WO2017153822A1 - Résinates de sels de qualité pharmaceutique de tofacitinib tels que le citrate de tofacitinib utilisables à des fins de masquage du goût - Google Patents

Résinates de sels de qualité pharmaceutique de tofacitinib tels que le citrate de tofacitinib utilisables à des fins de masquage du goût Download PDF

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WO2017153822A1
WO2017153822A1 PCT/IB2016/055491 IB2016055491W WO2017153822A1 WO 2017153822 A1 WO2017153822 A1 WO 2017153822A1 IB 2016055491 W IB2016055491 W IB 2016055491W WO 2017153822 A1 WO2017153822 A1 WO 2017153822A1
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Prior art keywords
tofacitinib
resinate
pharmaceutically acceptable
acceptable salt
resinates
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PCT/IB2016/055491
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English (en)
Inventor
Milind Vinayak SATHE
Saiesh Purushottam PHALDESAI
Srikant V PIMPLE
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Unichem Laboratories Limited
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Publication of WO2017153822A1 publication Critical patent/WO2017153822A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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:
  • step b) Adjusting the pH of the solution obtained in step a) preferably to 1 - 7 to prepare the pH adjusted solution;
  • step b) Contacting ion exchange resin with the pH adjusted solution obtained in step b) to obtain the resinate;
  • step d) Optionally washing the resinate obtained in step c) with a non-aromatic solvent to obtain washed resinate
  • step 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
  • 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:
  • 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:
  • step b) Adjusting the pH of the solution obtained in step a) preferably tol - 7 to prepare the pH adjusted solution;
  • step b) Contacting ion exchange resin with the pH adjusted solution obtained in step b) to obtain the resinate;
  • step d) Optionally washing the resinate obtained in step c) with a non-aromatic solvent to obtain washed resinate
  • step 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions of pharmaceutically acceptable salts of Tofacitinib such as Tofacitinib Citrate intended by this application / invention encompass all aforesaid compositions and similar 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.
  • 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.
  • compositions comprising resinate were given to 8 volunteers for testing palatability, mouth-feel, and taste.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 2 Taste masked Tofacitinib Citrate resinate.
  • the bitter taste was masked to different degree in case of different resins used and cake was not bitter as was the Tofacitinib Citrate.
  • the said resinates were found substantially free from the bitter taste that is associated with Tofacitinib Citrate.
  • Example 4 Rapid disintegrating taste masked tablet/ODT composition of Tofacitinib
  • Example 5 Rapid disintegrating taste masked tablet/ ODT composition of Tofacitinib
  • 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.
  • Example 8 Dry syrup composition comprising resinate of Tofacitinib citrate.
  • 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.
  • 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.
  • % 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
  • 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.
  • 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.
  • % 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
  • 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.
  • 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.
  • % of resinate in the composition is 89.4% or approximately 90% w/w of dry solids.
  • 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.

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Abstract

La présente invention concerne des résinates de sels de qualité pharmaceutique de tofacitinib tels que le citrate de tofacitinib, des compositions pharmaceutiques à désintégration rapide ou à libération rapide comprenant lesdits résinates et un procédé de préparation de ces résinates et compositions. La résine utilisée pour préparer le résinate est choisie parmi des copolymères d'acide méthacrylique et de divinylbenzène, un polymère réticulé d'acide méthacrylique et de divinylbenzène, des copolymères sulfonés de styrène et de divinylbenzène. La résine échangeuse d'ions est mise en contact avec la solution de citrate de tofacitinib à un pH contrôlé afin de former le résinate. Le résinate peut être utilisé de diverses façons dans la fabrication de préparations pharmaceutiques. Quelques-unes de ces préparations pharmaceutiques correspondent à des comprimés, des gélules, des sirops secs, des suspensions, des pastilles ou des films.
PCT/IB2016/055491 2016-03-08 2016-09-15 Résinates de sels de qualité pharmaceutique de tofacitinib tels que le citrate de tofacitinib utilisables à des fins de masquage du goût WO2017153822A1 (fr)

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IN201621007954 2016-03-08
IN201621007954 2016-03-08

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WO2017153822A1 true WO2017153822A1 (fr) 2017-09-14

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WO2020172714A1 (fr) * 2019-02-27 2020-09-03 Samson Clinical Pty Ltd Traitement de maladie auto-immune
AU2019201399B2 (en) * 2019-02-27 2021-11-04 Samson Clinical Pty Ltd Treatment of autoimmune disease

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US20130344149A1 (en) * 2011-01-27 2013-12-26 Ratiopharm Gmbh Oral Dosage Forms for Modified Release Comprising Tasocitinib

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WO2020172714A1 (fr) * 2019-02-27 2020-09-03 Samson Clinical Pty Ltd Traitement de maladie auto-immune
AU2019201399B2 (en) * 2019-02-27 2021-11-04 Samson Clinical Pty Ltd Treatment of autoimmune disease
GB2596942A (en) * 2019-02-27 2022-01-12 Samson Clinical Pty Ltd Treatment of autoimmune disease
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