Extended-release compositions of tofacitinib

Abstract

The present invention relates to Extended release compositions of Tofacitinib or salt thereof. The extended-release composition has a core containing Tofacitinib and at least one release controlling agent, hereinafter a first release controlling agent and the core is optionally coated with a second release controlling agent. The first and second release controlling agents are same or different. The first release controlling agent contains two polyelectrolytes which are cationic and anionic polymers. Second release controlling agent if present has again two poly electrolytes which are cationic and anionic polymers, or only anionic polyelectrolyte or a non- polyelectrolyte oorr aa combination of anionic polyelectrolyte and non- polyelectrolyte. The present invention also relates to process of preparing Extended release compositions of Tofacitinib or salt thereof by employing wet granulation or direct compression.

Description

[0001] Extended Release compositions of Tofacitinib

[0002] Field of the Invention

[0003] The present invention relates to Extended release compositions of Tofacitinib or salt thereof. Salt is preferably a salt of an acid. Preferably, salt is a Citrate salt. The extended-release composition has a core containing Tofacitinib and at least one release controlling agent, hereinafter a first release controlling agent and the core is optionally coated with a second release controlling agent. The first and second release controlling agents are same or different.

[0004] The first release controlling agent contains two polyelectrolytes which are cationic and anionic polymers. Second release controlling agent if present has again two polyelectrolytes which are cationic and anionic polymers, or only anionic polyelectrolyte or a non-polyelectrolyte or a combination of anionic polyelectrolyte and non-poly electrolyte.

[0005] Objects of the invention

[0006] The first object of the present invention is to provide an extended release composition of Tofacitinib or salt thereof which can replace administering two or more immediate release compositions.

[0007] The second object of the invention is to provide such extended-release composition but not an Osmotic-controlled release oral delivery system (OROS technology). Under this object, the present invention provides an extended release composition of Tofacitinib or salt thereof which is essentially free of Osmogen, an agent which increases osmotic pressure across barrier and releases the Tofacitinib.

[0008] A third object of the present invention is to reduce tablet weight as far as possible to below 400 mg, preferably below 350 mg and more preferably, below 300 mg. Yet another object is to provide a composition that is easy to manufacture employing simple and economical processes that can be scaled up easily and that can employ readily available and economical ingredients. Background of the invention

[0009] Literature reports extended-release compositions of Tofacitinib. In most, big tablet accommodates a dose of 22 mg of Tofacitinib (35.54 mg Tofacitinib citrate).

[0010] WO2022026519A1 reports a large tablet of 850 mg accommodating a dose of 11 mg of Tofacitinib (17.77 mg of citrate salt). It teaches adding large amounts of inactive amounting to 823 mg per tablet (refer to table 50). Also around 18 different inactive ingredients are added in the said formulation which are unnecessary.

[0011] Another prior art WO 2014174073 Al provides a sustained release formulation for oral administration comprising tofacitinib or a pharmaceutically acceptable salt thereof, a hydrophilic polymer and an alkalizing agent. The alkalizing agent is selected from the group consisting of magnesium oxide, calcium carbonate, calcium silicate, potassium citrate, sodium citrate and combinations thereof. Examples 1 - 15 and 17 provide tofacitinib tablet having a tablet weight of 400 mg accommodating dose of 35.53 mg of Tofacitinib citrate, 20 - 60 % release controlling polymer weighing almost 3 - 7 times of Tofacitinib citrate. Alkalizing agents are employed in large amounts such as 100 mg - 160 mg per tablet.

[0012] WO2014174073A1 refers in its specification to another prior art W02012100949A1. W02012100949A1 provides various compositions which drastically differ from one another in release controlling agent, mechanism of controlling release etc. W02012100949A1 does not provide any % Cumulative release data in buffer of pH 6.8. WO2014174073A1 provides under table 16, release of various batches of W02012100949A1 wherein % Cumulative release is reported at 100 RPM and release is very fast. WO2014174073A1 concludes as follows regarding compositions of W02012100949A1 (refer page 25).

[0013] All the tested reference formulations release tofacitinib too fast and would not provide a suitable plasma profile for a modified release formulation. Additionally all examples prepared did not show any mechanical robustness and thus possibly expose die patients to safety risks.

[0014] No prior art incorporates two polyelectrolytes in the release controlling agents. Summary of the invention

[0015] The present invention avoids use of an Osmotic-controlled release oral delivery system also termed as OROS technology in providing an extended release compositions of Tofacitinib or salt thereof. OROS technology has been described for Tofacitinib citrate in United States patents US 9,937,181 B2 and US 11,253,523 B2. OROS is an expensive technology and a lot of precision is needed to design the same and thereby have chances of complexity in drug release. The OROS tablet largely remains non-deformable and hence may cause irritation of GI tract and may cause its blockage.

[0016] A simpler technology which gives complete and reproducible drug dissolution for extended period is highly desired and when such reproducible results are obtained irrespective of food, it is more desirable. Such technology dispenses with fear of retaining non-deformable tablets.

[0017] Present invention provides an extended release composition of Tofacitinib or salt thereof.

[0018] Under the first aspect, the present invention provides an extended release composition of Tofacitinib or salt thereof which can replace administering two or more immediate release compositions.

[0019] Sustained release or Extended release compositions of the present invention cause sustained release of Tofacitinib over 8 hrs. such that in phosphate buffer of pH 6.8 i) at least 50%, preferably 60 % Tofacitinib is released in 4 hrs; ii) at least 65%, preferably 70 % Tofacitinib is released in 6 hrs; iii) at least 75%, preferably 80 % Tofacitinib is released in 8 hrs.

[0020] More preferably, in phosphate buffer of pH 6.8, at least 70% of Tofacitinib is released in 6 hrs. and at least 80% of Tofacitinib is released in 8 hrs.

[0021] Also, not more than 40 % should be released in 1 hr.

[0022] Under the second aspect the invention provides such extended-release composition which is not an Osmotic-controlled release oral delivery system (OROS technology). Under this aspect, the present invention provides an extended release composition of Tofacitinib or salt thereof which is essentially free of Osmogen, an agent which increases osmotic pressure across barrier and releases the Tofacitinib.

[0023] Under third aspect, the present invention successfully reduces tablet weight as far as possible to below 400 mg, preferably below 350 mg and more preferably, below 300 mg. This is done by controlling weight of inactives and by employing superior inactives providing better control over release. Preferably, inactives include two polyelectrolytes of opposing charges which may interact to produce a poly electrolyte complex.

[0024] Under yet another aspect, the invention provides a composition that is easy to manufacture employing simple and economical processes that can be scaled up easily and that can employ readily available and economical ingredients.

[0025] Brief Description of the Drawings

[0026] Figure 1 provides % w / w Cumulative release profile of Extended release compositions of Tofacitinib Citrate of batch no. F2 in phosphate buffer.

[0027] Figures 2A and 2B respectively provide % w / w Cumulative release profile of Extended release compositions of Tofacitinib Citrate of batch no. F39E in phosphate buffer and 0.1N HC1.

[0028] Figures 3A and 3B respectively provide % w / w Cumulative release profile of Extended release compositions of Tofacitinib Citrate of batch no. F43E in phosphate buffer and 0.1N HC1.

[0029] Figures 4A and 4B respectively provide % w / w Cumulative release profile of Extended release compositions of Tofacitinib Citrate of batch no. F47G in phosphate buffer and 0.1N HC1.

[0030] Figures 5A and 5B respectively provide % w / w Cumulative release profile of Extended release compositions of Tofacitinib Citrate of batch no. F47J in phosphate buffer and 0. IN HC1.

[0031] Figure 6 provides % w / w Cumulative release profile of Extended release compositions of Tofacitinib Citrate of batch no. F47K in phosphate buffer. Figures 7 A and 7B respectively provide % w / w Cumulative release profile of Extended release compositions of Tofacitinib Citrate of batch no. F50K in phosphate buffer.

[0032] Figures 8A, 8B and 8C respectively provide % w / w Cumulative release profile of Extended release compositions of Tofacitinib Citrate of batch no. F53B in phosphate buffer, 0.1 N HC1 and acetate buffer of pH 4.5.

[0033] Figures 9A and 9B provide comparative data on the % Cumulative release of Tofacitinib during pH transition.

[0034] Figure 9A provides the release of RED and batch F061 wherein the tablets were first subjected to media of pH 1.2 for 2 hrs. followed by media of pH 6.8 for 6 hrs. Figure 9B provides the release of RLD and batch F061 wherein the tablets were first subjected to media of pH 1.2 for 2 hrs. followed by media of pH 4.5 for 6 hrs.

[0035] Figures 10A and 11 A provide comparative data on the % Cumulative release of Tofacitinib for RLD and for batches F060 (core tablets) and F061 which is obtained after coating batch F060 in media of pH 1.2 and 6.8 respectively.

[0036] These figures reflect that there is no difference in release of batches F060G and F061G i.e in the said composition, coating does not play a functional role of controlling release.

[0037] Figures 10B and 11 B provide comparative data on the % Cumulative release of Tofacitinib for RLD and for batches F061 and F064B which is the same as F061G but compressed at half weight thus accommodating half of the dose of F061G. These two dose- weight proportionate batches exhibit similar release in media of pH 1.2 and 6.8 for 8 hrs. Detailed Description of the invention

[0038] The present invention provides novel compositions of Tofacitinib or salt thereof. Tofacitinib is indicated for rheumatoid arthritis, psoriatic arthritis, and polyarticular juvenile idiopathic arthritis. It is also used to treat ankylosing spondylitis and ulcerative colitis.

[0039] The present invention covers Sustained release or Extended release compositions of Tofacitinib or salt thereof.

[0040] Tofacitinib Salt is preferably a salt of an acid and covers any of the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate (preferably monotartrate and bitartrate), succinate, malate (preferably monomalate), maleate, oxalate (preferably monooxalate), fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [1,1 methylene-bis-(2-hydroxy-3-naphthoate)] salts.

[0041] More preferably, salt is a salt of an organic acid such as a Citrate salt. Hereinafter, the term Tofacitinib or salt thereof covers any salt, hydrate, solvate, prodrug, derivative, isomer, crystal form, or co-crystal of Tofacitinib.

[0042] Sustained or extended release Tofacitinib compositions are approved in various jurisdictions by Drug regulatory Authorities. Such compositions can be administered once daily and can replace immediate release compositions that are needed to administer twice daily.

[0043] One such extended release marketed composition with brand name Xeljanz by Pfizer has been employed in the studies and referred as RLD or reference listed drug.

[0044] Conventionally, such compositions employ an OROS technology and such compositions are in the form of non-deformable tablets which slowly release Tofacitinib over 8 hrs. This technology is very expensive. Also, the body shouldn't retain non-deformable tablets for long. The present invention provides a simple, economical, and completely dispersing yet sustained or extended-release compositions of Tofacitinib.

[0045] Sustained release or Extended release compositions of the present invention cause sustained release of Tofacitinib over 8 hrs. such that in phosphate buffer of pH 6.8 i) at least 50%, preferably 60 % Tofacitinib is released in 4 hrs; ii) at least 65%, preferably 70 % Tofacitinib is released in 6 hrs; iii) at least 75%, preferably 80 % Tofacitinib is released in 8 hrs.

[0046] More preferably, in phosphate buffer of pH 6.8, at least 70% of Tofacitinib is released in 6 hrs. and at least 80% of Tofacitinib is released in 8 hrs.

[0047] Also, not more than 40 % should be released in 1 hr.

[0048] More preferably, in phosphate buffer of pH 6.8, at least 70% of Tofacitinib is released in 6 hrs. and at least 80% of Tofacitinib is released in 8 hrs.

[0049] For most compositions, % cumulative release in phosphate buffer of pH 6.8 is provided. Additionally, % cumulative release in 0.1 N HC1 and % cumulative release in acetate buffer of pH 4.5 is also provided.

[0050] All dissolutions are conducted using USP Type II Apparatus in 900 mL of dissolution media at 50 RPM.

[0051] The extended release composition has at least one release modifying agent. The release modifying agent is composed of an element selected from a gum or a polymer and more preferably, of at least two elements such as two separate polymers or one gum and other polymer or two gums etc.

[0052] Preferably, Extended release compositions of Tofacitinib or salt thereof are coated compositions where a coat is deposited / layered on the core. Such coated composition can be preferably a coated tablet or coated capsule or tablet in tablet or coated pellets either encapsulated or compressed into a tablet. Release modifying agent is present in coating. Additionally, it can be present in core as well. The release modifying agent in the core can be same as that in coating or different.

[0053] In preferred embodiments, the Extended release compositions of Tofacitinib or salt thereof comprises a) a release modifying agent in core; and b) a release modifying agent in the coating.

[0054] When the release modifying agent is composed of two polymers, the first polymer is a sustained release or gastro resistant or a delayed release polymer which dissolve above pH 6.8, preferably above pH 6.0 and more preferably above pH 5.5 and the second polymer is an immediate release polymer or a polymer which dissolves in media of gastric pH i.e. acid soluble polymer wherein the said two polymers together cause sustained or extended release of Tofacitinib causing at least 75 - 80 % release over 8 hrs.

[0055] The polymers employed are easily available and economical. A sustained release or delayed release polymer includes cellulose derivatives, cellulose acetate derivatives etc. Preferred polymers include ethyl cellulose, hydroxy propyl methylcellulose acetate succinate, hydroxy propyl methylcellulose phthalate, cellulose acetate phthalate and polymethacrylates such as Eudragit RL, Eudragit RS, Eudragit L, Eudragit S, Eudragit FE30 D / NE 30D etc.

[0056] The second polymer is an immediate release polymer or a polymer which dissolves in media of gastric pH i.e. acid soluble polymer and includes hydroxy propyl methylcellulose, hydroxyprpyl cellulose, polyvinyl pyrrolidone. Eudragit EPO etc.

[0057] In few embodiments, where release modifying agent has two elements such as two polymers, both these polymers can be same in core and coating.

[0058] In an embodiment presented by batch F2, the release modifying agent in core and coating is same and made up of two polymers viz. Eudragit EPO and HPMCAS.

[0059] In few embodiments where release modifying agent has two elements such as two polymers, one or both these polymers can be different in core and coating.

[0060] In an embodiment presented by F47J, core contains a release modifying agent comprising two polymers as Eudragit EPO and HPMCAS whereas coating comprises a release modifying agent comprising two polymers ethyl cellulose and HPMC. One or more gums can also be employed to cause sustained action in place of or in addition to a release modifying agent and includes Xanthan Gum, gum. Acacia, locust bean gum , carrageenan, sodium alginate etc.

[0061] The amount of release modifying agent employed depends on the nature of such agent.

[0062] The amount of release modifying agent employed in core is from 10 % w / w to up to 50 % w / w of the core, preferably from 10 % w / w to up to 40 % w / w of the core and more preferably up to 35% w / w of the core and most preferably from 10 - to around 30 % w / w of the core.

[0063] Preferably, immediate release / water soluble / acid soluble polymer is added in amounts of from 1-15 % w / w, preferably 5 - 10 % w / w of core composition.

[0064] Preferably, sustained release / delayed release polymer is added in amounts of from 10 - 35 % w / w, preferably 15 - 25 % w / w of core composition.

[0065] The amount of release modifying agent employed in the coating is up to 10 % w / w preferably up to 5 % w / w of the coated composition, more preferably up to 4 % w / w of the coated composition and most preferably up to 3.5% w / w of the coated composition and most preferred range is from 1 - to around 3.5 % w / w of the coated composition.

[0066] The amount of release modifying agent employed in the sustained or extended release Tofacitinib composition is up to 60 % w / w of the coated composition, preferably up to 50 % w / w of the coated composition and more preferably up to 40 % w / w of the coated composition and most preferably from 15 % w / w - to around 35 % w / w or from 25 - 35 % w / w of the coated composition.

[0067] Interestingly, the present invention successfully produced sustained or extended release compositions of Tofacitinib even without incorporating any sustained or extended release agent. For example, several batches of compositions employed only hydroxy propyl methylcellulose acetate succinate which is a delayed release polymer in combination with Eudragit EPO (soluble in gastric pH) or hydroxy propyl methylcellulose (low viscosity immediate release polymer) produced sustained or extended release compositions of Tofacitinib exhibiting following release in phosphate buffer of pH 6.8.

[0068] Sustained release or Extended release compositions of the present invention cause sustained release of Tofacitinib over 8 hrs. such that in phosphate buffer of pH 6.8 i) at least 50%, preferably 60 % Tofacitinib is released in 4 hrs; ii) at least 65%, preferably 70 % Tofacitinib is released in 6 hrs; iii) at least 75%, preferably 80 % Tofacitinib is released in 8 hrs.

[0069] More preferably, in phosphate buffer of pH 6.8, at least 70% of Tofacitinib is released in 6 hrs. and at least 80% of Tofacitinib is released in 8 hrs.

[0070] Also, not more than 40 % should be released in 1 hr.

[0071] More preferably, in phosphate buffer of pH 6.8, at least 70% of Tofacitinib is released in 6 hrs. and at least 80% of Tofacitinib is released in 8 hrs.

[0072] Therefore, under one aspect the invention provides sustained or extended release compositions of Tofacitinib even without incorporating any sustained or extended release agent.

[0073] Tofacitinib sustained or extended release compositions of batch numbers F2, F43E, F47G, F50K and F53B provided under various examples do not contain any sustained or extended release agent and yet they provided sustained or extended release compositions of Tofacitinib.

[0074] Out of these compositions, Tofacitinib sustained or extended release compositions of batch numbers F2, F43E, F47G and F50K contain a unique combination of Eudragit EPO soluble in gastric pH and hydroxy propyl methylcellulose acetate succinate a delayed release polymer soluble in alkaline pH. This unique combination employed in the coating allows one polymer to dissolve and other to remain insoluble depending on the pH of the surrounding media. This unique combination employing acid soluble and alkali soluble polymers simultaneously provided sustained or extended release irrespective of any pH media. The inventors arrived at such invention serendipitously while selecting and working on several polymers. The inventors named this as In-situ polyelectrolyte complexation of Eudragit EPO with Hypromellose Acetate Succinate which is found to be a promising carrier for developing Tofacitinib sustained / extended release compositions.

[0075] In-situ polyelectrolyte complexation

[0076] Eudragit EPO and Hypromellose Acetate Succinate are poly electrolytes. Any macromolecule with repeating units that breaks down into a highly charged polymeric molecule when exposed to an ionising solvent (such as water) is referred to as a polyelectrolyte (PE). The polymeric chain might be positively or negatively charged.

[0077] The oppositely charged smaller counter ions tend to maintain electro neutrality by neutralising the charge on the repeating units of the PE. In their uncharged condition, PEs behave like typical macromolecules, but if the ionic groups are somewhat dissociated, there may be significant alterations in their characteristics. Electrostatic interactions may develop as a result of the partial or complete dissociation of ionic groups, which may cause variations in the behaviour of polymers. Viscosity, solubility, pH, ionisation constant, ionic strength, and diffusion coefficient are just a few of the properties of PEs that may be measured.

[0078] Polyelectrolytes have a propensity to create Polyelectrolytes complexes (PECs) when they combine with one or more ions that have opposing charges. When oppositely charged PEs in aqueous solutions are mixed, cooperative electrostatic interactions — which are predominate — between polycations and polyanions result in the creation of a dense phase that is distinct from the solvent. PE complexation primarily happens between ions that have opposite charges, such as PE-PE, PE- drugs, PE-nucleic acids, and PE-surfactants.

[0079] Hydrogen-bonding, van der Waals forces, hydrophobic contacts, and dipole interactions are a few examples of the inter-macromolecular interactions that are involved. Without the use of chemical cross-linkers, these interactions between the polymeric chains helped to construct non-permanent networks. PECs offer clear benefits as pharmaceutical excipients since they are generally well tolerated, biocompatible, and sensitive to changes in environmental circumstances, such as managing drug release. Degree of ionization of each of the oppositely charged PEs, the charge distribution over the polymeric chains, the concentration of the PEs, the mixing ratio, the nature and position of the ionic groups, the molecular weight of the PEs, the polymer chain flexibility, as well as the temperature, ionic strength and pH of the reaction medium the formation and stability are different factors on which PECs depends.

[0080] The inventors propose following hypothesis for polyelectrolyte complexation.

[0081] Hypothesis:

[0082] The inventors propose following hypothesis for generating polyelectrolytic complexes from Eudragit® EPO (EE) ), a cationic polymer and Hypromellose acetate succinate, also known as hydroxypropyl methylcellulose acetate succinate (HPMCAS), an enteric polymer.

[0083] • Eudragit® EPO (EE), a cationic polymer having a mean relative molecular mass of about 150,000, is prepared by copolymerization of butyl methacrylate, 2- dimethylaminoethylmethacrylate, and methyl methacrylate. The ratio of dimethylaminoethyl methacrylate groups to butyl methacrylate and methyl methacrylate groups is about 2:1:1.

[0084] Alternatively, other cationic polymers include chitosan, Eudragit EPO, Hyaluronic acid. Alginic acid, dextran, cationic peptides, etc.

[0085] • Hypromellose acetate succinate, also known as hydroxypropyl methylcellulose acetate succinate (HPMCAS), is an anionic enteric polymer developed by Shin-Etsu Chemical Co., Ltd. in Japan. This enteric polymer is soluble in aqueous media at a pH higher than 5.5, owing to the presence of carboxyl groups.

[0086] • As in the composition there is tendency of complex formation between the Cationic Eudragit EPO and Anionic HPMCAS.

[0087] • Also, the Tofacitinib Citrate exhibit pH dependent solubility, therefore there may be chances of complexation between the charged API and the charged polymer used. • Also, Polyelectrolytes and Surfactants tends to form complex hence anionic Surfactant i.e. SLS is incorporated which helps in complex formation.

[0088] • The intensity of polyelectrolyte complex formation is pH dependent i.e the strength of the complex formed is different at different pH.

[0089] Thus, it has been serendipitously found by the present inventors that when Eudragit EPO and HPMCAS come in contact with each other, the release of Tofacitinib is better controlled. One can add these two polymers together in direct blending in core or intra-granularly or in coating to achieve controlled release. With this it is possible to achieve controlled release without adding any sustained / extended release polymer.

[0090] Further, the two polymers together forming release modifying agents are employed in various ratios and proportions in core and in coating. Core compositions employed up to 50 % w / w of release modifying agent of the core weight, preferably up to 40 % w / w of the core weight and more preferably up to 35% w / w of the core weight and most preferably from 10 - to around 30 % w / w of the core weight.

[0091] The present invention preferably provides any one of the following three combinations to achieve the desired extended release of Tofacitinib or salt thereof. The said compositions comprise of a core and a coating and one or more releasecontrolling agents. One or more release-controlling agents are made up of one or more poly electrolytes.

[0092] The 3 combinations are as follows,

[0093] 1. The extended-release composition of Tofacitinib or salt thereof comprises a single-release controlling agent in the core containing two polyelectrolytes which are a cationic polymer and an anionic polymer. The need for coating is obviated by using a certain ratio of a cationic and an anionic polymer and a high concentration of surfactant which is also preferably anionic. The most preferred surfactant is sodium lauryl sulfate.

[0094] 2. The extended-release composition of Tofacitinib or salt thereof as claimed in claim 2 comprises two release controlling agents wherein the first release controlling agent is in the core and the second release controlling agent is in the coating. First release controlling agent comprises two poly electrolytes and the second release controlling agent comprises either a single polyelectrolyte or a non- polyelectrolyte, or both a single polyelectrolyte and a non -poly electrolyte wherein the single polyelectrolyte is the same or different from the two polyelectrolytes.

[0095] More preferably, the core has a cationic polymer and an anionic polymer. Coating has an anionic polymer or a non-ionic / non-polyelectrolyte which is a neutral polymer or gum, or both anionic polymer and neutral polymer.

[0096] 3. The extended-release composition of Tofacitinib or salt thereof comprises two release controlling agent wherein the first release controlling agent is in the core and the second release controlling agent is in the coating and wherein both the first and the second release controlling agents comprises two poly electrolytes. In this preferably, one anionic polymer and one cationic polymer are present in both core as well as coating.

[0097] The extended-release composition of Tofacitinib or salt thereof is unique in that the cationic polymer and the anionic polymer form an In situ polyelectrolyte complex controlling release of Tofacitinib or salt thereof.

[0098] Additionally, a surfactant is preferably added in the core. Surfactant forms an important part of the composition. Nevertheless, by using a ratio of cationic to anionic polymer from 1 : 1 to 1 :5, surfactant can be eliminated or can be incorporated in low amounts.

[0099] The surfactant is preferably an anionic surfactant. Sodium lauryl sulfate is the most preferred one.

[0100] In the core, cationic polymer to anionic polymer ratio is preferably from 1 : 1 to 1 : 10. Most preferred ratio of 1 :3 is noted between cationic polymer to anionic polymer when a lower amount of surfactant such as from 0.1 to 5 %, preferably from 0.25 - 2 % is employed. Release of Tofacitinib from such compositions is faster and a suitable coating is needed. The coating may have two polyelectrolytes which are again a cationic and anionic polymers or alternatively, only anionic polymer or non- polyelectrolyte or neutral polymer or a combination of anionic polymer and non- poly electrolyte or neutral polymer are employed to achieve desired results. Surprisingly when the ratio of cationic to anionic polymer changes from 1: 3 to 1:5 - 1:10 supplemented with a higher surfactant level of around 2 - 12 %, preferably, from 3 - 10 %, the need of controlling release by coating is obviated. In such cases, a simple film coating can be applied containing one or more film forming agent.

[0101] Disintegrant can be added if needed in the direct mixing step to enhance dissolution of coated composition.

[0102] Glidant, lubricant and if needed immediate release / acid soluble / water soluble polymer are added extra- granularly.

[0103] The aim of the present invention is to produce tofacitinib compositions which are broken down after ingestion and do not remain in a non-deformable form for long like marketed compositions having OROS technology.

[0104] The tablets are compressed at lower to moderate weight such as at less than 500 mg, preferably at less than 400 mg, and most preferably at less than 300 mg.

[0105] In an embodiment, tablet weight varies from 100 mg - 300 mg, preferably from 150 mg to 275 mg and most preferably not more than 250 mg.

[0106] Alternatively, minitablets can be prepared. Each minitablet has a weight of 30 mg to 60 mg. Few such minitablets can be filled in a capsule and such capsule can be administered.

[0107] In an embodiment, four micro tablets each having a weight of 50 mg. are prepared. In another embodiment, five micro tablets each having a weight of 40 mg are prepared filled in a capsule.

[0108] Other excipients that are included apart from Tofacitinib and release modifying agent includes excipients comprising one or more of diluent, binder, disintegrant, surfactant, glidant, lubricant, colorant, plasticizer, anti-tacking agent etc.

[0109] Diluents or filler can be selected from the group consisting of calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, maltitol, microcrystalline cellulose, powdered cellulose, pregelatinized starch, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, and xylitol and other materials known to one of ordinary skill in the art.

[0110] Preferred diluents or fillers include lactose, fructose, starch, sucrose, mannitol, maltitol, sorbitol, xylitol and microcrystalline cellulose.

[0111] Preferably, diluents are employed in amounts of from 20 - 60 % w / w, more preferably from 30 - 60 % w / w, most preferably from 40 - 60 % w / w.

[0112] Disintegrant can be selected from the group, but are not limited to a!ginic acid, carboxymethylcellulose calcium, carboxymethyl cellulose, carboxymethylcellulose sodium, cross-linked sodium carboxymethylcellulose, low substituted hydroxypropyl cellulose, colloidal silicon dioxide, croscarmellose sodium (CCS), crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose (MCC), methyl cellulose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidones, polacrifin potassium, starch, pregelatinized starch, sodium alginate, sodium lauryl sulphate, sodium starch glycolate, crystalline cellulose, hydroxypropyl starch and other materials known to one of ordinary skill in the art. The combination of above-mentioned disintegrants can also be used.

[0113] Preferably, disintegrants are employed in amounts of from 0.0- 5 % w / w, more preferably from 0.1 - 5 % w / w, most preferably from 0.2 - 2 % w / w.

[0114] Surfactants can be selected from i) Anionic surfactants including Sodium stearate, Sodium dodecyl sulfate (SDS), Sodium dodecyl benzene sulfonate, Sodium cholate; ii) cationic surfactants including Hexadecyltrimethylammonium bromide, Dodecyl pyridinium chloride ; iii) Nonionic surfactants including Sorbitan fatty acid esters (Span and Arlacel), polyoxyethylene stearates (Myrj), and the polyoxyethylene sorbitan fatty acid esters (tween); and iv) ; Ampholy tic (Zwitterionic) surfactants including N-dodecyl alanine and Lecithin.

[0115] The preferred surfactant is sodium lauryl sulfate.

[0116] Preferably, surfactants are employed in amounts of from 0.1- 5 % w / w, more preferably from 0.2- 5 % w / w, most preferably from 0.2 - 2 % w / w. Binder can be selected from the group, but is not limited to methylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, silicified microcrystalline cellulose(SMCC), polyvinyl pyrrolidone, gelatine, polyvinyl alcohol, acacia, tragacanth, guar, pectin, starch paste, pregelatinized starch, alginic acid, compressible sugar, liquid glucose, dextrates, dextrin, dextrose, maltodextrin, guar gum, magnesium aluminium silicate, polymethacrylates, sorbitol and other materials known to one of ordinary skill in the art. A mixture of binders may also be used. The binder is preferably used in an amount of from about 0 to about 15% w / w by weight, preferably from about 1 - 10 % w / w by weight of the composition.

[0117] Lubricants can be selected from the group consisting of vegetable oils, such as hydrogenated vegetable oil or hydrogenated castor oil; polyethylene glycols, such as polyethylene glycol (PEG)-4000 and PEG-6000; stearic acid; derivatives of stearic acid, such as magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate and sodium stearyl fumarate; mineral salts, such as talc; inorganic salts; organic salts, such as sodium benzoate, sodium acetate, sodium chloride and sodium oleate; and polyvinyl alcohols, microcrystalline cellulose, sodium lauryl sulphate, silica, colloidal silica, corn-starch, calcium silicate, magnesium silicate, silicon hydrogel and other materials known to one of ordinary skill in the art.

[0118] The preferred lubricant is magnesium stearate. Preferably, lubricant is used in an amount from about 0.5 to about 5% w / w by weight.

[0119] Glidants can be selected from the group, but is not limited to colloidal silicon dioxide, colloidal silica, corn-starch, talc, calcium silicate, magnesium silicate, magnesium trisilicate, amorphous silica, colloidal silicon, silicon hydrogel, powdered cellulose, silicon dioxide, talc, and other materials known to one of ordinary skill in the art.

[0120] The preferred glidant is colloidal silicon dioxide. Preferably, glidant is used in an amount from about 0.5 to about 5% w / w by weight. Coating preparation apart from release modifying agent contains plasticizer, colorants and anti-tacking agent.

[0121] Plasticizers are selected from citrate esters such as triethyl citrate, tributyl citrate, acetyl triethyl citrate and acetyl tributyl citrate, fatty acid esters such as butyl stearate, glycerol monostearate and stearyl alcohol, sebacate esters such as dibutyl sebacate, glycol derivatives such as polyethylene glycol and propylene glycol, phthalate esters such as diethyl phthalate, dibutyl phthalate, dioctyl phthalate, , Vitamin E TPGS and others such as triacetin, mineral oil castor oil etc.

[0122] The preferred plasticizer is dibutyl sebacate. Preferably, plasticizer is used in an amount from about 0.1 to about 2% w / w by weight.

[0123] Ferric oxides are used to arrive at the desired color.

[0124] Talc is used in amount of from 0.1 - 2 % w / w by weight as anti-tacking agent.

[0125] Coating composition usually employs two polymers forming release controlling / modifying agent in various ratios and proportions from 1:10 to 10:1 and preferably from 1:5 to 5:1. Three levels of the release controlling / modifying agent with respect to weight of coated composition are employed as provided in table 1 below:

[0126] Table 1: Amounts of polymers of coated composition

[0127] The usage of two polymers forming the release modifying agent are employed in the following proportions as provided in table 2 below: Table 2: Ratio of immediate release / water soluble / acid soluble polymer to water insoluble / acid insoluble / sustained release / delayed release polymer Preferred Compositions of the present invention are provided in table 3A below:

[0128] Table 3A: Preferred Compositions of the present invention

[0129] Process of preparing core tablets provides another important aspect of the invention. The inventors have successfully produced extended release tablets of Tofacitinib employing a direct compression as well as wet granulation.

[0130] Granulation can be done by water alone or with an aqueous solution of polymer / binder. Granulation with one or more polymers or with water alone after direct mixing / blending of intragranular ingredients has been found to cause better release of Tofacitinib. Wet granulation method is adopted for most batches where sustained release / delayed release polymer is added in granulation. Immediate release polymer is added either intra-granularly or extra- granularly.

[0131] More preferably, the process comprises, i) Weighing all ingredients and optionally dividing surfactant into two portions for granulation process; ii) Co-sifting polyelectrolyte, non-polyelectrolyte polymer, gum if present, and a surfactant or optionally a first portion of surfactant through ASTM#40 mesh iii) Co-sifting Tofacitinib or salt thereof, lactose monohydrate, and colloidal silicon dioxide (Aerosil 200) through ASTM#40 mesh and adding to the previous blend prepared in step 1 and transferring the co-sifted blends to a blender for dry mixing and mixing or to a Rapid mixer granulator for granulation and producing granules ready for lubrication; iv) Sifting Magnesium stearate through ASTM #60 and adding to the blend prepared in step iii and further blending for 5 minutes to prepare the final blend; v) Compressing final blend into tablets; vi) Preparing coating solution / suspension having at least one polymer and coating the tablets with coating solution to produce coated tablets.

[0132] Alternatively, blend can be compressed into minitablets. Instead of tablet of around 225 mg, 5 minitablets each of weight 45 mg or 4 minitablets, each of weight 56.25 mg can be filled in a capsule.

[0133] The process for preparing an extended-release composition by wet granulation comprises the following steps, i) Weighing all ingredients and optionally dividing surfactant into two portions for granulation process. This is done when higher percentage of surfactant is employed. For a lower percentage, entire surfactant can be employed without dividing. ii) Co-sifting anionic polyelectrolyte or both anionic and cationic polyelectrolytes, and entire or a first portion of surfactant through ASTM#40 mesh; iii) Co-sifting Tofacitinib or salt thereof, lactose monohydrate, and colloidal silicon dioxide (Aerosil 200) through ASTM#40 mesh and adding to the previous blend prepared in step 1 and transferring the co-sifted blends to a Rapid mixer granulator for granulation; iv) Granulating the blend of step iii) using water as a granulating agent in the RMG; v) Passing the granulate / granulation of step iv) through ASTM #12 and subjecting granulate / granulation to drying in fluid-bed drying process to produce dried granules (of desired LOD); vi) Optionally adding cationic polyelectrolyte to the dried granules obtained from step v after passing it through ASTM #40 mesh if not added in step ii vii) Adding the second portion of the sodium lauryl sulphate to the granules obtained from step v) and blending at 16 RPM for 10 minutes (to be done when higher percentage of surfactant is used); viii) Sifting the Magnesium stearate through ASTM # 60 and adding to step vi) and blending for 5 min at 16 rpm; ix) Compressing final blend into tablets or minitablets; x) Preparing coating solution / suspension having ai) two polyelectrolytes including a cationic polyelectrolyte and an anionic polyelectrolyte and a film forming agent; or bi) an anionic polyelectrolyte and a film forming agent; or ci) non-polyelectrolyte and a film forming agent; or di) a film forming agent or using a prepared coating solution of film forming agent; and coating the tablets with a coating solution / suspension.

[0134] Coating solution is prepared as follows:

[0135] A] for coating solution having two polyelectrolytes: i) Dissolving an anionic polyelectrolyte in acetone and adding a cationic polyelectrolyte in the dispersion of anionic polymer and then adding isopropyl alcohol in the dispersion to avoid any lump formation. ii) Adding plasticizers and stirring for 10 minutes. iii) Adding coloring agent and Talc and then stirring for few minutes; iv) Filtered the coating solution through ASTM mesh 60# and keeping the dispersion under continuous stirring throughout the process.

[0136] B] for coating solution having non-poly electrolyte: i) Dissolving a non-polyelectrolyte in isopropyl alcohol and stirring for 20 minutes; ii) Adding film forming agent in water and stirring for 15 minutes; iii) Adding the prepared solutions of step (ii) to step (i) and stirring for 10 minutes; iv) Adding plasticizer and stirring for another 10 minutes; v) Adding coloring agent and Talc and then stirring for a few minutes; vi) Filtering the coating solution through ASTM mesh 60# and continuously stirring the dispersion throughout the coating process.

[0137] B] for coating solution having anionic poly electrolyte: i) Dissolving an anionic poly electrolyte in acetone and then adding isopropyl alcohol in the dispersion to avoid any lump formation; ii) Adding film forming agent in water and stirring for 15 minutes; iii) Adding the prepared solutions of step (ii) to step (i) and stirring for 10 minutes; iv) Adding plasticizers and stirring for 10 minutes. v) Adding coloring agent and Talc and then stirring for few minutes; vi) Filtered the coating solution through ASTM mesh 60# and keeping the dispersion under continuous stirring throughout the process.

[0138] The desired release can be achieved by any one or more of the following: i) by changing amount of release modifying agent in core; ii) by changing amount of release modifying agent in coating; iii) by changing ratio of immediate release / water soluble / acid soluble polymer to sustained release / delayed release polymer; iv) by adding binder / disintegrant in the core composition (Batch F053B); v) by adopting dry / wet granulation to control / enhance dissolution; vi) by adding two polymers forming poly electrolytic complex in core (direct blending or intra-granular) or in coating to control dissolution.

[0139] Drug content as high as 35.54 mg corresponding to a dose of 22 mg Tofacitinib was successfully accommodated in tablet weight of up to 250 mg. Ratio of drug to inactive ingredients is from 1:4 to 1:7 which has helped in achieving a low tablet weight.

[0140] Ratio of immediate release / water soluble / acid soluble / cationic polymer to sustained release / delayed release / anionic polymer plays a crucial role in the release of Tofacitinib. It is surprisingly noted that compositions having from 1:1 to 1: 5 ratio of cationic to anionic polymer with lower amount of surfactant sodium lauryl sulfate such as from 0.1 % to below 5 such as 2 % required release controlling agent in the coating. By changing ratio of cationic to anionic poly electrolyte and adding higher amounts of surfactant such as sodium lauryl sulfate from 5 - 10 %, it is possible to eliminate coating and in such cases role of coating even if applied is limited to bringing in smoothness and aesthetics (film coating), and no functional role is assigned.

[0141] Sustained release or Extended release compositions of the present invention cause sustained release of Tofacitinib over 8 hrs. such that in phosphate buffer of pH 6.8 i) at least 50%, preferably 60 % Tofacitinib is released in 4 hrs; ii) at least 65%, preferably 70 % Tofacitinib is released in 6 hrs; iii) at least 75%, preferably 80 % Tofacitinib is released in 8 hrs.

[0142] More preferably, in phosphate buffer of pH 6.8, at least 70% of Tofacitinib is released in 6 hrs. and at least 80% of Tofacitinib is released in 8 hrs. Also, not more than 40 % should be released in 1 hr.

[0143] Table 3B : Release controlling agents having poly electrolyte and non- polyelectrolytes

[0144] (Detailed compositions are provided under examples)

[0145] The following table provides that employing different release controlling agents wherein first release controlling agent present in the core has two polyelectrolytes of opposite charges (cationic and anionic), all batches comply with the above set % Cumulative release criteria.

[0146] PEL - poly electrolyte; NPL - non-polyelectrolyte

[0147] It is apparent from the above studies that the main release controlling agent is two polyelectrolytes of opposing charges which form a polyelectrolytic complex sustaining the release of Tofacitinib citrate. Additionally, batch F061G was subjected to stability testing and no rise in the levels of total impurities from the initial level was found obviating need to add alkalizer as suggested by WO 2014174073A1.

[0148] Examples

[0149] Following examples describe the invention and do not limit the scope of the invention in any way. It is further possible to change all parameters one by one or simultaneously and make hundreds and thousands of formulations all of which will fall within the scope of the present invention.

[0150] Example 1A: Core Composition employing direct compression as well as wet granulation processes and employing combination of Eudragit EPO and HPMCAS in core Table 4: Core composition

[0151] Process for F039D:

[0152] 1. Eudragit EPO, HPMCAS MG, and SLS were co-sifted through ASTM #40 mesh and blended for 10 minutes in octagonal blender. 2. Tofacitinib citrate, lactose monohydrate and Aerosil 200 were co-sifted through ASTM #40 mesh and added to the previous blend as prepared in step 1 and further blended for 10 min. 3. Magnesium stearate was sifted through ASTM #60 and added to the blend prepared in step 2 and further blended for 5 minutes.

[0153] 4. The final blend as prepared in step 3 was taken for compression.

[0154] 5. Compression details: Hardness: 10-15 kPa, Thickness: 4.1-4.2 mm, Weight: 196-205 mg.

[0155] Process for F047C:

[0156] Wet granulation is adopted for batch F047C.

[0157] Example 1B1: Release profile of core Composition of batch F039D of example 1A (Direct Compression Core composition)

[0158] Table 5A: % Cumulative release profile of Core composition

[0159] Example 1B2: Release profile of core Composition of batch F047C of example 1A (Wet granulated Core composition).

[0160] Table 5B : % Cumulative release profile of Core composition

[0161] Example 2A: Composition employing direct compression process and employing combination of Eudragit EPO and HPMCAS in core; and also, in coating in an amount of greater than 3 % w / w of coated composition wherein the ratio of polymers in the coating is 1:3

[0162] Table 6: Compositions of Batches Fl - F6 Process

[0163] 1. Polymers and surfactant were co-sifted through ASTM #40 mesh and blended for 10 minutes in octagonal blender.

[0164] 2. Tofacitinib citrate, lactose monohydrate, and Aerosil 200 were co-sifted through ASTM #40 mesh and added to the previous blend as prepared in step 1 and further blended for 10 min.

[0165] 3. Magnesium stearate was sifted through ASTM #60 and added to the blend prepared in step 2 and further blended for 5 minutes.

[0166] 4. The final blend as prepared in step 3 was taken for compression.

[0167] 5. Compression details: Hardness: 10-15 kPa, Thickness: 4.1-4.2 mm, Weight: 196-205 mg

[0168] 6. Coating details: Dissolve HPMCAS in acetone and add Eudragit EPO in the HMPCAS dispersion. IPA was added in the dispersion to avoid any lump formation. Triethylcitrate and PEG 400 was added and stirred for another 10 minutes. Finally, coloring agent and Talc were added and then stirred for few minutes. At last the coating solution was filtered through ASTM mesh 60# and kept the dispersion under continuous stirring throughout the process.

[0169] Example 2B: Cumulative Release profile of extended release Composition of batch F2 of example 2A

[0170] Table 7: Cumulative Release profile of batch F2

[0171] *RLD - Reference listed Drug which is marketed sample of Tofacitinib employing OROS technology.

[0172] Example 3A: Composition employing direct compression process and employing combination of Eudragit EPO and HPMCAS in core; and also, in coating in an amount of up to 2.5 % w / w of coated composition wherein the ratio of polymers in the coating is 1:3 Table 8: Composition of batch F039E

[0173] Process:

[0174] 1. Eudragit EPO, HPMCAS MG, and SLS were co-sifted through ASTM #40 mesh and blended for 10 minutes in octagonal blender.

[0175] 2. Tofacitinib citrate, lactose monohydrate, and Aerosil 200 were co-sifted through ASTM #40 mesh and added to the previous blend as prepared in step 1 and further blended for 10 min.

[0176] 3. Magnesium stearate was sifted through ASTM #60 and added to the blend prepared in step 2 and further blended for 5 minutes.

[0177] 4. The final blend as prepared in step 3 was taken for compression.

[0178] 5. Compression details: Hardness: 10-15 kPa, Thickness: 4.1-4.2 mm, Weight: 196-205 mg

[0179] 6. Coating details: Dissolve HPMCAS in acetone and add Eudragit EPO in the HMPCAS dispersion. IPA was added in the dispersion to avoid any lump formation. Triethylcitrate and PEG 400 was added and stirred for another 10 minutes. Finally, coloring agent and Talc were added and then stirred for few minutes. At last, the coating solution was filtered through ASTM mesh 60# and kept the dispersion under continuous stirring throughout the process. Example 3B: % Cumulative Release profile of extended release Composition of example 3A

[0180] Table 9: % Cumulative Release profile of batch F039E

[0181] Example 4A: Composition employing wet granulation process and employing combination of Eudragit EPO and HPMCAS in core; and also, in coating in an amount of greater than 3 % w / w of coated composition wherein the ratio of polymers in the coating is 1:4 Table 10: Composition of batch F043E

[0182] Process:

[0183] 1. HPMCAS MG and SLS were co-sifted through ASTM #40 mesh and blended for 10 minutes. 2. Tofacitinib citrate, lactose monohydrate, and Aerosil 200 were co-sifted through ASTM #40 mesh and added to the previous blend as prepared in step 1 and further blended for 10 min.

[0184] 3. The mixture of step 2 was transferred into the bowl and granulated using water. The mass obtained was passed through ASTM mesh#12 and th granules obtained was dried at 60 °C for 1 hour.

[0185] 4. Dried granules were passed through ASTM mesh 30#.

[0186] 5. Eudragit EPO was passed through ASTM #40 mesh and added to the dried granules obtained from step 4.

[0187] 6. The blend of step 5 was mixed for 5 minutes. 7. Magnesium stearate was sifted through ASTM #60 and added to the blend prepared in step 6 and further blended for 5 minutes.

[0188] 8. The final blend as prepared in step 7 was taken for compression. 9. Compression details: Hardness: 10-15 kPa, Thickness: 4.1-4.3 mm, Weight: 196-205 mg

[0189] 10. Coating details: Dissolve HPMCAS in acetone and add Eudragit EPO in the HMPCAS dispersion. IPA was added in the dispersion to avoid any lump formation. Triethylcitrate and PEG 400 was added and stirred for another

[0190] 10 minutes. Finally, coloring agent and Talc were added and then stirred for few minutes. At last, the coating solution was filtered through ASTM mesh 60# and kept the dispersion under continuous stirring throughout the process.

[0191] Example 4B: Release profile of extended release Composition of example 4A Table 11: % Cumulative Release profile of batch F043E Example 5A: Composition employing wet granulation process and employing combination of Eudragit EPO and HPMCAS in core; and also, in coating in an amount of up to 2.5 % w / w of coated composition wherein the ratio of polymers in the coating is 1:4

[0192] Table 12: Composition of batch F047G

[0193] Process:

[0194] 1. HPMCAS MG and SLS were co-sifted through ASTM #40 mesh and blended for 10 minutes. 2. Tofacitinib citrate, lactose monohydrate, and Aerosil 200 were co-sifted through ASTM #40 mesh and added to the previous blend as prepared in step 1 and further blended for 10 min.

[0195] 3. The mixture of step 2 was transferred into the bowl and granulated using water. The mass obtained was passed through ASTM mesh#20 and the granules obtained was dried at 60 °C for 1.5 hour.

[0196] 4. Dried granules were passed through ASTM mesh 30#.

[0197] 5. Eudragit EPO was passed through ASTM #40 mesh and added to the dried granules obtained from step 4.

[0198] 6. The blend of step 5 was mixed for 10 minutes.

[0199] 7. Magnesium stearate was sifted through ASTM #60 and added to the blend prepared in step 6 and further blended for 5 minutes.

[0200] 8. The final blend as prepared in step 7 was taken for compression.

[0201] 9. Compression details: Hardness: 10-15 kPa, Thickness: 4.1-4.3 mm, Weight: 196-205 mg

[0202] 10. Coating details: Dissolve HPMCAS in acetone and add Eudragit EPO in the HMPCAS dispersion. IPA was added in the dispersion to avoid any lump formation. Triethylcitrate and PEG 400 was added and stirred for another 10 minutes. Finally, coloring agent and Talc were added and then stirred for few minutes. At last, the coating solution was filtered through ASTM mesh 60# and kept the dispersion under continuous stirring throughout the process.

[0203] Example 5B: Release profile of extended release Composition of example 5A Table 12: % Cumulative Release profile of batch F047G

[0204] Example 6A: Composition employing wet granulation process and employing combination of Eudragit EPO (extra-granular) and HPMCAS (intra- granular) in core and in an amount of around 2.5 - 3 % w / w of coated composition wherein the ratio of polymers in the coating is 1.86:1 (65:35)

[0205] Table 13: Composition of Batch F047J

[0206] Process:

[0207] 1. HPMCAS MG and SLS were co-sifted through ASTM #40 mesh and blended for 10 minutes.

[0208] 2. Tofacitinib citrate, lactose monohydrate, and Aerosil 200 were co-sifted through ASTM #40 mesh and added to the previous blend as prepared in step 1 and further blended for 10 min.

[0209] 3. The mixture of step 2 was transferred into the bowl and granulated using water. The mass obtained was passed through ASTM mesh#20 and the granules obtained was dried at 60 °C for 1.5 hour.

[0210] 4. Dried granules were passed through ASTM mesh 30#.

[0211] 5. Eudragit EPO was passed through ASTM #40 mesh and added to the dried granules obtained from step 4.

[0212] 6. The blend of step 5 was mixed for 10 minutes.

[0213] 7. Magnesium stearate was sifted through ASTM #60 and added to the blend prepared in step 6 and further blended for 5 minutes.

[0214] 8. The final blend as prepared in step 7 was taken for compression.

[0215] 9. Compression details: Hardness: 10-15 kPa, Thickness: 4.1-4.3 mm, Weight: 196-205 mg

[0216] 10. Coating preparation details: Ethylcellulose was dissolved in IPA and stirred for 20 minutes. HPMC 6cps was added to water and stirred for 15 minutes. HPMC solution was added to previously prepared Ethyl cellulose solution and stirred for 10 minutes. Dibutyl sebacate was added and stirred for another 10 minutes. Finally, coloring agent and Talc were added and then stirred for a few minutes. At last, the coating solution was filtered through ASTM mesh 60# and kept the dispersion under continuous stirring throughout the coating process.

[0217] Example 6B: Release profile of extended release Composition of example 6A Table 14: % Cumulative Release profile of batch F047J Example 7A: Composition employing wet granulation process and employing combination of Eudragit EPO and HPMCAS in core; and in coating HPMC and ethyl cellulose in an amount of up to 2.5 % w / w of coated composition wherein the ratio of polymers in the coating is 3:2 Table 15: Composition of Batch F047K

[0218] Example 7B: Release profile of extended release Composition of example 7A Table 16: % Cumulative Release profile of batch F047K

[0219] Example 8A: Composition employing wet granulation process and employing combination of Eudragit EPO and HPMCAS in core; and in coating HPMC and HPMCAS in an amount of around from 2.5 - 3 % w / w of coated composition wherein the ratio of polymers in the coating is 3:2

[0220] Table 17: Composition of Batch F050K Example 8B: Release profile of extended release Composition of example 8A

[0221] Table 18: % Cumulative Release profile of batch F050K Example 9A: Composition employing wet granulation process and employing combination of Eudragit EPO and HPMCAS in core; and in coating combination of HPMC and HPMCAS in an amount of around from 2.5 - 3 % w / w of coated composition wherein the ratio of polymers in the coating is 3:2 Table 19: Composition of Batch F053K

[0222] Example 9B: Release profile of extended release Composition of example 9A Table 20: % Cumulative Release profile of batch F053B

[0223] Example 10A: Role of different levels of SLS to modulate the release

[0224] Table 21: Composition with different percentages of SLS Manufacturing process for Core Tablets: -

[0225] 1. All the ingredients were weighed accurately and separately.

[0226] 2. Eudragit EPO, HPMCAS MG and SLS were passed through the ASTM # 40 sieve.

[0227] 3. API, Lactose monohydrate and Colloidal silicon dioxide were co-sifted through ASTM #40 sieve, added to step 2, and blended for 10 min at 16 rpm.

[0228] 4. Granulation was carried out using water as a granulating agent in the Rapid mixer granulator (RMG).

[0229] 5. Magnesium stearate after passing through ASTM # 60 and added to step 3 and blended for 5 min at 16 rpm.

[0230] Example 10B: Release profile of Compositions of example 10A

[0231] Table 22BI: Comparative release profile to establish the SLS as a release regulating agent:

[0232] Table 22BII: Comparative release profile to establish the SLS as a release regulating agent: Example 11A: Role of different levels of SLS to modulate the release

[0233] Table 23 A: Composition 1:6 ratio of Cationic polymer to Anionic polymer by weight and higher amount of SLS (> 5 %) obviates need of coating Manufacturing process for Core Tablets: -

[0234] 1. All the ingredients were weighed accurately and separately.

[0235] 2. Eudragit EPO, HPMCAS MG and SLS were passed through the ASTM # 40 sieve.

[0236] 3. API, Lactose monohydrate and Colloidal silicon dioxide were co-sifted through ASTM #40 sieve, added to step 2, and blended for 10 min at 16 rpm.

[0237] 4. Granulation was carried out using water as a granulating agent in the Rapid mixer granulator (RMG). 5. The granulate / granulation was then passed through ASTM #12 and subjected to fluid-bed drying process to produce dried granules (dried till desired LOD).

[0238] 6. The second portion of the SLS and the granules obtained from step 5 were then blended at 16 RPM for 10 minutes.

[0239] 7. Magnesium stearate after passing through ASTM # 60 was added to step 6 and blended for 5 min at 16 rpm.

[0240] Example 11B: Comparative release profile on Composition with 1:6 ratio of Cationic polymer to Anionic polymer and higher amount of SLS (> 5 %)

[0241] Table 23B: 1:6 ratio of Cationic polymer to Anionic polymer by weight and higher amount of SLS (> 5 %) obviates the need of coating Figures 10A and 10B provide an overlay of % Cumulative release of above batches in media of pH 1.2 . Table 23C: 1:6 ratio of Cationic polymer to Anionic polymer by weight and higher amount of SLS (from 5 - 10 %) obviates the need for coating. Figures 11 A and 1 IB provide an overlay of % Cumulative release of above batches in media of pH 6.8 .

[0242] Comparative dissolution profile during pH transition study

[0243] Two pH transition studies were performed on RLD and Batch F061G as follows: 1) pH 1.2 for 2 hrs, followed by pH 6.8 buffer; and

[0244] 2) pH 1.2 for 2 hrs, followed by pH 4.5 buffer.

[0245] The results are provided in Tables 23D and 23E and figures 9A and 9B.

[0246] Table 23 D: Comparative pH transition studies - pH 1.2 for 2 hrs. followed by pH 6.8 for 6 hrs.

[0247] Table 23 E: Comparative pH transition studies - pH 1.2 for 2 hrs. followed by pH 4.5 for 6 hrs. Example 12: Accelerated stability study of test formulation F061G:

[0248] Table 24: Accelerated stability study - Initial and 3 months Composition F061G is found stable for 3 months at accelerated conditions.

Claims

ClaimsWe claim1. An extended-release composition of Tofacitinib or salt thereof having a core and optionally a coating, the said composition is characterized by having Tofacitinib or salt thereof and one or more release controlling agents having one or more poly electrolytes.

2. The extended-release composition of Tofacitinib or salt thereof as claimed in claim 1 comprising a core and a coating; and the said composition comprises one or more release controlling agents having one or more polyelectrolytes.

3. The extended-release composition of Tofacitinib or salt thereof as claimed in claim 2 comprising a single-release controlling agent in the core containing two poly electrolytes.

4. The extended-release composition of Tofacitinib or salt thereof as claimed in claim 2 comprising two release controlling agents wherein the first release controlling agent is in the core comprises two polyelectrolytes and the second release controlling agent is in the coating comprises either a single polyelectrolyte or a non-polyelectrolyte, or both a single polyelectrolyte and a non-polyelectrolyte, wherein the single polyelectrolyte is same or different from the two poly electrolytes.

5. The extended-release composition of Tofacitinib or salt thereof as claimed in claim 2 comprising two release controlling agent wherein the first release controlling agent is in the core and the second release controlling agent is in the coating and , wherein both the first and the second release controlling agents comprises two poly electrolytes.

6. The extended-release composition of Tofacitinib or salt thereof as claimed in claim 3 wherein the first polyelectrolyte is a cationic polymer and the second polyelectrolyte is an anionic polymer.

7. The extended-release composition of Tofacitinib or salt thereof as claimed in claim 4 wherein two polyelectrolytes in the core comprise a cationic polymer and an anionic polymer; and wherein the single polyelectrolyte in the second-release controlling agent is an anionic polymer; and wherein a non-polyelectrolyte is a neutral polymer or gum.

8. The extended-release composition of Tofacitinib or salt thereof as claimed in claim 5 wherein both first and second-release controlling agents comprise two poly electrolytes; and wherein the first poly electrolyte is a cationic polymer and the second polyelectrolyte is an anionic polymer.

9. The extended-release composition of Tofacitinib or salt thereof as claimed in any preceding claims wherein the cationic polymer and the anionic polymer form an In situ polyelectrolyte complex.

10. The extended-release composition of Tofacitinib or salt thereof as claimed in any of the preceding claims wherein the cationic polymer is butyl methacrylate, dimethyl aminoethyl methacrylate, methyl methacrylate copolymer (Eudragit EPO).

11. The extended-release composition of Tofacitinib or salt thereof as claimed in any of the preceding claims wherein the anionic polymer is one or more of hydroxy propyl methylcellulose acetate succinate, hydroxy propyl methylcellulose phthalate, cellulose acetate phthalate, and methacrylic acid-melhyl methacrylate copolymer (1 : 1 ), methacrylic acid-methyl methacrylate copolymer (1:2) (Eudragit L 100 -55, Eudragit®L 30 D-55, Eudragit®L 100, Eudragit® L 12.5, Eudragit® S 100, Eudragit®S 12.5 , Eudragit FS 30D).

12. The extended-release composition of Tofacitinib or salt thereof as claimed in any of the preceding claims wherein the non- polyelectrolyte comprises one or more of Non-poly electrolyte is selected from hydroxy propyl methyl cellulose, hydroxy propyl cellulose, carboxy methyl cellulose, ethyl cellulose, ethyl acrylate and methyl methacrylate copolymer (Eudragit NE 30D), copolymer of ethylacrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups (Eudragit RL and Eudragit RS).

13. The extended-release composition of Tofacitinib or salt thereof as claimed in any of the preceding claims wherein gum is selected from one or more of Xanthan Gum, Guar gum. Gum Acacia, Locust bean gum , carrageenan, and sodium alginate.

14. The extended-release composition of Tofacitinib or salt thereof as claimed in any of the preceding claims wherein the anionic polymer is hydroxy propyl methylcellulose acetate succinate; and wherein the cationic polymer is butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate copolymer (Eudragit EPO).

15. The extended-release composition of Tofacitinib or salt thereof as claimed in any of the preceding claims wherein the cationic polymer butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate copolymer (Eudragit EPO) and the anionic polymer hydroxy propyl methylcellulose acetate succinate, together form an In situ polyelectrolyte complex.

16. The extended-release composition as claimed in claim 2 optionally comprises a surfactant selected from a cationic, an anionic, an Ampholytic (Zwitterionic) or a non-ionic surfactant.

17. The extended-release composition as claimed in claim 16 wherein the anionic surfactant is selected from Sodium stearate, Sodium dodecyl sulfate (SDS) / Sodium lauryl sulfate, Sodium dodecyl benzene sulfonate, Sodium cholate.

18. The extended-release composition as claimed in claim 13 wherein the nonionic surfactant is selected from Sorbitan fatty acid esters (Span and Arlacel), polyoxyethylene stearates (Myrj), and the polyoxyethylene sorbitan fatty acid esters (tween), Vitamin E TPGS.

19. The extended-release composition as claimed in claim 13 wherein the cationic surfactant is selected from hexadecyl trimethyl ammonium bromide and Dodecyl pyridinium chloride.

20. The extended-release composition as claimed in claim 16 comprising an anionic surfactant.

21. The extended-release composition as claimed in claim 17 wherein an anionic surfactant is Sodium dodecyl sulfate (SDS) / Sodium lauryl sulfate.

22. The extended-release composition according to any of the preceding claims is a tablet or mini tablets filled in capsule.

23. An extended-release tablet of Tofacitinib characterized by having i) a core having a release controlling agent comprising two poly electrolytes; and an additional ingredient. ii) a coating having a single polyelectrolyte or a non-polyelectrolyte or both a single polyelectrolyte and a non-polyelectrolyte.

24. The extended-release tablet of Tofacitinib as claimed in claim 23 wherein i) Two polyelectrolytes are cationic and anionic polymers; ii) Single polyelectrolyte is an anionic polymer and the non-polyelectrolyte is a neutral polymer or a gum; and iii) An additional ingredient is optionally a surfactant.

25. The extended -release tablet of Tofacitinib as claimed in claim 24 wherein i) Cationic polymer is butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate copolymer (Eudragit EPO); ii) Anionic polymer is selected from hydroxy propyl methylcellulose acetate succinate, hydroxy propyl methylcellulose phthalate, cellulose acetate phthalate, and methacrylic acid-methyl methacrylate copolymer (1 :1), methacrylic acid-methyl methacrylate copolymer (1:2) (Eudragit L 100 -55, Eudragit®L 30 D-55, Eudragit®L 100, Eudragit® L 12.5, Eudragit® S 100, Eudragit®S 12.5 , Eudragit FS 30D); iii) Surfactant is an anionic surfactant selected from Sodium stearate, Sodium dodecyl sulfate (SDS) / Sodium lauryl sulfate, Sodium dodecyl benzene sulfonate, Sodium cholate.iv) Non-poly electrolyte is selected from Non-poly electrolyte is selected from hydroxy propyl methyl cellulose, hydroxy propyl cellulose, carboxy methyl cellulose, ethyl cellulose, ethyl acrylate and methyl methacrylate copolymer (Eudragit NE 30D), copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups (Eudragit RL and Eudragit RS); and v) a gum is selected from Xanthan Gum, Guar gum. Gum Acacia, Locust bean gum , carrageenan, and sodium alginate.

26. The extended-release tablet of Tofacitinib as claimed in claim 25 comprising i) butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate copolymer (Eudragit EPO); and Hydroxy propyl methyl cellulose acetate succinate and Sodium dodecyl sulfate / Sodium lauryl sulfate in the core; ii) Hydroxy propyl methyl cellulose acetate succinate and hydroxy propyl methyl cellulose in the coating.

27. The extended-release tablet of Tofacitinib as claimed in claim 26 comprising i) butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate copolymer (Eudragit EPO); and Hydroxy propyl methyl cellulose acetate succinate and Sodium dodecyl sulfate / Sodium lauryl sulfate in the core; and optionally ii) Hydroxy propyl methyl cellulose in the coating.

28. The extended -release tablet of Tofacitinib as claimed in claim 27 form an In situ polyelectrolyte complex between butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate copolymer (Eudragit EPO) and Hydroxy propyl methyl cellulose acetate succinate.

29. The extended-release tablet of Tofacitinib as claimed in claim 25 whereini) Cationic polymer is butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate copolymer (Eudragit EPO); ii) Anionic polymer is hydroxy propyl methylcellulose acetate succinate; iii) An optionally surfactant, which is Sodium dodecyl sulfate (SDS) / Sodium lauryl sulfate; and iv) Non-poly electrolyte is hydroxy propyl methyl cellulose; wherein cationic polymer, anionic polymer and surfactant are present in the core and non-poly electrolyte is present in the coating.

30. A process for preparing an extended-release composition of Tofacitinib or salt thereof characterized in having following steps, i) Weighing all ingredients and optionally dividing surfactant into two portions for granulation process; ii) Co-sifting polyelectrolytes, and a surfactant or optionally a first portion of surfactant through ASTM#40 mesh; iii) Co-sifting Tofacitinib or salt thereof, lactose monohydrate, and colloidal silicon dioxide (Aerosil 200) through ASTM#40 mesh and adding to the previous blend prepared in step 1 and transferring the co-sifted blends ai) to a blender for dry mixing and carry out mixing for 10 mins; or bi) to a Rapid mixer granulator for granulation and producing granules ready for lubrication; iv) Sifting Magnesium stearate through ASTM #60 and adding to the blend prepared in step iii and further blending for 5 minutes to prepare final blend; v) Compressing final blend into tablets or minitablets; vi) preparing coating solution / suspension having at least one polymer and coating the tablets with coating solution.

31. The process for preparing an extended-release composition as claimed in claim 30 wherein the tablets are obtained by wet granulation comprising the steps of,i) Weighing all ingredients and optionally dividing surfactant into two portions for granulation process when used in higher amounts; ii) Co-sifting both anionic and cationic polyelectrolyte or only anionic polyelectrolyte, and a first portion of surfactant through ASTM#40 mesh; iii) Co-sifting Tofacitinib or salt thereof, lactose monohydrate, and colloidal silicon dioxide (Aerosil 200) through ASTM#40 mesh and adding to the previous blend prepared in step 1 and transferring the co-sifted blends to a Rapid mixer granulator for granulation; iv) Granulating the blend of step iii) using water as a granulating agent in the RMG; v) Passing the granulate / granulation of step iv) through ASTM #12 and subjecting granulate / granulation to drying in fluid-bed drying process to produce dried granules (of desired LOD); vi) Optionally adding cationic polyelectrolyte to the dried granules obtained from step v after passing it through ASTM #40 mesh if not added in step ii; vii) Adding the second portion of the sodium lauryl sulphate if divided in step i to the granules obtained from step v) and blending at 16 RPM for 10 minutes; viii) Sifting the Magnesium stearate through ASTM # 60 and adding to step vi) and blending for 5 min at 16 rpm; ix) Compressing final blend into tablets or minitablets; x) Preparing coating solution / suspension having ai) two polyelectrolytes including a cationic polyelectrolyte and an anionic polyelectrolyte and a film forming agent; or bi) an anionic polyelectrolyte and a film forming agent; or ci) non-polyelectrolyte and a film forming agent; or di) a film forming agent or using a prepared coating solution of film forming agent; and coating the tablets with a coating solution / suspension.

32. The process for preparing coating solution / suspension as claimed in claim 31 containing two polyelectrolytes comprising the steps of i) Dissolving an anionic polyelectrolyte in acetone and adding a cationic polyelectrolyte in the dispersion of anionic polymer and then adding isopropyl alcohol in the dispersion to avoid any lump formation; ii) Adding plasticizers and stirring for 10 minutes; iii) Adding coloring agent and Talc and then stirring for few minutes; iv) Filtered the coating solution through ASTM mesh 60# and keeping the dispersion under continuous stirring throughout the process.

33. The process for preparing an extended-release composition as claimed in any of the preceding claims wherein the preparation of coating solution / comprises the steps of i) Dissolving a non-polyelectrolyte in isopropyl alcohol and stirring for 20 minutes; ii) Adding film forming agent in water and stirring for 15 minutes; iii) Adding the prepared solutions of step (ii) to step (i) and stirring for 10 minutes; iv) Adding plasticizer and stirring for another 10 minutes; v) Adding coloring agent and Talc and then stirring for a few minutes; vi) Filtering the coating solution through ASTM mesh 60# and continuously stirring the dispersion throughout the coating process.

34. The process for preparing coating solution / suspension as claimed in claim 31 containing an anionic polyelectrolyte comprising the steps of i) Dissolving an anionic poly electrolyte in acetone and then adding isopropyl alcohol in the dispersion to avoid any lump formation; ii) Adding film forming agent in water and stirring for 15 minutes; iii) Adding the prepared solutions of step (ii) to step (i) and stirring for 10 minutes; iv) Adding plasticizers and stirring for 10 minutes; v) Adding coloring agent and Talc and then stirring for a few minutes;vi) Filtered the coating solution through ASTM mesh 60# and keeping the dispersion under continuous stirring throughout the process.

35. The process for preparing an extended-release composition as claimed in claim 30 wherein i) Cationic polymer is butyl methacrylate, dimethylaminoethyl methacrylate, methyl methacrylate copolymer (Eudragit EPO); ii) Anionic polymer is selected from hydroxy propyl methylcellulose acetate succinate, hydroxy propyl methylcellulose phthalate, cellulose acetate phthalate, and methacrylic acid-methyl methacrylate copolymer (1: 1), methacrylic acid-methyl methacrylate copolymer (1:2) (Eudragit L 100 -55, Eudragit®L 30 D-55, Eudragit®L 100, Eudragit® L 12.5, Eudragit® S 100, Eudragit®S 12.5 , Eudragit FS 30D); iii) Surfactant is an anionic surfactant selected from Sodium stearate, Sodium dodecyl sulfate (SDS) / Sodium lauryl sulfate, Sodium dodecyl benzene sulfonate, Sodium cholate. iv) Non-poly electrolyte is selected from hydroxy propyl methyl cellulose, hydroxy propyl cellulose, carboxy methyl cellulose, ethyl cellulose, ethyl acrylate and methyl methacrylate copolymer (Eudragit NE 30D), copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups (Eudragit RL and Eudragit RS); v) a gum is selected from Xanthan Gum, Guar gum. Gum Acacia, Locust bean gum, carrageenan, and sodium alginate; vi) film former is low viscosity grade of hydroxy propyl methyl cellulose.

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