Tofacitinib citrate composition

Abstract

The invention relates to a tofacitinib citrate composition. The tofacitinib citrate composition is prepared by mixing active ingredients with a thickening agent, an osmotic pressure regulator, an adhesive and a lubricant, and then tabletting and coating. The tofacitinib citrate composition provided by the invention has the advantages of good stability and suitability for large-scale production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a tofacitinib citrate composition. Background Art

[0002] Tofacitinib citrate (tofacitinib citrate), chemically named 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile citrate, is an oral small molecule Janus kinase (JAK) inhibitor that can effectively inhibit the activity of JAK1 and JAK3 and block the signal transduction of multiple inflammatory cytokines. Unlike most other rheumatoid arthritis drugs currently used, which mainly act on extracellular targets, tofacitinib citrate targets intracellular signal transduction pathways and directly acts on the core part of the cytokine network. The inhibitory intensity of tofacitinib citrate on JAK3 is 5 to 100 times that of JAK1 and JAK2, and it is an important drug for the treatment of rheumatoid arthritis.

[0003] The treatment of rheumatoid arthritis often requires long-term medication, or even lifelong medication. Ordinary sustained-release preparations are taken twice a day, which greatly reduces compliance. On February 23, 2016, the U.S. FDA approved Pfizer's application for the marketing of tofacitinib citrate sustained-release preparations, with an approved specification of 11 mg and a dosage form of tablets. This drug is the first once-daily sustained-release preparation approved for marketing.

[0004] Drug stability is the basis for reliable drug quality, safety and effectiveness. The current tofacitinib citrate sustained-release preparation also has the defects of poor stability and more impurities. For example, the listed preparation and WO2014147526A1 use sorbitol (also known as sorbitol) as an osmotic source (i.e., osmotic pressure forming agent) to prepare tofacitinib citrate osmotic pump sustained-release tablets. Sorbitol has a low melting point and strong hygroscopicity. Because of its strong hygroscopicity, the obtained sustained-release preparation is easily affected by the external environment during storage, resulting in changes in related substances, etc.

[0005] Therefore, the prior art still lacks a tofacitinib citrate sustained-release preparation that meets the feasibility of production process and has stable and reliable quality. Summary of the invention

[0006] The object of the present invention is to provide a tofacitinib citrate solid preparation that meets the feasibility of the production process and has good preparation stability.

[0007] The present invention solves the above technical problems through the following technical solutions:

[0008] The present invention provides a tofacitinib citrate composition, comprising a tablet core and a coating, characterized in that the tablet core comprises tofacitinib citrate, a thickener, and an osmotic pressure regulator; the thickener is selected from one or more of methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose; the osmotic pressure regulator is selected from one or more of sorbitol, microcrystalline cellulose, mannitol, sodium chloride, and lactose; preferably one or more of sorbitol, microcrystalline cellulose, and mannitol; more preferably a combination of sorbitol, microcrystalline cellulose, and mannitol; the ratio of sorbitol, microcrystalline cellulose, and mannitol is 4.8:1:2.

[0009] The amount of sorbitol in the present invention is 20-50%wt, preferably 30-50%wt, more preferably 48.115%wt; the amount of microcrystalline cellulose is 5-15%wt, preferably 8-15%, more preferably 10%wt; the amount of mannitol is 15-30%wt, preferably 18-25%, more preferably 20%wt.

[0010] The thickener of the present invention is preferably hydroxyethyl cellulose; the amount of the hydroxyethyl cellulose is 6-8%wt, preferably 6%wt.

[0011] The content of the beta crystal mannitol of the present invention is 1%-80%wt, preferably 35%-70%wt, preferably 35%-60%wt, preferably 38-59%wt, preferably 48.75%wt.

[0012] Furthermore, the composition of the present invention contains a binder, which is selected from one or more of sodium carboxymethylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, and copovidone, preferably copovidone; the amount of the copovidone is 1-10%wt, preferably 2-8%wt, and more preferably 6%wt.

[0013] Furthermore, the composition of the present invention contains a lubricant, which is selected from one or more of magnesium stearate, micro-powdered silica gel, talc, and polyethylene glycol, preferably magnesium stearate; the amount of magnesium stearate is 0.1-5%wt, 0.5-3%wt, preferably 1%wt.

[0014] Furthermore, the coating described in the present invention is cellulose acetate and hydroxypropyl cellulose; the ratio of cellulose acetate and hydroxypropyl cellulose is 3:2.

[0015] In certain embodiments, the tofacitinib citrate composition contains the following components and contents:

[0016] The core is:

[0017] Tofacitinib citrate 1-15%wt Sorbitol 20-50%wt Microcrystalline Cellulose 5-15%wt Mannitol 15-30%wt Hydroxyethyl Cellulose 6-8%wt Copolyvidone 1-10%wt Magnesium Stearate 0.1-5%wt

[0018] The coating is cellulose acetate and hydroxypropyl cellulose; the ratio of cellulose acetate and hydroxypropyl cellulose is 3:2.

[0019] In certain embodiments, the tofacitinib citrate composition contains the following components and contents:

[0020] The core is:

[0021]

[0022]

[0023] The coating is cellulose acetate and hydroxypropyl cellulose; the ratio of cellulose acetate and hydroxypropyl cellulose is 3:2.

[0024] In certain embodiments, the tofacitinib citrate composition contains the following components and contents:

[0025] The core is:

[0026] Tofacitinib citrate 8.885%wt Sorbitol 48.115%wt Microcrystalline Cellulose 10%wt Mannitol 20%wt Hydroxyethyl Cellulose 6%wt Copolyvidone 6%wt Magnesium Stearate 1%wt

[0027] The coating is cellulose acetate and hydroxypropyl cellulose; the ratio of cellulose acetate and hydroxypropyl cellulose is 3:2.

[0028] The present invention is beneficial in that it provides a tofacitinib citrate tablet that meets the feasibility of the production process and has good preparation stability. DETAILED DESCRIPTION

[0029] The present invention is further described in detail by the following examples, which are not intended to limit the protection scope of the present invention.

[0030] The dissolution test and stability study methods in the following examples are as follows:

[0031] Dissolution experiment: According to the requirements of the Technical Guidelines for Dissolution Test of Ordinary Oral Solid Preparations, the paddle method was selected for the dissolution curve, with a rotation speed of 50 rpm and a medium volume of 900 ml. The pH 6.8 phosphate buffer was used to carry out the dissolution curve test to examine its dissolution.

[0032] Stability study: A portion of the tofacitinib citrate tablets prepared in Comparative Example 1 and Example 3 was randomly selected, and the bare chips were placed at a high temperature of 60° C. The impurity content of the tofacitinib citrate tablets was measured by high performance liquid chromatography.

[0033] Comparative Example 1

[0034] According to the prescription ratios in Table 1, Tofacitinib Citrate Tablets were prepared using the following preparation method.

[0035] Table 1

[0036]

[0037] Preparation method:

[0038] Weigh each raw material and auxiliary material according to the prescription, sieve sorbitol, hydroxyethylcellulose, copolyvidone, and magnesium stearate respectively for standby use. Add about half of the batch of sorbitol to the mixer hopper, then add the prescription amount of copolyvidone, tofacitinib citrate, hydroxyethylcellulose, and the remaining sorbitol to mix, and sieve and disperse the mixture. Add the prescription amount of magnesium stearate and continue mixing to obtain the total mixed powder. Use ZP-9B rotary tablet press to calculate the theoretical tablet weight according to the total mixed powder content for tableting to obtain tofacitinib citrate sustained-release tablets.

[0039] Take the prescribed amount of acetone and purified water respectively, add them to the liquid preparation tank, and mix them. Slowly add the prescribed amount of hydroxypropyl cellulose to the liquid preparation tank while stirring, stir until completely dispersed, then slowly add the prescribed amount of cellulose acetate, stir while adding until completely dispersed, continue stirring until completely dissolved, and prepare a coating solution. The plain tablets are coated with a high-efficiency coating machine to obtain tofacitinib citrate sustained-release tablets. The coated tablets are punched with a CER-D100A-Ⅲ laser punching machine to obtain tofacitinib citrate sustained-release tablets punched tablets.

[0040] Example 1

[0041] According to the prescription ratio in Table 2, Tofacitinib citrate tablets were prepared using the following preparation method.

[0042] Table 2

[0043]

[0044]

[0045] Preparation method:

[0046] About half of the batch of sorbitol is sieved, and the prescribed amount of copovidone is added, followed by the prescribed amount of tofacitinib citrate, followed by the prescribed amount of hydroxyethylcellulose, and finally the remaining sorbitol is added and sieved; the sieved material is added to a three-dimensional motion mixer and mixed; after mixing, magnesium stearate is added and continued to mix to obtain a total mixed powder, and a single-punch tablet press is used to calculate the theoretical tablet weight according to the content of the total mixed powder for tableting to obtain tofacitinib citrate sustained-release tablets.

[0047] Take the prescribed amount of acetone and purified water respectively, add them to the liquid preparation tank, and mix them. Slowly add the prescribed amount of hydroxypropyl cellulose to the liquid preparation tank while stirring, stir until completely dispersed, then slowly add the prescribed amount of cellulose acetate, stir while adding until completely dispersed, continue stirring until completely dissolved, and prepare a coating solution. The plain tablets are coated with a high-efficiency coating machine, and the coated tablets are punched and punched to obtain tofacitinib citrate sustained-release tablets.

[0048] Example 2

[0049] According to the prescription ratios in Table 3, tofacitinib citrate tablets were prepared using the following preparation method.

[0050] Table 3

[0051]

[0052]

[0053] Preparation method:

[0054] The preparation process of prescription 3 is as follows: weigh the raw materials and excipients according to the prescription, mix lactose and tofacitinib citrate, sieve, continue to add the prescribed amount of microcrystalline cellulose, mix, sieve, add the prescribed amount of hydroxyethyl cellulose and copovidone, mix, sieve; finally, add the prescribed amount of magnesium stearate and sorbitol, mix, and obtain a total mixed powder;

[0055] In prescription 4, microcrystalline cellulose was replaced with sodium chloride, and the rest of the mixing process was the same;

[0056] In prescriptions 5 and 6, lactose is replaced with mannitol, and the mixing process is the same as above;

[0057] A single-punch tablet press was used to calculate the theoretical tablet weight according to the total mixed powder content to obtain tofacitinib citrate sustained-release tablets.

[0058] Take the prescribed amount of acetone and purified water respectively, add them to the liquid preparation tank, and mix them. Slowly add the prescribed amount of hydroxypropyl cellulose to the liquid preparation tank while stirring, stir until completely dispersed, then slowly add the prescribed amount of cellulose acetate, stir while adding until completely dispersed, continue stirring until completely dissolved, and prepare a coating solution. The plain tablets are coated with a high-efficiency coating machine to obtain tofacitinib citrate sustained-release tablets. The coated tablets are punched with a punching machine to obtain tofacitinib citrate sustained-release tablets punched tablets.

[0059] Investigation results: The tofacitinib citrate tablets prepared from Comparative Example 1, Prescriptions 1 and 2 of Example 1, and Prescriptions 3-6 of Example 2 were taken to investigate dissolution. The dissolution results are shown in Table 4:

[0060] Table 4

[0061]

[0062] Example 3

[0063] According to the prescription ratio in Table 5, Tofacitinib Citrate Tablets were prepared using the following preparation method.

[0064] Table 5

[0065]

[0066]

[0067] Preparation method:

[0068] Weigh the raw materials and excipients according to the prescription amount, sieve sorbitol, mannitol, microcrystalline cellulose, hydroxyethyl cellulose, copovidone, and magnesium stearate for later use. Mix the tofacitinib citrate API with microcrystalline cellulose, sieve and disperse, then add mannitol to mix, sieve and disperse, continue to add hydroxyethyl cellulose and copovidone to mix, sieve and disperse, and obtain mixture one; add about half of the batch of sorbitol to the mixer hopper, then add mixture one and the remaining sorbitol to mix to obtain mixture two. Put magnesium stearate into the mixer and continue mixing to obtain the total mixed powder of tofacitinib citrate sustained-release tablets. Use a high-speed tablet press to press tablets according to the target tablet weight to obtain tofacitinib citrate sustained-release tablets.

[0069] Take the prescribed amount of acetone and purified water respectively, add them to the liquid preparation tank, and mix them. Slowly add the prescribed amount of hydroxypropyl cellulose to the liquid preparation tank while stirring, stir until completely dispersed, then slowly add the prescribed amount of cellulose acetate, stir while adding until completely dispersed, continue stirring until completely dissolved, and prepare a coating solution. The plain tablets are coated with a high-efficiency coating machine to obtain tofacitinib citrate sustained-release tablets. The coated tablets are punched with a laser punching machine to obtain tofacitinib citrate sustained-release tablets.

[0070] Stability study: The preparation prepared according to the prescription in Table 5 of Example 3 was subjected to stability study together with the bare chip prepared in Comparative Example 1. The results are shown in Table 6.

[0071] Table 6

[0072]

[0073]

Claims

1. A tofacitinib citrate composition, comprising a tablet core and a coating, characterized in that The tablet core comprises tofacitinib citrate, a thickener, and an osmotic pressure regulator; the thickener is selected from one or more of methyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose; the osmotic pressure regulator is selected from one or more of sorbitol, microcrystalline cellulose, mannitol, sodium chloride, and lactose; preferably one or more of sorbitol, microcrystalline cellulose, and mannitol; more preferably a combination of sorbitol, microcrystalline cellulose, and mannitol; the ratio of sorbitol, microcrystalline cellulose, and mannitol is 4.8:1:

2.

2. The tofacitinib citrate composition according to claim 1, characterized in that The amount of sorbitol is 20-50%wt, preferably 30-50%wt, more preferably 48.115%wt; the amount of microcrystalline cellulose is 5-15%wt, preferably 8-15%, more preferably 10%wt; the amount of mannitol is 15-30%wt, preferably 18-25%, more preferably 20%wt.

3. The tofacitinib citrate composition according to claim 1, characterized in that The thickener is preferably hydroxyethyl cellulose; the amount of hydroxyethyl cellulose is 6-8%wt, preferably 6%wt.

4. The tofacitinib citrate composition according to claim 1, characterized in that The composition contains a binder, which is selected from one or more of sodium carboxymethylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, and copovidone, preferably copovidone; the amount of the copovidone is 1-10%wt, preferably 2-8%wt, and more preferably 6%wt.

5. The tofacitinib citrate composition according to claim 1, characterized in that The composition contains a lubricant, which is selected from one or more of magnesium stearate, micro-powdered silica gel, talc, and polyethylene glycol, preferably magnesium stearate; the amount of magnesium stearate is 0.1-5%wt, 0.5-3%wt, preferably 1%wt.

6. The tofacitinib citrate composition according to claim 1, characterized in that The coating is cellulose acetate and hydroxypropyl cellulose; the ratio of cellulose acetate to hydroxypropyl cellulose is 3:

2.

7. The tofacitinib citrate composition according to claims 1-6, characterized in that The core is: The coating is cellulose acetate and hydroxypropyl cellulose; the ratio of cellulose acetate and hydroxypropyl cellulose is 3:2; The core is preferably: The coating is cellulose acetate and hydroxypropyl cellulose; the ratio of cellulose acetate and hydroxypropyl cellulose is 3:2; the core is more preferably: The coating is cellulose acetate and hydroxypropyl cellulose; the ratio of cellulose acetate and hydroxypropyl cellulose is 3:2.

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