Tofacitinib citrate sustained release tablet preparation and preparation method thereof

Abstract

The invention discloses a tofacitinib citrate sustained-release tablet preparation and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations, the sustained-release tablet comprises a double-layer tablet core and a coating layer; the double-layer tablet core comprises a medicine-containing layer and a pushing layer; wherein the medicine-containing layer comprises tofacitinib citrate, an adhesive, polyoxyethylene, a flow aid and a lubricant; the pushing layer comprises mannitol, an adhesive, red iron oxide, polyoxyethylene, a flow aid and a lubricant; the coating layer comprises cellulose acetate, a pore-foaming agent, a plasticizer, water and acetone. According to the sustained-release tablet preparation disclosed by the invention, the technical problems in the prior art are solved by adopting a double-layer osmotic pump prescription design, mannitol and other non-hygroscopic materials, a standard round tablet design, no methanol for preparing a sustained-release coating layer, a coating machine for coating, curing and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a tofacitinib citrate sustained-release tablet preparation and a preparation method thereof. Background Art

[0002] Tofacitinib citrate extended-release tablets are a Janus kinase (JAK) inhibitor developed by Pfizer. JAK is an intracellular enzyme that transmits signals generated by cytokine or growth factor-receptor interactions on the cell membrane, thereby affecting the cell hematopoietic process and cellular immune function; within this signal transduction pathway, JAK phosphorylates and activates signal transducers and activators of transcription (STAT), thereby regulating intracellular activities including gene expression. Tofacitinib citrate exerts its therapeutic effect by regulating the JAK signal transduction pathway to prevent STAT phosphorylation and activation. It is currently mainly used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis.

[0003] The first tofacitinib citrate to be launched on the market was an immediate-release dosage form. Adult patients need to take the medicine twice a day, and patient compliance is poor. Pfizer subsequently developed a once-daily sustained-release preparation. The original tofacitinib citrate sustained-release tablet XR consists of a tablet core, a semipermeable membrane sustained-release coating and a color coating layer. The sample is a pink oval film-coated tablet, which appears white or off-white after removing the coating. Laser means are used to punch small drug-releasing holes on the drug-containing coating film at the top of the side of the oval tablet. The punching machine has extremely high requirements for the control accuracy of the punching position, low production efficiency, high production costs, and the production process uses methanol and other excipients that are harmful to the body and even cause blindness.

[0004] Meanwhile, relevant existing technologies have been studied and improved, but they all have different shortcomings. For example, patent CN105101952B mainly uses 60-85% sorbitol as the tablet core osmogen, and the semipermeable membrane coating is mainly composed of cellulose acetate and hydroxypropyl cellulose in a weight ratio of 6:4. Since sorbitol is extremely hygroscopic, the environmental humidity needs to be strictly controlled during the production process to ensure that it does not absorb moisture during the mixing and tableting process. In addition, since a large proportion of hydroxypropyl cellulose is used as a pore-forming agent in the semipermeable membrane coating, polar solvent methanol is required for dissolution and subsequent coating, which introduces toxic reagents that are prone to blindness and brings safety hazards. Moreover, the dissolution data range under this patent is relatively wide, and the release behavior cannot be better and more accurately controlled. The dissolution rate of the preparation slows down after long-term storage.

[0005] Patent CN112755000A adjusts the composition of the osmotic pressure former and its dosage ratio with the sustained-release agent, further optimizes the composition and coating weight gain of the sustained-release layer, and replaces a small portion of sorbitol with sodium chloride. This only reduces the defect of slow dissolution rate after long-term storage when sorbitol is used alone as an osmotic pressure former. However, since it still contains at least 50% sorbitol, this defect is not fundamentally avoided. In addition, the other components are consistent with the original formulation, and methanol toxic reagents are also introduced.

[0006] Although some diluents are added in patent CN117982440A to replace sorbitol, the use of sorbitol is still not completely avoided. Therefore, the environmental humidity still needs to be strictly controlled during the production process to ensure that the mixing and tableting process does not absorb moisture and the dissolution rate slows down after long-term storage.

[0007] Patent CN117653609A adopts skeleton tablet technology, but it is well known that one of the disadvantages of this technology is that the release pattern is different in different media, and it is easily affected by pH and food inside and outside the body to cause sudden release, and it is also easy to absorb moisture during storage; osmotic pumps use osmotic pressure as a sustained release mechanism, and in the gastric juice in the body, osmotic pumps are less affected by gastric peristalsis, while skeleton tablets use diffusion and dissolution as a sustained release mechanism, and in the gastric juice in the body, skeleton tablets may be greatly affected by gastric peristalsis.

[0008] Patent CN113712932A mainly adopts a single-layer osmotic pump tablet design, which can easily cause incomplete drug release. Although the patent claims to use osmotic pump technology, it does not have laser drilling and even uses HPMC as a sustained-release coating material, which is obviously not in line with the principle of osmotic pumps. At the same time, the in vitro dissolution data is not disclosed, so the research is insufficient.

[0009] The single-layer tablet osmotic pump design used in patent CN111728953A is prone to incomplete release; in addition, the patent requires a layer of isolation coating, which will affect drug release and increase process complexity. Hydroxypropyl cellulose is used as a pore-forming agent and acetone is used as a coating solvent in the sustained-release layer coating liquid, which can easily cause the pore-forming agent to be incompletely dissolved in acetone, thereby causing the coating liquid to settle and the coating film to be uneven, which in turn leads to large differences in dissolution batches.

[0010] Therefore, it is an urgent problem to be solved by those skilled in the art to provide a tofacitinib citrate sustained-release tablet preparation with complete release and simple preparation process. Summary of the invention

[0011] In order to solve the above problems, the present invention provides a tofacitinib citrate sustained-release tablet preparation and a preparation method thereof.

[0012] In order to achieve the above object, the present invention adopts the following technical solution:

[0013] A tofacitinib citrate sustained-release tablet preparation, the sustained-release tablet comprising a double-layer tablet core and a coating layer; the double-layer tablet core comprises a drug-containing layer and a push layer;

[0014] Wherein, the drug-containing layer comprises: tofacitinib citrate, an adhesive, polyethylene oxide, a glidant and a lubricant;

[0015] The push layer comprises: mannitol, adhesive, red iron oxide, polyethylene oxide, flow aid and lubricant;

[0016] The coating layer comprises: cellulose acetate, a pore-forming agent, a plasticizer, water and acetone.

[0017] Preferably, the mass ratio of tofacitinib citrate, binder, polyethylene oxide, silicon dioxide and magnesium stearate in the drug-containing layer is 11:8-12:130-170:1.7:1.7.

[0018] Preferably, the mass ratio of mannitol, adhesive, red iron oxide, polyethylene oxide, silicon dioxide and magnesium stearate in the push layer is 20-40:12-18:1:80-120:1.3:1.3.

[0019] Preferably, the mass ratio of cellulose acetate, pore-forming agent, plasticizer, water and acetone in the coating layer is 30:3-9:0.3-0.9:40:424.

[0020] Preferably, the mass ratio of the tofacitinib citrate, the mannitol and the cellulose acetate is 11:20-40:30.

[0021] Preferably, the binder is hydroxypropyl cellulose;

[0022] The glidant is silicon dioxide;

[0023] The lubricant is magnesium stearate;

[0024] The porogen is lactose;

[0025] The plasticizer is polyethylene glycol.

[0026] Preferably, the sustained-release tablet is a round tablet, and a hole is punched on the side of the drug-containing layer.

[0027] According to the above-mentioned method for preparing a tofacitinib citrate sustained-release tablet preparation, the method comprises the following specific steps:

[0028] (1) Weigh each raw material according to the mass ratio:

[0029] Drug-containing layer: tofacitinib citrate, adhesive, polyethylene oxide, glidant and lubricant; push layer: mannitol, adhesive, red iron oxide, polyethylene oxide, glidant and lubricant; coating layer: cellulose acetate, pore-forming agent, plasticizer, water and acetone;

[0030] (2) The raw materials of the drug-containing layer and the push layer are mixed evenly, and then prepared into a double-layer tablet core by a tablet press;

[0031] (3) adding the cellulose acetate, the pore-forming agent, and the plasticizer to a mixed solution of the water and the acetone to obtain a coating solution;

[0032] (4) spraying the coating liquid onto the double-layer tablet core to obtain a coated tablet; punching holes on the drug-containing layer side of the coated tablet and curing the tablet using a coating machine to obtain a tofacitinib citrate sustained-release tablet.

[0033] Preferably, the curing time is 2-4 hours.

[0034] The existing preparation process of tofacitinib citrate sustained-release tablets mainly includes the steps of crushing, mixing, tablet pressing, sustained-release layer coating, laser drilling, curing, color coating and the like, and the preparation equipment required includes air flow mill, mixer, tablet press, coating machine, laser drilling machine for special-shaped tablets, drying oven and the like; while the present invention only adopts mixing, tablet pressing, sustained-release layer coating, laser drilling and curing to complete the preparation, and the main equipment used includes mixer, tablet press, coating machine and ordinary laser drilling machine; the use of equipment is reduced, the manufacturing cost and threshold are lowered, and the preparation time is shortened.

[0035] It can be seen from the above technical solution that compared with the prior art, the beneficial effects of the present invention are as follows:

[0036] (1) Both the drug-containing layer and the push layer of the sustained-release tablet of the present invention are directly compressed, which simplifies the production process and energy consumption. The curing process adopts a coating machine for curing, which significantly shortens the time, reduces the use of equipment, and reduces the cost of equipment use;

[0037] (2) The sustained-release tablets of the present invention are made by punching holes in the middle of round tablets, which can be done by ordinary punching machines, thereby improving production efficiency. At the same time, after using round tablets, the RSD value of dissolution is unexpectedly reduced;

[0038] (3) The sustained-release tablet of the present invention adopts a double-layer osmotic pump design, which avoids the disadvantage of incomplete release at the dissolution endpoint of a single-layer preparation; it adopts non-hygroscopic materials such as mannitol, which avoids the influence of humidity during the production process, avoids the increase of moisture during storage, and avoids the phenomenon of slow dissolution during long-term storage; methanol is not used in the preparation of the sustained-release coating layer, which reduces solvent residue and reduces damage to the human body; the use of coating pore-forming agents reduces the use of coating materials and coating time. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying creative work.

[0040] Figure 1 A front view of the product prepared for the embodiment;

[0041] Figure 2 A side view of a product prepared for the example. DETAILED DESCRIPTION

[0042] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0043] The present invention provides a method for preparing a tofacitinib citrate sustained-release tablet preparation, the specific steps of which are as follows:

[0044] (1) Weigh the raw materials and excipients of the drug-containing layer according to the mass ratio: tofacitinib citrate, binder, polyethylene oxide, glidant and lubricant; the raw materials and excipients of the push layer: mannitol, binder, red iron oxide, polyethylene oxide, glidant and lubricant; the raw materials and excipients of the coating layer: cellulose acetate, pore-forming agent, plasticizer, water and acetone;

[0045] (2) After the raw materials and excipients of the drug-containing layer and the push layer are mixed evenly, they are added to a double-layer tablet press and pressed using a round punch to obtain a double-layer tablet core;

[0046] (3) adding cellulose acetate, pore-forming agent and plasticizer into a mixed solution of water and acetone, and stirring the mixture to obtain a coating solution;

[0047] (4) The coating liquid is evenly sprayed onto the double-layer tablet core through a coating machine to obtain a coated tablet; a hole is punched on the drug-containing layer side of the coated tablet using a laser punching machine, and then the tablet is placed in a coating machine for curing for 2-4 hours to obtain a tofacitinib citrate sustained-release tablet. The relevant product picture is shown in Figure 1 and 2 .

[0048] Examples 1-3 and Comparative Examples 1-2

[0049] Using the above preparation method, the relevant proportions of raw materials and auxiliary materials of Examples 1-3 and Comparative Examples 1-2 are shown in Table 1.

[0050] Table 1 Relevant proportions of raw materials and auxiliary materials of Examples 1-3 and Comparative Examples 1-2

[0051]

[0052] Comparative Example 3

[0053] The tofacitinib citrate double-layer sustained-release tablet sample was prepared using Example 2 of patent CN117653609A.

[0054] Comparative Example 4

[0055] An 11 mg tablet sample was prepared using Example 2 of patent CN105101952B.

[0056] The sustained-release tablets prepared in Examples 1-3 and Comparative Examples 1-2, Comparative Examples 3-4 and the original formulation (Shangjie R 11mg batch number: FN6775) for relevant performance tests, as follows:

[0057] Dissolution Testing

[0058] Take this product, add a sinker, and measure it according to the dissolution and release test method (Chinese Pharmacopoeia 2020 Edition Part IV General Rules 0931 Second Method); use phosphate buffer (weigh 40.8g of potassium dihydrogen phosphate, dissolve and dilute to 6000ml with water, and adjust the pH to 6.8±0.05 with 3mol / L potassium hydroxide) 900ml as the dissolution medium, the speed is 50 revolutions per minute, operate according to the law, take 10ml of the dissolution solution after 1h, 2.5h, and 6h, filter, discard 3ml of the initial filtrate, take the subsequent filtrate as the test solution, and replenish the dissolution medium of the same temperature and volume in time;

[0059] Take about 18 mg of tofacitinib citrate reference substance, accurately weigh it, put it in a 100 ml volumetric flask, add solvent to dissolve and quantitatively dilute to the scale, shake well, accurately measure 5 ml, put it in a 50 ml volumetric flask, add dissolution medium to dilute to the scale, shake well, as the reference substance solution;

[0060] Take the test solution and the reference solution, and determine the dissolution amount at different times according to the chromatographic method under the content determination item. The results are shown in Table 2 and Table 3.

[0061] Table 2 Dissolution test results of products of Examples 1-3 and Comparative Examples 1-2

[0062]

[0063] Table 3 Dissolution test results of comparative examples 3-4 and original preparation products

[0064]

[0065] From the results in Table 2 and Table 3, it can be seen that the release of the products of Examples 1-3 can reach more than 90% in 6 hours, and the release of the original preparation is about 85%, which is obviously more complete than the original preparation, and the drug efficacy is improved. In addition, the dissolution RSD of the examples is obviously better than that of the original preparation; while the release of Comparative Example 1 is slower, and the release is not complete in 6 hours, and the release of Comparative Example 2 is obviously faster, and the sustained release effect is not obvious; Comparative Example 3 has the risk of sudden release in 1 hour, and the release of Comparative Example 4 is 85% in 6 hours, and the release is incomplete.

[0066] Residual solvent detection

[0067] Determined according to the residual solvent determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0861, Method 2);

[0068] Test solution: Take 5 tablets of this product, weigh accurately, place in a 100ml volumetric flask, add appropriate amount of N,N-dimethylacetamide, oscillate on a reciprocating / vibrating oscillator at a rate of 200 times per minute for about 60 minutes, dilute to the scale with N,N-dimethylacetamide, shake well, centrifuge, accurately measure 5ml of the supernatant, place in a 20ml headspace bottle, and seal;

[0069] Reference solution: Take appropriate amount of methanol and acetone, weigh accurately, dissolve and dilute with N,N-dimethylacetamide to make a mixed solution containing about 34μg methanol and 56μg acetone per 1ml, accurately measure 5ml, place in a 20ml headspace bottle, and seal;

[0070] Chromatographic conditions: a capillary column with 6% cyanopropylphenyl-94% dimethylsiloxane (or similar polarity) as the stationary phase; nitrogen as the carrier gas, with a flow rate of 1.6 ml per minute; the starting temperature is 40°C, maintained for 5 minutes, then increased to 90°C at a rate of 2°C per minute, and then increased to 225°C at a rate of 30°C per minute, and maintained for 2 minutes. The detector is a hydrogen flame ionization detector (FID) at a temperature of 260°C; the injection port temperature is 180°C; the headspace bottle equilibrium temperature is 105°C, the injection loop temperature is 110°C, the transfer line temperature is 115°C, and the equilibrium time is 30 minutes; the split ratio is 30:1;

[0071] Take the test solution and the reference solution for headspace injection respectively, record the chromatogram, and the results are shown in Table 4.

[0072] Table 4 Residual solvent detection results

[0073]

[0074] According to the residual solvent detection results in Table 4, methanol was not used in the examples and thus was not detected, while the original preparation and the samples prepared in Comparative Example 4 both contained methanol residues.

[0075] Dose dumping experiment

[0076] The dissolution behavior of the example preparation and the original preparation was evaluated according to the "Technical Guidelines for Pharmaceutical Research on Ethanol Dose Dumping Test of Oral Modified Release Preparations of Generic Chemical Drugs", and the results are shown in Table 5;

[0077] Table 5 Dose dumping test results

[0078]

[0079] It can be seen from the relevant data in Table 5 that the results of the dose dumping experiments of Examples 1-3 and Comparative Example 1 are significantly better than those of the original preparation, which reduces the risk of dose dumping in patients taking the medicine after drinking; the dose dumping of Comparative Example 3 is significantly worse than that of the original preparation, and Comparative Examples 2 and 4 are basically the same as the original preparation.

[0080] Bottle Opening Test Study - Moisture

[0081] Refer to the instruction manual, simulate opening the bottle to take medicine every morning, each time for 10 minutes, and observe the changes in moisture index. The relevant results are shown in Table 6;

[0082] Table 6 Opening stability results

[0083]

[0084] From the data in Table 6, it can be seen that the moisture growth of Examples 1-3 and Comparative Examples 1-2 is slower than that of the original preparation, indicating that the original preparation is more hygroscopic; while the moisture growth of Comparative Example 3 is the fastest and most hygroscopic; Comparative Example 4 is basically the same as the original preparation.

[0085] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A tofacitinib citrate sustained-release tablet preparation, characterized in that: The sustained-release tablet comprises a double-layer tablet core and a coating layer; the double-layer tablet core comprises a drug-containing layer and a push layer; Wherein, the drug-containing layer comprises: tofacitinib citrate, an adhesive, polyethylene oxide, a glidant and a lubricant; The push layer comprises: mannitol, adhesive, red iron oxide, polyethylene oxide, flow aid and lubricant; The coating layer comprises: cellulose acetate, a pore-forming agent, a plasticizer, water and acetone.

2. A tofacitinib citrate sustained-release tablet preparation according to claim 1, characterized in that: The mass ratio of tofacitinib citrate, adhesive, polyethylene oxide, glidant and lubricant in the drug-containing layer is 11:8-12:130-170:1.7:1.

7.

3. The tofacitinib citrate sustained-release tablet preparation according to claim 1, characterized in that: The mass ratio of mannitol, adhesive, red iron oxide, polyethylene oxide, glidant and lubricant in the push layer is 20-40:12-18:1:80-120:1.3:1.

3.

4. The tofacitinib citrate sustained-release tablet preparation according to claim 1, characterized in that: The mass ratio of cellulose acetate, pore-forming agent, plasticizer, water and acetone in the coating layer is 30:3-9:0.3-0.9:40:

424.

5. The tofacitinib citrate sustained-release tablet preparation according to claim 1, characterized in that: The mass ratio of the tofacitinib citrate, the mannitol and the cellulose acetate is 11:20-40:

30.

6. The tofacitinib citrate sustained-release tablet preparation according to claim 1, characterized in that: The binder is hydroxypropyl cellulose; The glidant is silicon dioxide; The lubricant is magnesium stearate; The porogen is lactose; The plasticizer is polyethylene glycol.

7. The tofacitinib citrate sustained-release tablet preparation according to claim 1, characterized in that: The sustained-release tablet is a round tablet, and a hole is punched on the side of the drug-containing layer.

8. A method for preparing a tofacitinib citrate sustained-release tablet preparation according to any one of claims 1 to 7, characterized in that: The specific steps include: (1) Weigh each raw material according to mass ratio: Drug-containing layer: tofacitinib citrate, adhesive, polyethylene oxide, glidant and lubricant; push layer: mannitol, adhesive, red iron oxide, polyethylene oxide, glidant and lubricant; coating layer: cellulose acetate, pore-forming agent, plasticizer, water and acetone; (2) The raw materials of the drug-containing layer and the push layer are mixed evenly, and then prepared into a double-layer tablet core by a tablet press; (3) adding the cellulose acetate, the pore-forming agent, and the plasticizer to a mixed solution of the water and the acetone to obtain a coating solution; (4) spraying the coating liquid onto the double-layer tablet core to obtain a coated tablet; punching holes on the drug-containing layer side of the coated tablet and curing the tablet using a coating machine to obtain a tofacitinib citrate sustained-release tablet.

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