Tofacitinib citrate controlled release tablet and preparation method thereof

Abstract

The invention discloses a tofacitinib citrate controlled release tablet and a preparation method thereof. According to the controlled-release tablet disclosed by the invention, through the unique design of the coating film, the slow and continuous release of the medicine is realized, and meanwhile, the controlled-release tablet is stable in performance, can be stored for a long time, is simple in preparation process, is suitable for industrial production, and is beneficial to reducing the production cost and improving the market competitiveness of the product.

Description

Technical Field

[0001] The present invention relates to a tofacitinib citrate controlled-release tablet and a preparation method thereof. The controlled-release tablet is a single-chamber osmotic pump controlled-release preparation. Background Art

[0002] Tofacitinib is a Janus kinase (JAK) inhibitor. JAK belongs to intracellular enzymes and can transmit signals generated by the interaction of cytokines or growth factor-receptors on the cell membrane, thereby affecting the cell hematopoiesis process and cell immune function. Within this signal transduction pathway, JAK phosphorylates and activates signal transducer and activator of transcription (STAT), thereby regulating intracellular activities including gene expression. Tofacitinib regulates this signal transduction pathway at the point of JAK, preventing STAT phosphorylation and activation. JAK enzymes transmit cytokine signals through paired JAKs (such as, JAK1 / JAK3, JAK1 / JAK2, JAK1 / TyK2, JAK2 / JAK2). Tofacitinib inhibits the in vitro activities of JAK1 / JAK2, JAK1 / JAK3 and JAK2 / JAK2 combined enzymes, and the IC50 values are 406, 56 and 1377 nM respectively. However, the correlation between specific AK combined enzymes and treatment effectiveness has not been clarified.

[0003] Tofacitinib citrate is a white to off-white powder, and its chemical name is (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-β-oxo-1-piperidinepropionitrile citrate, and its structural formula is shown as follows:

[0004]

[0005] Pfizer Inc (Tofacitinib Citrate Controlled-Release Tablets) with specifications of 5 mg, 10 mg, 11 mg, and 22 mg tablets have been approved in the United States, and 5 mg and 11 mg have also been marketed in China. Currently, It is mainly used for the treatment of various immune-related diseases.

[0006] Patent document CN105101952B discloses a sustained-release pharmaceutical dosage form containing tofacitinib, specifically relating to a composition that defines the dosage of the osmotic agent in the tablet core, the weight gain of the semipermeable membrane coating, the composition and ratio of the semipermeable membrane coating, the pore diameter of the punching, etc. Through the experiments of the inventor, it is found that for the sustained-release tablets disclosed in this patent application, the related substances are relatively high, the long-term stability is relatively poor, and it is unstable during storage. Summary of the Invention

[0007] The object of the present invention is to provide a tofacitinib citrate controlled-release tablet, which has a gentler and more sustained release, a better release effect, stable performance, reduces the frequency of taking medicine, improves patient compliance, can be stored for a long time, has a simple preparation process, and is suitable for industrial production.

[0008] In order to achieve the above technical effects, the present invention provides a number of technical solutions.

[0009] On the one hand, the present invention provides a tofacitinib citrate controlled-release tablet, comprising a tablet core and a functional semi-permeable membrane coating layer, characterized in that the tablet core contains tofacitinib citrate, an osmotic pressure agent, a thickening agent and / or a binder and a lubricant, and the functional semi-permeable membrane coating layer contains a film-forming material and a pore-forming agent, and the pore-forming agent is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol, polyethylene oxide, and polyvinylpyrrolidone.

[0010] As a preferred technical solution, the osmotic pressure agent of the tablet core is selected from saccharide osmotic pressure agents and salt osmotic pressure agents; preferably, the saccharide osmotic pressure agent is selected from one or more of mannitol, xylitol, sorbitol, and sucrose, and more preferably sorbitol; preferably, the salt osmotic pressure agent is selected from one or more of potassium chloride, sodium chloride, sulfates, and phosphates.

[0011] As a preferred technical solution, the thickening agent and / or binder of the tablet core is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and copovidone.

[0012] As a more preferred technical solution, the thickening agent and / or binder of the tablet core is selected from the combination of hydroxyethyl cellulose and copovidone.

[0013] As a preferred technical solution, the lubricant of the tablet core is selected from one or more of magnesium stearate, stearic acid, and calcium stearate.

[0014] As a more preferred technical solution, the lubricant of the tablet core is selected from magnesium stearate.

[0015] As a preferred technical solution, the film-forming material is selected from hydrophilic polymers, and the hydrophilic polymers are selected from one or two of cellulose acetate and ethyl cellulose.

[0016] As a more preferred technical solution, the film-forming material is selected from cellulose acetate.

[0017] As a preferred technical solution, the pore-forming agent is selected from hydroxypropyl methylcellulose.

[0018] As a preferred technical solution, the functional semi-permeable membrane coating layer contains cellulose acetate and hydroxypropyl methylcellulose.

[0019] As a preferred technical solution, the weight ratio of cellulose acetate to hypromellose is 6:5 to 6:1, more preferably 6:4 to 6:2, and most preferably 6:3.

[0020] The present invention also provides a method for preparing tofacitinib citrate controlled-release tablets, which is characterized by comprising the following steps:

[0021] (1) Pass tofacitinib citrate through a 60-mesh sieve;

[0022] (2) Mix the prescribed amount of tofacitinib citrate, 1 / 2 of the prescribed amount of sorbitol, hydroxyethyl cellulose, copovidone, and the remaining sorbitol;

[0023] (3) Then add the prescribed amount of magnesium stearate and mix;

[0024] (4) Compress the mixed material into tablets, controlling the tablet weight and hardness;

[0025] (5) Using acetone-water as the coating solvent, prepare a semi-permeable membrane coating solution of hypromellose and cellulose acetate, and spray it onto the drug cores obtained in step (4) to form coated tablets;

[0026] (6) Age the coated tablets, and after aging, perform laser drilling to obtain the product;

[0027] As a preferred technical solution, the weight ratio of cellulose acetate to hypromellose in the semi-permeable membrane coating layer is 6:3.

[0028] As a preferred technical solution, when preparing the semi-permeable membrane coating solution, hypromellose should be added first and stirred until completely dissolved, and then cellulose acetate should be added and stirred for dissolution.

[0029] The beneficial effects of the present invention are as follows: Through a unique coating film design, the tofacitinib controlled-release tablets of the present invention achieve slow and sustained release of the drug. At the same time, the controlled-release tablets have stable performance and can be stored for a long time. Their preparation process is simple, suitable for industrial production, conducive to reducing production costs, and improving the market competitiveness of products. Specific Embodiments

[0030] The present invention will be further elaborated below in combination with examples and comparative examples. The following description is only for explaining the present invention and does not impose any limitations on its content. The experimental methods described in the following examples are all conventional methods unless otherwise specified, and the reagents and materials can be obtained from commercial channels unless otherwise specified.

[0031] The tofacitinib controlled-release tablets and their preparation methods in the examples and comparative examples of the present invention will be specifically described below.

[0032] Example 1: By fixing the amounts of the penetrant, thickening agent / binder, and lubricant in the tablet core in Formulations 1 to 3, and fixing the film-forming material in the semipermeable membrane coating layer, the effects of the weight ratio of the film-forming material to the pore-forming agent in the semipermeable membrane coating layer on the stability and release of the formulated combination formulations were investigated.

[0033] Table 1 Amounts of pore-forming agent in Formulations 1 to 3

[0034]

[0035] According to the formulations in the above table, the preparation was carried out based on the following preparation method of tofacitinib controlled-release tablets:

[0036] (1) Pass tofacitinib citrate through a 60-mesh sieve;

[0037] (2) Mix the prescribed amount of tofacitinib citrate, 1 / 2 of the prescribed amount of sorbitol, hydroxyethyl cellulose, copovidone, and the remaining sorbitol;

[0038] (3) Then add the prescribed amount of magnesium stearate and mix;

[0039] (4) Compress the mixed material into tablets, controlling the tablet weight and hardness;

[0040] (5) Using acetone-water as the coating solvent, prepare a semipermeable membrane coating solution containing cellulose acetate and hypromellose, and spray it onto the drug tablet core to form a coated tablet;

[0041] (6) Age the coated tablets in an oven at 40°C, and perform laser drilling at one end of the side of the aged coated tablets. The laser drilling aperture is 0.6 mm to obtain the product.

[0042] Experimental Example 2: Stability investigation

[0043] Place the naked coated tablets of the above formulations under accelerated conditions (40°C / 75% RH) for 0, 10 days, and 30 days respectively, investigate and determine the properties and related substances of the coated tablets, and screen out the better formulations.

[0044] The results of the stability test are shown in Table 2 below:

[0045] Table 2 Results of stability investigation of the amount of pore-forming agent

[0046]

[0047] In summary, when the pore-forming agent in the semipermeable membrane coating layer is hypromellose, the stability of the corresponding preparation formulation is better.

[0048] Experimental Example 3: Comparison of the stability of self-made prescription preparations and reference preparations

[0049] Coat the self-made Formulations 1 to 3 and measure their stability, and compare with the reference preparation (Specification: 11 mg, Manufacturer: Pfizer) was compared for stability, and the release curves were simultaneously investigated. The results are shown in Table 3.

[0050] Table 3 Results of the stability comparison between the preparations of Formulations 1 - 3 and the reference preparation

[0051]

[0052]

[0053] The dissolution was determined according to the second method (paddle method) in General Chapter 0931 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition, and the cumulative dissolution of Formulations 1 - 3 and the reference preparation in pH 6.8 phosphate buffer solution was determined. The dissolution results are shown in Table 4.

[0054] Table 4 Results of the stability comparison between the preparations of Formulations 1 - 3 and the reference preparation (release curve)

[0055]

[0056] As can be seen from Tables 3 - 4, the properties and related substances of the self - made preparation formula provided by the present invention and the reference preparation meet the drug requirements. The quality levels of the self - made preparation and the reference preparation are equivalent on day 0, the release curves are similar, and they meet the drug requirements. After accelerating the sampling for 6 months, the dissolution of the reference preparation becomes slower, while there is no obvious change in the self - made preparation. The self - made preparation is unexpectedly stable compared with the reference preparation.

Claims

1. A tofacitinib citrate controlled-release tablet, comprising a tablet core and a functional semipermeable membrane coating layer, characterized in that, The tablet core contains tofacitinib citrate, an osmotic agent, a thickening agent and / or a binder, and a lubricant. The functional semi-permeable membrane coating layer contains a film-forming material and a pore-forming agent, and the pore-forming agent is selected from one or more of hydroxypropyl methylcellulose, polyethylene glycol, polyethylene oxide, and povidone.

2. The tofacitinib citrate controlled-release tablet according to claim 1, characterized in that, The osmotic agent in the tablet core is selected from saccharide osmotic agents and salt osmotic agents; preferably, the saccharide osmotic agent is selected from one or more of mannitol, xylitol, sorbitol, and sucrose, and more preferably from sorbitol; preferably, the salt osmotic agent is selected from one or more of potassium chloride, sodium chloride, sulfate, and phosphate.

3. The tofacitinib citrate controlled-release tablet according to claim 1, characterized in that, The thickening agent and / or binder in the tablet core is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and copovidone, and preferably from the combination of hydroxyethyl cellulose and copovidone.

4. The tofacitinib citrate controlled-release tablet according to claim 1, wherein The lubricant in the tablet core is selected from one or more of magnesium stearate, stearic acid, and calcium stearate, and preferably from magnesium stearate.

5. The tofacitinib citrate controlled-release tablet according to claim 1, characterized in that, The film-forming material is selected from hydrophilic polymers, and the hydrophilic polymer is selected from one or two of cellulose acetate and ethyl cellulose, and preferably from cellulose acetate.

6. The tofacitinib citrate controlled-release tablet according to claim 1, characterized in that, The pore-forming agent is selected from hydroxypropyl methylcellulose.

7. The tofacitinib citrate controlled-release tablet according to claim 1, characterized in that, The functional semi-permeable membrane coating layer contains cellulose acetate and hydroxypropyl methylcellulose.

8. The tofacitinib citrate controlled-release tablet according to claim 7, wherein The weight ratio of cellulose acetate to hydroxypropyl methylcellulose is 6:5 to 6:1, preferably 6:4 to 6:2, and more preferably 6:

3.

9. A preparation method of a tofacitinib citrate controlled-release tablet, characterized in that, Comprising the following steps: (1) Pass tofacitinib citrate through a 60-mesh sieve; (2) Mix the prescribed amount of tofacitinib citrate, 1 / 2 of the prescribed amount of sorbitol, hydroxyethyl cellulose, copovidone, and the remaining sorbitol; (3) Then add the prescribed amount of magnesium stearate and mix; (4) Compress the mixed material into tablets, controlling the tablet weight and hardness; (5) Using acetone-water as the coating solvent, prepare a semi-permeable membrane coating solution of hydroxypropyl methylcellulose and cellulose acetate, and spray it onto the drug tablet core obtained in step (4) to form a coated tablet; (6) Age the coated tablet, and after aging, perform laser drilling to obtain the product; Preferably, the weight ratio of cellulose acetate to hydroxypropyl methylcellulose is 6:

3.

10. The preparation method of the tofacitinib citrate controlled-release tablet according to claim 9, characterized in that, When preparing the semi-permeable membrane coating solution, hydroxypropyl methylcellulose should be added first and stirred until completely dissolved, and then cellulose acetate should be added and stirred to dissolve.

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