A direct compressed pharmaceutical tablet of ruxolitinib

Abstract

The present invention relates to a direct compressed pharmaceutical tablet comprising a) about 1 wt.% to 10 wt.% ruxolitinib phosphate, b) about 35 wt.% to 55 wt.% of silicified microcrystalline cellulose, c) about 0.1 wt.% to 3 wt.% of one or more binder; and d) at least one more pharmaceutically acceptable excipient, wherein wt.% is based on the total weight of the tablet. The said tablet has a desirable pharmacokinetic characteristic, favorable storage stability and comparative dissolution properties. The invention further relates to a process for the preparation of said pharmaceutical composition and use thereof as medicament in the treatment of myelofibrosis, polycythemia vera, graft versus host disease.

Description

[0001] A DIRECT COMPRESSED PHARMACEUTICAL TABLET OF RUXOLITINIB

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a direct compressed pharmaceutical tablet comprising a) about 1 wt.% to 10 wt.% ruxolitinib phosphate, b) about 35 wt.% to 55 wt.% of silicified microcrystalline cellulose, c) about 0.1 wt.% to 3 wt.% of one or more binder; and d) at least one more pharmaceutically acceptable excipient, wherein wt.% is based on the total weight of the tablet. The said tablet has a desirable pharmacokinetic characteristic, favorable storage stability and comparative dissolution properties. The invention further relates to a process for the preparation of said pharmaceutical composition and use thereof as medicament in the treatment of myelofibrosis, polycythaemia vera, graft versus host disease.

[0004] BACKGROUND OF THE INVENTION

[0005] Ruxolitinib is chemically known as (R)-3-(4-(7H-Pyrrolo[2,3d]pyrimidin-4-yl)-lH-pyrazol-l- yl)-3 -cyclopentylpropanenitrile, having the following formula (I),

[0006] Janus kinase family known as JAK characterized with seven JAK homolog (JH) domains consists of JAK1, JAK2, JAK3 and non-receptor tyrosine kinase 2 (TYK2). JAK family kinases create JAK-STAT signal transmission pathway with STAT (signal transducer and activator of transcription) containing STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 transcription factors. 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 potent ATP competitive inhibitor of JAK1 and JAK2, with modest selectivity against TYK2 and marked selectivity against JAK3, when assessed at 1 mM ATP concentrations.

[0007] Ruxolitinib is a new class of antineoplastic agents / protein kinase inhibitor being developed for the treatment of multiple disorders including psoriasis and rheumatoid arthritis. Ruxolitinib inhibits phosphorylation of the non-receptor Janus Associated Kinase 1 (JAK1) and JAK2 kinases and downstream signalling in the JAK-STAT (JAK signal transducer and activator of transcription) pathway. The JAK non-receptor kinases are the major downstream targets for cytokine, chemokine and growth factor receptors and cytokines like interferon, erythropoietin and growth hormone use this pathway for signal transduction. JAK1 and JAK2 signalling is important in haematopoiesis and immune function. Disruption of signalling through mutations of these kinases leads to abnormal cellular proliferation. JAK2 mutations (commonly V617F) occur in myeloproliferative cancers including primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF).

[0008] Ruxolitinib is marketed under the brand name of Jakavi® as a tablet in 5 mg, 10 mg, 15 mg and 20 mg strengths in Europe since 2012.

[0009] Ruxolitinib tablet marketed under the brand name of Jakavi® is indicated for the treatment of;

[0010] • Myelofibrosis (MF): disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis.

[0011] • Polycythaemia vera (PV): adult patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. • Graft versus host disease (GvHD): patients aged 12 years and older with acute graft versus host disease or chronic graft versus host disease who have inadequate response to corticosteroids or other systemic therapies.

[0012] Ruxolitinib is also available as cream in 15 mg / g strength under the brand name of Opzelura® in EU since 2023. Opzelura® is indicated for the treatment of non-segmental vitiligo with facial involvement in adults and adolescents from 12 years of age.

[0013] Jakavi® contains Ruxolitinib phosphate salt as active substance and microcrystalline cellulose, magnesium stearate, colloidal anhydrous silica, sodium starch glycolate (Type A), povidone K30, hydroxypropylcellulose 300 to 600 cps and lactose monohydrate as excipient.

[0014] According to Australian Public Assessment Report & EPAR (European Public Assessment Report), wet granulation method is used to produce Ruxolitinib phosphate tablet i.e. Jakavi®. As mentioned in literatures, common knowledge in the art, wet granulation has many advantages like better flow properties and improving cohesion during and after compaction with respect to other manufacturing methods.

[0015] Ruxolitinib and its pharmaceutically acceptable salts thereof were first disclosed in WO 2007070514 Al.

[0016] Different salts of ruxolitinib, apart from the commercial ruxolitinib phosphate (Compound I), have been disclosed in the literature.

[0017] WO 2008157208 A2 discloses, apart from ruxolitinib phosphate (Compound I), salts of ruxolitinib with maleic acid and sulfuric acid.

[0018] WO 2016026974 Al discloses the oxalate salt of ruxolitinib and tablets comprising the same.

[0019] WO 2016026975 Al discloses the besylate salt of ruxolitinib. WO 2016063294 A2 reports crystalline forms of salts of ruxolitinib with (+)-dibenzoyl tartaric acid and hydrochloric acid. WO 2016074650 Al discloses amorphous salts of ruxolitinib with hydrobromic acid, hydrochloric acid, citric acid, fumaric acid, L-tartaric acid, p- toluenesulfonic acid, benzoic acid, benzenesulfonic acid, ethenesulfonic acid, 2-naphthalenesulfonic acid and 4- chlorobenzenesulfonic acid.

[0020] WO 2017008772 Al reports several crystalline forms of ruxolitinib salt with hydrobromic and hydrochloric acid. WO 2017125097 Al describes specific crystalline forms of salts of ruxolitinib with hydrochloric acid, fumaric acid and L-tartaric acid. IN 202141008799 Al discloses a crystalline mesylate salt, an edisylate salt, a napadisylate salt and an acesulfam salt of ruxolitinib and crystalline forms thereof.

[0021] WO 2023245053 Al discloses sustained release pharmaceutical composition or cream composition of Ruxolitinib dihydrate and Ruxolitinib free base and its process.

[0022] IN 202221000710 A discloses 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.

[0023] WO 2024028193 Al discloses solid oral immediate-release formulations of ruxolitinib hemifumarate (Compound II) prepared with wet granulation method.

[0024] Ruxolitinib phosphate (Compound I) is described as Biopharmaceutics Classification system (BCS) Class I active ingredient with rapid oral absorption and a short half-life of about 3 hours. See, Shi et al, J. Clin. Pharmacol. 2012 Jun, 52 (6), 809-818.

[0025] As discussed in above mentioned prior arts, immediate released composition of Ruxolitinib phosphate is prepared with wet granulation method to have better flow properties and improved cohesion during and after compaction. However, instead of many advantages of wet granulation method, the method requires longer production time, more effort, being more costly when it compare with the direct compression method. Therefore, there still exist a need for a simple manufacturing method, which provides a tablet with the desired characteristics like physically and chemically stable, showing favorable dissolution profile, having easy to scale up, suitable on a commercial scale and allows an effective production with regard to time and cost.

[0026] The inventors of the present invention have surprisingly developed a direct compressed pharmaceutical tablet comprising Ruxolitinib phosphate, about 35 wt% to 55 wt% of silicified microcrystalline cellulose, about 0.1 wt% to 3 wt% of one or more binder and at least one more pharmaceutically acceptable excipient, which is not only plant viable but also provides a tablet with desired characteristics. Also, inventors have found simple manufacturing process to save time and cost to produce tablet of Ruxolitinib phosphate. The composition of the present invention is not only stable but also exhibits a similar dissolution profile when compared to the reference product Jakavi® tablet.

[0027] OBJECT OF THE INVENTION

[0028] An object of the present invention is to provide a direct compressed pharmaceutical tablet of Ruxolitinib phosphate having similar in-vitro profile to the reference product i.e. Jakavi® tablet.

[0029] Another object of the present invention is to provide a direct compressed pharmaceutical tablet of Ruxolitinib phosphate, which allows an effective commercial scale manufacturing with regard to time and costs.

[0030] Another object of the present invention is to provide a direct compressed pharmaceutical tablet of Ruxolitinib phosphate, which is devoid of sticking and capping during the production process of the composition.

[0031] Yet another object of the present invention is to provide a direct compressed pharmaceutical tablet of Ruxolitinib phosphate with simple and robust process. Yet another object of the present invention is to provide a direct compressed pharmaceutical tablet of Ruxolitinib phosphate, which remains stable during the shelf life.

[0032] Yet another object of the present invention is to provide a direct compressed pharmaceutical tablet of Ruxolitinib phosphate, which overcomes the problems of the prior art.

[0033] Yet another object of the present invention is to provide a pharmaceutical tablet as mentioned herein above in the treatment of diseases related to activity of Janus kinases.

[0034] SUMMARY OF THE INVENTION

[0035] In one aspect, the present invention provides a direct compressed pharmaceutical tablet comprising: a. about 1 wt.% to 10 wt.% ruxolitinib phosphate; b. about 35 wt.% to 55 wt.% of silicified microcrystalline cellulose; c. about 0.1 wt.% to 3 wt.% of one or more binder; and d. at least one more pharmaceutically acceptable excipient, wherein wt.% is based on the total weight of the tablet, and wherein the tablet, when tested in 500 ml of 6.8 pH potassium phosphate buffer at a temperature of 37°C ± 0.5°C and at a rotation speed of 100 rpm in standard USP apparatus I, basket, releases at least 85% of ruxolitinib within the first 15 minutes.

[0036] In another aspect, the present invention provides a direct compressed pharmaceutical tablet comprising: a. about 1 wt.% to 10 wt.% ruxolitinib phosphate; b. about 35 wt.% to 55 wt.% of silicified microcrystalline cellulose; c. about 0.1 wt.% to 3 wt.% of one or more binder; and d. at least one more pharmaceutically acceptable excipient, wherein wt.% is based on the total weight of the tablet, and wherein the tablet, when tested in 500 ml of 6.8 pH potassium phosphate buffer at a temperature of 37°C ± 0.5°C and at a rotation speed of 100 rpm in standard USP apparatus I, basket, releases at least 85% of ruxolitinib within the first 15 minutes, and wherein the binder is selected from hydroxyethyl cellulose, hydroxypropyl cellulose, low- substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, ethyl cellulose, methylcellulose, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, pullulan, and mixture thereof.

[0037] In another aspect, the present invention provides a direct compressed pharmaceutical tablet comprising: a. about 1 wt. % to 10 wt. % of ruxolitinib phosphate; b. about 30 wt. % to 50 wt. % of one or more diluent; c. about 35 wt. % to 55 wt. % of silicified microcrystalline cellulose; d. about 1 wt. % to 6 wt. % of one or more disintegrant; e. about 0.1 wt. % to 3 wt. % of one or more binder; f. about 0.01 wt. % of one or more glidant; and g. about 1 wt. % of one or more lubricant, wherein wt.% is based on the total weight of the tablet, and wherein the tablet, when tested in 500 ml of 6.8 pH potassium phosphate buffer at a temperature of 37°C ± 0.5°C and at a rotation speed of 100 rpm in standard USP apparatus I, basket, releases at least 85% of ruxolitinib within the first 15 minutes.

[0038] In another aspect, the present invention provides a direct compressed pharmaceutical tablet comprising: a. about 1 wt. % to 10 wt. % of ruxolitinib phosphate; b. about 30 wt. % to 50 wt. % of lactose or its hydrate; c. about 35 wt. % to 55 wt. % of silicified microcrystalline cellulose; d. about 1 wt. % to 6 wt. % of sodium starch glycolate; e. about 0.1 wt. % to 3 wt. % of polyvinylpyrrolidone and / or hydroxypropylcellulose; f. about 0.01 wt. % of silicon dioxide; and g. about 1 wt. % of magnesium stearate, wherein wt.% is based on the total weight of the tablet, and wherein the tablet, when tested in 500 ml of 6.8 pH potassium phosphate buffer at a temperature of 37°C ± 0.5°C and at a rotation speed of 100 rpm in standard USP apparatus I, basket, releases at least 85% of ruxolitinib within the first 15 minutes.

[0039] In another aspect, the present invention provides a direct compressed pharmaceutical tablet comprising: a. about 1 wt. % to 10 wt. % of ruxolitinib phosphate; b. about 30 wt. % to 50 wt. % of lactose or its hydrate; c. about 35 wt. % to 55 wt. % of silicified microcrystalline cellulose; d. about 1 wt. % to 6 wt. % of sodium starch glycolate; e. about 0.1 wt. % to 3 wt. % of polyvinylpyrrolidone; f. about 0.01 wt. % of silicon dioxide; and g. about 1 wt. % of magnesium stearate, wherein wt.% is based on the total weight of the tablet, and wherein the tablet, when tested in 500 ml of 6.8 pH potassium phosphate buffer at a temperature of 37°C ± 0.5°C and at a rotation speed of 100 rpm in standard USP apparatus I, basket, releases at least 85% of ruxolitinib within the first 15 minutes. In another aspect, the present invention provides a direct compressed pharmaceutical tablet comprising: a. about 1 wt. % to 10 wt. % of ruxolitinib phosphate; b. about 30 wt. % to 50 wt. % of lactose or it’s hydrate; c. about 35 wt. % to 55 wt. % of silicified microcrystalline cellulose; d. about 1 wt. % to 6 wt. % of sodium starch glycolate; e. about 0.1 wt. % to 3 wt. % of hydroxypropylcellulose; f. about 0.01 wt. % of silicon dioxide; and g. about 1 wt. % of magnesium stearate, wherein wt.% is based on the total weight of the tablet, and wherein the tablet, when tested in 500 ml of 6.8 pH potassium phosphate buffer at a temperature of 37°C ± 0.5°C and at a rotation speed of 100 rpm in standard USP apparatus I, basket, releases at least 85% of ruxolitinib within the first 15 minutes.

[0040] In another aspect, the present invention provides a direct compressed pharmaceutical tablet comprising: a. about 1 wt. % to 10 wt. % of ruxolitinib phosphate; b. about 30 wt. % to 50 wt. % of lactose or it’s hydrate; c. about 35 wt. % to 55 wt. % of silicified microcrystalline cellulose; d. about 1 wt. % to 6 wt. % of sodium starch glycolate; e. about 0.1 wt. % to 3 wt. % mixture of polyvinylpyrrolidone and hydroxypropylcellulose; f. about 0.01 wt. % of silicon dioxide; and g. about 1 wt. % of magnesium stearate, wherein wt.% is based on the total weight of the tablet, and wherein the tablet, when tested in 500 ml of 6.8 pH potassium phosphate buffer at a temperature of 37°C ± 0.5°C and at a rotation speed of 100 rpm in standard USP apparatus I, basket, releases at least 85% of ruxolitinib within the first 15 minutes.

[0041] In another aspect, the present invention provides a direct compressed pharmaceutical tablet of any of the above aspects, wherein the said tablet remains stable after storage for at least 3 months at 40°C and 75% relative humidity (RH).

[0042] In another aspect, the present invention provides a direct compressed pharmaceutical tablet as mentioned herein above in combination with one or more additional therapeutic agent.

[0043] In another aspect, the present invention discloses a use of such pharmaceutical composition as medicament in the treatment of myelofibrosis, polycythaemia vera, graft versus host disease.

[0044] The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

[0045] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0046] The present invention will now be more specifically illustrated as hereunder.

[0047] The term % used in this specification means the percentage by weight unless otherwise stipulated.

[0048] The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. The term ' Ruxolitinib phosphate ' as used in the present invention includes, but is not limited to, Ruxolitinib phosphate per se, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.

[0049] The term "similarity factor" or f2 factor as used herein refers to one way of comparing dissolution profiles of two different products (Multisource Pharmaceutical Products: Guidelines on Registration Requirements to establish Interchangeability, Quality Assurance and Safety: Medicines, Essential Drugs and Medicines Policy, World Health Organization, 1211 Geneva 27, Switzerland). This model independent mathematical approach compares the dissolution profile of the two products: test and reference (or two strengths, or pre- and post-approved products from the same manufacturer). Tests are recommended to be performed under the same test conditions. The dissolution time points for both the profiles should be the same, for example for immediate release products e.g. 10, 15, 30, 45, 60 minutes and for extended release products, e.g., 1, 2, 3, 5 and 8 hours. Only one time point should be considered after 85% dissolution of the reference product. An f2 value of 50 or greater (50-100) ensures sameness or equivalence of the two curves, and thus the performance of the two products. The similarity factor f2 should be computed using the equation: f2 =50 log {[l+(l / n) t=l n (Rt - Tt )2 ]-0-5 100} where Rt and Tt are the cumulative percentage of the drug dissolved at each of the selected n time points of the comparator (reference) and (test) product respectively.

[0050] The term “direct compressed” as used herein the present invention refers to pharmaceutical composition comprises the mass of two or more solid species including active ingredient and one or more pharmaceutically acceptable excipient prepared with direct compression.

[0051] In general embodiment, the present invention provides a direct compressed pharmaceutical tablet comprising: a. about 1 wt.% to 10 wt.% ruxolitinib phosphate; b. about 35 wt.% to 55 wt.% of silicified microcrystalline cellulose; c. about 0.1 wt.% to 3 wt.% of one or more binder; and d. at least one more pharmaceutically acceptable excipient, wherein wt.% is based on the total weight of the tablet, and wherein the tablet, when tested in 500 ml of 6.8 pH potassium phosphate buffer at a temperature of 37°C ± 0.5°C and at a rotation speed of 100 rpm, releases at least 85% of ruxolitinib within the first 15 minutes.

[0052] In one embodiment, a direct compressed pharmaceutical tablet of the present invention comprises mixture of polyvinylpyrrolidone and hydroxypropylcellulose as binder.

[0053] In one embodiment, a direct compressed pharmaceutical tablet comprises: a. about 1 wt. % to 10 wt. % of ruxolitinib phosphate; b. about 30 wt. % to 50 wt. % of lactose or it’s hydrate; c. about 35 wt. % to 55 wt. % of silicified microcrystalline cellulose; d. about 1 wt. % to 6 wt. % of sodium starch glycolate; e. about 0.1 wt. % to 3 wt. % of polyvinylpyrrolidone and / or hydroxypropylcellulose; f. about 0.01 wt. % of silicon dioxide; and g. about 1 wt. % of magnesium stearate.

[0054] In one embodiment, a direct compressed pharmaceutical tablet comprises: a. about 1 wt. % to 10 wt. % of ruxolitinib phosphate; b. about 30 wt. % to 50 wt. % of lactose or it’s hydrate; c. about 35 wt. % to 55 wt. % of silicified microcrystalline cellulose; d. about 1 wt. % to 6 wt. % of sodium starch glycolate; e. about 0.1 wt. % to 3 wt. % mixture of polyvinylpyrrolidone and hydroxypropylcellulose; f. about 0.01 wt. % of silicon dioxide; and g. about 1 wt. % of magnesium stearate. In another embodiment, a direct compressed pharmaceutical tablet of the present invention further comprises one or more pharmaceutically acceptable excipients. The excipients to be used in accordance with the present invention are well known and are those excipients which are conventionally used by the person skilled in the art. Depending on the dosage form chosen for the pharmaceutical composition, the person skilled in the art will be able to select suitable pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient can be selected from diluent, disintegrant, lubricant and glidant.

[0055] The amount of diluent is from about 30 wt% to about 50 wt% based on the total weight of the tablet.

[0056] Diluent includes, but are not limited to, lactose or it’s hydrate, mannitol, xylitol, dextrose, sucrose, sorbitol, starch, pregelatinized starch, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, and mixtures thereof.

[0057] The amount of the disintegrant used in the present invention is from about 1 wt% to about 6 wt% based on the total weight of the tablet.

[0058] Disintegrant includes, but are not limited to, sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, starch, pregelatinized starch, sodium alginate, and mixtures thereof.

[0059] The amount of the lubricant used in the present invention is from about 0.01 wt% to about 3 wt%, more preferably about 1 wt.% based on the total weight of the tablet.

[0060] Lubricant includes, but are not limited to, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate and mixtures thereof. The amount of the glidant used in the present invention is preferably from about 0 wt% to about 3 wt%, more preferably from 0.01 wt% to about 1 wt% based on the total weight of the tablet.

[0061] Glidants includes, but are not limited to, colloidal silicon dioxide, talc, magnesium carbonate, and combinations thereof.

[0062] The pharmaceutical composition of the present invention may further be coated with a filmforming polymer and one or more pharmaceutically acceptable excipients, using techniques well known in the art e.g., spray coating in a conventional coating pan, or a fluidized bed processor, or dip coating. Alternatively, coating can also be performed using a hot melt technique. The film coating may contain one or more film-forming polymers, and optionally one or more pharmaceutically acceptable excipients. A suitable film-forming polymer is selected from the group comprising hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers e.g., Eudragit®, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, or mixtures thereof. A preferred film forming polymer is hydroxypropyl methyl cellulose. Other suitable film forming polymers which are known in art may also be used. The film coating may also contain opacifiers like titanium dioxide, flow aids like talc and pigment like iron oxide yellow.

[0063] The pharmaceutical composition in accordance with the present invention may be used as a medicament for the treatment of myelofibrosis, polycythaemia vera, graft versus host disease.

[0064] Moreover, the pharmaceutical composition of the present invention is very suitable for production on commercial scale making use of equipment and techniques commonly used in industry.

[0065] The following examples are intended to illustrate the scope of the present invention but not to limit it thereto. Examples:

[0066] Example 1: Preparation of a direct compressed tablet of Ruxolitinib phosphate

[0067] Table-1

[0068] Process for the Preparation:

[0069] 1. Lactose monohydrate and Ruxolitinib phosphate were sieved through a suitable mesh size and added into the container.

[0070] 2. Povidone K30 and hydroxypropylcellulose (HPC) were sieved through a suitable mesh size and added into the container of Step-1.

[0071] 3. A portion of microcrystalline cellulose was sieved through a suitable mesh size and added into the container of Step-2.

[0072] 4. Sodium starch glycolate was sieved through a suitable mesh size and added into the container of Step-3.

[0073] 5. Colloidal silica anhydrous and remaining part of microcrystalline cellulose were sieved through a suitable mesh size and were added into the container of Step-4 and mixed. 6. Magnesium stearate was sieved through a suitable mesh and added into the blend of step- 5 and mixed.

[0074] 7. The obtained blend of step 6 was compressed to obtain a tablet.

[0075] Observation: The powder during the tableting process was observed to stick to the surface of punch and ejection of the tablet from the punch wasn’t performed smoothly.

[0076] Example 2: Preparation of a direct compressed tablet of Ruxolitinib phosphate

[0077] Table-2

[0078] Process for the Preparation:

[0079] 1. Lactose monohydrate and Ruxolitinib phosphate were sieved through a suitable mesh size and added into the container.

[0080] 2. Povidone K30 and hydroxypropylcellulose (HPC) were sieved through a suitable mesh size and added into the container of Step-1. 3. A portion of microcrystalline cellulose was sieved through a suitable mesh size and added into the container of Step-2.

[0081] 4. Sodium starch glycolate was sieved through a suitable mesh size and added into the container of Step-3.

[0082] 5. Colloidal silica anhydrous and remaining part of microcry stalline cellulose were sieved through a suitable mesh size and were added into the container of Step-4 and mixed.

[0083] 6. Magnesium stearate was sieved through a suitable mesh and added into the blend of step- 5 and mixed.

[0084] 7. The obtained blend of step 6 was compressed to obtain a tablet.

[0085] Observation: The powder during the tableting process was observed to stick to the punch and ejection of the tablet from the punch wasn’t performed smoothly even though more amount of lubricant has been used as compared to example- 1.

[0086] Example 3: Preparation of a direct compressed tablet of Ruxolitinib phosphate

[0087] Table-3 Process for the Preparation:

[0088] 1. Lactose monohydrate and Ruxolitinib phosphate were sieved through a suitable mesh size and added into the container.

[0089] 2. Povidone K30 and hydroxypropylcellulose (HPC) were sieved through a suitable mesh size and added into the container of Step-1.

[0090] 3. A portion of silicified microcrystalline cellulose was sieved through a suitable mesh size and added into the container of Step-2.

[0091] 4. Sodium starch glycolate was sieved through a suitable mesh size and added into the container of Step-3.

[0092] 5. Colloidal silica anhydrous and remaining part of silicified microcrystalline cellulose were sieved through a suitable mesh size and were added into the container of Step-4 and mixed.

[0093] 6. Magnesium stearate was sieved through a suitable mesh and added into the blend of step- 5 and mixed.

[0094] 7. The obtained blend of step 6 was compressed into tablets.

[0095] Observation: There was no sticking problem observed during tableting and ejection of tablet was also smooth.

[0096] Example 4: Dissolution Data of Example 3

[0097] Table-4

[0098] (** = More than 85% drug release at 15 minutes for both reference and test product. Therefore, f2 calculation is not necessary.)

[0099] Dissolution of test products of Example-3 and reference product Jakavi® 20 mg were performed using standard USP apparatus I, basket, at 100 rpm in 500 ml at pH=6.8 potassium phosphate buffer. The drug release was determined by using an HPLC method. From the above dissolution data given in table-4, it is evident that more than 85% of drug released within 15 minutes establishes sameness or equivalence of both products i.e. test products (of Example-3) and reference product in terms of its dissolution and performance.

[0100] Example 5: Stability Result of Ruxolitinib phosphate composition prepared according to Example 3

[0101] The tablets prepared according to Example-3, were placed in PVC / aluminum blisters, and stored for 3 months under conditions of 40°C / 75% RH. 3 month stability result is presented herein below table-5.

[0102] Table-5

Claims

Claims:

1. A direct compressed pharmaceutical tablet comprising: a. about 1 wt.% to 10 wt.% ruxolitinib phosphate; b. about 35 wt.% to 55 wt.% of silicified microcrystalline cellulose; c. about 0.1 wt.% to 3 wt.% of one or more binder; and d. at least one more pharmaceutically acceptable excipient, wherein wt.% is based on the total weight of the tablet, and wherein the tablet, when tested in 500 ml of 6.8 pH potassium phosphate buffer at a temperature of 37°C ± 0.5°C and at a rotation speed of 100 rpm in standard USP apparatus I, basket, releases at least 85% of ruxolitinib within the first 15 minutes.

2. A direct compressed pharmaceutical tablet according to claim 1, wherein the binder is selected from hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose (L-HPC), hydroxypropyl methylcellulose, carbomers, carboxymethylcellulose sodium, ethyl cellulose, methylcellulose, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, pullulan, and mixture thereof.

3. A direct compressed pharmaceutical tablet according to claim 1 or claim 2, wherein the binder is mixture of polyvinylpyrrolidone and hydroxypropylcellulose.

4. A direct compressed pharmaceutical tablet according to claim 1, wherein at least one more pharmaceutically acceptable excipient is selected from diluent, disintegrant, glidant and lubricant.

5. A direct compressed pharmaceutical tablet according to claim 4, wherein the diluent is selected from lactose or it’s hydrate, mannitol, xylitol, dextrose, sucrose, sorbitol, starch, pregelatinized starch, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, calcium sulfate, magnesium carbonate, and mixtures thereof.

6. A direct compressed pharmaceutical tablet according to claim 4 or claim 5, wherein diluent is lactose.

7. A direct compressed pharmaceutical tablet according to claim 4, wherein disintegrant is selected from sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, starch, pregelatinized starch, sodium alginate, and mixtures thereof.

8. A direct compressed pharmaceutical tablet according to claim 4 or claim 7, wherein the disintegrant is sodium starch glycolate.

9. A direct compressed pharmaceutical tablet according to claim 4, wherein the glidant is selected from colloidal silicon dioxide, talc, magnesium carbonate, and combinations thereof.

10. A direct compressed pharmaceutical tablet according to claim 4 or claim 9, wherein the glidant is colloidal silicon dioxide.

11. A direct compressed pharmaceutical tablet according to claim 4, wherein lubricant is selected from magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, waxes, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate and mixtures thereof.

12. A direct compressed pharmaceutical tablet according to claim 4 or claim 11, wherein lubricant is magnesium stearate.

13. A direct compressed pharmaceutical tablet according to claim 1 comprising:a. about 1 wt. % to 10 wt. % of ruxolitinib phosphate; b. about 30 wt. % to 50 wt. % of lactose or it’s hydrate; c. about 35 wt. % to 55 wt. % of silicified microcrystalline cellulose; d. about 1 wt. % to 6 wt. % of sodium starch glycolate; e. about 0.1 wt. % to 3 wt. % of polyvinylpyrrolidone and / or hydroxypropylcellulose; f. about 0.01 wt. % of silicon dioxide; and g. about 1 wt. % of magnesium stearate.

14. A direct compressed pharmaceutical tablet according to any of claim 1 to claim 13 is useful in the treatment of diseases related to activity of Janus kinases.

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