A drug composition of roscovitine

Abstract

The present application relates to a drug composition of Rociiletinib. Specifically, the present application belongs to the field of pharmaceutical preparations, and relates to a method for preparing a solid dispersion of Rociiletinib by hot melt extrusion (HME) technology, and a drug composition with high solubility and stability obtained therefrom. Both Rociiletinib phosphate and Rociiletinib dihydrate are poorly water-soluble substances, and the dissolution and bioavailability of the existing tablets do not reach a satisfactory level. The present application improves the formulation and preparation process, and provides a new Rociiletinib tablet, which has an ideal dissolution, and the preparation method is simple and easy to operate, and is suitable for industrialized scale production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulations, specifically relating to a method for preparing ruxolitinib solid dispersions by hot melt extrusion (HME) technology, and the resulting pharmaceutical composition with high solubility and high stability. Background Technology

[0002] Ruxolitinib phosphate is a selective JAK1 / JAK2 inhibitor developed by Incyte for the treatment of myelofibrosis (MF), polycythemia vera (PV), and acute graft-versus-host disease (aGVHD). The chemical name of ruxolitinib phosphate is (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropionitrile phosphate, and its structure is as follows:

[0003] .

[0004] Ruxolitinib phosphate and ruxolitinib dihydrate are both poorly soluble in water, and formulations obtained through conventional processing methods often fail to achieve the expected dissolution rates. Currently known formulations include tablets and creams, but the dissolution and bioavailability of existing tablets remain unsatisfactory. Creams are administered transdermally, but they are frequently accompanied by skin side effects such as itching, redness, and peeling. Furthermore, because JAK inhibitors may suppress the immune system, patients using ruxolitinib creams have an increased risk of bacterial and fungal infections.

[0005] Existing technologies mention methods for preparing solid dispersions, such as Chinese patent application CN107205931A. However, it does not teach solid dispersions for ruxolitinib, and its preparation method uses microfluidic co-precipitation to obtain a suspension of amorphous particles, followed by spray drying, which requires sophisticated equipment and results in high production costs. Chinese patent application CN105902508A mentions ruxolitinib dispersible tablets, but its preparation method involves simply mixing ruxolitinib with conventional fillers, disintegrants, and binders, then directly compressing the powder into tablets. Those skilled in the art would find it difficult to believe that this method can achieve good dissolution.

[0006] Therefore, there is still a need for a new ruxolitinib tablet with ideal dissolution and a simple and easy preparation method suitable for industrial-scale production. Summary of the Invention

[0007] In a first aspect, the present invention provides a ruxolitinib tablet, characterized in that the tablet comprises a solid dispersion, the solid dispersion comprising:

[0008] (a) The active ingredient, which is ruxolitinib or a pharmaceutically acceptable salt or hydrate thereof, comprising 1.5%-4% of the total weight of the tablets, preferably 2.5%-4% based on ruxolitinib, and

[0009] (b) A solid dispersion carrier, comprising 14%-21% of the total weight of the tablets, wherein the solid dispersion carrier is selected from copovidone, Soluplus, etc. ® One or more of the following: hydroxypropyl methylcellulose acetate succinate and povidone.

[0010] In one embodiment, the solid dispersion carrier is Soluplus. ® .

[0011] In one embodiment, the ruxolitinib tablets of the present invention further comprise a filler, a disintegrant, and a lubricant.

[0012] Soluplus ® It is an amphiphilic block copolymer composed of polyvinyl alcohol (PVA), polyethylene glycol (PEG), and polyvinyl acetate (PVAc). Its hydrophilic segments (PEG and PVA) provide water solubility, promote drug dissolution, and can also capture free radicals to reduce the oxidative degradation of ruxolitinib. The hydrophobic segment (PVAc) is compatible with the hydrophobic part of ruxolitinib (such as the pyrazolopyrimidine ring), enhances intermolecular interactions, and can reduce water penetration, so that the tablet has good stability in high humidity environments. The long-chain flexible structure can encapsulate drug molecules and form a physical barrier.

[0013] The cyclic nitrogen atom and pyridine nitrogen in the ruxolitinib molecule can interact with Soluplus. ® The hydroxyl groups (-OH) in the PVA segments form a hydrogen bond network, immobilizing drug molecules within the polymer matrix and reducing molecular migration. The hydrophobic PVAc segments bind to the aromatic ring of ruxolitinib via van der Waals forces, further inhibiting drug aggregation. Soluplus ® The long-chain structure forms a "molecular cage" around the drug, which physically prevents ruxolitinib molecules from getting close to each other, inhibiting crystal nucleus formation and crystal growth.

[0014] In one embodiment, the ruxolitinib or its pharmaceutically acceptable salt or hydrate, based on ruxolitinib, constitutes 1.5%-4% of the total weight of the tablet, preferably 2.5%-4%, more preferably 3%-4%.

[0015] In one embodiment, the solid dispersion carrier accounts for 14%-21% of the total weight of the tablets, preferably 15%-20%, more preferably 17%-18%.

[0016] In one embodiment, the active ingredient is ruxolitinib dihydrate.

[0017] In one embodiment, the filler is selected from one or more of mannitol, starch, lactose, and microcrystalline cellulose, preferably from one or two of lactose and microcrystalline cellulose. The amount of the filler can be 60%-80% of the total weight of the tablet, for example 66%-78%, preferably 68-75%, more preferably 70%-74%. In a preferred embodiment, the filler is lactose and microcrystalline cellulose, and the amount of the filler is 70%-74% of the total weight of the tablet; more preferably, lactose accounts for 35%-37% of the total weight of the tablet and microcrystalline cellulose accounts for 35%-37% of the total weight of the tablet.

[0018] In one embodiment, the disintegrant is selected from one or more of sodium carboxymethyl starch, crospovidone, and low-substituted hydroxypropyl cellulose; preferably, the disintegrant is sodium carboxymethyl starch. The amount of the disintegrant can be 4%-6% of the total weight of the tablet, preferably 4.5%-5.5%, and more preferably 5.0%.

[0019] In one embodiment, the lubricant is selected from one or more of magnesium stearate, calcium stearate, and sodium stearate fumarate; preferably, the lubricant is selected from one or more of magnesium stearate and calcium stearate; more preferably, the lubricant is magnesium stearate. The amount of the lubricant may be 0.2%-1.0% of the total weight of the tablet, preferably 0.3%-0.7%, more preferably 0.5%.

[0020] In one embodiment, the above-described ruxolitinib tablets are characterized in that the solid dispersion is prepared by the following method:

[0021] Ruxolitinib or its pharmaceutically acceptable salt or hydrate and a solid dispersion carrier are mixed to obtain a mixture; and

[0022] The mixture obtained in the above steps is added to a hot melt extrusion device for hot melt extrusion, and then the extruded material is crushed to obtain a solid dispersion.

[0023] In one embodiment, the hot melt extrusion is performed at a hot melt extrusion temperature of 60-80°C, for example, 60-75°C.

[0024] In one embodiment, the ruxolitinib tablets described above are prepared by the method described in the second aspect below.

[0025] The inventors were surprised to find that when Soluplus was chosen as the solid dispersion carrier... ® At the same time, the resulting formulation exhibits additional, unexpected technical effects. Soluplus ®Using it as a carrier can not only achieve better-than-expected in vitro dissolution results, but also significantly reduce the extrusion temperature, thereby improving the chemical stability of the tablets.

[0026] In a second aspect, the present invention provides a method for preparing ruxolitinib tablets as described in the first aspect, the method comprising:

[0027] Step (1): Mix ruxolitinib or its pharmaceutically acceptable salt or hydrate with a solid dispersion carrier to obtain a mixture;

[0028] Step (2): Add the mixture obtained in step (1) into a hot melt extrusion device for hot melt extrusion, and crush the extruded material to obtain a solid dispersion; and

[0029] Step (3): Mix the solid dispersion obtained in step (2) with filler, disintegrant and lubricant evenly, and compress it into tablets.

[0030] In one embodiment, the solid dispersion carrier is Soluplus. ® .

[0031] In one embodiment, the active ingredient is ruxolitinib dihydrate.

[0032] In some embodiments, the fillers, disintegrants, and lubricants, and the amounts thereof, are as described in the first aspect above.

[0033] In one embodiment, in step (2), the hot melt extrusion is carried out under the following conditions: the screw speed is 120-400 rpm, for example 120-200 rpm; the hot melt extrusion temperature is 60-80℃, for example 60-75℃; and the feeding speed is 0.8-3.0 kg / h, for example 0.8-1.2 kg / h.

[0034] In one embodiment, in step (3), the hardness of the tablet core obtained after compression into tablets is 50N-200N.

[0035] In terms of technical effects, the ruxolitinib tablets of the present invention increase the dissolution rate of ruxolitinib, thus resulting in better absorption and higher bioavailability in vivo. Furthermore, the ruxolitinib tablets of the present invention employ a simple and easy-to-operate hot-melt extrusion method. Compared with existing technologies, this preparation method does not use organic solvents, has low equipment requirements, and can still meet dissolution requirements while reducing energy consumption and increasing production capacity.

[0036] Unless otherwise expressly stated to the contrary, all percentages given in this application are by weight. Those skilled in the art will understand that the sum of the weight percentages of the components in a composition is less than or equal to 100%.

[0037] As used herein, the term "about" means that the numerical value given thereafter can be extended by plus or minus 10%, preferably plus or minus 5%. For example, "about 5%" means any number in the range of 4.5% to 5.5%, preferably any number in the range of 4.75% to 5.25%.

[0038] As used in this article, the term "solid dispersion carrier" refers to an excipient that can disperse a drug within or on its surface through physical or chemical methods to form a solid dispersion. The formation of solid dispersions often enhances the drug release characteristics.

[0039] As used herein, the terms “optionally” or “optionally” mean that an event or situation subsequently described may or may not occur, and include both scenarios where the event or situation occurs and scenarios where the event or situation does not occur. For example, “optionally includes” means that a step subsequently described may or may not be present. Detailed Implementation

[0040] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and are not intended to limit the scope of the invention.

[0041] Examples 1-4

[0042] The recipe is as follows:

[0043]

[0044] Ruxolitinib tablets were prepared according to the following method:

[0045] Step (1): Mix the above amount of ruxolitinib dihydrate and solid dispersion carrier material to obtain a mixture;

[0046] Step (2): Add the mixture obtained in step (1) into a hot melt extrusion device for hot melt extrusion. The process parameters are as follows:

[0047]

[0048] The extruded material is obtained, and the extruded material is hammer-crushed to obtain a solid dispersion;

[0049] Step (3): Add the solid dispersion obtained in step (2) and the above-mentioned amounts of microcrystalline cellulose, lactose, sodium carboxymethyl starch and colloidal silica to a mixing device for mixing for 5-30 minutes. Then add magnesium stearate and mix for another 5-10 minutes to obtain a mixture. Compress the mixture into tablets using a rotary tablet press. The hardness of the tablet core is 50N-200N.

[0050] As can be seen from the above parameters, the copovidone VA64 and Soluplus, as solid dispersion carriers, ® Povidone K12, PVA, and the active pharmaceutical ingredient can all be mixed and processed using a hot melt extrusion process. Furthermore, during the experiment, it was unexpectedly discovered that Soluplus... ® As a carrier, the experiment can be completed at a very low extrusion temperature, which is beneficial to the chemical stability of the tablet.

[0051] Example 5: Dissolution test.

[0052] Dissolution tests were conducted on the tablets of Examples 1-4 and the original formulation Novartis Pharma Stein AG (National Drug Approval Number HJ20170127).

[0053] Dissolution was determined according to the Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II).

[0054] Instruments: High performance liquid chromatograph and dissolution tester.

[0055] Dissolution medium: pH 6.8 phosphate buffer solution.

[0056] Dissolution medium volume: 900 mL.

[0057] Rotation speed: 50 rpm.

[0058] Sampling time: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min.

[0059] The tablets and original formulations from Examples 1-4 were used for dissolution and release assay (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). 900 mL of pH 6.8 phosphate buffer solution was used as the dissolution medium. The paddle method was performed at 50 revolutions per minute. The solution was measured according to the sampling time. The dissolution data are shown in Table 1.

[0060] Table 1

[0061]

[0062] As shown in the table above, the tablets of Examples 1-4 all achieved a dissolution rate of over 85% in vitro within 20 minutes, with the tablet of Example 2 achieving over 85% dissolution within 15 minutes. Therefore, the tablets of Examples 1-4 have a significantly better dissolution rate than the original formulation (which took 30 minutes to reach over 85% in vitro). Consequently, the tablets of the present invention have better dissolution performance and are more conducive to in vivo absorption.

[0063] Example 6: Stability under high temperature and high humidity conditions.

[0064] The tablets and original formulations from Examples 1-4 were placed in a constant temperature and humidity chamber at 60℃ / 75%RH for 10 days to examine the relevant substances (degradation impurities or other impurities). The test results are shown in Table 2.

[0065] Table 2

[0066]

[0067] Conclusion: After being placed at 60°C / 75%RH for 10 days, the related substances content of the tablets in Examples 1-4 remained essentially unchanged, especially in Example 2, which had excellent related substance data from day 0, while the related substance content of the original formulation increased by 550% on day 10 compared to the initial level.

[0068] The above experimental results show that using a certain amount of the solid dispersion carrier Soluplus... ® It not only lowers the extrusion temperature but also significantly improves the chemical stability of the tablets.

[0069] Examples 7-10

[0070] The tablet formulation is as follows:

[0071]

[0072] Ruxolitinib tablets of Examples 7-10 were prepared using the same method as in Example 2.

[0073] Example 11: Dissolution test.

[0074] Dissolution tests were conducted on the tablets of Examples 7-10 and the original formulation Novartis Pharma Stein AG (National Drug Approval Number HJ20170127).

[0075] Dissolution was determined according to the Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II).

[0076] Instruments: High performance liquid chromatograph and dissolution tester.

[0077] Dissolution medium: pH 6.8 phosphate buffer solution.

[0078] Dissolution medium volume: 900 mL.

[0079] Rotation speed: 50 rpm.

[0080] Sampling time: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min.

[0081] Tablets from Examples 7-10, the original formulation, and tablets from Example 2 were taken and tested according to the dissolution and release assay method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Dissolution data were obtained based on the sampling time and are shown in Table 3.

[0082] Table 3

[0083]

[0084] As shown in the table above, the tablets of Examples 8, 2, 9, and 10 all achieved a dissolution rate of over 85% in vitro within 20 minutes, with the tablet of Example 2 achieving over 85% dissolution within 15 minutes. Therefore, the tablets of this invention have a better dissolution rate than the original formulation (which took 30 minutes to reach over 85%), thus facilitating in vivo absorption and resulting in higher bioavailability. Considering that Example 10 was developed using Soluplus... ® Excessive dosage may cause sticking and clogging of the tablets, affecting the Soluplus content. ® A dosage of 14%-21% may be appropriate.

[0085] Comparative Example 1

[0086] The tablet formulation is as follows:

[0087]

[0088] Ruxolitinib tablets are prepared as follows:

[0089] Step (1): Add the specified amounts of ruxolitinib dihydrate, microcrystalline cellulose, lactose, hydroxypropyl cellulose, and half the amount of sodium carboxymethyl starch in the prescription to the wet granulation equipment for mixing;

[0090] Step (2): Water is added to the mixture obtained in step (1) using a peristaltic pump for wet granulation;

[0091] Step (3): Dry the material obtained in step (2);

[0092] Step (4): Add the material obtained in step (3) and half of the prescribed amount of sodium carboxymethyl starch and colloidal silica to a mixing device and mix for 5-30 minutes. Then add magnesium stearate and mix for another 5-10 minutes to obtain a mixture. Compress the mixture into tablets using a rotary tablet press. The hardness of the tablet core is 50N-200N.

[0093] Comparative Example 2: Dissolution test.

[0094] Dissolution tests were conducted using tablets from Comparative Example 1, the original formulation of Novartis Pharma Stein AG (National Drug Approval Number HJ20170127), and tablets from Example 2.

[0095] Dissolution was determined according to the Dissolution and Release Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II).

[0096] Instruments: High performance liquid chromatograph and dissolution tester.

[0097] Dissolution medium: pH 6.8 phosphate buffer solution.

[0098] Dissolution medium volume: 900 mL.

[0099] Rotation speed: 50 rpm.

[0100] Sampling time: 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min.

[0101] Take the tablets of Comparative Example 1, the original formulation, and the tablets of Example 2, and dissolve and release them according to the method of determination of dissolution and release (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). Use 900 mL of pH 6.8 phosphate buffer solution as the dissolution medium, and operate the paddle method at 50 revolutions per minute. Take the solution according to the sampling time for determination. The dissolution data are shown in Table 4.

[0102] Table 4

[0103]

[0104] As shown in the table above, the tablets of Comparative Example 1 exhibited extremely poor in vitro dissolution, indicating that tablets obtained by conventional wet granulation cannot achieve the expected dissolution without using the solid dispersion of this invention. The tablets of Example 2, prepared using the method of this invention, demonstrated significantly better dissolution than the original formulation, achieving a dissolution rate of over 85% in vitro within 15 minutes, half the time required for the original formulation (which took 30 minutes to reach over 85%).

Claims

1. A ruxolitinib tablet, characterized in that... The tablet comprises a solid dispersion, the solid dispersion comprising: (a) The active ingredient, which is ruxolitinib or its pharmaceutically acceptable salt or hydrate, comprising 1.5%-4% of the total weight of the tablet based on ruxolitinib, and (b) A solid dispersion carrier comprising 14%-21% of the total weight of the tablets, wherein the solid dispersion carrier is Soluplus. ® ; The solid dispersion is prepared by the following method: Ruxolitinib or its pharmaceutically acceptable salt or hydrate and a solid dispersion carrier are mixed to obtain a mixture; and The mixture obtained in the above steps is added to a hot melt extrusion device and hot melt extrusion is carried out at a temperature of 60-75℃. Then the extruded material is crushed to obtain a solid dispersion. The ruxolitinib tablets also contain fillers, disintegrants, and lubricants.

2. The ruxolitinib tablet according to claim 1, wherein the ruxolitinib or its pharmaceutically acceptable salt or hydrate comprises 2.5%-4% of the total weight of the tablet, based on ruxolitinib; and the solid dispersion carrier comprises 14%-21% of the total weight of the tablet.

3. The ruxolitinib tablet according to claim 1, wherein the active ingredient is ruxolitinib dihydrate.

4. The ruxolitinib tablet according to claim 1, wherein the filler is selected from one or more of mannitol, starch, lactose and microcrystalline cellulose; the amount of the filler is 60%-80% of the total weight of the tablet.

5. The ruxolitinib tablet according to claim 1, wherein the disintegrant is selected from one or more of sodium carboxymethyl starch, crospovidone, and low-substituted hydroxypropyl cellulose; the amount of the disintegrant is 4%-6% of the total weight of the tablet.

6. The ruxolitinib tablet according to claim 1, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, and sodium stearate fumarate; the amount of the lubricant is 0.2%-1.0% of the total weight of the tablet.

7. A method for preparing ruxolitinib tablets according to any one of claims 1-6, the method comprising: Step (1): Mix ruxolitinib or its pharmaceutically acceptable salt or hydrate with a solid dispersion carrier to obtain a mixture; Step (2): Add the mixture obtained in step (1) into a hot melt extrusion device and perform hot melt extrusion at a temperature of 60-75℃. Crush the extruded material to obtain a solid dispersion. and Step (3): Mix the solid dispersion obtained in step (2) with filler, disintegrant and lubricant evenly, and compress it into tablets.

8. The method according to claim 7, wherein in step (2), the hot melt extrusion is carried out under the following conditions: screw speed is 120-400 rpm; hot melt extrusion temperature is 60-75℃; and feeding speed is 0.8-3.0 kg / h.

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