DESC:Technical Field of Invention
The present subject matter relates to an oral sustained release pharmaceutical composition comprising ruxolitinib or pharmaceutically acceptable salt thereof as an active ingredient and at least one polymer or combination of polymers that provide sustained-release of the active ingredient, and process for preparation of such composition.

Background of Invention
The Janus kinase inhibitor or JAK family is composed of four tyrosine kinases (JAK1, JAK2, JAK3 and Tyk2) that are involved in the signaling of a number of cytokines and growth factors. JAKs are central to a number of biologic processes including the formation and development of blood cells and the regulation of immune functions. JAK signaling involves recruitment of STATs to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Disruption in regulation of the JAK-STAT (signal transducers and activators of transcription) signaling pathway has been associated with a number of diseases, including myeloproliferative neoplasms, other hematological malignancies, rheumatoid arthritis and other chronic inflammatory diseases.
Ruxolitinib is a JAK1 and JAK2 inhibitor approved by the U.S. Food and Drug Administration (FDA) in the form of immediate release tablets for the treatment of adults with intermediate or high-risk myelofibrosis, with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea steroid-refractory acute graft-versus-host disease (GVHD), and cGVHD after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. It mediates the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. Ruxolitinib is also approved for the topical treatment of mild to moderate atopic dermatitis in non-immunocompromised patients, 12 years of age and older.
Ruxolitinib and its pharmaceutically acceptable salts including the approved phosphate salt form have been described in described in WO 2007/070514 and WO 2008/157208 respectively
Ruxolitinib is a BCS Class I molecule with rapid oral absorption and a short half-life of about 3 hours which result in a high peak/trough plasma concentration ratio in human subjects leading to multiple daily doses for optimal treatment, and potentially contributing to problems with patient compliance and unwanted side effects. The approved therapy of ruxolitinib has been reported to be associated with the adverse events of thrombocytopenia (low platelet count) and anemia (low hemoglobin).
US patent number US 10,166,191 discloses sustained release dosage form of ruxolitinib containing sustained-release matrix former hydroxypropyl methylcellulose (HPMC or hypromellose), as an attempt to mitigate such side effects.
US patent publication US 2015/0246043 discloses certain modified release ruxolitinib formulations containing a non-erodible material.
The present subject matter discloses a new and improved sustained release oral formulations of ruxolitinib that are useful for the treatment of JAK-associated diseases and mitigation of the adverse side-effects in patients, and also facilitate administration of the drug by reducing the number of doses required to achieve therapeutic effect.
Summary of Invention
The subject matter of the present application relates to a sustained release solid oral pharmaceutical composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof and at least one polymer or combination of polymers that provide sustained-release of the active ingredient. The present subject matter further relates to a method of preparing such composition and use of such composition for the treatment of patients with intermediate or high-risk Myelofibrosis, Polycythemia Vera who have had an inadequate response to or are intolerant of hydroxyurea, steroid-refractory acute Graft-versus-Host disease (GVHD), and chronic graft-versus-host disease (cGVHD).
In one aspect, the present subject matter relates to an oral sustained release pharmaceutical composition comprising ruxolitinib or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
In one aspect, the sustained release composition of present subject matter comprises ruxolitinib in an amount of about 10 mg to about 60 mg on a free base basis, more preferably in an amount of about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, and about 50 mg on a free base basis.
In one aspect, the sustained release composition comprising ruxolitinib may be administered orally once daily for the treatment of a disease associated with JAK activity in a patient in need thereof.
In one aspect, the sustained release composition comprising ruxolitinib provides a release profile and a pharmacokinetic profile that are suitable for once-daily administration.
In another aspect, said sustained release composition administered once daily has a bioavailability comparable to a corresponding dose of commercially available immediate release tablet of ruxolitinib administered twice daily.
Detailed description:
Description provided herein is not meant to be limited. Embodiments and different ways to practice the subject matter of the present application are expressly included and variations in those embodiments are considered part of the present subject matter.
Ruxolitinib is a BCS class I molecule with rapid oral absorption and a short half-life. These properties result in a high peak/trough plasma concentration ratio in human subjects leading to multiple daily doses for optimal treatment, and unwanted side effects. The present subject matter is directed to a sustained release composition of ruxolitinib that can be administered once daily to reduce such side-effects associated with commercially available immediate release formulation of ruxolitinib without affecting therapeutic efficacy, and also facilitate administration of the drug by reducing the number of doses required to achieve therapeutic effect.
The present subject matter provides an oral sustained-release pharmaceutical composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, as an active ingredient.
In one aspect, the sustained release composition comprises ruxolitinib or a pharmaceutically acceptable salt thereof, in an amount of about 10 to about 60 mg, about 10 to about 40 mg, about 20 to about 40 mg, or about 20 to about 30 mg on a free base basis. In some embodiments, said composition comprises about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg or about 60 mg on a free base basis. In some embodiments, the dosage form contains about 25 mg of ruxolitinib on a free base basis.
The phrase "on a free base basis" indicates that the amount of ruxolitinib salt in the composition is measured based on the molecular weight of ruxolitinib free base.
In some embodiments, said salt forms of ruxolitinib, include, for example, the maleic acid salt, sulfuric acid salt, or phosphoric acid salt. In some embodiments, ruxolitinib is present in the composition in the form of ruxolitinib phosphate.
In one embodiment, once daily administration of sustained-release dosage form comprising ruxolitinib or pharmaceutically acceptable salt thereof described herein, is bioequivalent to twice a day administration of corresponding dose of commercially available immediate release formulation of ruxolitinib, at least on the basis of exposure (AUC).
In one aspect, the present subject matter relates to a sustained-release composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, one or more polymers that provide sustained-release of the active agent, and one or more other pharmaceutically acceptable excipients.
In one aspect, the present subject matter relates to a sustained-release composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, one or more polymers that provide sustained-release of the active agent, and one or more other pharmaceutically acceptable excipients, wherein said polymers include one or more hydrophilic or hydrophobic polymers, physical mixtures of polymers, one or more copolymers or any combinations thereof, and said other excipients include one or more fillers, binders, disintegrants, glidants, lubricants, wetting agents, coating agents, and the like.
In one aspect, the present subject matter relates to a sustained-release composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, one or more polymers that provide sustained-release of the active agent, and one or more other pharmaceutically acceptable excipients, wherein said polymers include for example, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl acetate, polyvinyl alcohol, polyethylene oxide, mixtures of polyvinyl acetate and povidone (ex: Kollidon SR), alginates, carbopol, gelatin, methylcellulose, xanthan gum, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate succinate, polyvinyl alcohol phthalate, polyvinyl acetate phthalate and polyvinylbutyl phthalate, ethylcellulose, methacrylate copolymer, polyamide, polyethylene and polyvinyl acetate, cetyl alcohol, hydrogenated vegetable oils, monoglycerides, triglycerides, polyethylene glycol (PEG), PEG monostearate, polypropylene glycol, poly(acrylic) acid, poly(methacrylic) acid, methacrylic acid-ethyl acrylate copolymers, polyvinylpyrrolidone (PVP, also called povidone), polyvinyl alcohol, polyvinyl pyrrolidne-vinyl acetate copolymes, polyethylene glycol-polyvinyl alcohol copolymers, or any combinations thereof.
In one embodiment, the present subject matter relates to a sustained-release composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, one or more polymers that provide sustained-release of the active agent, and one or more other pharmaceutically acceptable excipients, wherein said polymers are selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl acetate, polyvinyl alcohol, polyethylene oxide, mixtures of polyvinyl acetate and povidone (ex: Kollidon SR), ethylcellulose, polyvinyl acetate phthalate, polyvinyl pyrrolidone, polyethylene glycol, PEG monostearate, and polyvinyl acetate, hydrogenated vegetable oils, polyvinyl pyrrolidne-vinyl acetate copolymes, polyethylene glycol-polyvinyl alcohol copolymers, or any combinations thereof.
In one embodiment, the present subject matter relates to a sustained-release composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, one or more polymers that provide sustained release of the active agent, and one or more other pharmaceutically acceptable excipients, wherein said polymers are selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl acetate, polyvinyl alcohol, polyethylene oxide, mixtures of polyvinyl acetate and povidone (ex: Kollidon SR), ethylcellulose, or any combinations thereof.
In one embodiment, the present subject matter relates to a sustained-release composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, a combination of polymers that provide sustained release of the active agent, and one or more other pharmaceutically acceptable excipients, wherein said combination comprises, for example, combination of hydroxypropyl cellulose and Kollidon SR, combination of hydroxypropyl cellulose and polyethylene oxide, or combination of polyvinyl alcohol and Kollidon SR.
In one embodiment, the present subject matter relates to a sustained-release composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, Kollidon SR, and one or more other pharmaceutically acceptable excipients.
In one embodiment, the present subject matter relates to a sustained-release composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, polyethylene oxide, and one or more other pharmaceutically acceptable excipients.
In one embodiment, the present subject matter relates to a sustained-release composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, polyvinyl alcohol, Kollidon SR, and one or more other pharmaceutically acceptable excipients.
In some embodiments, said sustained-release composition of the present subject matter may include about 10 to about 45%, about 20 to about 45%, or about 18 to about 35% by weight of polymer or combination of polymers, based on the total weight of the composition. .
In one embodiment, said sustained-release composition of the present subject matter comprises about 25 to about 45% by weight of polymer or combination of polymers for sustained-release. In some embodiments, formulation has about 14%, about 20%, about 25%, about 27%, about 30%, about 35% or about 43% by weight of polymer or combination of polymers, based on the total weight of the composition.
In one aspect said sustained release composition is administered in the form of suitable dosage forms, for example, tablets, caplets, capsules, etc.
In one embodiment, the sustained-release dosage form of ruxolitinib or pharmaceutically acceptable salt thereof provides sustained release of the active agent for at least about 4 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 18, or at least about 24 hours.
In one embodiment, the dissolution medium for sustained-release dosage form of present subject matter is 0.1 N HCl, the type of apparatus is USP-II (Paddle) and the stirring speed is 75 RPM. In one embodiment, the dissolution medium is pH 4.5 acetate buffer and the stirring speed is 50 RPM. In one embodiment, the dissolution medium is pH 6.8 phosphate buffer and the stirring speed is 50 RPM.
In one embodiment, the sustained-release dosage form of ruxolitinib or pharmaceutically acceptable salt thereof releases about 10% to about 45% of ruxolitinib in about 1 hour, about 20% to about 60% of ruxolitinib in about 2 hours, about 30% to about 80% of ruxolitinib in about 4 hours, about 50% to about 96% of ruxolitinib in about 8 hours, or about 60% to about 99% of ruxolitinib in about 12 hours, when tested in 900mL 0.1 N HCl using USP-II (Paddle) at 75 RPM.
In another embodiment, the sustained-release dosage form of ruxolitinib or pharmaceutically acceptable salt thereof releases about 5% to about 30% of ruxolitinib in about 1 hour, about 10% to about 40% of ruxolitinib in about 2 hours, about 20% to about 55% of ruxolitinib in about 4 hours, about 45% to about 75% of ruxolitinib in about 8 hours, or about 50% to about 90% of ruxolitinib in about 12 hours, when tested in 900mL pH 4.5 acetate buffer using USP-II (Paddle) at 50 RPM.
In some embodiments, the administration of the sustained-release dosage form of the present subject matter to a human results in a therapeutically effective plasma level of ruxolitinib for at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 18, or at least about 24 hours.
In the sustained dosage form of the present subject matter, ruxolitinib can be present in amorphous form, in crystalline form or as a mixture of amorphous and crystalline forms. In one embodiment of the present subject matter, ruxolitinib is present as the phosphate salt. In another embodiment, the dosage form of present subject matter comprises crystalline form of ruxolitinib phosphate.
The other pharmaceutically acceptable excipients of sustained-release composition of the present subject matter may include one or more fillers, glidants, disintegrants, binders, or lubricants, wetting agents, coating agents, and the like, as inactive ingredients.
Examples of fillers that may be used in the composition of the present subject matter include, but not limited to, lactose monohydrate, lactose anhydrous, microcrystalline cellulose, starch, dextrose, dextrin, mannitol, maltodextrin, isomalt, sorbitol, sucrose, dextrates, sugar spheres, xylitol, fructose, lactitol, maltitol, erythritol, maltose, raffinose, polydextrose, trehalose, calcium carbonate, calcium sulphate, dibasic calcium phosphate, chitin, chitosan, kaolin, ethylcellulose, magnesium carbonate, magnesium oxide, sodium bicarbonate, sodium carbonate, powdered cellulose, pregelatinized starch, di- and tri-basic calcium phosphate and combinations thereof. In some embodiments, the filler comprises microcrystalline cellulose, or, lactose monohydrate or both. In some embodiments, said filler can be present in the formulations in an amount of 5 to about 80% by weight, based on the total weight of the composition. In some embodiments, said fillers can be present in an amount of about 40 to about 80%, about 40 to about 75%, or about 45 to about 70% by weight, based on the total weight of the composition. In some embodiments, said fillers can be present in an amount of about 40%, about 45%, about 50%, about 55%, about 60% or about 65%, based on the total weight of the composition.
Suitable disintegrants that may be used in the composition of the present subject matter are known in the art and may include, but not limited to, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidones such as crospovidone, polacrilin potassium, cross-linked alginic acid, sodium alginate, chitosan, pregelatinized starch, hydroxypropyl cellulose, methyl cellulose, gums such as gellan gum and xanthan gum, calcium silicate sodium starch glycolate, cross-linked PVP, alginic acid, croscarmellose sodium and combinations thereof. In some embodiments the disintegrant may comprise sodium starch glycolate or croscamellose sodium, or both. In one embodiment, the disintegrant is croscarmellose sodium. In some embodiments, the amount of disintegrant(s) present in the composition may be about 1% to about 40%, or about 1 to about 30%, or about 1 to about 20%, or about 1 to about 15%, or about 1 to about 10%, or about 1 to about 8%, or about 1 to about 5%, or about 3% to about 7%, or about 4 to about 6%, based on the total weight of the composition. In some embodiments the amount of disintegrant may be about 1% or about 2% or about 3% or about 4% or about 5% or about 6% or about 7% or about 8% or about 9% or about 10% or about 11% or about 12% or about 13% or about 14% or about 15% based on total weight of composition.
Suitable lubricants that may be used in the composition of the present subject matter are known in the art and may include but not limited to, magnesium stearate, calcium stearate, stearic acid, myristic acid, palmitic acid, hydrogenated vegetable oils, tribehenin, polyethylene glycol, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of benenate esters of glycerine, myristic acid, sodium stearyl fumarate, sodium lauryl sulfate and combinations thereof. In some embodiments, the lubricants comprise magnesium stearate, stearic acid or both. In some embodiments, amount of lubricant(s) present in the composition may be from about 0.2 to about 5%, or from about 0.2 to about 4%, or from about 0.2 to about 3%, or from about 0.2 to about 2%, based on the total weight of the composition. In some embodiments, the amount of lubricant may be about 0.2% or about 0.3% or about 0.4% or about 0.5% or about 0.6% or about 0.7% or about 0.8% or about 0.9% or about 1% or about 1.1% or about 1.2%, or about 1.3%, or about 1.4% or about 1.5% or about 1.6% or about 1.7% or about 1.8% or about 1.9% or about 2% or about 3% or about 4%, based on the total weight of the composition.
Suitable glidants that may be used in the composition of the present subject matter include, but not limited to, calcium phosphate tribasic, dibasic calcium phosphate, calcium silicate, cellulose, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc, sodium stearyl fumarate and mixtures thereof. In some embodiments, the glidant is colloidal silicon dioxide. In some embodiments, the amount of glidant(s) present in the composition may be from about 0.2 to about 10%, or from about 0.2 to about 8%, or from about 0.2 to about 5%, or from about 0.2 to about 4%, or from about 0.2 to about 3%, or from about 0.2 to about 2%, based on the total weight of the composition. In some embodiments, the amount of glidant may be about 0.2% or about 0.3% or 0.4% or about 0.5% or about 0.6% or about 0.7% or about 0.8% or about 0.9% or about 1% or about 1.1% or about 1.2% or about 1.3% or about 1.4% or about 1.5% or about 1.6% or about 1.7% or about 1.8% or about 1.9% or about 2% or about 2.5% or about 3% or about 3.5% or about 4% or about 4.5% or about 5%, based on the total weight of the composition.
Suitable binders that may be used in the composition of the present subject matter are known in the art and include, but not limited to, pregelatinized starch, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose copovidone, acacia, alginate, alginic acid, candelilla wax, carnuba wax, liquid glucose, sucrose, tragacanth, polyethylene glycol, polyvinyl alcohol, polymethacrylates, corn starch, erythrosine sodium, gelatin, glyceryl monostearate, sodium carboxymethyl cellulose and povidone. In some aspects, the binder is copovidone, povidone, pregelatinized starch, and combinations thereof. In some further aspects, the binder is copovidone. The amount of binder(s) present in the composition may be from about 1 to about 10%, or from about 2 to about 8%, or from about 3 to about 7%, or from about 4 to about 6%, based on the total weight of the composition. In some embodiments the amount of binder may be about 3% or about 4% or about 5% or about 6%, based on the total weight of the composition.
Film-coating agents in the composition of the present subject matter can be present in an amount of 0 to about 5% by weight, based on the total weight of the composition. Non-limiting illustrative examples of film-coating agents include hypromellose or polyvinyl alcohol based coating with titanium dioxide, talc and optionally colorants available in several commercially available complete coating systems. The film coating may be applied using conventional methods. A coating can be used to provide protection against, for example, moisture ingress or degradation by light, to color the formulation, or to modify or control the release of the active pharmaceutical ingredient from the formulation.
In some aspects, the present subject matter relates to a method of preparing an oral sustained release pharmaceutical composition comprising ruxolitinib or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient wherein said method may be direct compression, dry granulation or wet granulation.
In one embodiment, a method for preparing the oral sustained release pharmaceutical composition of the present subject matter as described herein is prepared by direct compression process. Direct compression is well known method in the art for the preparation of tablets and comprises the steps of dispensing, sieving, blending, lubrication and compression into tablets. Direct compression is the most straightforward manufacturing option, with the fewest manufacturing steps, making it the easiest to control and least expensive. Apart from process simplicity, the key advantages of direct compression include reduced costs for manufacture.
In one embodiment, the oral sustained release pharmaceutical composition of the present subject matter as described herein is prepared by a dry granulation process such as slugging or roller compaction. Dry granulation process is well known method in the art and comprises the steps of dispensing, sieving, blending, and formation of granules by slugging/roller compaction of the blended material, followed by blending the obtained granular material with extra-granular material, lubrication and final compression into tablets.
In one embodiment, the oral sustained release pharmaceutical composition of the present subject matter as described herein is prepared by a wet granulation process such as high-shear granulation (or rapid mixer granulation) or top spray granulation using fluidized bed processor, other granulation techniques such as twin screw granulation, etc., or one or more combinations thereof. Wet granulation methods comprise the steps of dispensing, sieving, blending, formation of granules using a binder solution comprising water or organic solvents, a binder, a surfactant, or mixtures thereof, followed by blending with extra-granular material, lubrication and final compression into tablets. In conventional wet granulation method, process of size enlargement occurs in which fine powder particles are agglomerated or brought together into larger, strong and relatively permanent structure using a suitable granulating fluid such as water, isopropanol or ethanol or mixtures thereof. The granulating fluid can be used alone or as a solvent containing binder or granulating agent. Powder mixing, in conjunction with the cohesive properties of the granulating agent, enables the formation of granules.
In some embodiments, the oral sustained release pharmaceutical composition of the present subject matter as described herein is prepared by wet granulation process. Wet granulation method provides processing ease by avoiding sticking. Further, wet granulation method provides the formulation with desired hardness.
Definitions:
The terms “composition”, “pharmaceutical composition” or “formulation” or “dosage form” or “pharmaceutical dosage form” are synonymously and interchangeably used in the present specification and may be in the form of, e.g., tablet, capsule, granule, powder etc. The term "tablet" refers to tablet without a coating or tablet with one or more coatings.
As used herein "sustained-release” refers to a formulation designed to slowly release the active ingredient upon oral administration for at least about 4 hours, at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 18, or at least about 24 hours, and to maintain an essentially steady, therapeutically effective plasma level of active ingredient over a relatively long period of time, such as about 8 to about 24 hours or longer. The term "sustained-release” is meant to encompass “slow-release”, “extended-release” and “modified-release” compositions that release the active ingredient in a manner described herein. The phrase “polymers that provide sustained release of the active agent” as used herein can be interchangeably referred to as “sustained release polymers”.
As used in certain contexts of the present specification, the terms ”drug”, “active agent”, “active pharmaceutical ingredient (API)” are interchangeably used with the term “ruxolitinib”, and these terms encompass free base a pharmaceutically acceptable salt or hydrate thereof. In one aspect, term “ruxolitinib” may be used interchangeably with ruxolitinib phosphate.
The term “stable” as used herein refers to a composition comprising drug or drug substance, which has total amount of impurities at the end of three months or six months under the temperature and relative humidity conditions of 40°C ± 2°C/75% RH ± 5% RH, may not exceed 10%. More preferably the total amount of impurity is < 8% or <5% at the end of three months or six months under conditions specified above. Further, said stable composition retains at least about 90% w/w of the drug under said conditions.
The term “crystalline form” as used herein refers to a solid having a highly regular chemical structure. In an embodiment, crystalline nature of a compound or a composition is represented by the presence of sharp characteristic peaks in X-ray diffractogram (XRD) analysis.
As used herein, the term "amorphous" refers to a solid material having no regular structure. Method for determination of crystalline or amorphous form are well known in the art. In an embodiment, amorphous nature of a compound or a composition is represented by the absence of sharp peaks in XRD analysis.
The term "polymer” or “polymers” are used interchangeably and are meant to encompass the presence of at least one or more than one polymer, physical mixtures of different polymers, at least one or more than one copolymers, mixture of a polymer and a copolymer, etc., that provide similar sustained and pharmacokinetic release profile or that are suitable for once-daily administration of the oral sustained release composition of ruxolitinib or a pharmaceutically acceptable salt thereof, of the present subject matter.
The term "once daily" as used herein is interchangeably used with ‘once-a-day’, and refers to the administration of the sustained release dosage form one time in a day.
Unless otherwise indicated, all numbers used herein to express quantities, dimensions, and so forth used should be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numbers or numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained.
As used herein, the singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a process” includes one or more process, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.
Some aspects of the present subject matter can be further illustrated by following examples:
Example 1
Table 1: Compositions by Dry Granulation/ Roller Compaction/ Direct Compression
Ingredient % w/w
Compositions
Intra-granular 1 2 3 4 5 6 7
Ruxolitinib Phosphate 11.79 12.22 12.05 10.63 12.42 12.22 12.22
Microcrystalline cellulose 35.89 37.52 36.64 32.62 43.29 21.56 32.47
Lactose monohydrate 21.43 22.23 21.92 19.33 - 32.15 17.24
Polyvinyl alcohol - - - - 43.29 - 21.30
Kollidon SR 14.29 - - - - - 7.41
Polyethylene Oxide - 20.00 27.39 17.39 - - -
Hydroxypropyl cellulose - - - - - 11.46 -
Colloidal Silicon Dioxide 0.54 0.50 1.00 0.43 0.25 1.00 0.49
Magnesium stearate 0.71 0.50 1.00 0.43 0.25 0.50 0.49
Extra-granular
Kollidon SR 14.29 - - - - - 7.41
Polyethylene Oxide - 5.00 - 17.39 - 9.00 -
Microcrystalline cellulose - - - - - 9.61 -
Colloidal Silicon Dioxide 0.54 1.01 - 0.88 0.25 1.00 0.49
Magnesium stearate 0.54 1.01 - 0.88 0.25 1.50 0.49

Manufacturing Process: The material of composition 3 as shown in the above table were processed by direct compression wherein the ingredients were sifted, blended, lubricated and compressed into tablets. Material of compositions 1, 2 and 4 to 7 were processed by dry granulation using slugging or roller compaction wherein intra-granular portion includes ruxolitinib phosphate, sustained release polymer and other excipients followed by blending with extra-granular material which may include sustained release polymer, lubrication and final compression into tablets or alternatively filling into capsules. The tablets obtained may be further coated by film-coating material.
Example 2
Table 2: Compositions by Wet Granulation
Ingredient % w/w
Compositions
Intra-granular 8 9 10
Ruxolitinib Phosphate 11.78 12.22 12.12
Lactose Monohydrate 35.69 33.33 32.41
Hydroxypropyl cellulose 30.34 11.46 11.46
Microcrystalline cellulose 20.70 22.33 24.02
Purified water q.s.@ q.s. q.s.
Extra-granular
Kollidon SR 19.10 17.41
Colloidal Silicon Dioxide 1.00 1.04 1.00
Magnesium stearate 0.50 0.5 1.48
@: quantity sufficient
Manufacturing Process: Intra-granular material provided above in the table were sifted and blended followed by granulation with water using rapid mixer granulator or top spray method. The granules so obtained were blended with extra-granular material. The material so obtained was subjected to compression in to tablets. The tablets obtained may be further coated by film-coating material.
Example 3
Table 3: Dissolution data of compositions 1-9.
Media: 0.1 N HCl / 900mL / USP-II (Paddle) / 75 RPM
Time (Hour) Compositions
1 2 3 4 5 6 7 8 9
1 35 27 25 27 35 29 31 25 33
2 53 45 45 45 51 45 47 37 50
4 78 74 76 76 71 68 66 53 74
6 90 - 92 - 83 - - 66 -
8 95 96 95 101 90 91 84 78 94
10 97 - 94 - 92 - - 86 -
12 99 95 93 102 96 94 90 92 97

Table 4: Dissolution data of compositions 1-9.
Media: pH 4.5 Acetate buffer / 900mL / USP-II (Paddle) / 50 RPM
Time (Hour) Compositions
1 2 3 4 5 6 7 8 9 10
1 16 10 9 8 25 20 20 69 12 18
2 24 22 19 16 39 26 28 88 21 28
4 38 49 41 33 54 36 47 94 32 44
6 - - 63 - 65 - - 95 -
8 60 92 81 65 73 54 61 96 52 73
10 - - 89 - 90 - - 96 -
12 76 96 94 82 95 70 67 97 63 86

Table 5: Dissolution data of compositions 1-9.
Media: pH 6.8 Phosphate buffer / 900mL / USP-II (Paddle) / 50 RPM
Time (Hour) Compositions
1 2 3 4 5 6 7 8 9 10
1 6 9 8 8 52 - 60 18 19
2 8 20 16 16 58 - 79 33 33
4 19 45 34 33 89 - 95 48 50
6 24 - - - - - - 96 -
8 27 86 70 70 80 - - 96 62 72
10 31 - - - - - - 96 -
12 38 99 86 86 84 - - 97 72 83

The above description discloses several aspects and embodiments directed to compositions and methods of the present subject matter. This subject matter is susceptible to modifications in the methods and compositions, as well as alterations in the equipment. Such modifications will become apparent to those skilled in the art from a consideration of this disclosure or practice of the subject matter disclosed herein. Consequently, it is not intended that this subject matter be limited to the specific embodiments or aspects disclosed herein, but that it cover all modifications and alternatives coming within the true scope and spirit of the present subject matter.
Table 6: Stability Data for composition 09
Condition Initial 1 month, 40°C/75%RH 3 month, 40°C/75%RH
% Assay 97.9 97.4 98.0
Water by KF 4.2 3.90 4.88
Impurities RRT* % w/w % w/w % w/w
Unknown-1 0.612 ND ND ND
Unknown-2 0.655 ND ND ND
Unknown-3 0.776 ND ND ND
Unknown-4 0.808 ND ND ND
Unknown-5 1.066 ND ND ND
Unknown-6 1.402 ND ND ND
Max Unknown ND ND ND
Total Impurities ND ND ND
Post-Stability Dissolution in 0.1 N HCl / 900mL / USP-II (Paddle) / 75 RPM
Time Points (Hour) 1 month, 40°C/75%RH 3 month, 40°C/75%RH
0 0 0
1 31 31
2 46 46
4 70 70
8 94 94
12 99 99
* Relative retention time; ND – Not detected
,CLAIMS:We Claim:

1. An oral sustained-release composition comprising ruxolitinib or a pharmaceutically acceptable salt thereof, one or more sustained-release polymers and one or more other pharmaceutically acceptable excipients.

2. The oral sustained-release composition as claimed in claim 1, wherein said polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl acetate, polyvinyl alcohol, polyethylene oxide, mixtures of polyvinyl acetate and povidone (ex: Kollidon SR), ethylcellulose, polyvinyl acetate phthalate, polyvinyl pyrrolidone, polyethylene glycol, PEG monostearate, and polyvinyl acetate, hydrogenated vegetable oils, polyvinyl pyrrolidone-vinyl acetate copolymes, polyethylene glycol-polyvinyl alcohol copolymers, or any combinations thereof.

3. The oral sustained-release composition as claimed in claim 1, wherein said polymer is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl acetate, polyvinyl alcohol, polyethylene oxide, mixtures of polyvinyl acetate and povidone (ex: Kollidon SR), ethylcellulose, or any combinations thereof.

4. The oral sustained-release composition as claimed in claim 1, wherein said composition comprises a combination of at least two polymers selected hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl acetate, polyvinyl alcohol, polyethylene oxide, mixtures of polyvinyl acetate and povidone (ex: Kollidon SR), ethylcellulose, polyvinyl acetate phthalate, polyvinyl pyrrolidone, polyethylene glycol, PEG monostearate, and polyvinyl acetate, hydrogenated vegetable oils, polyvinyl pyrrolidone-vinyl acetate copolymers, and polyethylene glycol-polyvinyl alcohol copolymers.

5. The oral sustained-release composition as claimed in claim 1, wherein said composition comprises about 10 to about 45% w/w of said one or more sustained-release polymers.

6. The oral sustained-release composition as claimed in claim 1, wherein said composition provides sustained release of the active agent for at least about 4 hours or at least about 8 hours, at least about 10 hours, at least about 12 hours, at least about 18, or at least about 24 hours.

7. The oral sustained-release composition as claimed in claim 1, wherein said composition comprises:
(a) an intra-granular portion comprising from about 10 % to about 50 % of one or more sustained-release polymers; and one or more other pharmaceutical acceptable excipients; and
(b) an extra granular portion comprising from about 4 % to about 25 % of one or more sustained-release polymers; and one or more other pharmaceutical acceptable excipients.

8. The oral sustained-release composition as claimed in claim1, wherein the composition releases about 5% to about 30% of ruxolitinib in about 1 hour, about 10% to about 40% of ruxolitinib in about 2 hours, about 20% to about 55% of ruxolitinib in about 4 hours. about 45% to about 75% of ruxolitinib in about 8 hours, or about 50% to about 90% of ruxolitinib in about 12 hours, when tested in 900mL pH 4.5 acetate buffer using USP-II (Paddle) at 50 RPM.

9. The oral sustained-release composition as claimed in claim1, wherein said composition releases about 10% to about 45% of ruxolitinib in about 1 hour, about 20% to about 60% of ruxolitinib in about 2 hours, about 30% to about 80% of ruxolitinib in about 4 hours, about 50% to about 96% of ruxolitinib in about 8 hours, or about 60% to about 99% of ruxolitinib in about 12 hours, when tested in 900mL 0.1 N HCl using USP-II (Paddle) at 75 RPM.

10. The oral sustained-release as claimed in claim 1, wherein said composition is stable at least for a period of at least three months under the conditions of 40°C ± 2°C/75% RH ± 5% RH, and exhibits not more than 5% w/w of total impurities.