Direct compression formulation for the preparation of ruxolitinib tablets

Abstract

The oral solid dosage form of the present invention comprises ruxolitinib or its pharmaceutically acceptable salts thereof, and at least one excipient. Specifically, it involves an immediate-release tablet containing the ruxolitinib salt, as well as a method for preparing this dosage form via direct compression. This method is designed to offer simplified manufacturing processes and ensure long-term stability of the product.

Description

[0001] DIRECT COMPRESSION FORMULATION FOR THE PREPARATION OF RUXOLITINIB TABLETS

[0002] DESCRIPTION

[0003] Technical field:

[0004] The present invention relates to an oral solid dosage form comprising ruxolitinib or pharmaceutically acceptable salts thereof, and at least one excipient. In particular, the present invention relates to an immediate release tablet comprising said ruxolitinib salt, to a method for the preparation of the oral solid dosage form by direct compression which is providing ease of manufacture and long-term stability.

[0005] Prior Art:

[0006] Ruxolitinib is the first FDA-approved Janus kinase (JAK) inhibitor and the only drug currently approved for treating myelofibrosis. Its chemical name is ((3R)-3-cyclopentyl- 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile), and its empirical formula is Ci7Hi8N6with the following structural formula;

[0007] Ruxolitinib is a potent kinase inhibitor that specifically targets Janus Associated Kinases (JAKs) JAK1 and JAK2. By inhibiting these kinases, Ruxolitinib effectively disrupts the signaling of various cytokines and growth factors that play a crucial role in hematopoiesis and immune function. The specificity and potency of Ruxolitinib make it a promising therapeutic option for a range of diseases associated with dysregulated JAK signaling. This inhibition prevents the recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, ultimately leading to the modulation of gene expression.

[0008] A formulation in which Ruxolitinib phosphate salt is used is currently marketed as an oral immediate release tablet under the tradename of Jakafi® / Jakavi®. Jakafi® is a confident treatment option for intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis, as well as polycythemia vera patients who have not responded well to or cannot tolerate hydroxyurea. The oral immediate release tablets are administered twice daily (BID) in 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg dose strengths for the treatment of Janus kinase (JAK)-associated diseases, such as myelofibrosis (MF), polycythemia vera (PV), and graft-versus-host disease (GvHD) in adult patients.

[0009] Ruxolitinib phosphate is a heteroaryl-substituted pyrrolo[2,3-d] pyrimidines, also known as 3(R)-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 H-pyrazol-1-yl]propanenitrile phosphate inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2. These kinases are crucial for hematopoiesis and immune function, mediating the signaling of several cytokines and growth factors. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression.

[0010] Various sources report on Ruxolitinib salts and their crystalline forms; for example, WO 2007 / 070514 A1 , WO 2008 / 157208 A2, WO 2016 / 026974 A 1 , WO 2016 / 026975 A 1 , WO 2016 / 035014 A1 , WO 2016 / 063294 A2, WO 2016 / 074650 A 1 , WO 2017 / 008772 A 1 , WO 2017 / 125097 A1 , WO 2019 / 241504 A1 , and WO 2023 / 087101 A1.

[0011] W02007 / 070514 A1 discloses the trifluoroacetate salt of Ruxolitinib as a synthetic intermediate.

[0012] W02008 / 157208 A1 discloses salt forms of Ruxolitinib, namely Ruxolitinib phosphate, Ruxolitinib sulfate and Ruxolitinib maleate.

[0013] WO 2016 / 026974 A1 discloses solid-state forms of Ruxolitinib oxalate, processes for preparing the solid state forms, as well as pharmaceutical compositions and formulations comprising said solid state forms.

[0014] WO 2016 / 026975 A1 discloses solid state forms of Ruxolitinib besylate, processes for their preparation, and pharmaceutical compositions and formulations comprising said solid state forms.

[0015] WO 2016 / 074650 A1 discloses a pharmaceutically acceptable salt of (3R)-3-cyclopentyl- 3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]propanenitrile and an acid component selected from a group of benzoic acid, benzenesulphonic acid, 4-chlorobenzene sulphonic acid, citric acid, ethanesulphonic acid, fumaric acid, hydrobromic acid, hydrochloric acid, 2-naphthalenesulphonic acid, L-tartaric acid and p-toluenesulphonic acid. These ruxolitinib salts possess favourable physical and chemical characteristics, which make them suitable for use in the formulation of a dosage form.

[0016] WO 2017 / 008772 A1 relates to crystalline forms of (3R)-3-cyclopentyl-3-[4-(7H- pyrolo[2,3-d] pyrimidin-4-yl) pyrazol-l-yl]propanenitrile salts.

[0017] WO 2019 / 241504 A1 relates to kinase inhibitor Cs-Ci6 aliphatic sulfate salts.

[0018] WO 2023 / 087101 A1 discloses salts comprising ruxolitinib and an acid having a sulfonyl group in the form of sulfamate ester (acesulfame) or an organic sulfonic acid selected from methanesulfonic acid, 1 ,2-ethanedisulfonic acid, and 1 ,5-naphthalenedisulfonic acid.

[0019] Different salt forms of an active pharmaceutical ingredient may possess different properties. The choice of a particular salt formulation is based on numerous factors such as API chemistry, intended dosage form, pharmacokinetics, and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API. Salt formation approaches have widely been utilized to increase solubility, and therefore, the dissolution rate of a drug. Hydrochloride, mesylate, hydrobromide, acetate, and fumarate are the most common counterions that are used for basic chemical entities in the past 20 years, while sodium, calcium, and potassium continue to be the most common counterions for weakly acidic drugs. Such variations in the properties of different salts may provide a basis for improving certain aspects of the API, such as its formulation, for example, by facilitating better processing or handling characteristics, changing the dissolution profile in a favorable direction, or improving stability and shelflife.

[0020] Ruxolitinib is a Biopharmaceutical Classification System (BCS) class 1 compound, with high permeability, high solubility and rapid dissolution characteristics. It is a water-soluble drug with pH dependent solubility exhibiting increased solubility at lower pH. In clinical studies, ruxolitinib is rapidly absorbed after oral administration with maximal plasma concentration (Cmax) achieved approximately 1-hour post-dose.

[0021] Besides the solubility of Ruxolitinib, it showed significant instability in hydrolytic conditions during degradation behavior tests. The hygroscopic nature of the active substance in this composition causes stability issues. Hygroscopicity is defined as the ability of a material to absorb and retain moisture at various temperatures and humidity conditions. Readily hydrolysable drugs are more easily degraded due to the presence of water and pH alterations. Therefore, there is a need to develop formulation for preparing a stable Ruxolitinib tablet that providing long-term storage stability.

[0022] The present invention addresses this problem and provides a solution thereto. In this way, the present inventors have developed a free-flowing and cohesive composition that can be directly compressed into strong tablets with an acceptable in vitro dissolution profile.

[0023] Description of the Invention:

[0024] The objective of the present invention is to produce a stable solid oral pharmaceutical composition comprising therapeutically effective amount of ruxolitinib or pharmaceutically acceptable salts thereof, and at least one excipient, wherein the composition is prepared by direct compression.

[0025] Another aspect of the invention provides a stable oral pharmaceutical immediate release tablet composition comprising therapeutically effective amount of ruxolitinib or pharmaceutically acceptable salts thereof, wherein the said ruxolitinib salt is ruxolitinib phosphate or ruxolitinib hydrochloride.

[0026] It has surprisingly been found by the present inventors, that the inventive solid oral composition comprising ruxolitinib or pharmaceutically acceptable salts thereof, can be prepared by direct compression using at least one excipient.

[0027] The invention relates a process for preparing the tablets by blending the active ingredient and specific excipients into the new formulations and then directly compressing the formulations into the direct compression tablets.

[0028] The active substance ruxolitinib or a pharmaceutically acceptable salt thereof, in aqueous medium shows degradation mainly due to oxidation. Temperature and oxygen trigger an increase in oxidative degradation. Therefore, development of a stable and having acceptable in vitro dissolution profile oral immediate release formulation for ruxolitinib is challenging due to pH dependent solubility of the drug substance with mainly oxidation degradation products at higher temperatures / moisture content and / or in presence of oxygen.

[0029] Pharmaceutical industries are actively seeking innovative methods to reduce costs and accelerate drug development, while simultaneously enhancing the quality of their products. The objective of the present invention is to provide a pharmaceutical composition comprising the compound prepared by direct compression which will avoid additional equipments such as granulators and dryers.

[0030] There are three commercially important processes for making compressed tablets: wet granulation, direct compression and dry granulation (slugging or roller compaction). The method of preparation and type of excipients are selected to give the tablet formulation the desired physical characteristics that allow for the rapid compression of the tablets.

[0031] Direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug. The advantages of direct compression include uniformity of blend, few manufacturing steps involved, i.e., the overall process involves weighing of powders, blending and compression, hence less cost; elimination of heat and moisture, prime particle dissociation and physical stability.

[0032] Pharmaceutical manufacturers would prefer to use direct compression techniques over wet or dry granulation methods because of quick processing time and cost advantages.

[0033] In spite of the advantages afforded by wet granulation in general, due to the instability of the compounds in the presence of water, it is desirable to directly compress tablets containing instable active substance, namely ruxolitinib in this invention. There is a need in the industry for techniques and pharmaceutical excipients which will allow manufacturers to prepare Ruxolitinib tablets by direct compression.

[0034] The present invention provides a direct tableting, free-flowing particulate ruxolitinib or a pharmaceutically acceptable salt formulation, preferably ruxolitinib phosphate or ruxolitinib hydrochloride, in the form of a tableting powder, capable of being directly compressed into a tablet having adequate hardness, rapid disintegration time and an acceptable dissolution pattern.

[0035] In a further embodiment, the present invention concerns a pharmaceutical composition comprising;

[0036] (a) 2-10% by weight on a dry weight basis of a Ruxolitinib or pharmaceutically acceptable salt;

[0037] (b) 40-90% by weight on a dry weight basis of a pharmaceutically acceptable filler (diluent);

[0038] (c) 1-20% by weight on a dry weight basis of a pharmaceutically acceptable binder; (d) 0-5% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant;

[0039] (e) 0-2% by weight on a dry weight basis of a pharmaceutically acceptable glidant;

[0040] (f) 0-1 % by weight on a dry weight basis of a pharmaceutically acceptable lubricant. Preferably, the present invention concerns a pharmaceutical composition comprising;

[0041] (a) 2-10% by weight on a dry weight basis of a Ruxolitinib or pharmaceutically acceptable salt, preferably Ruxolitinib phosphate or ruxolitinib hydrochloride;

[0042] (b) 40-90% by weight on a dry weight basis of a pharmaceutically acceptable filler (diluent);

[0043] (c) 1-20% by weight on a dry weight basis of a pharmaceutically acceptable binder;

[0044] (d) 0-5% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant;

[0045] (e) 0-2% by weight on a dry weight basis of a pharmaceutically acceptable glidant;

[0046] (f) 0-1 % by weight on a dry weight basis of a pharmaceutically acceptable lubricant.

[0047] As used herein the term "ruxolitinib" refers to the free base of ruxolitinib or any pharmaceutically acceptable salts thereof (e.g., ruxolitinib phosphate, ruxolitinib hydrochloride). In this invention ruxolitinib phosphate and ruxolitinib hydrochloride salts are used.

[0048] The term "active substance" or "active pharmaceutical ingredient" means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. In the present invention, the active substance is ruxolitinib or its pharmaceutically acceptable salts thereof.

[0049] As used herein the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms, which are, within the scope of sound medical judgment, suitable for contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response and other problem complications commensurate with a reasonable benefit / risk ratio.

[0050] The term “therapeutically effective amount” refers to the amount of ruxolitinib or its pharmaceutically acceptable salts, esters, and solvates thereof, that is an amount sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment. In the present invention, tablet composition comprises 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg ruxolitinib. The term "immediate release" as described herein refers to release of the active ingredient immediately on reaching the stomach.

[0051] "Powder mixture" refers to mixing of each component individually not obtaining by granulation method such as wet granulation and dry granulation.

[0052] In addition to the active or therapeutic substances, tablets may contain a number of inert materials known as excipients. The pharmaceutical compositions described herein can, if desired, include one or more pharmaceutically acceptable excipients. The term "excipient" herein means any substance, not itself a therapeutic agent, which may be used as a carrier or vehicle for delivery of a therapeutic agent to a subject or combined with a therapeutic agent (e.g., to create a pharmaceutical composition) to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition. Excipients include, by way of illustration and not limitation, binders, disintegrants, taste enhancers, solvents, thickening or gelling agents (and any neutralizing agents, if necessary), penetration enhancers, solubilizing agents, wetting agents, antioxidants, lubricants, emollients, emulsifying agents, surfactants, substances added to mask or counteract a disagreeable odor, fragrances or taste, and substances added to improve appearance or texture of the composition. Any such excipients can be used in any dosage forms according to the present disclosure. The foregoing classes of excipients are not meant to be exhaustive but merely illustrative as a person of ordinary skill in the art would recognize that additional types and combinations of excipients could be used to achieve the desired goals for release and stability of ruxolitinib tablet composition.

[0053] The present invention relates to an oral solid dosage form comprising ruxolitinib or pharmaceutically acceptable salts thereof, and at least one excipient. Preferably, ruxolitinib tablet comprises at least one glidant, at least one binder, at least one filler (diluent), at least one disintegrant and at least one lubricant. The excipients may be classified according to the role they play in the final tablet. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed.

[0054] The glidant is added to impart a pharmaceutical compositions with enhanced flow properties. Also, the lubricant is typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1 % by weight. According to one embodiment of the invention, the composition comprises at least one lubricant and at least one glidant selected from the group comprising calcium stearate, magnesium stearate, colloidal silicon dioxide, sodium stearyl fumarate, sodium lauryl sulfate, zinc stearate, calcium stearate, mineral oil, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, magnesium lauryl sulfate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof.

[0055] The filler (diluents) is added to increase the bulk weight of the blend resulting in a practical size for compression. This is often necessary where the dose of the drug is relatively small. According to one embodiment of the invention, the composition comprises at least one filler (diluent) selected from the group comprising microcrystalline cellulose, lactose, mannitol, spray dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dibasic calcium phosphate anhydrate, sodium chloride, dextrates, lactitol, maltodextrin , sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate polyols, dextrose, maltitol, or mixtures thereof.

[0056] The binders are agents, which impart cohesive qualities to the powdered material. According to one embodiment of the invention, the composition comprises at least one binder selected from the group comprising polyvinyl pyrrolidone, microcrystalline cellulose, cellulose ether, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, corn starch, maize starch, pregelatinised starch, polymethacrylate, or mixtures thereof. The binder can be present in a range of 0.5 to 25 weight %, preferably 1 to 20 weight % on the weight of the composition.

[0057] The disintegrants are often included to ensure that the tablet has an acceptable rate of disintegration. According to one embodiment of the invention, the composition comprises at least one disintegrant selected from the group comprising of croscarmellose sodium, sodium carbonate, hydroxypropyl cellulose (HPC), cross-linked polyvinylpyrrolidone (crospovidone), copovidone, polycarbophil, low substituted poloxamer, sodium starch glycol late, starch, pregelatinized starch, alginic acid and alginates, ion exchange resins, magnesium aluminum silicate, sodium dodecyl sulfate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, sodium docusate, guar gum, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, or mixtures thereof. In the present invention, sodium starch glycollate is selected for disintegrant. Considering the moisture retention properties of the disintegrants; the amount of disintegrant is kept below 10%, more preferably below 5% by weight of the composition, in order to ensure continuity of stability. The following examples represent various embodiments of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention. Examples:

[0058] The scope of present invention is the preparation of a stable pharmaceutical dosage form for oral administration comprising Ruxolitinib or pharmaceutically acceptable salts thereof, and exhibiting an immediate drug release profile.

[0059] Example 1. Compositions prepared by wet granulation process

[0060] For 25mg, 20mg, 15mg, 10mg, 5mg tablet % Component

[0061] F-01 F-02

[0062] Ruxolitinib phosphate 2-10

[0063] Ruxolitinib hydrochloride - 2-10

[0064] Lactose 40-60 40-60

[0065] Microcrystalline cellulose 40-60 40-60

[0066] Sodium starch glycolate 0-5 0-5

[0067] Hidroxypropyl cellulose 0-10 0-10

[0068] Polyvinyl pyrrolidone 0-10 0-10

[0069] Aerosil 0-2 0-2

[0070] Magnesium stearate 0-1 0-1

[0071] Required amounts of selected active substance ruxolitinib salt, a part of microcrystalline cellulose, hidroxypropyl cellulose, polyvinyl pyrrolidone and lactose are blended in a granulator and the prepared powder is wet granulated and dried in fluid bed dryer to obtain granules comprising ruxolitinib. The prepared granules are mixed with remained excipients. The final blends were compressed using a rotary tablet press.

[0072] Example 2. Composition prepared by dry granulation process

[0073] For 25mg, 20mg, 15mg, 10mg, 5mg tablet % Component

[0074] F-03

[0075] Ruxolitinib hydrochloride 2-10

[0076] Lactose 40-60

[0077] Microcrystalline cellulose 40-60

[0078] Sodium Starch Glycolate 0-5

[0079] Hidroxypropyl cellulose 0-10

[0080] Polyvinyl pyrrolidone 0-10

[0081] Aerosil 0-2

[0082] Magnesium Stearate 0-1 Required amounts of Ruxolitinib hydrochloride, a part of microcrystalline cellulose, hidroxypropyl cellulose, polyvinyl pyrrolidone and lactose are mixed for 10 minutes. Then, magnesium stearate is added and mixed for 5 minutes. The resulting powder mixture is passed through the compactor for dry granulation. The granules passed through the compactor are ground, and the required amount of remained excipients are added to the granules obtained as a result of grinding and mixed for 5 minutes. Finally, magnesium stearate is added and mixed for 5 minutes. The final ruxolitinib containing granule mix is compressed in tablet specifications.

[0083] Example 3. Compositions prepared by direct compression process

[0084] For 25mg, 20mg, 15mg, 10mg, 5mg tablet % Component

[0085] F-04 F-05

[0086] Ruxolitinib hydrochloride 2-10

[0087] Ruxolitinib phosphate - 2-10

[0088] Lactose 40-60 40-60

[0089] Microcrystalline cellulose 40-60 40-60

[0090] Sodium starch glycolate 0-5 0-5

[0091] Hidroxypropyl cellulose 0-10 0-10

[0092] Polyvinyl pyrrolidone 0-10 0-10

[0093] Colloidal Silicon Dioxide 0-2 0-2

[0094] Magnesium Stearate 0-1 0-1

[0095] Required amounts of selected Ruxolitinib salt and a part of microcrystalline cellulose to obtain mixture and mixed. Then, rest of microcrystalline cellulose, sodium starch glycolate, hydroxypropyl cellulose, lactose, colloidal silicon dioxide, and polyvinyl pyrrolidone are added. Finally, magnesium stearate is added and mixed for 5 minutes. The final ruxolitinib containing powder mixture is compressed in tablet specifications.

[0096] Example 4. In-Vitro Dissolution

[0097] The in-vitro dissolution profile of Formulation Trials (F-01 to F-05) were recorded in Buffer 0.1 N HCI 100 rpm, 500 mL basket apparatus in comparison to reference product (Jakafi® 20 mg Tablet). An in-vitro comparative dissolution test was performed for the test and the reference product in accordance to the Guideline on Investigation of Bioequivalence, was performed using the chosen dissolution conditions (500 mL dissolution medium, basket at 100 rpm at 37°C ±0.5°C at 0.1 N HCI medium). The above exemplified compositions (Formulations F-01 to F-05) comprising ruxolitinib were tested in vitro and they were compared with a commercial reference product Jakafi® Tablet.

[0098] An immediate-release Ruxolitinib Tablet has a dissolution rate of releasing more than 85% within 15 minutes. In the present invention, the dissolution rates of Formulations F- 01 to F-05 are fast enough that at least 85% of ruxolitinib is released within 15 minutes.

[0099] The dissolution profiles were compared; the dissolution profiles obtained were evaluated by similarity factor (fp) (Helmy & Bedaiwy, 2013). An fp value between 50 and 100 suggests that the all-dissolution profiles are similar (EMEA Guideline on the Investigation of Bioequivalence, 2010). The similarity factor (fp) values of test products (Formulations F-01 to F-05) and reference product (Jakafi® Tablet) for the different pH media are found between 50 and 100.

[0100] Example 5. Stability Studies

[0101] The stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product. The rules in force (e.g. "Note for Guidance on Impurities in New Drug Products" CPMP / ICH / 2738 / 99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances.

[0102] The stability of a pharmaceutical dosage form is related to maintaining its physical, chemical, microbiological, therapeutic, and toxicological properties when stored, i.e., in a particular container and environment.

[0103] It is known that many drugs exhibit poor or modest shelf stability. The presence of degradation products of these drugs can give rise to efficacy or toxicity issues, but even if they do not, the diminution of the concentration of a drug as a result of its degradation is inherently undesirable, as it makes therapy with the drug less certain. Stability issues can be caused by environmental factors such as humidity, temperature and the like. However, degradation may result from, or be accelerated by, interactions of drug substances with pharmaceutical excipients such as fillers, binders, lubricants, glidants and disintegrating agents or impurities contained in any of these excipients. Firstly, accelerated stability tests are performed by storing a product in stress conditions. These tests allow predicting the shelf life of the product over the years when it will be stored in normal storage conditions. Forced degradation studies of Ruxolitinib tablets were conducted in accordance with the ICH guidelines. Ruxolitinib tablets were exposed to thermall stress (60°C for 1 week), photolytic stress (ultraviolet light 200 W-hours per square meter, and fluorescence light 1.2 million lux-hours for 8 days) and humidity stress (75%±5% Relative Humidity for 2 months). Especially in the results obtained from the studies on Ruxolitinib HCI salt, it was observed that the amount of degradation products in the tablets obtained by wet granulation process was 1.5 times higher than the tablets obtained by direct compression process.

[0104] Then, stability tests in this case were performed according to the EMEA Guideline on Stability Testing (CPMP / QWP / 122 / 02, rev 1), i.e. by maintaining the product in its container at a temperature of 40°C ± 2°C and 75% ± 5 %RH (Relative Humidity) for six months and at a temperature of 25°C ± 2°C and 60% ± 5% RH for twenty-four months. In the stability studies, no unexpected degradation impurity formation was observed especially in the products obtained by direct compression of ruxolitinib tablets. The formulation is stable based on chemical / physical stability with an accelerated and longterm stability test conditions.

Claims

CLAIMS1. A stable solid oral pharmaceutical composition comprising therapeutically effective amount of ruxolitinib or pharmaceutically acceptable salt thereof, and at least one excipient; wherein the composition is prepared by direct compression.

2. The stable pharmaceutical composition according to claim 1 , wherein ruxolitinib or pharmaceutically acceptable salt thereof, is ruxolitinib phosphate.

3. The stable pharmaceutical composition according to claim 1 , wherein ruxolitinib or pharmaceutically acceptable salts thereof, is ruxolitinib hydrochloride.

4. The stable pharmaceutical composition according to claim 1 , wherein the composition is in the form of tablet.

5. The stable pharmaceutical composition according to claim 4, wherein the composition is in the form of immediate release tablet.

6. The stable pharmaceutical composition according to claim 1 , wherein the composition comprises at least one glidant, at least one binder, at least one filler (diluent), at least one disintegrant and at least one lubricant.

7. The stable pharmaceutical composition according to any of the preceding claims, wherein the composition comprises;(a) 2-10% by weight on a dry weight basis of a Ruxolitinib or pharmaceutically acceptable salt thereof;(b) 40-90% by weight on a dry weight basis of a pharmaceutically acceptable filler (diluent);(c) 1-20% by weight on a dry weight basis of a pharmaceutically acceptable binder;(d) 0-5% by weight on a dry weight basis of a pharmaceutically acceptable disintegrant;(e) 0-2% by weight on a dry weight basis of a pharmaceutically acceptable glidant;(f) 0-1 % by weight on a dry weight basis of a pharmaceutically acceptable lubricant.

8. The stable pharmaceutical composition according to any of the preceding claims, wherein said composition comprises corresponding one of the dosage amounts of 25mg, 20 mg, 15 mg, 10 mg and 5 mg Ruxolitinib.The stable pharmaceutical composition according to any of the preceding claims, wherein said composition is used for the treatment of intermediate or high-risk myelofibrosis.

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