Ruxolitinib phosphate control release formulation

Abstract

The present invention relates to tablet composition for oral administration of Ruxolitinib phosphate, with a combination of low viscosity HPMC and high viscosity HPMC.

Description

[0001] P1796EP00

[0002] RUXOLITINIB PHOSPHATE CONTROL RELEASE FORMULATION

[0003] BACKGROUND OF THE PRESENT INVENTION

[0004] Ruxolitinib phosphate or (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)pyrazol-l-yl]propanenitrile phosphate of the formula: is an inhibitor of the Janus kinase family of kinases (JAK1, JAK2) that has been first disclosed in W02007070514.

[0005] Ruxolitinib is indicated for the treatment of Myelofibrosis (MF), Polycythaemia vera (PV) and Acute Graft Versus Host Disease (GVHD). It is marketed as an immediate release tablet under the brand name JAKAVI® in Europe and JAKAFI® in US. The tablets need to be administered twice daily for optimal treatment, this potentially contributes to problems with patient compliance and unwanted side effects.

[0006] WO2014078486 discloses controlled release dosage forms of Ruxolitinib having up to 30% of Hydroxypropyl methylcellulose (HPMC). The dosage form is to be administered once daily.

[0007] The formulations described in WO2014078486 have the advantage of once-daily dosing but have some processability drawbacks. Therefore, there is still a need for additional oral formulations of Ruxolitinib which overcome the problems of the prior art, are advantageous to manufacture and are bioequivalent to multiple daily doses of the commercial Ruxolitinib capsules JAKAVI® or JAKAFI®.

[0008] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0009] A first aspect of the invention relates to controlled release pharmaceutical tablet composition comprising Ruxolitinib phosphate and one or more pharmaceutically acceptable excipients, the composition having an intragranular part comprising; a) Ruxolitinib phosphate; b) HPMC having a viscosity of 15 to 100 mPas at 2% solution in water at 20°C in an amount of 20% to 40% by weight relative to the total weight of the tablet; and an extragranular part comprising HPMC having a viscosity of 110 to 100000 mPas at 2% solution in water at 20°C, in an amount of 1% to 30% by weight relative to the total weight of the tablet, wherein the total amount of HPMC in the tablet is more than 30% by weight relative to the total weight of the tablet.

[0010] In a preferred embodiment the amount of Ruxolitinib phosphate is between 10% and 15% by weight relative to the total weight of the tablet.

[0011] In a another preferred embodiment the controlled release tablet of the invention comprises Ruxolitinib phosphate in an amount equivalent to 10 mg, 20 mg, 30 mg, or 55 mg of Ruxolitinib free base.

[0012] HPMC having a viscosity of 15 to 100 mPas at 2% solution in water at 20°C is considered a low viscosity grade.

[0013] HPMC having a viscosity of 110 to 100000 mPas at 2% solution in water at 20°C is considered a high viscosity grade.

[0014] HPMC is a versatile polymer used in a variety of industries, including pharmaceuticals. It is derived from cellulose, a natural polymer found in plants, and modified through chemical reactions to obtain different grades with different properties. These grades are classified based on molecular weight, degree of substitution, and viscosity.

[0015] The HPMC is available in several pharmaceutically approved grades with various viscosities and different degrees of substitution of the hydroxypropoxyl and methoxyl groups. Since all of these parameters regulate the drug release rate (Nellore et al., 1998), there is an opportunity during the development of hydrophilic matrix tablets to obtain a specific drug release profile simply by changing the grade of the HPMC and percentage. As the water penetrates into the tablet, the distribution of HPMC concentration and viscosity gradient from matrices is varied as a function of time, resulting in the change of gel thickness and strength. Higher viscosity grades, due to the high degree of entanglement and at high molecular weights, reduce effective molecular diffusion area decreasing dissolution profile.

[0016] The viscosity of the HPMC is an important parameter, which has to be taken into account during granulation, since the HPMC viscosity impacts the strength of the resulting granules.

[0017] Therefore, when adjusting the viscosity grade or concentration of HPMC, the modulation of the dissolution profile has to be balanced with the processability of the granules. It is important that HPMC powders can be processed to produce well-defined granules and tablets. Granules with optimal properties enable efficient processing, high throughput, and the production of tablets that meet the desired critical quality attributes.

[0018] There are many conventional methods and equipment well-known in the art to produce granules, one of the most common being wet granulation. Wet granulation techniques that require the use of an organic solvent or a mixture of organic solvent and water are undesirable for environmental and health care reasons, whereas the use of pure water as the granulation liquid for hydrophilic matrix compositions may cause lump formation. The use of water as the only granulating fluid often leads to processing difficulties when relatively high levels of HPMC are present, owing to the hydrophilic nature of this excipient. Specifically, when HPMC with high viscosity grades is used in the formulation, the excipient forms a kind of viscous gel that is not easy to homogenize, forming lumps during the granulation phase that are very hard after drying and too strong to be milled. These granules not only have poor compression properties but may also cause segregation issues during compression.

[0019] To avoid these problems, prior art WO2014078486 proposes to prepare the formulation comprising both low- and high-viscosity grades of HPMC, with a total HPMC content limited to up to 30% of the formulation.

[0020] However, when the present inventors prepared the formulations disclosed in WO2014078486, they faced processability problems such as weight variability during compression. Furthermore, due to the low quantity of HPMC used, the formed matrix was less robust, resulting in formulations that exhibited variability in the dissolution profiles.

[0021] The present inventors have surprisingly found that a formulation comprising Ruxolitinib phosphate with low-viscosity grade HPMC incorporated intragranularly and high-viscosity grade HPMC incorporated extragranularly solves the aforementioned problems, while allowing wet granulation without the need for organic solvents.

[0022] Commonly used grades of HPMC in pharmacy include low viscosity (LV) and high viscosity (HV) HPMC.

[0023] Examples of low viscosity HPMC include HPMC K100LV and HPMC E50 LV.

[0024] Example of high viscosity HPMC include HPMC K15M, HPMC K4M, and HPMC KI OOM.

[0025] The formulation of the invention comprises a low viscosity grade HPMC intragranularly and a high viscosity grade HPMC extragranularly. The amount of intragranular low viscosity HPMC is preferably in an amount from 20% to 40% , more preferably from 25% to 35%, most preferably from 27% to 32% by weight relative to the total weight of the tablet.

[0026] The low viscosity HPMC has a viscosity grade of 5 to lOOmPas, preferably 15 to 100 mPas, more preferably 50 to 100 mPas at 2% solution in water at 20°C; measured using a capillary viscosity method as described in USP monograph.

[0027] The amount of extragranular high viscosity HPMC is preferably from 1% to 30%, more preferably from 4% to 25%, most preferably from 7% to 20% by weight relative to the total weight of the tablet.

[0028] The high viscosity HPMC has a viscosity grade of 110 to 200000 mPas, more preferably from 4000 to 100000 mPas at 2% solution in water at 20°C; measured using a capillary viscosity method as described in USP monograph.

[0029] The tablet of the invention may contain additional excipients such as fillers, glidants or lubricants.

[0030] Fillers are excipients that are used to increase the bulk volume of a tablet. By combining a filler with the active pharmaceutical ingredient, the final product is given adequate weight and size to assist in production and handling.

[0031] The tablet of the present invention may contain at least one filler preferably in the intragranular part . Fillers are preferably used in an amount of from 25% to 70%, more preferably 30% to 60%, most preferably 36% to 50% by weight relative to the total weight of the tablet.

[0032] Suitable examples of fillers to be used in accordance with the present invention include mannitol, sorbitol, microcrystalline cellulose, lactose, phosphates, starch, pregelatinized starch, and combinations thereof. In a preferred embodiment the fillers to be used are microcrystalline cellulose, lactose or mixtures thereof. In a further preferred embodiment of the present invention, the fillers to be used are microcrystalline cellulose and lactose.

[0033] The tablet may also contain glidants and / or lubricants, preferably extragranularly.

[0034] Glidants enhance product flow by reducing interparticulate friction. A suitable example is colloidal silicon dioxide. Glidants are preferably used in a total amount of from 0.05% to 5%, more preferably 0.1% to 2%, and most preferably 0.2% to 1.0% by weight relative to the total weight of the tablet.

[0035] Lubricants are generally used in order to reduce sliding friction. In particular, to decrease friction at the interface between a tablet’s surface and the die wall during ejection, and reduce wear on punches and dies. Suitable lubricants to be used in accordance with the present invention include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, hydrogenated vegetable oil, and sodium stearyl fumarate. Lubricants are preferably used in a total amount of from 0.05% to 5%, more preferably 2% to 5%, even more preferably form 2.5% to 4% by weight relative to the total weight of the tablet. In a preferred embodiment of the present invention, the lubricants to be used are magnesium stearate, stearic acid or mixtures thereof. In a further preferred embodiment of the present invention, the lubricants to be used are magnesium stearate and stearic acid.

[0036] In a preferred embodiment, the tablet comprises: an intragranular part comprising: a. Ruxolitinib phosphate in an amount of from 10% to 15% by weight relative to the total weight of the tablet; b. Hydroxypropyl methylcellulose low viscosity grade in an amount of from 20 % to 40%, preferably 25% to 35% by weight relative to the total weight of the tablet; c. One or more filler in an amount of from 30% to 60% by weight relative to the total weight of the tablet; an extragranular part comprising: d. Hydroxypropyl methylcellulose high viscosity grade in an amount of from 1% to 30%, preferably 4% to 25% by weight relative to the total weight of the tablet; e. One or more glidants in an amount of from 0.05% to 5.0% by weight relative to the total weight of the tablet; and f. One or more lubricants in an amount of from 2% to 5% by weight relative to the total weight of the tablet, wherein the total amount of HPMC in the tablet is more than 30% by weight relative to the total weight of the tablet.

[0037] The tablet of the invention can be made using conventional methods and equipment well- known in the art; such as wet granulation or dry granulation. In a preferred embodiment the tablet of the invention is prepared by wet granulation comprising the steps of a. Combining Ruxolitinib phosphate, low viscosity HPMC in an amount of from 20% to 40%, preferably 25% to 35% by weight relative to the total weight of the tablet and optionally one or more pharmaceutically acceptable excipients; b. Wet granulating the resulting mixture with granulation solvent; c. Drying the resulting granulate; d. Further mixing the obtained granulate with high viscosity HPMC in an amount of from 1% to 30%, preferably 4% to 25% by weight relative to the total weight of the tablet and one or more pharmaceutically acceptable excipients to form a further mixture; e. Compressing the mixture obtained in step (d) into a tablet; and optionally; f. Coating the tablet, wherein the total amount of HPMC in the tablet is more than 30% by weight relative to the total weight of the tablet. Solvents suitable to perform the wet granulation are water and / or alcohols. In a preferred embodiment water without addition of any organic solvent is used as a granulation liquid.

[0038] The present invention is illustrated by the following Example.

[0039] Example 1 Control release tablets containing Ruxolitinib phosphate, 30 % of HPMC (K100LV) and 7% of HPMC (K4M).

[0040] 181.63 grams of Ruxolitinib phosphate, 234.21 grams of cellulose microcrystalline, 445.87 grams of HPMC (K100LV) and 468.47 grams of lactose monohydrate are mixed for 5 min in a high shear mixer (61). Mixed materials are granulated adding 559 g of water in the same equipment. Resulted granules are dried in a fluid bed drier at 60°C until reaching a product temperature of 45°C. Resulting granules are mixed with 104.04 g of HPMC (K4M) and 14.86 g of colloidal silicon dioxide in a diffusion blender for 15 minutes at 20 rpm. The resulting blend is mixed with 21.19 grams of magnesium stearate and 29.73 g of stearic acid for 5 minutes at 20 rpm. The lubricated blend is then compressed in a tabletting machine to get tablets with the target weight of 109 mg tablets corresponding to 13,199 mg of Ruxolitinib phosphate, or a target weight of 218 mg corresponding to 26,397 mg of Ruxolitinib phosphate per tablet or a target weight of 327 mg corresponding to 39.596 mg of Ruxolitinib Phosphate or a target weight of 599.5 mg corresponding to 72.592 mg of Ruxolitinib phosphate. Tablets are then coated with an aesthetic coating agent up to a weight gain of 3 %.

[0041] No sticking issues occurred during compression and the obtained core tablets exhibited correct appearance.

[0042] As can be seen in table 1, the weight variation of obtained tablets is low, both target average weight and individual weight fulfil the limits. In consequence, the uniformity of dosage units of the tablets is correct.

Claims

CLAIMS1. A controlled release pharmaceutical tablet composition comprising Ruxolitinib phosphate and one or more pharmaceutically acceptable excipients, the composition having an intragranular part comprising: a) Ruxolitinib phosphate; and b) HPMC having a viscosity of 15 to 100 mPas at 2% solution in water at 20°C in an amount of 20 to 40% by weight relative to the total weight of the tablet; and an extragranular part comprising HPMC having a viscosity of 110 to 100000 mPas at 2% solution in water at 20°C, in an amount of 1 to 30% by weight relative to the total weight of the tablet; wherein the total amount of HPMC in the tablet is more than 30% by weight relative to the total weight of the tablet.

2. A tablet composition according to claim 1, wherein the amount of Ruxolitinib phosphate is from 10% to 15% by weight based on the total weight of the tablet.

3. A controlled release pharmaceutical tablet composition according to claim 1 or 2, wherein the amount of Ruxolitinib phosphate equivalent to Ruxolitinib free base is 10 mg, or 20 mg, or 30 mg or 55 mg.

4. A controlled release pharmaceutical tablet composition according to claim 1 to 3 wherein the HPMC having a viscosity of 15 to 100 mPas at 2% solution in water at 20°C is in an amount of from 25 to 35% by weight relative to the total weight of the tablet.

5. A controlled release pharmaceutical tablet composition according to claim 1 to 4 wherein the HPMC having a viscosity of 110 to 100000 mPas at 2% solution in waterat 20°C in an amount of from 4 to 25% by weight relative to the total weight of the tablet.

6. A tablet composition according to any one of claims 1 to 5, wherein the composition further comprises at least one filler in an amount of from 30% to 60% by weight based on the total weight of the tablet;7. A tablet composition according to claim 6, wherein the filler is microcrystalline cellulose and / or lactose.

8. A tablet composition according to claim 6 to 7, wherein the filler is an intragranular excipient.

9. A tablet composition according to any one of claims 1 to 8, wherein the composition further comprises a glidant in a total amount of from 0.05% to 5% by weight based on the total weight of the composition.

10. A tablet composition according to claim 9 wherein the glidant is silicone dioxide.

11. A tablet composition according to any one of claims 1 to 10, wherein the composition further comprises a lubricant in a total amount of from 2% to 5% by weight based on the total weight of the composition.

12. A tablet composition according to claim 11 wherein the lubricant is magnesium stearate and stearic acid.

13. A tablet composition according to any one of claims 1 to 12 comprising an intragranular part comprising: a. Ruxolitinib phosphate in an amount of from 10% to 15% w / w by weight relative to the total weight of the tablet; b. Hydroxypropyl methylcellulose having a viscosity of 15 to 100 mPas at 2% solution in water at 20°C in an amount of from 20% to 40% by weight relative to the total weight of the tablet;c. One or more fillers in an amount of from 30% to 60% by weight relative to the total weight of the tablet; an extragranular part comprising: d. Hydroxypropyl methylcellulose having a viscosity of 110 to 100000 mPas at 2% solution in water at 20°C in an amount of from 1% to 30% by weight relative to the total weight of the tablet; e. One or more glidants in an amount of from 0.05% to 5.0% by weight relative to the total weight of the tablet; f. One or more lubricants in an amount of from 2% to 5% by weight relative to the total weight of the tablet; wherein the total amount of HPMC in the tablet is more than 30% by weight relative to the total weight of the tablet.

14. A wet granulation process for preparing a tablet composition according to any one of claims 1 to 13 the process comprising: a) Mixing Ruxolitinib phosphate and HPMC having a viscosity of 15 to 100 mPas at 2% solution in water at 20°C in an amount of from 20 to 40% by weight relative to the total weight of the tablet, and optionally one or more pharmaceutically acceptable excipients to form a mixture; b) Wet-granulating the resulting mixture; c) Further mixing the obtained granulate with HPMC having a viscosity of110 to 100000 mPas at 2% solution in water at 20°C, in an amount of from1 to 30% by weight relative to the total weight of the tablet; and optionally one or more further pharmaceutically acceptable excipients to form a further mixture; d) Compressing the mixture obtained in step (c) into a tablet; and optionallye) Coating the tablet.

15. A process according to claim 14, wherein water is used as the granulation solvent without the addition of organic solvents.

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