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

Abstract

The present invention discloses a tofacitinib citrate sustained-release tablet preparation and a preparation method thereof, which belongs to the technical field of pharmaceutical preparations. The sustained-release tablet comprises a double-layer core and a coating layer; the double-layer 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, an adhesive, red iron oxide, polyethylene oxide, a glidant and a lubricant; the coating layer comprises: cellulose acetate, a pore-forming agent, a plasticizer, water and acetone. The sustained-release tablet preparation of the present invention solves the technical problems existing in the prior art by adopting a double-layer osmotic pump prescription design, adopting non-hygroscopic materials such as mannitol, adopting a standard round tablet design, preparing a sustained-release coating layer without using methanol, and adopting a coating machine for coating and curing.

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. JAKs are intracellular enzymes that transmit signals generated by cytokine or growth factor-receptor interactions on the cell membrane, thereby influencing cellular hematopoiesis and cellular immunity. Within this signal transduction pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), thereby regulating intracellular activities including gene expression. Tofacitinib citrate exerts its therapeutic effects by modulating the JAK signal transduction pathway, preventing STAT phosphorylation and activation. It is currently used primarily 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 needed to take the medicine twice a day, and patient compliance was 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 in the drug-containing coating film at the top of the side of the oval tablet. The punching machine requires extremely high precision in controlling the drilling position, resulting in low production efficiency and high production costs. In addition, methanol and other excipients that are harmful to the body and even cause blindness are used in the production process.

[0004] At the same time, 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 with a weight ratio of 6:4. Since sorbitol is extremely hygroscopic, the environmental humidity must 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 easily blinding, posing a safety hazard. 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 the osmotic pressure former. However, because 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 toxicity reagent is also introduced.

[0006] Although some diluents are added as a substitute in patent CN117982440A, 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 processes do not absorb moisture and the dissolution rate slows down after long-term storage.

[0007] Patent CN117653609A uses 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 both in vivo and in vitro, causing burst release. It is also more susceptible to moisture absorption during storage. Osmotic pumps use osmotic pressure as a sustained-release mechanism, and are less affected by gastric peristalsis in gastric juice in vivo. However, skeleton tablets use diffusion and dissolution as a sustained-release mechanism, and may be more affected by gastric peristalsis in gastric juice in vivo.

[0008] Patent CN113712932A mainly adopts a single-layer osmotic pump tablet design, which is prone to incomplete drug release. Although the patent claims to use osmotic pump technology, it does not have laser drilling and does not even use HPMC as a sustained-release coating material, which is obviously inconsistent with the principle of osmotic pumps. At the same time, no in vitro dissolution data is 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 within 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 solutions:

[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 comprising a drug-containing layer and a push layer;

[0014] Wherein, the drug-containing layer comprises: tofacitinib citrate, adhesive, polyethylene oxide, glidant and 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 with holes 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 the raw materials 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 porogen, 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 crushing, mixing, tableting, sustained-release layer coating, laser drilling, curing, color coating and other processes. The preparation equipment required includes air flow mill, mixer, tablet press, coating machine, special-shaped tablet laser drilling machine, drying oven and the like. The present invention only uses mixing, tableting, sustained-release layer coating, laser drilling and curing to complete the preparation. 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 punched in the middle of round tablets, which can be processed by ordinary punching machines, thereby improving production efficiency. At the same time, the use of round tablets unexpectedly reduces the RSD value of dissolution.

[0038] (3) The sustained-release tablets of the present invention adopt a double-layer osmotic pump design, which avoids the disadvantage of incomplete release at the end point of dissolution of single-layer preparations; the use of non-hygroscopic materials such as mannitol avoids the influence of humidity during the production process, avoids the growth 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 following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are merely embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the provided drawings without paying any creative work.

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

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

[0042] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts 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 auxiliary materials of the drug-containing layer according to the mass ratio: tofacitinib citrate, adhesive, polyethylene oxide, flow aid and lubricant; the raw materials and auxiliary materials of the push layer: mannitol, adhesive, red iron oxide, polyethylene oxide, flow aid and lubricant; the raw materials and auxiliary materials of the coating layer: cellulose acetate, pore-forming agent, plasticizer, water and acetone;

[0045] (2) The raw materials and excipients of the drug-containing layer and the push layer are mixed evenly, 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, porogen, and plasticizer to a mixed solution of water and acetone, and stirring evenly 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 laser punch is used to punch holes on the drug-containing layer side of the coated tablet, 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 Ratios 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) and related performance tests were conducted 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 Chapter 0931 Second Method); use 900 ml of phosphate buffer (weigh 40.8 g of potassium dihydrogen phosphate, dissolve it in water and dilute it to 6000 ml, and adjust the pH to 6.8±0.05 with 3 mol / L potassium hydroxide) as the dissolution medium, rotate at 50 revolutions per minute, operate according to the method, take 10 ml of the dissolution solution after 1 h, 2.5 h, and 6 h, filter, discard 3 ml of the initial filtrate, take the subsequent filtrate as the test solution, and replenish the dissolution medium at the same temperature and volume in time;

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

[0064]

[0065] The results in Tables 2 and 3 show that the release rates of the products of Examples 1-3 can reach over 90% in 6 hours, and the release rate of the original formulation is about 85%, which is significantly more complete than the original formulation, thereby improving the drug efficacy. In addition, the dissolution RSD of the examples is significantly better than that of the original formulation. However, the release rate of Comparative Example 1 is slower, and the release rate is not complete in 6 hours. The release rate of Comparative Example 2 is significantly faster, and the sustained-release effect is not obvious. The release rate of Comparative Example 3 has the risk of burst release in 1 hour, and the release rate of Comparative Example 4 is 85% in 6 hours, indicating incomplete release.

[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, accurately weigh them, place them in a 100ml volumetric flask, add appropriate amount of N,N-dimethylacetamide, shake on a reciprocating / vibrating shaker 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 it in a 20ml headspace bottle, and seal it;

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

[0070] Chromatographic conditions: A capillary column with a stationary phase of 6% cyanopropylphenyl and 94% dimethylsiloxane (or similar polarity); nitrogen carrier gas at a flow rate of 1.6 ml / min; initial temperature of 40°C, held for 5 minutes, then increased to 90°C at a rate of 2°C / min, then to 225°C at a rate of 30°C / min, held for 2 minutes. Detector: flame ionization detector (FID) at 260°C; inlet temperature of 180°C; headspace vial equilibration temperature of 105°C, injection loop temperature of 110°C, transfer line temperature of 115°C, equilibration time of 30 minutes; split ratio of 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 test results

[0073]

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

[0075] Dose dumping experiment

[0076] The dissolution behavior of the example preparations and the original preparation was evaluated according to the "Guidelines for Pharmaceutical Research Technology of Ethanol Dose Dumping Test for 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] As can be seen from the relevant data in Table 5, the results of the dose dumping experiments of Examples 1-3 and Comparative Example 1 are significantly better than those of the original formulation, reducing the risk of dose dumping in patients taking the medicine after drinking alcohol; the dose dumping of Comparative Example 3 is significantly worse than that of the original formulation, and Comparative Examples 2 and 4 are basically the same as the original formulation.

[0080] Bottle Opening Test Study - Moisture

[0081] Refer to the instructions and simulate opening the bottle and taking medicine every morning for 10 minutes each time to observe the changes in moisture indicators. 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 is the most hygroscopic; Comparative Example 4 is basically the same as the original preparation.

[0085] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be readily 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 is not limited to the embodiments shown herein but is intended to conform 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 core and a coating layer; the double-layer core comprises a drug-containing layer and a push layer; The drug-containing layer comprises: tofacitinib citrate, a binder, polyethylene oxide, a glidant and a lubricant; the mass ratio of tofacitinib citrate, the binder, polyethylene oxide, the glidant and the lubricant in the drug-containing layer is 11:8-12:130-170:1.7:1.7; The push layer comprises: mannitol, adhesive, red iron oxide, polyethylene oxide, glidant and lubricant; 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; The coating layer comprises: cellulose acetate, a porogen, a plasticizer, water and acetone; the mass ratio of cellulose acetate, porogen, plasticizer, water and acetone in the coating layer is 30:3-9:0.3-0.9:40:424; Wherein, the pore-forming agent is lactose, the binder is hydroxypropyl cellulose, the glidant is silicon dioxide, the lubricant is magnesium stearate, and the plasticizer is polyethylene glycol; The mass ratio of the tofacitinib citrate, the mannitol and the cellulose acetate is 11:20-40:

30.

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

3. A method for preparing a tofacitinib citrate sustained-release tablet preparation according to any one of claims 1 to 2, characterized in that: The specific steps include: (1) Weigh the raw materials according to the 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 porogen, 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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