A tofacitinib citrate sustained-release tablet and a preparation method thereof

Abstract

The application discloses a tofacitinib citrate sustained-release tablet and a preparation method thereof. The tofacitinib citrate sustained-release tablet comprises the following components in parts by weight: tofacitinib citrate 35.54 parts, a filling agent 90-130 parts, a binding agent 20-40 parts, a skeleton material 20-40 parts, a flow aid 0.5-1.5 parts, a lubricant 1-3 parts and a sustained-release coating 25.5-53 parts. The sustained-release coating is a mixture of hydroxypropyl methyl cellulose, a plasticizer and a mineral hydrophobic material. The plasticizer is polyethylene glycol, and the mineral hydrophobic material is any one of kaolin, talcum powder and heavy calcium carbonate. The application can achieve a dissolution curve close to the existing Xeljanz XR through the combination of the skeleton material tablet and the sustained-release coating, has a sustained-release effect in the first one hour, is rapidly dissolved in one to four hours, and can reduce the production cost, improve the production speed and be environment-friendly.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmacy, in particular to a tofacitinib citrate sustained-release tablet and a preparation method thereof. BACKGROUND

[0002] Tofacitinib citrate is a prescription drug of oral Janus kinase (JAK) inhibitor originally researched by Pfizer, which can selectively inhibit JAK kinase, block JAK / STAT pathway, and then inhibit cell signal transduction and related gene expression and activation. Tofacitinib citrate sustained-release tablets are clinically used for treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and ulcerative colitis.

[0003] The existing tofacitinib citrate includes a rapid-release preparation Xeljanz taken twice a day and a sustained-release preparation Xeljanz XR taken once a day. Xeljanz XR can reduce the administration frequency to once a day, reduce the fluctuation of blood drug concentration, and has the same efficacy as Xeljanz taken twice a day, which can significantly improve the convenience and compliance of patients.

[0004] The sustained-release preparation Xeljanz XR of Pfizer is prepared by using an osmotic pump process. In addition to the active ingredient tofacitinib citrate and conventional excipients, sorbitol is added as an osmotic pressure promoter in the tablet core. After coating, a laser hole is punched at one end of the tablet. After Xeljanz XR is taken orally and enters the body, body fluid enters the tablet core through the semi-permeable membrane, the osmotic pressure of the tablet core increases, and the active ingredient is extruded through the laser hole to release the drug.

[0005] The preparation process of Xeljanz XR in the prior art is relatively complex, the production cost is high, it is not conducive to environmental protection, and the production capacity is low. Sorbitol needs to be added in the prescription, which is easy to absorb moisture and needs to control the production workshop to be a low-humidity environment. The semi-permeable membrane coating material is cellulose acetate, which needs to be dissolved in acetone for coating. Acetone has certain toxicity and is not easy to remove after coating. The laser punching equipment has high cost and slow punching speed, which seriously limits the production speed. In addition, the osmotic pump preparation has inherent defects. As the drug in the semi-permeable membrane is released, the osmotic pressure decreases, and the drug cannot be completely released in the later stage. Therefore, there is an urgent need for a tofacitinib citrate sustained-release tablet preparation method which has a simple preparation process, low production cost, does not need to use laser punching equipment, has a sustained-release function, and can completely release the drug. SUMMARY

[0006] In view of the defects in the prior art, the present application provides a tofacitinib citrate sustained-release tablet and a preparation method thereof.

[0007] The present application provides a tofacitinib citrate sustained-release tablet, which comprises the following components in parts by weight:

[0008] Tofacitinib citrate 35.54 parts;

[0009] Filling agent 90-130 parts;

[0010] Binder 20-40 parts;

[0011] Skeleton material 20-40 parts;

[0012] Glidant 0.5-1.5 parts;

[0013] Lubricant 1-3 parts;

[0014] Sustained-release coating 25.5-53 parts;

[0015] The sustained-release coating is a mixture of hydroxypropyl methyl cellulose, plasticizer and mineral hydrophobic material; wherein the plasticizer is polyethylene glycol; the mineral hydrophobic material is any one or several of kaolin, talc powder, heavy calcium carbonate. Hydroxypropyl methyl cellulose macromolecular material as binder or film-forming material; mineral hydrophobic material as coating anti-sticking agent and improve the hydrophobicity of the coating film. The viscosity of the hydroxypropyl methyl cellulose is 20-300 cp (test method refers to ChP2020 edition four methods), preferably 35-80 cp. The particle size of the mineral hydrophobic material is 500-2000 mesh (test method refers to ChP2020 edition 0982 particle size and particle size distribution determination method).

[0016] Further, the filling agent is any one or several of microcrystalline cellulose, lactose, pregelatinized starch, mannitol, calcium hydrogen phosphate dihydrate.

[0017] Further, the binder is any one or several of povidone K29 / 32, hydroxypropyl cellulose LF.

[0018] Further, the skeleton material is any one or several of hydroxypropyl methyl cellulose K100LV, hydroxypropyl methyl cellulose K4M, hydroxypropyl cellulose GXF, hydroxypropyl cellulose EXF, ethyl cellulose, carbomer 971P NF, polyoxyethylene.

[0019] Further, the glidant is colloidal silicon dioxide.

[0020] Further, the lubricant is any one or more of stearic acid and magnesium stearate.

[0021] Further, the weight parts of the sustained-release coating is 32-50 parts.

[0022] Further, the weight parts of the hydroxypropyl methyl cellulose in the sustained-release coating is 20-30 parts, the weight parts of the polyethylene glycol is 0.5-3 parts, and the weight parts of the mineral hydrophobic material is 5-20 parts.

[0023] Further, the plasticizer has a weight average molecular weight of 2000-8000.

[0024] The application also provides a preparation method of the toracitabine citrate sustained-release tablet, comprising the following steps:

[0025] S1: sieving the toracitabine citrate, the filler and the matrix material once, mixing them in a granulating kettle, and then granulating by adding a binder;

[0026] S2: drying the granules by using a fluidized bed after granulation, sizing the dried granules, then mixing the glidants and lubricants, and compressing the tablets;

[0027] S3: preparing a coating liquid by using the sustained-release coating material, coating the tablets, and aging the coated tablets in an oven.

[0028] Further, the drying inlet temperature of the fluidized bed in step S2 is 50-70 DEG C; and the sizing screen aperture is 1.0-2.0 mm.

[0029] Further, in step S3, the solid content of the coating liquid ranges from 5-10%; the material temperature during coating is 32-40 DEG C, preferably 35-38 DEG C; the solid content of the coating liquid is the weight of solid materials in the coating liquid / the weight of the coating liquid*100%; the aging temperature after coating is 50-70 DEG C, preferably 55-65 DEG C; and the aging time after coating is 12-36 h, preferably 16-24 h.

[0030] Compared with the prior art, the application achieves the following technical effects:

[0031] (1) This invention uses a matrix tablet with an extended-release coating to achieve a release effect similar to Xeljanz XR. The active ingredient, tofacitinib citrate, is granulated with fillers, binders, and matrix materials. A flow aid and lubricant are added, and the tablets are compressed to form plain tablets. The plain tablets are then coated with an extended-release coating. The extended-release coating material is a mixture of hydroxypropyl methylcellulose, plasticizers, and hydrophobic mineral materials. The hydroxypropyl methylcellulose polymer material serves as a binder or film-forming material; the hydrophobic mineral materials serve as anti-sticking agents and improve the hydrophobicity of the coating film. In the prior art, Xeljanz XR is an osmotic pump formulation. During dissolution, the medium enters the tablet core through a semi-permeable membrane, forming a high osmotic pressure within the tablet core. This osmotic pressure forces the tablet core through small holes on the side of the formulation, thereby releasing the drug. Therefore, Xeljanz XR releases less drug in the first hour. The extended-release coating of this invention combines polymer materials with hydrophobic mineral materials. During the coating process, the coating material continuously deposits, solidifies, and forms a film on the tablet surface, creating a dense and uniform coating film. After coating, placing the tablets in an oven at a certain temperature for aging tests can better promote the integrity, density, and uniformity of the coating film. During dissolution, the sustained-release coating can prevent the medium from penetrating into the tablet core and the drug from dissolving. As the sustained-release coating continues to dissolve and fall off, the drug is released only after the tablet core is exposed, achieving the purpose of sustained release for about 1 hour.

[0032] (2) The preparation method of the present invention does not require the use of laser drilling equipment, which can reduce production costs and increase production speed.

[0033] (3) The preparation method of the present invention does not require the use of sorbitol and acetone, has low humidity requirements for the production workshop, and is environmentally friendly. Attached Figure Description

[0034] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0035] Figure 1 The figures are the uncoated tablets, sustained-release coated tablets, and reference curves prepared in Example 1 of this invention; the horizontal axis represents time (h), and the vertical axis represents the cumulative release rate (%). Detailed Implementation

[0036] In the following, the technical solutions in the embodiments of the present application will be described clearly and completely in combination with the drawings in the embodiments of the present application, so that those skilled in the art can better understand the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work should fall within the protection scope of the present application.

[0037] Embodiments

[0038] The present application will be further described in combination with specific embodiments and comparative examples. The following specific embodiments are preferred embodiments of the present application, but the embodiments of the present application are not limited to the following examples, in particular, not limited to the types of raw materials used in the following specific embodiments.

[0039] I. Raw material sources of the embodiments and comparative examples are as follows:

[0040] Tofacitinib citrate: brand TFBB-707-221107, Nanqunyou Pharmaceutical Technology Co., Ltd.;

[0041] Filler #1: microcrystalline cellulose, brand 101, manufacturer JRS;

[0042] Filler #2: mannitol, brand M100, manufacturer Merck;

[0043] Binder #1: hydroxypropyl cellulose, brand LF, manufacturer Ashland;

[0044] Binder #2: povidone, brand K29 / 32, manufacturer Ashland;

[0045] Skeletal material #1: ethyl cellulose, brand 10 cp, manufacturer DOW;

[0046] Skeletal material #2: carbomer, brand 971P NF, manufacturer Lubrizol;

[0047] Glidant: colloidal silicon dioxide, the same substance is used in parallel experiments;

[0048] Lubricant: stearic acid, the same substance is used in parallel experiments;

[0049] Hydroxypropyl methyl cellulose #1: brand E50LV, viscosity 50 cp, manufacturer DOW;

[0050] Hydroxypropyl methyl cellulose #2: brand E30, viscosity 30 cp, manufacturer Huzhou Zhanwang;

[0051] Hydroxypropyl methyl cellulose #3: brand K100LV, viscosity 100 cp, manufacturer DOW;

[0052] Hydroxypropyl methyl cellulose #4: grade E6LV, viscosity 6 cp, manufacturer DOW;

[0053] Plasticizer: Polyethylene glycol #1, grade D684L7DBG1, weight average molecular weight 4000, manufacturer DOW;

[0054] Plasticizer: Polyethylene glycol #2, grade D210K3GJD2, weight average molecular weight 400, manufacturer DOW;

[0055] Mineral hydrophobic material: Kaolin #1: grade R116001 / NA, particle size 1250 mesh, manufacturer MLA;

[0056] Mineral hydrophobic material: Kaolin #2: grade KN-29C102020, particle size 300 mesh, manufacturer MLA;

[0057] Mineral hydrophobic material: Talc: grade Pharma M, particle size 1250 mesh, manufacturer Imerys;

[0058] Mineral hydrophobic material: Heavy calcium carbonate: grade R020136, particle size 1250 mesh, manufacturer SUDEEP.

[0059] The preparation method of the tofacitinib citrate sustained-release tablets of Examples 1-9 and Comparative Examples 1-5 of the present application is as follows:

[0060] Tofacitinib citrate, filler and matrix material are passed through a 30 mesh sieve once, mixed in a granulating pot, and granulated by adding a binder solution. After granulation, the granules are dried in a fluidized bed at an inlet air temperature of 60°C until the loss on drying of the granules is less than 3%, the dried granules are sized, the sizing screen aperture is 1.5 mm, then the glidant and lubricant are added and mixed for 5 min, and the tablets are compressed. The sustained-release coating material is added to 70% ethanol aqueous solution to prepare a coating solution, the material temperature during coating is 37°C, the coating time is 3.5-5 h, the solid content of the coating solution is 7.55%, and the tablets are coated. After sustained-release coating, the tablets are aged in an oven, the aging temperature is 60°C, and the aging time is 20 h.

[0061] Table 1 Technical solutions of Examples 1-9 (in weight parts)

[0062]

[0063] Table 2 Technical solutions of Comparative Examples (in weight parts)

[0064]

[0065] Example 10

[0066] The composition of the tofacitinib citrate sustained-release tablets of the present example and the amount of each component are the same as those of Example 1, and the drying inlet temperature of the fluidized bed in the preparation method is slightly different, and is as follows:

[0067] The tofacitinib citrate, the filler and the matrix material are sieved through a 30-mesh sieve once, and then mixed in a granulating pot. The granulation is performed by adding a binder solution. After granulation, the granules are dried in a fluidized bed at 40°C until the loss on drying of the granules is less than 3%. The dried granules are sized, and the sizing screen aperture is 1.5 mm. Then, the glidant and the lubricant are added and mixed for 5 min, and the raw tablets are compressed. The sustained-release coating material is added to 70% ethanol aqueous solution, and the material temperature during coating is 37°C. The solid content of the coating liquid is 7.55%, and the raw tablets are coated. After the sustained-release coating, the tablets are subjected to aging in an oven, and the aging temperature is 60°C, and the aging time is 20 h.

[0068] The results show that when the drying inlet temperature is outside the range of 50-70°C, the loss on drying is 4.56% after 3 h of drying, and the loss on drying is 4.28% after 3.5 h of drying. It is difficult to dry the granules to less than 3% at a drying inlet temperature of 40°C.

[0069] Example 11

[0070] The composition of the tofacitinib citrate sustained-release tablets of the present example and the amount of each component are the same as those of Example 1, and the sizing screen aperture in the preparation method is slightly different, and is as follows:

[0071] The tofacitinib citrate, the filler and the matrix material are sieved through a 30-mesh sieve once, and then mixed in a granulating pot. The granulation is performed by adding a binder solution. After granulation, the granules are dried in a fluidized bed at 60°C until the loss on drying of the granules is less than 3%. The dried granules are sized, and the sizing screen aperture is 3 mm. Then, the glidant and the lubricant are added and mixed for 5 min, and the raw tablets are compressed. The sustained-release coating material is added to 70% ethanol aqueous solution, and the material temperature during coating is 37°C. The solid content of the coating liquid is 7.55%, and the raw tablets are coated. After the sustained-release coating, the tablets are subjected to aging in an oven, and the aging temperature is 60°C, and the aging time is 20 h.

[0072] The results show that when the sizing screen aperture is outside the range of 1.0-2.0 mm, there are still large granule lumps after sizing, and the sizing purpose is not achieved. The bulk density of the granules is 0.413 g / mL, the tap density is 0.624 g / mL, and the calculated Carr index is 33.81%, indicating that the flowability of the granules is poor.

[0073] Example 12

[0074] The composition of the tofacitinib citrate sustained-release tablets of the present example and the amount of each component are the same as those of Example 1, and the material temperature during coating in the preparation method is slightly different, and is as follows:

[0075] The tofacitinib citrate, filler and matrix material are passed through a 30 mesh sieve once, mixed in a granulating pot, and granulated by adding a binder solution. After granulation, the granules are dried in a fluid bed at 60°C until the loss on drying of the granules is less than 3%, the dried granules are sized, the sizing sieve aperture is 1.5 mm, then the glidant and lubricant are added and mixed for 5 min, and the tablets are compressed. The sustained release coating material is added in 70% ethanol aqueous solution, the material temperature during coating is 33°C, the solid content of the coating liquid is 7.55%, and the tablets are coated. After sustained release coating, the tablets are aged in an oven, the aging temperature is 60°C, and the aging time is 20 h.

[0076] The results show that, using a non-optimal coating temperature, the temperature is too low, causing moisture to penetrate into the tablet core during coating, the coating yield is more than 100%, 110.49%, indicating that moisture has penetrated into the tablet core, the loss on drying of the tablet is 5.36%, and the moisture is too high.

[0077] Example 13

[0078] The composition of the tofacitinib citrate sustained release tablets and the amount of each component in this example are the same as in Example 1, and the material temperature during coating in the preparation method is slightly different, as follows:

[0079] The tofacitinib citrate, filler and matrix material are passed through a 30 mesh sieve once, mixed in a granulating pot, and granulated by adding a binder solution. After granulation, the granules are dried in a fluid bed at 60°C until the loss on drying of the granules is less than 3%, the dried granules are sized, the sizing sieve aperture is 1.5 mm, then the glidant and lubricant are added and mixed for 5 min, and the tablets are compressed. The sustained release coating material is added in 70% ethanol aqueous solution, the material temperature during coating is 33°C, the solid content of the coating liquid is 7.55%, and the tablets are coated. After sustained release coating, the tablets are aged in an oven, the aging temperature is 60°C, and the aging time is 20 h.

[0080] The results show that, using a coating temperature outside the range of 32-40°C, the temperature is too low, causing the tablet surface to stick together and the coating film to be incomplete, resulting in an unqualified appearance.

[0081] Example 14

[0082] The composition of the tofacitinib citrate sustained release tablets and the amount of each component in this example are the same as in Example 1, and the material temperature during coating in the preparation method is slightly different, as follows:

[0083] The tofacitinib citrate, filler and matrix material are passed through a 30 mesh sieve once, mixed in a granulating pot, and granulated by adding the binder solution. After granulation, the granules are dried in a fluid bed at 60°C until the loss on drying of the granules is less than 3%, the dried granules are sized, the sizing sieve aperture is 1.5 mm, then the glidant and lubricant are added and mixed for 5 min, the cores are compressed. The sustained release coating material is added in 70% aqueous ethanol solution, the material temperature during coating is 37°C, the solid content of the coating solution is 7.55%, and the cores are coated. After sustained release coating, the coated tablets are subjected to aging investigation in an oven, the aging temperature is 50°C, and the aging duration is 20 h.

[0084] The results show that, by observing the cross-section structure of the coated tablets under a microscope, a small amount of bubble-like pores are observed in the coating film when a non-optimal aging temperature is used, indicating that the coating film has not completely healed and has not reached a stable state. No pores are observed in Example 1.

[0085] Example 15

[0086] The composition of the tofacitinib citrate sustained release tablets and the amount of each component in this example are the same as in Example 1, and the aging temperature after coating in the preparation method is slightly different, as follows:

[0087] The tofacitinib citrate, filler and matrix material are passed through a 30 mesh sieve once, mixed in a granulating pot, and granulated by adding the binder solution. After granulation, the granules are dried in a fluid bed at 60°C until the loss on drying of the granules is less than 3%, the dried granules are sized, the sizing sieve aperture is 1.5 mm, then the glidant and lubricant are added and mixed for 5 min, the cores are compressed. The sustained release coating material is added in 70% aqueous ethanol solution, the material temperature during coating is 37°C, the solid content of the coating solution is 7.55%, and the cores are coated. After sustained release coating, the coated tablets are subjected to aging investigation in an oven, the aging temperature is 40°C, and the aging duration is 20 h.

[0088] The results show that, by observing the cross-section structure of the coated tablets under a microscope, a large amount of bubble-like pores are observed in the coating film when an aging temperature outside the range of 50-70°C is used, indicating that the coating film has not completely healed and has not reached a stable state. No pores are observed in Example 1.

[0089] Example 16

[0090] The composition of the tofacitinib citrate sustained release tablets and the amount of each component in this example are the same as in Example 1, and the aging duration after coating in the preparation method is slightly different, as follows:

[0091] The tofacitinib citrate, filler and matrix material are passed through a 30 mesh sieve once, mixed in a granulating pot, and granulated by adding the binder solution. After granulation, the granules are dried in a fluid bed at 60°C until the loss on drying of the granules is less than 3%, the dried granules are sized, the sizing sieve aperture is 1.5 mm, then the glidant and lubricant are added and mixed for 5 min, the cores are compressed. The sustained release coating material is added in 70% aqueous ethanol solution, the material temperature during coating is 37°C, the solid content of the coating liquid is 7.55%, and the cores are coated. After sustained release coating, the aging investigation is carried out in an oven, the aging temperature is 60°C, and the aging duration is 12 h.

[0092] The results show that, by observing the cross-section structure of the coated tablets under a microscope, a small amount of bubble-like pores are observed in the coating film when a non-optimal aging duration is used, indicating that the coating film has not completely healed and has not reached a stable state. No pores are observed in Example 1.

[0093] Example 17

[0094] The composition of the tofacitinib citrate sustained release tablets and the amount of each component in this example are the same as in Example 1, and the aging duration after coating in the preparation method is slightly different, as follows:

[0095] The tofacitinib citrate, filler and matrix material are passed through a 30 mesh sieve once, mixed in a granulating pot, and granulated by adding the binder solution. After granulation, the granules are dried in a fluid bed at 60°C until the loss on drying of the granules is less than 3%, the dried granules are sized, the sizing sieve aperture is 1.5 mm, then the glidant and lubricant are added and mixed for 5 min, the cores are compressed. The sustained release coating material is added in 70% aqueous ethanol solution, the material temperature during coating is 37°C, the solid content of the coating liquid is 7.55%, and the cores are coated. After sustained release coating, the aging investigation is carried out in an oven, the aging temperature is 60°C, and the aging duration is 10 h.

[0096] The results show that, by observing the cross-section structure of the coated tablets under a microscope, a large amount of bubble-like pores are observed in the coating film when an aging duration outside the range of 12-36 h is used, indicating that the coating film has not completely healed and has not reached a stable state. No pores are observed in Example 1.

[0097] Example 18

[0098] The composition of the tofacitinib citrate sustained release tablets and the amount of each component in this example are the same as in Example 1, and the solid content of the coating liquid in the preparation method is slightly different, as follows:

[0099] The tofacitinib citrate, filler and matrix material are passed through a 30 mesh sieve once, mixed in a granulating pot, and granulated by adding the binder solution. After granulation, the granules are dried in a fluid bed at 60°C until the loss on drying of the granules is less than 3%, the dried granules are sized, the sizing sieve size is 1.5 mm, then the glidant and lubricant are added and mixed for 5 min, and the tablets are compressed. The tablets are coated with the sustained release coating material in 70% ethanol aqueous solution, the material temperature during coating is 37°C, the solid content of the coating solution is 4%, and the tablets are coated. After sustained release coating, the tablets are aged in an oven, the aging temperature is 60°C, and the aging time is 20 h.

[0100] The results show that when the solid content of the coating solution is outside the range of 5-10%, when the solid content of the coating solution is 4%, the concentration is low, and to achieve the target weight gain, more coating solution needs to be used, and the coating time is too long, which is extended from the ideal coating time of 3.5-5 h to about 8 h.

[0101] II. Performance test method

[0102] Drug cumulative release test: The cumulative release of tofacitinib citrate sustained release tablets prepared in Example 1, reference preparation (FK3384) and tablets without coating of Example 1 (i.e. after tablet compression, the process ends without subsequent coating steps) is tested at different times. The specific method is as follows: take the sample, refer to the release test method (Chinese Pharmacopoeia 2015 edition four parts general preparation 0931 second method) + the device of the sinker basket, the dissolution medium is 900 mL of pH 6.8 phosphate buffer, the rotation speed is 50 revolutions; take samples at different times and filter online. Detect at 286 nm. Calculate the cumulative release of the tablets, the results are shown in Table 3 (n=10 tablets, representing 10 sample tablets, the results are averaged), and the in vitro drug release curve is shown in Figure 1 .

[0103] Table 3: Tablet, sustained release coated tablet and reference dissolution data

[0104]

[0105] The above results show that by combining the matrix tablet with the sustained release coating, the composition and ratio of Example 1 can achieve a dissolution curve similar to the original research, i.e. the first hour of dissolution has a sustained release effect, 1-4 h is a relatively fast dissolution, the sustained release coated tablet is similar to the original research with a similarity factor f2 = 63. f2> 50, indicating that the sustained release coated tablet is similar to the original research, i.e. Example 1 is close to the original research in vitro, which achieves the research goal in the laboratory stage, and has the conditions to carry out in vivo bioequivalence study of self-research samples and original research.

[0106] The same test is carried out on other examples and comparative examples in the same way, and the results are shown in Table 4:

[0107] Table 4 Cumulative release (%) of examples and comparative examples

[0108] Time (h) 0 0.5 1 1.5 2 2.5 3 4 6 8 Example 1 0 1 5 18 34 49 63 82 95 96 Example 2 0 2 8 23 39 55 69 87 99 101 Example 3 0 0 2 13 29 42 57 79 92 95 Example 4 0 0 4 17 33 47 61 80 94 97 Example 5 0 1 5 19 35 49 64 84 97 100 Example 6 0 3 8 21 39 55 66 89 97 100 Example 7 0 0 2 14 31 43 58 80 92 96 Example 8 0 3 7 24 40 55 70 88 98 102 Example 9 0 0 2 14 31 45 60 79 93 96 Comparative Example 1 0 4 10 25 42 56 67 85 98 100 Comparative Example 2 0 7 13 28 48 61 72 90 100 101 Comparative Example 3 0 0 1 9 25 40 54 76 92 97 Comparative Example 4 0 11 33 51 63 73 86 99 100 101

[0109] Example 6 uses hypromellose with viscosity of 30 cp, which is lower than that of Example 1, and the release after coating is faster. Example 7 uses hypromellose with viscosity of 100 cp, which is higher than that of Example 1, and the release after coating is slower. The above examples show that hypromellose with viscosity of 35-80 cp has better effect. Example 8 uses polyethylene glycol with molecular weight outside the range, and the effect is not as good as that of Example 1, which shows that polyethylene glycol with weight average molecular weight of 2000-8000 has better effect.

[0110] Comparative Examples 1-5 all have a single variable compared with Example 1. Comparative Example 1 lacks polyethylene glycol in the sustained-release coating material. Comparative Example 2 has too low weight fraction of the sustained-release coating material mixture. Comparative Example 3 has too high weight fraction of the sustained-release coating material mixture, and the weight gain is too high, and the release is too slow. Comparative Example 4 uses hypromellose with viscosity outside the range, which has lower viscosity and faster release, and does not achieve the purpose of sustained-release coating. Comparative Example 5 uses kaolin with particle size outside the range, which has too large particle size, and the coating liquid is easy to settle, which can cause coating gun blockage and cannot be successfully prepared. The above comparative examples cannot be successfully prepared or cannot achieve the sustained-release performance of the examples, i.e., the dissolution in the first 3 h is about 5-15% slower than the reference, the dissolution curve intersects with the reference at about 3-4 h, and the dissolution is faster than the reference after about 4 h until reaching the dissolution plateau.

[0111] Based on the cumulative release test results in Table 4, the tofacitinib citrate sustained-release tablets prepared by Examples 1-9 have sustained-release effect in the first 1 h, and fast dissolution in 1-4 h, which can effectively meet the high standard needs of customers and market.

[0112] The above only describes the preferred embodiments of the present application, and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A tofacitinib citrate sustained-release tablet, characterized in that, Based on parts by weight, it comprises the following components: Tofacitinib citrate 35.54 parts; 90-130 parts of filler; 20-40 parts of adhesive; 20-40 parts of skeleton material; 0.5-1.5 parts of gliding agent; 1-3 parts lubricant; Sustained-release coating 25.5-53 parts; The sustained-release coating is a mixture of hydroxypropyl methylcellulose, plasticizer, and mineral hydrophobic material; The plasticizer is polyethylene glycol; the hydrophobic mineral material is any one or more of kaolin, talc, and heavy calcium carbonate. The viscosity of the hydroxypropyl methylcellulose is 20-300 cp; The particle size of the mineral hydrophobic material is 500-2000 mesh; The filler is any one or more of microcrystalline cellulose and mannitol; The adhesive is any one or more of polyvinylpyrrolidone and hydroxypropyl cellulose; The skeleton material is any one or more of ethyl cellulose and carbomer.

2. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that, The sustained-release coating is 32-50 parts by weight.

3. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that, The sustained-release coating contains 20-30 parts by weight of hydroxypropyl methylcellulose, 0.5-3 parts by weight of polyethylene glycol, and 5-20 parts by weight of the mineral hydrophobic material.

4. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that, The weight-average molecular weight of the plasticizer is 2000-8000.

5. The method for preparing tofacitinib citrate sustained-release tablets according to any one of claims 1-4, characterized in that, Includes the following steps: S1: Sift the tofacitinib citrate, filler, and skeleton material once, mix them in a granulation pot, and then add the binder to granulate; S2: After granulation, the granules are dried in a fluidized bed, sized, and then mixed with a flow aid and lubricant before being pressed into tablets. S3: Prepare a coating solution for the slow-release coating material, coat the uncoated tablets, and then age them in an oven.

6. The preparation method according to claim 5, characterized in that, In step S2, the drying air inlet temperature of the fluidized bed is 50-70℃; the sieve aperture for granulation is 1.0-2.0mm.

7. The preparation method according to claim 5, characterized in that, In step S3, the liquid-solid content of the coating is 5-10%; the material temperature during coating is 32-40℃; the aging temperature after coating is 50-70℃; and the aging time after coating is 12-36h.

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