WO2017153822A1

WO2017153822A1 - Resinates of pharamceutically acceptable salts of tofacitinib such as tofacitinib citrate, for taste masking

Info

Publication number: WO2017153822A1
Application number: PCT/IB2016/055491
Authority: WO
Inventors: Milind Vinayak SATHE; Saiesh Purushottam PHALDESAI; Srikant V PIMPLE
Original assignee: Unichem Laboratories Limited
Priority date: 2016-03-08
Filing date: 2016-09-15
Publication date: 2017-09-14

Abstract

The present invention relates to resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate, fast disintegrating and or quick release pharmaceutical compositions comprising the said resinates and process for the preparation of resinates and compositions. The resin used to prepare the resinate is selected from copolymers of methacrylic acid and divinylbenzene, cross linked polymer of methacrylic acid and divinylbenzene, sulphonated copolymers of styrene and divinylbenzene. Ion exchange resin is contacted with the solution of Tofacitinib citrate under controlled pH in order to form the resinate. The resinate has versatile use in making of pharmaceutical preparations. Few such pharmaceutical preparations are Tablets, capsules, dry syrups, suspensions, lozenges, films.

Description

RESINATES OF PHARAMCEUTICALLY ACCEPTABLE SALTS OF TOFACITINIB SUCH AS TOFACITINIB CITRATE, FOR TASTE MASKING FIELD OF INVENTION

The present invention relates to resinates of pharmaceutically acceptable salts of

Tofacitinib such as Tofacitinib Citrate, fast disintegrating and or quick release pharmaceutical compositions comprising the said resinates and process for the preparation of resinates and compositions.

BACKGROUND OF THE INVENTION

Oral dosage forms containing pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate have bitter taste. Therefore these are provided in coated form prefereably film coated. Bitter tatse of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate do not support their use without coating. Fast disintegrating and or quick release taste masked oral dosage forms containing pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate are not available. Therefore there is a need to provide fast disintegrating and or quick release taste masked oral dosage forms containing pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate.

Conventional means to mask the taste is to sugar coat it or film coat it. But such tablets are not readily dispersible in the mouth and have to be swallowed with water. Swallowing with water as method of administration of drugs has several disadvantages.

Taste masking is also done by various other means such as formation of new salt, various types of coatings, resinates and inclusion complexes. Rapid melt, Fast melt or quick disintegrating techniques also enable oral dispersion of compositions. Each of these methods is associated with peculiar disadvantages which are method specific.

Selecting the appropriate resin to form desirable resinate is a difficult task. The resin has to be drug compatible. It has to be drug specific otherwise desirable drug release profile may not be achieved. Formulating a stable composition is an important aspect in drug development. Composition in which an improper resin is used can jeopardize drug stability and or drug availability for absorption. Therefore formation of appropriate resinate is a problematic, complicated and challenging process.

A taste masked composition of a bitter tasting drug in combination with two enteric polymers comprising, a methacrylic acid copolymer and a phthalate polymer is taught by US 6565877. In preparing the taste masked composition, it alarms against the use of cation-exchange resins such as polysulfonic acid and polycarboxylic acid polymers for adsorbing amine drugs. Loading active substances onto an ion exchange resin is also discloed by US 2990332 and is told to be dependent upon several factors such as equilibrium constant, temperature, the rate of diffusion and the presence of other ions.

IN 225628 teaches resinate complexes of Cetirizine, levocetirizine, its enantiomers salts and the compositions thereof.

IN 207068 teaches a manufacturing process for the preparation of mouth dispersible tablets using active pharmaceutical substance Alprazolam.

IN 206560 teaches a novel method for the preparation of mouth dispersible tablet of active pharmaceutical substance Ondansetron using Betacyclodextrin.

US 5188825 teaches freeze-dried dosage forms prepared by bonding or complexing a water- soluble active agent to or with an ion exchange resin to form a substantially water insoluble complex.

US 5219563 teach use of synthetic cation exchange resins such as copolymers of styrene and divinylbenzene which are sulphonated and copolymers of methacrylic acid and divinylbenzene for masking the bitter taste of ranitidine .

Patent application number 2842/MUM/2015 which is not published on the date of application refers to orally disintegrating tablets of Tofacitinib but is silent on resinate formation or resinates of Tofacitinib or its pharmaceutically acceptable salts.

Prior art does not teach the resinate of Tofacitinib or its salts such as Tofacitinib citrate, rapidly disintegrating and or quick release taste masked pharmaceutical compositions comprising the said resinates and process for the preparation of resinates and compositions. There are quite a few papers describing Fast dissolving tablets. The Publication "Critical Reviews™ in Th erapeutic Drug Carrier Systems, 21(6):433-475 (2004)" by Yourong Fu, Shicheng Yang, Seong Hoon Jeong, Susumu Kimura, & Kinam Park provides insight to many technologies such as Freeze drying, molding, Sublimation, effervescent, humidity treatment to produce fast disintegrating tablets. It enlists the drawbacks associated with each of the technologies.

Tablets produced by Freeze drying technology have high cost of production, besides sensitive to humidity. Their soft, fragile nature renders them unsuitable for conventional blister packing. Useful only for low dose water soluble drugs, poor stability at higher temperature and humidity and very poor physical resistence are additional disadventages. Claritin, Reditab, Dimetapp, Zofran, Lorazepam, Loperamide and few more products are available based on Zydis Tecnology, freeze drying technology. Tablets produced by Molding, lack mechanical strength. These often get eroded and damaged during handling or opening the blister pack. Increasing hardness results into undesirable effect on disintegration. Improvement of mechanical strength and disintegration is possible but with huge investments.

Orally disintegrating or fast dissolving tablets produced by other technologies necessitate use of robotic techniques such as robotic pick and pack type of packaging systems which are costly.

Dysphagia, or difficulty in swallowing, is common among all age groups and is more pronounced in infants, small age and geriatric populations. It is also prominent in physically challenged, elderly institutionalized individuals. Swallowing with water is a difficult task for them.

Size, form, surface and taste of tablets accentuate problem of swallowing. Geriatric and pediatric patients and traveling patients may not have ready access to water. These and such other difficulties jeopardize patient compliance. These facts emphasize the need for a new dosage form of Tofacitinib or its pharmaceutically acceptable salt such as Tofacitinib Citrate that can improve patient compliance.

Solid dosage forms that can be dissolved in water or suspended in the mouth, promote easy swallowing and are highly desirable for the pediatric, geriatric population and for other patients who prefer the convenience.

Orally disintegrating tablets have added adventage that bioavailability of drugs is enhanced due to absorption from mouth, pharynx and oesophagus, besides rapid or fast onset of therapeutic action. Orally dispersible tablets have other adventages such as cost effective and simple packaging if appropriate method is selected to produce and pack it. Enhanced palatability, ease of administration and hence patient compliance are its pronounced advantages.

Resinate of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate and or the fast relase or quick release compositions such as orally disintegrating tablets, dry syrups and such other dosage forms made form such resinates are not reported as yet.

There is an urgent and unfulfilled need to provide resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate in which bitter taste is masked and their compositions that rapidly disintegrate and or provide quick release, optionally containing other actives.

Further in view of safety issues and in view of providing a better composition, it is always desirable to prepare such compositions without the use of aromatic solvents. Tofacitinib orally dispersible compositions comprising the resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate, without the use of aromatic solvents are not known. The invention discloses use of non aromatic solvents to prepare resinate of pharmaceutical salts of Tofacitinib such as Tofacitinib Citrate.

There is a need to provide the process to produce resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate and rapid disintegrating and or quick release taste masked pharmaceutical compositions containing the resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate which does not require the use of costly and sophisticated packaging machinery.

OBJECTS OF THE INVENTION

The main object of the invention is to provide resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate, rapid disintegrating and or quick release taste masked pharmaceutical compositions comprising the said resinates and process for the preparation of resinates and compositions.

Another object of the invention is to prepare stable resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate, rapid disintegrating and or quick release taste masked pharmaceutical compositions comprising the said resinates and process for the preparation of resinates and compositions.

Yet another object of the invention is to provide easily dispersible resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate, rapid disintegrating and or quick release taste masked pharmaceutical compositions comprising the said resinates and process for the preparation of resinates and compositions.

Yet another aspect of the invention is to provide resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate, a rapidly disintegrating and or quick release taste masked pharmaceutical compositions of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate without the use of aromatic solvents and without the use of sophisticated packaging machinery.

Yet another object of the invention to provide taste masked rapidly disintegrating and or quick release composition of pharmaceutically acceptable salt of Tofacitinib with at least one more active ingredient. SUMMARY OF INVENTION

The present invention relates to resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate. The invention also relates to taste masked, stable and readily dispersible resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate, rapidly disintegrating and or quick release taste masked pharmaceutical compositions comprising the said resinates and process for the preparation of resinates and compositions. Further the invention relates to the preparation of resinates without the use of aromatic solvents and the compositions comprising the resinates and produced without the use of sophisticated packaging machinery.

The process for preparation of resinates comprises steps:

1) Contacting solution of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate with ion exchange resin at pH 1 - 7,

2) Separating the resinate and optionally washing and drying it at temperatures below 110°C.

The process of preparation of taste masked resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate and compositions comprising these resinates comprises steps of:

a) Dissolving pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate in a non-aromatic solvent;

b) Adjusting the pH of the solution obtained in step a) preferably to 1 - 7 to prepare the pH adjusted solution;

c) Contacting ion exchange resin with the pH adjusted solution obtained in step b) to obtain the resinate;

d) Optionally washing the resinate obtained in step c) with a non-aromatic solvent to obtain washed resinate

e) Optionally drying the washed resinate obtained in step d);

f) Processing the resinate obtained in step c) or d) or e) with at least one pharmaceutical excipient to obtain rapidly disintegrating and or quick release compositions with or without other actives.

Resinates prepared by the above process are stable resinates. These resinates and the compositions are prepared without the use of aromatic solvents and without the use of sophisticated packaging machinery

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate. The invention also relates to process to prepare the resinates and the compositions comprising the resinates.

The process for preparation of resinates comprises steps:

1) Contacting solution of pharmaceutically acceptable salts of Tofacitinib such as

Tofacitinib Citrate with ion exchange resin at pH 1 - 7,

a) Dissolving pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate in a non-aromatic solvent to obtain solution;

b) Adjusting the pH of the solution obtained in step a) preferably tol - 7 to prepare the pH adjusted solution;

e) Optionally drying the washed resinate obtained in step d);

Resinate formation takes place when ion exchange resin is contacted with drug solution. Thereafter depending upon the dosage form to be produced it may be washed and it may be dried. In order to prepare suspension, the resinate can be used without drying. The resinate obtained in step d) or e) can be incorporated into suitable liquid base with the processes known in the art to obtain taste masked liquid suspension of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate.

If solid dosage forms are to be prepared, it is advisable to dry the resinate before it is incorporated into solid dosage forms. The process of preparation of solid dosage form compositions with the resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate comprises steps of:

g) Taking suitable quantity of resinate, preferably dried resinate,

h) mcorporating it with other pharmaceutically acceptable excipients in order to formulate a desired pharmaceutical composition.

The dried resinate is processed to obtain fast disintegrating and or quick release compositions. Fast disintegrating and or quick release compositions of resinate are prepared as illustrated in the exmaples.

Spray drying in which fluidized bed processor is used is also an efficient process to form the resinates. Dried free flowing resinates in powder form are produced which are useful in designing the solid dosage forms.

The resinate of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate has a versatile use. It is processed to obtain several oral dosage compositions such as granules for dispersion either in sachet pack or as a dry syrup, or such granules dispersed into flavored syrupy base to obtain liquid suspension, quick dispersing tablets. Incorporation of resinate into chewing gum base gives chewing gum composition or dispersed into lozenge base to have a lozenge. The resinate when used with cooked glucose or similar base, gives a lollypop. Resinate can be incorporated into a wafer base or a soluble film base to have medicated wafer or soluble film.

As illustrated by exmaples, desired composition is prepared by incorporating the resinate with other pharmaceutically acceptable excipients.

The cation exchange resin used for resinate formation is selected from Methacrylic acid polymer with divinylbenzene and Acrylic acid Potassium salt or Methacrylic acid polymer with divinylbenzene and Potassium salt, Methacrylic acid polymer with divinylbenzene and Acrylic acid, sulphonated copolymers of styrene and divinylbenzene, copolymers of methacrylic acid and divinylbenzene, cross linked polymer of methacrylic acid and divinylbenzene. These resins are commercially available including those available as Indion resins, Tulsion resins, Dowex resins, Amberlite IRP resins and their equivalents in the form of salt with alkali metals or in acid form. Resinate formation takes place even when ratio of resin to pharmaceutically acceptable salt of Tofacitinib such as Tofacitinib Citrate is 0.5: 1. It was observed that resinate formation taking place when the ratio of resin to pharmaceutically acceptable salt of Tofacitinib such as Tofacitinib Citrate in the range of 8: 1 to 0.5: 1, is acceptable. For effective and better taste masking it is advisable to take more quantity of resin. As the ratio of resin to pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate increases we get better taste masked resinates. Therefore preferable ratios of resin to pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate are 8: 1 to 4: 1.

Non aromatic solvent can be used singularly or in presence of another non aromatic solvent i.e. co-solvent. Non aromatic solvent and or co-solvent is selected from ethanol, isopropyl alcohol, water, Dicholoromethane, organic polar and non-polar solvents, glycerin, propylene glycol and their suitable mixtures. Tofacitinib salts such as Tofacitinib Citrate dissolve easily in water. Solubility of Tofacitinib salts such as Tofacitinib Citrate, in solvents other than water is less. Solubility of Tofacitinib salts such as Tofacitinib Citrate is very good in water, and it diminishes in mixture of water and other non-aromatic solvent and further diminishes in solvents other than water, in general.

Non aromatic solvents as per the present invention includes open chain aliphatic solvents and mixtures thereof. These solvents are selected from compounds having carbon atoms ranging from CI - C6. It includes solvents such as ethers, esters, aldehydes, Ketones, alcohols, chlorinated solvents, water miscible and water immiscible solvents. Alcohols includes acohols having carbon atoms CI to C6. Aldehydes and ketones having carbon atoms from CI to C6. Ethers, alcohols and esters having carbon atoms CI to C6 are covered by present invention. Chlorinated solvents having carbon atoms from CI to C6 are included in the present invention. Preferred alcohols are methanol, ethanol, straight and branched propyl alcohol and mixtures thereof. Preferred ketone being acetone and preferred aldehyde being acetaldehyde. Preferred chlorinated solvents include dichloromethane or methylelne dichloride.

Preferred solvent is one in which the pharmaceutically acceptable salt of Tofacitinib such as Tofacitinib Citrate is soluble, which can be removed to conform to GMP and or ICH standards and which is physiologically acceptable.

pH of the solution of pharmaceutically acceptable salt of Tofacitinib such as Tofacitinib Citrate is kept in the range of 1 - 7 by the methods known in the art.

Resinate is dried in one embodiment by heating in hot air oven. In another embodiment it is air dried at room or slightly elevated temperatures. Evaporation, vacuum evaporation, tray drying, microwave drying, spray drying, drum and belt film drying are other effective drying techniques. Centrifuging and optionally followed by drying is yet another methtod of removing the solvent. Drying method is selected depending on solvent to be removed.

Resinate is dried at a temperature less than 110°C. It is advisable to carry out drying at temperature range of above 20°C to about 110°C. Suitable temperature is selected to ensure removal of solvent from the resinate. Preferable range for drying is 30°C to 105°C, more preferable range being 40°C to 90°C, most preferable range being 50°C to 80°C. The resinates were found to be stable in the temperature range of 40°C to 70°C when exposed for 30 minutes duration. There was no impact on taste masking ability. Active ingredient is pharmaceutically acceptable salt of Tofacitinib such as Tofacitinib Citrate. The process of forming resinate as illustrated by the invention provides sufficient motivation to form resinates of other acid addition salts of Tofacitinib and hence other pharmaceutically acceptable salts are covered by the invention.

The content of active ingredient in the resinate is in the range of about 11% to about 67%w/w, preferably from about 1 l%to about 20% w/w. Content of active in the resinate in the preferred range is useful for orally disintegrating tablets or orally disintegrating compositions. Content of active ingredient can be adjusted in the range of about 21% to 50% w/w or from 51% to 67% w/w of that of resinate by taking lesser quantity of resin. 67% of active content would mean resin to pharmaceutically acceptable salt of Tofacitinib such as Tofacitinib Citrate ratio of 1 :2.

Resinate wherein active content is in the range of 11% to about 67% can be conveniently filled into empty hard gelatin capsules with or without other excipients. In case of dry syrups or granules ready for suspension, addiotnal sweetening agents such as aspartame, sucralose or flavors such as Peppermint, strwbaerry, mint, orange flavours also enable incorporation of resinate with higher content of active. Similar granular preparation can be prepared by known methods which is to be taken directly from the container without dilution with any solvent such as water. These are powders to be taken orally.

The resinate is processed with pharmaceutically acceptable excipients to obtain rapidly disintegrating or fast disintegrating and or quick release compositions such as quick dispersing tablets, granules for dispersion to prepare suspension just before consumption or as a dry syrup. The resinate when dispersed into flavored syrupy base gives a liquid suspension. When mixed with chewing gum base, gives chewing gum composition. When dispersed into lozenge base, gives a lozenge. When the resinate is incorporated into cooked glucose or similar base, gives a lollypop. It can be incorporated into a wafer base or a soluble film base to obtain wafer or medicated soluble film by the known processes. Resinate with suitable active content is conveniently filled into empty hard gelatin capsules with or without other excipients. Capsule filling can be done either manually on hand filling machines or by mechanized means on automatic or semiautomatic machines.

Taste masked pharmaceutical compositions of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate intended by this application / invention encompass all aforesaid compositions and similar dosage forms.

It is possible to vary the content of the resinate in the composition in various dosage forms. Resinate can be easily incorporated into various dosage forms in various percentages weight by weight. Resinate content from 0.1 %w/w to 99%w/w of the weight of composition provides suitable Tasteless, rapidly disintegrating and quick release dosage form. The percentage of the resinate in the composition is also decided by the quantity and extent of other ingredients used and other desired attributes. Although 0.1% w/w or such lower concentrations of resinate can be incorporated to form a composition, use of 0.1% w/w or such lower concentrations of resinate in the composition would make the composition bulky or voluminous and hence not desirable. It is preferable to keep content of the resinate in the composition from 10% w/w to 90% w/w. Preferred resinate percentage in the composition is in the range of about 25% w/w to about 90% w/w. Resinate along with additional one or more active pharmaceutical ingredient provides fixed dose combination dosage form.

Additional sweteining agents that can be employed for preparation of Tofacitinib resinate compositions can be selected from sugars such as Mannitol, Sucrose, Maltitol, Fructose, Sorbitol, Sucralose, Dextrose; Aspartame; Saccharin Sodium, Acesulfame Potassium and the like pharmaceutically acceptable sweeteners. The resinate was given to 8 volunteers for testing palatability and was found to be substantially free from bitter taste which is otherwise associated with pharmaceutically acceptable salt of Tofacitinib such as Tofacitinib Citrate. The compositions comprising resinate were given to 8 volunteers for testing palatability, mouth-feel, and taste. The compositions were found to be substantially free from the bitter taste, otherwise associated with pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate, and were found to be palatable and had acceptable mouth feel. Use of taste enhancing agents improves the taste further. The disintegration time of the tablet in the oral cavity was well below 2 minutes and was about 40 - 50 seconds.

Quickly disintegrating or fast release compoisitions means a composition that disintegrates quickly in oral cavity or outh. The fast disintegrating tablet is a tablet which disintegrates fast in oral cavity or mouth. Compositions of the invention disintegrate in oral cavity within 2 mniutes.

Thus the invention provides resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate and the process to preare the same. So prepared resinates are found to be stable at drying temperatures mentioned hereinabove. These are also easily dispersible. These resinates and the compositions comprising the resinates are prepared without the use of aromatic solvents and without the use of sophisticated packaging machinery.

Orally disintegrating, quick release compositions with improved palatability, mouth-feel, and taste, eliminate the use of the water and support patient compliance. As these resinates are stable, it is easy to incorporate them with another active ingredient, to provide fixed dose combination dosage form comprising multiple active pharmaceutical ingredients in addition to Tofacitinib.

Although no specific example is given of incorporation of other active, use of resinate would bring fixed dose combination within the purview of this invention and application.

Fixed dose combination dosage forms including fast disintegrating or quick release compositions, are rendered stable by using techniques known the prior art including but not limited to multi-layered tablets, tablets in capsules, compressed coating, capsule in capsule and so on. Such dosage forms comprising active pharmaceutical ingredients in addition to resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate are covered by this invention. In this manner it is possible to combine other active ingredients which are used to treat rheumatoid arthritis, or auto-immune diseases and the other indications on which Tofacitinib is useful, with the resinates of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate.

Resinates and the compositions such as rapid disintegrating and or quick release taste masked pharmaceutical compositions comprising the said resinates and process for the preparation of resinates and compositions is described by non-limiting examples.

Examples:

Example 1:

1. Approximately 350 ml of purified water was taken and 1 gm of Tofacitinib citrate was dissolved into it under continuous stirring till clear solution was formed. 3 such solutions were prepared, each one for individual resin.

2. 0.5 gm of resin of selected grade was added slowly and stirred for 3 hours. pH was adjusted to 5.2. Simultaneous taste check was carried out.

3. The solution was kept under stationary mode till cake formation was seen.

4. Upper part of the solution was decanted and cake was dried at 75°C for 3 hours.

5. Dried cake was tasted.

There was reduction of different degree in bitter taste than the taste of Tofacitinib Citrate. Example 2: Taste masked Tofacitinib Citrate resinate.

Approximately 350 ml of purified water was taken and 1 gm of Tofacitinib citrate was dissolved into it under continuous stirring till clear solution was formed. 3 such solutions were prepared, each one for individual resin.

1 gm of resin of selected grade was added slowly and stirred for 3 hours. pH was adjusted to 5.2. Simultaneous taste check was carried out. Further incremental quantities of lgm of resin were added and stirring continued for 30 minutes till the removal of bitter taste .

. The solution was kept under stationary mode till cake formation was seen.

. Upper part of the solution was decanted and cake was dried at 75°C for 3 hours.

. Dried cake was tasted.

The bitter taste was masked to different degree in case of different resins used and cake was not bitter as was the Tofacitinib Citrate. When tasted by different volunteers the said resinates were found substantially free from the bitter taste that is associated with Tofacitinib Citrate.

Exam le 3: Taste masked Tofacitinib Citrate resinate.

1. 1 gm of Tofacitinib citrate was dissolved into approximately 350 ml of purified water under continuous stirring till clear solution was obtained. Three such solutions were prepared. pH was adjusted to 5.2.

2. 1 gm Resin was added slowly and stirred for 45 minutes. Separate solution was used for individual resin. Simultaneous taste check was carried out after about 45 minutes, lgm of incremental resin was added and stirred for further period of 45 minutes. This was carried out till satisfactory taste masking was observed. 3. Maximum time observed was about 3.5 hours. The pH of solution Tofacitinib Citrate Resinate in water was found to be 5.6.

4. The solution was kept under stationary mode till cake formation was seen.

5. Upper part of the solution was decanted and cake was dried at 75 °c for 3 hours.

Dried cake when tasted by different volunteers the said resinates was found substantially free from the bitter taste associated with Tofacitinib base.

Example 4: Rapid disintegrating taste masked tablet/ODT composition of Tofacitinib

Citrate resinate with Indion 294. [26.66% w/w resinate in the composition]

Example 5: Rapid disintegrating taste masked tablet/ ODT composition of Tofacitinib

Citrate resinate with Indion 234. [33.33% w/w resinate in the composition]

Example 6: Rapid disintegrating taste masked tablet/ ODT composition of Tofacitinib Citrate resinate with Indion 204. [46.66% w/w resinate in the composition]

Example 7: Manufacturing Process for Example 4, 5 and 6.

Formulae represent unit composition. Input materials taken in multiples depending upon available equipments to produce 10 tablets.

1. Passed Tofacitinib Citrate resinate through 40# and collected in a polybag of suitable size.

2. Transferred MCC into the Polybag containing resinate and mixed it for 5 minutes to prepare the blend.

3. Co-sifted step 2 blend with half quantity of Pearlitol 200SD through 40 #.

4. Sifted Crospovidone, Aspartame, Peppermint Flavour and Colloidal anhydrous silica through 40 #.

5. Rinsed resinate containing polybag with remaining quantity of Pearlitol 200SD and sifted through mesh 40 #.

6. Transferred sifted blend into 500cc HDPE bottle and mixed for 15 min at 16 rpm by attaching HDPE bottle with blender.

7. Sifted Magnesium stearate through 40# and mixed with step 6 blend for 3 min.

8. Compressed the tablet on compression machine. Hardness was 40-45N & Friability of 0.8% for 100 revolutions. Tablets disintegrated rapidly in the mouth.

Example 8: Dry syrup composition comprising resinate of Tofacitinib citrate.

[Resinate w/w % is 80.16%.]

Ingredient Qty / 5ml (mg) Tofacitinib Citrate resinate (Indion 294) (mg) 40.078

Sodium CMC(mg) 7.000

Sucrose(mg) 1.592

Propyl Paraben(mg) 1.330

Water to (ml) 5

Tofacitinib resinate 40.078 mgs in 5 ml is equal to 5mg of Tofacitinib base or 8.078mg of Tofacitinib citrate per 5ml. Tofacitinib resinate, Sodium CMC, Sucrose and Propyl Paraben were mixed. Water was added to make volume to 5 ml. Similarly in another experiment 500 ml were prepared without sugar. The compositions were studied for 7 days. Subjective evaluation testing was done during and after 7 days. Composition with sugar was not bitter. The composition without sugar had acceptable taste even after 7 days. The suspensions remain easily re-dispersible at the end of 7 days and were palatable.

When the same composition is prepared without sugar, % of resinate in the composition is 82.8% or approximately 83% w/w of dry solids.

Example 9: Dry syrup composition comprising resinate of Tofacitinib Citrate resinate

(Indion 234) [Resinate w/w % is 83.46%]

Tofacitinib resinate 50.078 mgs in 5 ml is equal to 5mg of Tofacitinib base or 8.078mg of Tofacitinib citrate per 5ml. Tofacitinib resinate, Sodium CMC, Sucrose and Propyl Paraben were mixed in mixer. Water was added to make volume to 5 ml. Similarly in another experiment 500 ml were prepared without sugar. The compositions were studied for 7 days. Subjective evaluation testing was done during and after 7 days. Composition with sugar was not bitter. The composition without sugar had acceptable taste even after 7 days. The suspensions remain easily re-dispersible at the end of 7 days and were palatable. When the same composition is prepared without sugar, % of resinate in the composition is 85; or approximately 86% w/w of dry solids.

Example 10: Dry syrup composition comprising resinate of Tofacitinib Citrate resinate

(Indion 204) [Resinate w/w % is 87.6%.]

Tofacitinib resinate 70.078 mgs in 5 ml is equal to 5mg of Tofacitinib base or 8.078mg of Tofacitinib citrate per 5ml. Tofacitinib resinate, Sodium CMC, Sucrose and Propyl Paraben were mixed in mixer. Water was added to make volume to 5 ml. Similarly in another experiment 500 ml were prepared without sugar. The compositions were studied for 7 days. Subjective evaluation testing was done during and after 7 days. Composition with sugar was not bitter. The composition without sugar had acceptable taste even after 7 days. The suspensions remain easily re-dispersible at the end of 7 days and were palatable.

When the same composition is prepared without sugar, % of resinate in the composition is 89.4% or approximately 90% w/w of dry solids.

Example 11:

Dry Syrup compositions as listed above were prepared without sugar. The composition without sugar had acceptable taste even after 7 days.

Dry syrup composition without sugar contain higher % of resinate as compared to dry syrup compositions containing sugar if quantity of rest of the ingredients is kept same.

Example 12: Stability of resinates of Tofacitinib Citrate at 70°C with respect to taste. Resinates when kept at 40°C, 50°C, 60°C and 70°C in hot air oven for 30 minutes, did not show any change with respect to its taste masking ability. Resinates had acceptable taste.

Claims

We claim,

1) A resinate of pharmaceutically acceptable salts of Tofacitinib.

2) The resinate as claimed in claim 1 wherein the pharmaceutically acceptable salt is Tofacitinib Citrate.

3) The resinate as claimed in claim 1 - 2, wherein the resin is selected from copolymers of methacrylic acid and divinylbenzene, cross linked polymer of methacrylic acid and divinylbenzene, sulphonated copolymers of styrene and divinylbenzene.

4) The resinate as claimed in claims 1 - 3, wherein the resin is used in its free acid form or in the form of alkali metal salt.

5) The resinate as claimed in claims 1 -4, wherein pharmaceutically acceptable salt of Tofacitinib is present upto 67%w/w.

6) The resinate as claimed in claims 1 -4, wherein pharmaceutically acceptable salt of Tofacitinib is present in the range of 11% to 20%w/w.

7) The resinate as claimed in claims 1 -4, wherein pharmaceutically acceptable salt of Tofacitinib is present in the range of 21% to 50%w/w.

8) The resinate as claimed in claims 1 -4, wherein pharmaceutically acceptable salt of Tofacitinib is present in the range of 51% to 67%w/w.

9) The resinate as claimed in claims 1-4, wherein the ratio of resin to pharmaceutically acceptable salt of Tofacitinib is in the range of 8: 1 to 0.5: 1, preferable being 8: 1 to 4: 1.

10) A process of preparation of resinate of pharmaceutically acceptable salt of Tofacitinib, comprises steps of:

a) Dissolving pharmaceutically acceptable salt of Tofacitinib in an non-aromatic solvent to obtain solution;

b) Adjusting the pH of the solution obtained in step a) to 1 - 7 to prepare the pH adjusted solution;

d) Optionally washing the resinate obtained in step c) with solvent to obtain washed resinate and

e) Optionally drying the washed resinate obtained in step d);

f) Optionally processing the resinate obtained in step c) or d) or e) with at least one pharmaceutical excipient to obtain rapidly disintegrating and or quick release compositions with or without other actives.

The process of preparation of resinate of pharmaceutically acceptable salt of Tofacitinib as claimed in claim 10 wherein the salt is Tofacitinib is Tofacitinib Citrate.

The process as claimed in claim 10-11, wherein the resin is used in its free acid form or in the form of alkali metal salt.

The process as claimed in claim 10-12 , wherein the resin is selected from copolymers of methacrylic acid and divinylbenzene, cross linked polymer of methacrylic acid and divinylbenzene, sulphonated copolymers of styrene and divinylbenzene.

The process as claimed in claims 10-13, wherein pharmaceutically acceptable salt of Tofacitinib is present upto 67%w/w.

The process as claimed in claims 10-13, wherein pharmaceutically acceptable salt of Tofacitinib is present in the range of 11% to 20%w/w

The process as claimed in claims 1 0- 1 3 , wherein pharmaceutically acceptable salt of Tofacitinib is present in the range of 21% to 50%w/w.

The process as claimed in claims 10-13, wherein pharmaceutically acceptable salt of Tofacitinib is present in the range of 51% to 67%w/w.

The process, as claimed in claim 10-13, wherein solvent used is selected from water, alcohol, dichloromethane, isopropyl alcohol, glycerin, propylene glycol, pharmaceutically acceptable organic or inorganic solvents, non aromatic solvent selected from ethers, esters, aldehydes, Ketones, alcohols, chlorinated solvents, water miscible and water immiscible solvents or their mixtures. The process as claimed in claim 10-13 wherein the preferred solvent is water. The process, as claimed in claims 10- 13 , wherein the ratio of resin to pharmaceutically acceptable salt of Tofacitinib is in the range of 8: 1 to 0.5: 1, preferable being 8: 1 to 4: 1.

The process, as claimed in claim 10-13, wherein drying is carried out at temperature range of 20°C to 110°C, preferable range being 30°C to 105°C, more preferable range being 40°C to 90°C, most preferable range being 50°C to 80°C. The composition, comprising resinate as claimed in claims 1-2, wherein resinate content is from 0.1 %w/w to 99%w/w of the weight of composition, preferable being 10% w/w to 90% w/w.

A fast disintegrating composition comprising a resinate of pharmaceutically acceptable salt of Tofacitinib wherein the resinate content is 0.1 %w/w to 99% w/w of the weight of composition, preferable being 10% w/w to 90% w/w. The fast disintegrating composition as claimed in claim 23 which is a tablet composition.

The composition as claimed in claims 22 - 24, comprising pharmaceutically acceptable one or more additional active ingredients.