to about 10 mg of magnesium stearate;
f) about 5 mg to about 15 mg of film coating; and
g) optionally other pharmaceutically acceptable excipients.
In yet another aspect, the present invention relates to the process for preparation of an extended release pharmaceutical composition, wherein process comprises steps of:
a) All materials weighed properly.
b) Tofacitinib citrate and lacose monohydrate were co-sifted through #18 sieve and Hydroxypropylmethyl cellulose K4M, Hydroxypropylmethyl cellulose K 100 and sodium lauryl sulfate were also sifted through #18 sieve.
c) Binder solution was prepared by mixing Isopropyl alcohol and water by stirring under overhead stirrer for 5 minutes.
d) Dry mixing of material of step b) was carried out for 15 minutes.
e) Wet granulation was carried out by addition of binder solution obtained in step c) to dry mix material of step d).
f) The wet granules of step e) were dried in Fluidized bed drier (FBD) and the granules passed through co-mill.
g) The granules obtained in step f) were lubricated with magnesium stearate and compressed into tablet.
h) The tablets obtained in step g) were film coated with solution of ethyl cellulose which was added to the opadry coating solution and the granules were subsequently dried.
i) The tablets obtained in step h) were packed in suitable bottle or blister pack.
In yet another aspect of the present invention provides a stable extended release pharmaceutical composition comprising tofacitinib, wherein the total impurity in the said pharmaceutical composition is not more than 2% w/w after subjecting the said pharmaceutical composition to a storage condition of 40°C/75%RH for a period of at least 1 month and also the amount of nitrosamine impurity is less than the FDA acceptable limit based on maximum daily dose of tofacitinib.
In yet another aspect, the present invention relates to an extended release pharmaceutical composition comprising tofacitinib or pharmaceutically acceptable salt used for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA).
In yet another aspect, the present invention relates to a method of treating rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA) by extended release pharmaceutical composition comprising tofacitinib or pharmaceutically acceptable salt.
In yet another aspect, the present invention relates to a use of extended release pharmaceutical composition comprising tofacitinib or pharmaceutically acceptable salt for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA).

DESCRIPTION OF THE INVENTION:
The present invention can be more readily understood by reading the following description of the invention and study of the included examples.
The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."
The term "about" as used herein means a deviation within 10%, more preferably within 5%, and even more preferably, within 2% of the numbers reported.
The term ‘‘stable’’ refers to formulations that substantially retain the labelled amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.
The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.
The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response, when administered to the patient.
As used herein, the term "bioavailability" denotes the degree to which a drug or other substance becomes available to the target tissue after administration.
“Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient. Pharmaceutically acceptable excipient(s) includes, but not limited to, release controlling polymers, diluent, binder, disintegrant, lubricant/glidants, antioxidant, plasticizer, surfactants, solvent/vehicle, flavors or colorants, coating materials and any other excipient known to the art for making solid oral pharmaceutical composition.
The term ‘‘w/w’’ refers to total weight of substance/excipients with respect to total composition weight or the proportion of a particular substance within a mixture, as measured by weight or mass.
The term “excipient” means a pharmacologically inactive component such as a ion exchange resin, binder, solvent, diluent, disintegrant, carrier, lubricant, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, inert, non-toxic and are acceptable for human use.
By the term “pharmaceutical composition” or “solid oral pharmaceutical composition" or "composition" or "formulation" as used herein refers to a solid dosage form comprising tofacitinib suitable for administration such as a granule, hard or soft gelatin capsule, tablet, caplet, mini-tablets, pellets, pills, granules or powder for suspension, suspension and the like.
The pharmaceutical dosage form can be prepared by methods known in the art, such as dry granulation or wet granulation or direct compression. The granules can be dried by any suitable technique known in the art, the preferred technique used is fluidized bed process technique. The compression of the blend to tablet cores can be carried out using a conventional tabletting machine or a rotary compression machine. The tablet cores may vary in shape and can be, for example, round, oval, oblong, cylindrical or any other suitable shape. The cores may also vary in size depending on the concentration of the therapeutic agent. The material obtained by suitable methods known in the art can be filled into sachets, bottles, capsules or made into tablets.
The term "Extended release" (ER) as used herein means a controlled release of an active agent from a dosage form into an environment for (over or during) an extended period of time, for example greater than or equal to one hour. As used herein, the term "extended-release" profile assumes the definition widely recognized in the art of pharmaceutical sciences. An extended release dosage form will release the drug at a substantially constant rate over an extended period of time or a substantially constant amount of the drug will be incrementally released over an extended period of time. The term "extended release," in relation to drug release, includes the terms "controlled release," "prolonged release," "sustained release," or "slow release," as these terms are used in pharmaceutical sciences.
The term “active ingredient” or “active agent” or “drug” used interchangeably, is defined to mean active drug i.e. tofacitinib and its salt, solvate, esters, isomers, polymorphs that induce a desired pharmacological or physiological effect.
The term “tofacitinib” includes all pharmaceutically acceptable salts, esters, isomers, stereo isomers, crystalline and amorphous forms. Pharmaceutically acceptable salts of tofacitinib include but not limited to oxalate, phosphate or acid phosphate, hydrochloride, hydrobromide, sulphate, mesylate, acetate, maleate, fumarate, lactate, tartrate, citrate, methanesulfonate, pamoate, palmitate, and gluconate salts.
The term "water-insoluble polymer" as used herein refers to a polymer having a solubility in water lower than 0. 05g/100 ml water, measured at 20 °C at 1 atm pressure. The water-insoluble polymer functions as controlled release of the drug that is in the core. The term "pore former", as used herein, refers to a material added to the coating solution that has low or no volatility relative to the solvent such that it remains as part of the coating following the coating process but that is sufficiently water swellable or water soluble such that, in the aqueous use environment it provides a water-filled or water-swollen channel or "pore" to allow water penetration and the release of the drug that is in the core.
Suitable water-insoluble polymers for the coating are ethylcellulose, cellulose acetate, methacrylic ester copolymers, polyvinyl acetates. In a preferred embodiment of the present invention, the water-insoluble polymer is ethylcellulose. Suitable pore former for the tablet of the current invention are hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, povidone, maltodextrin, saccharides such as glucose, isomalt, sucrose, polyols such as maltitol, xylitol. In a preferred embodiment of the present invention, the pore former is hydroxypropyl methylcellulose.
The preferred weight ratio of the water-insoluble polymer and the pore former in the coating is 0.5:99.5. More preferably the weight ratio of the water-insoluble polymer and the pore former is 1.4: 98.6.
The present invention provides a tofacitinib or pharmaceutically acceptable salt thereof may be present in an amount of about 5 % w/w to about 20 % w/w, preferably about 8 % w/w to about 12 % w/w, more preferably about 9 % w/w to about 11 % w/w of the composition.

The present invention provides a tofacitinib or pharmaceutically acceptable salt thereof having D90 particle size in the range of 1 to 75 µm, D50 particle size in range of 1 to 30 µm and D10 particle size in range of 1 to 10 µm.
The present invention provides a pharmaceutical composition comprising tofacitinib or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
Another aspect of the invention, the pharmaceutical composition comprises tofacitinib or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from the group consisting of diluents, release controlling polymers, surfactants, binders, lubricants/glidants and suitable solvents.
In one aspect of the invention, an oral stable pharmaceutical composition comprising amount of about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients, preferably about 8 % w/w to about 12 % w/w, more preferably about 9 % w/w to about 11 % w/w of the composition.
In another aspect of the invention, there is provided a stable extended release pharmaceutical composition comprising:
a) Tofacitinib or its pharmaceutically acceptable salt thereof;
b) one or more extended release polymers or mixtures thereof;
c) one or more pharmaceutically acceptable excipients; and
d) optionally coated with film coating agent.
In yet another aspect, there is provided a pharmaceutical composition comprising:
a) about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 80 % w/w to about 95% w/w of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of extended release tablets.
wherein a coating in an amount of 1% to 10.0% w/w in relation to the total tablet weight comprising a water-insoluble polymer and a pore former in a weight ratio of 0.5:99.5 w/w respectively.
Diluents according to the present invention are selected from, but not limited to, silicon dioxide, titanium dioxide, talc, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, mannitol, sorbitol or other sugar alcohols, isomalt, sucrose, lactose, and the like used either alone or in combinations thereof and the most preferably used diluent is Lactose. Diluent may be present in an amount of about 40 % w/w to about 70 % w/w, preferably about 50 % w/w to about 65% w/w, more preferably about 48 % w/w to about 60 % w/w of the composition.
Release controlling pH independent polymer according to present invention are selected from, but not limited to, polyethylene oxide (for example (MW:900.000 g/mol; Polyox® 1105 WSR)), hydroxypropyl methylcellulose (for example Methocel K4M premium, Methocel® K100 Premium low viscosity (LVCR) grade), hydroxypropyl cellulose, polyvinyl alcohol (for example Parteck® SRP 80), guar gum, carrageenan and combinations thereof. A preferred release controlling pH independent polymers are soluble polymers such a polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol and combinations thereof. More preferably a pH independent gelling control release polymers are polyethylene oxide and hydroxypropyl methyl cellulose, most preferably used release controlling release polymer is hydroxypropyl methyl cellulose. pH independent gelling control release polymer may be present in an amount of 4 % w/w to about 40% w/w, preferably 5 % w/w to about 30 % w/w, more preferably about 5 % w/w to about 20% w/w of the composition.
Lubricants according to the present invention are selected from, but not limited to, magnesium stearate, calcium stearate, aluminium stearate, sucrose stearate, sucrose fatty acid ester, stearic acid, fumaric acid, palmitic acid, sodium stearyl fumarate, talc, and the like used either alone or in combinations thereof. Lubricants may be present in an amount of about of about 0.5 % w/w to about 5 % w/w, preferably about 1 % w/w to about 3 % w/w, more preferably about 1.5 % w/w to about 3 % w/w of the composition.
A ‘‘Solvent/vehicle’’ is a substance that dissolves a solute (a chemically distinct liquid, solid or gas), resulting in a suspension or solution. Examples include but not limited to purified water, dichloromethane, alcoholic solvents such as methanol, ethanol, isopropyl alcohol; ketones such as acetone, propanone; esters such as ethyl acetate, n-propyl acetate, isopropylacetate and n-butyl acetate and the like; ethers such as dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, and dioxane.
Surfactants or surface-active agents or wetting agents improve wettability of the dosage form and/or enhance its dissolution. Few active ingredients are fluffy in nature and not suspend properly. Examples include but not limited to polysorbate 80 (tween 80), Sodium Lauryl Sulfate (SLS), Cetyltrimethylammonium Bromide (CTAB), Pluronic F127 (Poloxamer 407), Span 80, Sorbitan Monostearate (Span 60), certain Polyethylene Glycol 30 (PEG) derivatives, and Tetrahydrofurfuryl Alcohol Polyethylene Glycol Ether (TPEG).The surfactant or wetting agents may be present in an amount of about 1% w/w to about 10% w/w, preferably from about 2% w/w to about 8% w/w and more preferably from about 2.5 % w/w to about 5% w/w.
In another aspect of the invention, an oral pharmaceutical composition comprising about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
In yet another aspect, there is provided an extended release pharmaceutical composition comprising:
a) about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 80 % w/w to about 95% w/w of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of extended release tablets.
wherein a coating in an amount of 1% to 10.0% w/w in relation to the total tablet weight comprising a water-insoluble polymer and a pore former in a weight ratio of 0.5:99.5 w/w respectively.
In yet another aspect of the present invention provides extended release pharmaceutical composition comprising:
a) about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 40 % w/w to about 70 % w/w of diluent;
c) about 4 % w/w to about 40 % w/w of release controlling polymer;
d) about 1 % w/w to about 10 % w/w of surfactant;
e) about 0.5 % w/w to about 5 % w/w of lubricant;
f) about 1 % w/w to about 10 % w/w of film coating; and
g) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides extended release pharmaceutical composition comprising:
a) about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 40 % w/w to about 70 % w/w of diluent;
c) about 4 % w/w to about 40 % w/w of release controlling polymer;
d) about 1 % w/w to about 10 % w/w of surfactant;
e) about 0.5 % w/w to about 5 % w/w of lubricant;
f) about 1 % w/w to about 10 % w/w of film coating; and
g) optionally other pharmaceutically acceptable excipients.
wherein said composition is stable for at least 3 months of storage at 40°C/75%RH.
In yet another aspect of the present invention provides extended release pharmaceutical composition comprising:
a) about 16.4 % w/w tofacitinib or pharmaceutically acceptable salt thereof;
b) about 48.06 % w/w of lactose;
c) about 25.76 % w/w of hydroxypropyl methylcellulose;
d) about 3.7 % w/w of sodium lauryl sulfate;
e) about 2.8 % w/w of magnesium stearate;
f) about 3.3 % w/w of film coating; and
g) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides extended release pharmaceutical composition comprising:
a) about 35.5 mg of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 100 mg to about 130 mg of lactose;
c) about 10 mg to about 60 mg of hydroxypropyl methylcellulose;
d) about 4 mg to about 12 mg of sodium lauryl sulfate;
e) about 1 mg to about 10 mg of magnesium stearate;
f) about 5 mg to about 15 mg of film coating; and
g) optionally other pharmaceutically acceptable excipients.
In yet another aspect, the present invention relates to the process for preparation of an extended release pharmaceutical composition, wherein process comprises steps of:
a) All materials weighed properly.
b) Tofacitinib citrate and lacose monohydrate were co-sifted through #18 sieve and Hydroxypropylmethyl cellulose K4M, Hydroxypropylmethyl cellulose K 100 and sodium lauryl sulfate were also sifted through #18 sieve.
c) Binder solution was prepared by mixing Isopropyl alcohol and water by stirring under overhead stirrer for 5 minutes.
d) Dry mixing of material of step b) was carried out for 15 minutes.
e) Wet granulation was carried out by addition of binder solution obtained in step c) to dry mix material of step d).
f) The wet granules of step e) were dried in Fluidized bed drier (FBD) and the granules passed through co-mill.
g) The granules obtained in step f) were lubricated with magnesium stearate and compressed into tablet.
h) The tablets obtained in step g) were film coated with solution of ethyl cellulose which was added to the opadry coating solution and the granules were subsequently dried.
i) The tablets obtained in step h) were packed in suitable bottle or blister pack.
In yet another aspect of the present invention provides a stable pharmaceutical composition comprising tofacitinib, wherein the total impurity in the said pharmaceutical composition is not more than 2% w/w after subjecting the said pharmaceutical composition to a storage condition of 40°C/75%RH for a period of at least 1month and also the amount of nitrosamine impurity is less than the FDA acceptable limit based on maximum daily dose of tofacitinib.
In yet another aspect of the present invention provides stable pharmaceutical composition is in the form of extended release tablet dosage form comprising: a) about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof; b) about 80 % w/w to about 95 % w/w of of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of extended release tablets.
In yet another aspect, the extended release tablets obtained in present invention were packed in suitable bottles or blister packs.
In yet another aspect, the present invention relates to the administration of a particular dose of pharmaceutical composition is based on the total body weight of the patient.
In yet another aspect, the present invention provides a pharmaceutical composition of tofacitinib or its pharmaceutically acceptable salts, which is bioequivalent to the marketed tofacitinib product.
In yet another aspect, the present invention provides a process for preparation of a stable, reproducible and bioequivalent pharmaceutical composition of tofacitinib or its pharmaceutically acceptable salts.
In yet another aspect, the present invention relates to a pharmaceutical composition comprising tofacitinib or pharmaceutically acceptable salt used for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA).
In yet another aspect, the present invention relates to a pharmaceutical composition comprising tofacitinib or pharmaceutically acceptable salt used for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA).
In yet another aspect, the present invention relates to method for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA) by a pharmaceutical composition comprising tofacitinib or pharmaceutically acceptable salts.
In yet another aspect, the present invention relates to a use of pharmaceutical composition comprising tofacitinib or pharmaceutically acceptable salt for treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA).
The composition of the invention can be packed into suitable packaging system e. g. Blister packs, strip packs, alu-alu packs, bottles such as glass and plastic bottles, etc.
Additionally, N-nitrosamine impurities are possible in the synthesis of tofacitinib and its pharmaceutical salt thereof. The N-nitrosamine impurities may originate from any or all of the active pharmaceutical ingredient, excipients, pharmaceutical packaging materials, and/or manufacturing process and equipment. Examples of N-nitrosamine impurities include, but are not limited to, N-Nitroso tofacitinib, N-Nitrosodimethyl amine (“NDMA”), N-Nitrosodiethyl amine (“NDEA”), N-Nitrosodiisopropylamine (“NDIPA”), N-Nitrosoethylisopropylamine (“NIPEA”), N-nitroso-N-methyl-4-aminobutyric acid (“NMBA”), N-Nitrosodibutylamine (“NDBA”), and N-Methyl-N-phenylnitrosamine (“NMPA”). N-nitrosamines are generally formed when a secondary or tertiary amine reacts with a nitrosating agent. While the amounts of the N-nitrosamine impurities in drugs is generally low, some levels have been above the US Food and Drug Administration’s acceptable daily limit, potentially exposing many people to a slightly increased risk of cancer. Because of the aforementioned health-related effects, stringent limitations have been placed upon the permissible amounts of N-nitrosamine impurities in drug products. Because of the exceptionally low allowable limits for N-nitrosamine impurities in these products it become important to control the nitrosamine impurities during synthesis of active pharmaceutical ingredient or drug formulation.
In an embodiment of the present invention the Nitrosamine impurities are controlled within the permissible limits as per FDA guidelines.

EXAMPLES
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 invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example – 1: Tofacitinib Extended Release Tablets- 11mg

Sr. No. Ingredient 1A 1B 1C
mg/ tablet
A. Dry mixing
1. Tofacitinib Citrate 17.77 17.77 17.77
2. Lactose Monohydrate 121 113.4 106
3. Hydroxypropylmethyl cellulose-K4M 20 16.00 25
4. Hydroxypropylmethyl cellulose-K100 30 40.00 35
5. Sodium lauryl sulfate 7 8.00 10
Total 196.00 196.00 196.00
B. Binder Solution
6. Isopropyl alcohol q.s. q.s. q.s.
7. Purified water q.s. q.s. q.s.
Total 196.00 196.00 196.00
C. Lubrication
8. Magnesium Stearate 4.20 4.80 6.2
Total 200.00 200.00 200.00
D. Film Coating
9. Ethyl Cellulose 7 CPS 0.65 0.72 0.8
10. Opadry Pink 03F540554 6.4 6.2 6.2
11. Isopropyl Alcohol 31.1 35.72 35.72
12. Dichlromethane 20 15.31 15.31
Total 207.00 207.00 207.00

Example – 2: Tofacitinib Extended Release Tablets- 22mg

Sr. No. Ingredient 2A 2B 2C
mg/ tablet
A. Dry mixing
1. Tofacitinib Citrate 35.53 35.54 35.53
2. Lactose Monohydrate 110.47 104.46 126.47
3. Hydroxypropylmethyl cellulose-K4M 18.00 16.00 14.00
4. Hydroxypropylmethyl cellulose-K100 30.00 40.00 22.00
5. Sodium lauryl sulfate 10.00 8.00 6.00
Total 204.00 204.00 204.00
B. Binder Solution
6. Isopropyl alcohol q.s. q.s. q.s.
7. Purified water q.s. q.s. q.s.
Total 204.00 204.00 204.00
C. Lubrication
8. Magnesium Stearate 6.00 6.00 6.00
Total 210.00 210.00 210.00
D. Film Coating
9. Ethyl Cellulose 7 CPS 0.7 0.76 1
10. Opadry Yellow 03F520744 6.6 6.590 6.3
11. Isopropyl Alcohol 37.51 37.51 37.51
12. Dichlromethane 16.07 16.07 16.07
Total 217.35 217.35 217.35

Manufacturing process for example 1 & 2:
a) All materials weighed properly.
b) Tofacitinib citrate and lactose monohydrate were co-sifted through #18 sieve and Hydroxypropylmethyl cellulose-K4M, Hydroxypropylmethyl cellulose-K100 and sodium lauryl sulfate were also sifted through #18 sieve.
c) Binder solution was prepared by mixing Isopropyl alcohol and water by stirring under overhead stirrer for 5 minutes.
d) Dry mixing of material of step b) was carried out for 15 minutes.
e) Wet granulation was carried out by addition of binder solution obtained in step c) to dry mix material of step d).
f) The wet granules of step e) were dried in Fluidized bed drier (FBD) and the granules passed through co-mill.
g) The granules obtained in step f) were lubricated with magnesium stearate and compressed into tablet.
h) The tablets obtained in step g) were film coated with solution of ethyl cellulose which was added to the opadry coating solution and the granules were subsequently dried.
g) The tablets obtained in step h) were packed in suitable bottle or blister pack.

Stability Study: Stability study conducted on composition of example 1 in order to ensure the stable composition for longer period of time and data is given in Table 1 as below:

Table 1: Stability study results of example 1B at 40°C / 75% RH:
Test Initial 3M
Assay (%) 97.1 97.6
Water Content (%w/w) NA 4.67
Organic impurities
Tofacitinib Amine Impurity 0.02 0.00
Tofacitinib N-Formyl Impurity 0.01 0.01
Tofacitinib N-Acetyl Impurity 0.02 0.01
Total degradation products 0.25 0.37
Dissolution
Time (Hours)
1 9 8
1.5 14 12
2 19 16
2.5 24 20
3 28 24
4 37 31
5 - 39
6 53 45
8 66 58
10 77 67
12 85 73

Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

We Claim:
1. A stable extended release pharmaceutical composition comprising:
a) Tofacitinib or its pharmaceutically acceptable salt thereof;
b) one or more extended release polymers or mixtures thereof;
c) one or more pharmaceutically acceptable excipients; and
d) optionally coated with film coating agent.

2. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the composition comprises about 5-20 %w/w of tofacitinib citrate based on the total weight of the composition.

3. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the composition is coated with water insoluble film coating material ethyl cellulose.

4. A stable extended release pharmaceutical composition comprising:
a) about 16.4 % w/w tofacitinib or pharmaceutically acceptable salt thereof;
b) about 48.06 % w/w of lactose;
c) about 25.76 % w/w of hydroxypropyl methylcellulose;
d) about 3.7 % w/w of sodium lauryl sulfate;
e) about 2.8 % w/w of magnesium stearate;
f) about 3.3 % w/w of film coating; and
g) optionally other pharmaceutically acceptable excipients.

5. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the extended release layer comprises one or more rate-controlling polymers selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, guar gum, carrageenan and combinations thereof.

6. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the release controlling polymer is about 4-40% w/w of the total composition.

7. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the composition is manufactured using direct compression, dry granulation or wet granulation method.

8. The stable extended release pharmaceutical composition as claimed in preceding claims, wherein the composition is indicated for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA).

9) The stable extended release pharmaceutical composition as claimed in any of the preceding claims, wherein the composition is stable for at least 24 hours at 25 ± 2°C / 60 ± 5 % relative humidity.

10. A stable extended release pharmaceutical composition comprising:
a) about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 40 % w/w to about 70 % w/w of diluent;
c) about 4 % w/w to about 40 % w/w of release controlling polymer;
d) about 1 % w/w to about 10 % w/w of surfactant;
e) about 0.5 % w/w to about 5 % w/w of lubricant;
f) about 1 % w/w to about 10 % w/w of film coating; and
g) optionally other pharmaceutically acceptable excipients.

Dated this 28th February 2025

Mr. Thirupathi Bendram
VP & Head - IPR
Alkem Laboratories Limited
,CLAIMS:We Claim:
1. A stable extended release pharmaceutical composition comprising:
a) Tofacitinib or its pharmaceutically acceptable salt thereof;
b) one or more extended release polymers or mixtures thereof;
c) one or more pharmaceutically acceptable excipients; and
d) optionally coated with film coating agent.

2. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the composition comprises about 5-20 %w/w of tofacitinib citrate based on the total weight of the composition.

3. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the composition is coated with water insoluble film coating material ethyl cellulose.

4. A stable extended release pharmaceutical composition comprising:
a) about 16.4 % w/w tofacitinib or pharmaceutically acceptable salt thereof;
b) about 48.06 % w/w of lactose;
c) about 25.76 % w/w of hydroxypropyl methylcellulose;
d) about 3.7 % w/w of sodium lauryl sulfate;
e) about 2.8 % w/w of magnesium stearate;
f) about 3.3 % w/w of film coating; and
g) optionally other pharmaceutically acceptable excipients.

5. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the extended release layer comprises one or more rate-controlling polymers selected from the group consisting of polyethylene oxide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, guar gum, carrageenan and combinations thereof.

6. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the release controlling polymer is about 4-40% w/w of the total composition.

7. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the composition is manufactured using direct compression, dry granulation or wet granulation method.

8. The stable extended release pharmaceutical composition as claimed in preceding claims, wherein the composition is indicated for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis (UC) and polyarticular course juvenile idiopathic arthritis (pcJIA).

9) The stable extended release pharmaceutical composition as claimed in any of the preceding claims, wherein the composition is stable for at least 24 hours at 25 ± 2°C / 60 ± 5 % relative humidity.

10. A stable extended release pharmaceutical composition comprising:
a) about 5 % w/w to about 20 % w/w of tofacitinib or pharmaceutically acceptable salt thereof;
b) about 40 % w/w to about 70 % w/w of diluent;
c) about 4 % w/w to about 40 % w/w of release controlling polymer;
d) about 1 % w/w to about 10 % w/w of surfactant;
e) about 0.5 % w/w to about 5 % w/w of lubricant;
f) about 1 % w/w to about 10 % w/w of film coating; and
g) optionally other pharmaceutically acceptable excipients.