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CN-112755000-B - Tofacitinib citrate sustained-release tablet

CN112755000BCN 112755000 BCN112755000 BCN 112755000BCN-112755000-B

Abstract

The invention provides a tofacitinib citrate sustained-release preparation which consists of a tablet core, a sustained-release layer coating and a color layer coating, wherein the sustained-release layer coating is provided with drug release pores. The invention further optimizes the composition of the slow release layer coating and the weight gain of the coating by adjusting the composition of the osmotic pressure forming agent and the dosage proportion of the osmotic pressure forming agent and the slow release agent, thereby not only avoiding the defect of slow dissolution speed after long-term storage by taking sorbitol as the osmotic pressure forming agent, but also improving the initial release speed of the tofacitinib citrate slow release tablet, being capable of keeping slow and continuous release after 6 hours, ensuring more complete drug release, keeping the blood concentration at a uniform and stable level for a long time, reducing the fluctuation of the blood concentration during the administration interval, further improving the bioavailability condition, reducing adverse reaction and being beneficial to ensuring the clinical curative effect and the safety.

Inventors

  • JIA GUANGHUI
  • WEI JUNQING
  • WANG YAPING
  • BAI YANLING
  • WANG JIANMING

Assignees

  • 石药集团欧意药业有限公司

Dates

Publication Date
20260512
Application Date
20210121

Claims (8)

  1. 1. A slow-release preparation of tofacitinib citrate is composed of a tablet core, a slow-release layer coating and a color layer coating, wherein the slow-release layer coating is provided with drug release pores, The tablet core is prepared from the following components in percentage by weight: Tofacitinib citrate 8.885% Sorbitol 50% Sodium chloride 16.115% Hydroxyethyl cellulose 250L 13% Hydroxyethyl cellulose 250G 5% Copovidone 6% Magnesium stearate 1% The slow-release coating is prepared from cellulose acetate and hydroxypropyl cellulose, wherein the weight ratio of the cellulose acetate to the hydroxypropyl cellulose is 5:5, the weight of the slow-release coating is 9-12% of the weight of the tablet core, or the weight ratio of the cellulose acetate to the hydroxypropyl cellulose is 6:4, and the weight of the slow-release coating is 8-9% of the weight of the tablet core; The color layer coating accounts for 2.5% -3.5% of the weight of the perforated tablet; Each preparation unit contains a drug release pore, and the pore diameter of the drug release pore is 0.45mm-0.85mm.
  2. 2. The tofacitinib citrate sustained-release preparation according to claim 1, wherein the sustained-release layer coating comprises cellulose acetate, hydroxypropyl cellulose=5:5, and the weight gain of the sustained-release layer coating is 10% -11% of the weight of the tablet core.
  3. 3. The tofacitinib citrate sustained-release preparation according to any one of claims 1-2, wherein the color layer coating accounts for 3.0% -3.5% of the weight of the perforated tablet.
  4. 4. A tofacitinib citrate sustained-release preparation according to any one of claims 1-2, wherein the pore size of the drug release pores is 0.55mm-0.80mm.
  5. 5. The tofacitinib citrate sustained-release preparation according to claim 4, wherein the pore diameter of the drug release pores is 0.60mm-0.75mm.
  6. 6. The tofacitinib citrate sustained-release preparation according to claim 5, wherein the pore diameter of the drug release pores is 0.65mm.
  7. 7. The method for preparing the tofacitinib citrate sustained-release preparation according to any one of claims 1 to 6, which is characterized by comprising the following steps of pretreatment of raw and auxiliary materials, granulation, tabletting, sustained-release coating, perforation and color coating.
  8. 8. The method of claim 7, comprising the steps of: (1) Pre-treating raw materials and auxiliary materials, namely weighing ① tablet core components of tofacitinib citrate, sorbitol, sodium chloride, 250L of hydroxyethyl cellulose, 250G of hydroxyethyl cellulose, copovidone, magnesium stearate and ② slow-release coating materials of cellulose acetate and hydroxypropyl cellulose and ③ color coating materials according to the prescription, respectively crushing and sieving for later use; (2) Granulating ① Premixing, namely adding sorbitol, tofacitinib citrate, 250L of hydroxyethyl cellulose, 250G of hydroxyethyl cellulose, copovidone and sodium chloride into a granulator, and uniformly mixing; ② Granulating, namely adding absolute ethyl alcohol into a granulator, stirring, granulating, wet finishing and drying; ③ Finishing and total mixing, namely adding magnesium stearate, and drying and finishing the granules by a finishing machine; (3) Tabletting, namely tabletting by a tablet press to obtain tablet cores; (4) Sustained release coating ① Preparing a slow-release layer coating liquid, namely pouring a proper amount of purified water and acetone into a liquid preparation barrel, adding the prescription amount of hydroxypropyl cellulose, uniformly stirring, adding the prescription amount of cellulose acetate, and uniformly stirring for later use; ② Preheating and edging, namely preheating a coating pan body, putting a tablet core into the coating pan body, and edging; ③ Coating the slow release layer, namely spraying the slow release layer coating liquid prepared in the step ①, coating, and drying to obtain a slow release layer coated tablet; (5) Perforating, namely taking a slow-release layer coated tablet, and perforating the slow-release layer coated tablet by laser to obtain a perforated tablet; (6) Color layer coating ① Preparing color layer coating liquid, namely adding the prescribed amount of color layer coating material into a proper amount of purified water, and stirring uniformly for standby; ② Spraying a small amount of color layer coating liquid and drying; ③ Color layer coating, namely placing the perforated tablet into a coating pan, preheating the pan body of the coating pan, spraying the residual color layer coating liquid, and drying.

Description

Tofacitinib citrate sustained-release tablet Technical Field The invention belongs to the field of pharmaceutical preparations, and in particular relates to a tofacitinib citrate sustained-release tablet and a preparation method thereof. Background Tofacitinib citrate is a prescription drug of an oral Janus kinase (JAK) inhibitor of the best-effort, can selectively inhibit the JAK kinase, block the JAK/STAT pathway, further inhibit cell signal transduction and related gene expression and activation, and is used for treating various immune diseases such as rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and the like. The products currently on the market are Xeljanz and Xeljanz XR from the company pyroxene. Wherein Xeljanz is tofacitinib citrate immediate release tablet, which is taken twice a day, lacks convenience and has poor compliance. Xeljanz XR is the first oral once daily JAK inhibitor for the treatment of rheumatoid arthritis. The sustained release dosage form can reduce the administration times to once daily (11 mg, QD), and the curative effect is consistent with Xeljanz (5 mg BID), so that the convenience and the compliance of patients can be effectively improved. However, the inventors of the present patent application found that the 1h dissolution rate of the commercial Xeljanz XR formulation was only 2% (in the ph6.8 dissolution medium, at 50 rpm), the time lag of initial release was significant, the onset of action was slow in the first-taken patients, and the superposition of the blood concentration of the two-taken drug was affected at the time of multiple administrations, which was not favorable for maintaining a uniform and stable blood concentration. There is therefore a need for further improvement of the initial release rate of a slow release formulation of tofacitinib citrate to reduce the time-lag effect. WO2014147526A1 (chinese syngeneic CN105101952 a) is a sustained release formulation patent laid out by the original research company, and provides a tofacitinib citrate osmotic pump type sustained release tablet, which dissolves out not more than 30% in 1 hour, not less than 35% and not more than 75% in 2.5 hours, and not less than 75% in ph6.8 dissolution medium at a rotation speed of 50 rpm. However, the inventors of the present patent found that the limitation of the in vitro dissolution behavior of the preparation is too wide during the development process, and it is difficult to precisely control the in vivo bioavailability. WO2014147526A1 (chinese homolog CN105101952 a) also believes that for sustained release formulations, the bioavailability of tofacitinib citrate decreases with prolonged release duration, preferably in dosage forms with shorter sustained release times. Studies show that the Tmax of the tofacitinib citrate sustained-release preparation is about 3-4h and t 1/2 is about 6-7h when the preparation is taken in a single time in a human body. The inventors have found that a slow sustained release after 4 hours, especially after 6 hours, is very important for maintaining blood levels during the dosing interval, and that a shorter sustained release time leads to increased fluctuations in blood levels over multiple doses. In addition, the formulations on the market and WO2014147526A1 all use sorbitol (also known as sorbitol) as the osmotic agent (i.e. osmotic pressure forming agent) to prepare the tofacitinib citrate osmotic pump sustained release tablets. Sorbitol has a low melting point and strong hygroscopicity, and the humidity needs to be specially controlled in the preparation process, so that certain challenges are brought to the industrial production process of the product. Sorbitol is easy to bond with other materials in a premixing step due to strong hygroscopicity, so that the fluidity of the materials is reduced, and the content uniformity and dissolution uniformity of the preparation are reduced. And the obtained sustained release preparation is easily influenced by external environment in the storage process, so that related substances, active ingredient content, dissolution rate and the like are changed. Therefore, there is an urgent need to develop a sustained release preparation of tofacitinib citrate which has better dissolution uniformity and stability and is more suitable for industrial production. Disclosure of Invention Based on the defects in the prior art, the invention aims to provide the tofacitinib citrate sustained-release preparation, which improves the initial release speed, reduces time lag, improves the stability of blood concentration and bioavailability under the condition of keeping the overall release time basically unchanged, further improves the dissolution uniformity and the preparation stability, and ensures the product quality. The invention provides a tofacitinib citrate sustained-release preparation which consists of a tablet core, a sustained-release layer coating and a color layer coating, wherein the sustained-