CN119157848A - A tofacitinib citrate sustained-release tablet preparation and preparation method thereof - Google Patents

Abstract

The invention discloses a tofacitinib citrate sustained-release tablet preparation and a preparation method thereof, belonging to the technical field of pharmaceutical preparations, wherein 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 glidant and a lubricant, the pushing layer comprises mannitol, an adhesive, red ferric oxide, polyoxyethylene, a glidant and a lubricant, and the coating layer comprises cellulose acetate, a pore-forming agent, a plasticizer, water and acetone. The sustained-release tablet preparation solves the technical problems in the prior art by adopting a double-layer osmotic pump prescription design, adopting mannitol and other non-hygroscopic materials, adopting a standard round tablet design, preparing a sustained-release coating layer without using methanol, adopting a coating machine for coating, solidifying and other methods.

Description

Tofacitinib citrate sustained-release tablet preparation and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a tofacitinib citrate sustained-release tablet preparation and a preparation method thereof.

Background

Tofacitinib citrate sustained release tablet is a Janus kinase (JAK) inhibitor developed by the company of pyroxene. JAK belongs to intracellular enzymes, and can conduct signals generated by cytokine or growth factor-receptor interactions on cell membranes, thereby affecting the hematopoietic process and cellular immune function of cells, and in the signal transduction pathway, JAK phosphorylates and activates signal transduction factors and transcription activator (STAT), thereby regulating intracellular activities including gene expression. Tofacitinib citrate plays a therapeutic role by regulating a JAK signal transduction pathway and preventing STAT phosphorylation and activation, and is mainly used for treating rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis and the like at present.

The tofacitinib citrate is a quick-release dosage form firstly marketed, an adult patient needs to take the medicine twice a day, the patient compliance is poor, a slow-release preparation for once a day is developed by a gabion preparation later, an original tofacitinib citrate slow-release tablet XR consists of a tablet core, a semipermeable membrane slow-release coating and a color coating layer, a sample is a pink oval film coated tablet, white or off-white color is formed after the coating is removed, a medicine-containing coating film at the top end of the side surface of the oval tablet is provided with a small medicine hole by using a laser means, the perforating position of a perforating machine has extremely high control precision requirement, the production efficiency is lower, the production cost is high, and auxiliary materials which harm the body even cause blindness, such as methanol, are used in the production process.

Meanwhile, related prior art is improved by related research, but the related prior art has different defects, for example, 60-85% of sorbitol is mainly used as a tablet core permeation source in the CN105101952B, a semipermeable membrane coating mainly comprises cellulose acetate and hydroxypropyl cellulose with the weight ratio of 6:4, the hygroscopicity of the sorbitol is extremely strong, the environmental humidity is required to be strictly controlled in the production process, the non-hygroscopicity in the mixed tabletting process is ensured, and in addition, the semipermeable membrane coating adopts a larger proportion of hydroxypropyl cellulose as a pore-foaming agent, so that polar solvent methanol is required for dissolution and then coating, a toxic reagent which is easy to cause blindness is introduced, potential safety hazards are brought, the dissolution data range under the patent is wider, the release behavior cannot be precisely controlled, and the dissolution speed of the preparation is slowed down after long-term storage.

The patent CN112755000A further prefers the composition of the slow-release coating and the weight gain of the coating by adjusting the composition of the osmotic pressure forming agent and the dosage proportion of the osmotic pressure forming agent and further prefers the composition of the slow-release coating and the weight gain of the coating, and only reduces the defect that the dissolution speed is slow after long-term storage by singly using sorbitol as the osmotic pressure forming agent, but the defect is not fundamentally avoided because the sorbitol is still contained by at least 50 percent, other components are consistent with the original developing agent, and the methanol toxic agent is also introduced.

Although some diluents are added to replace the diluent in the CN117982440a, the sorbitol is still not completely avoided, so that the ambient humidity is still strictly controlled in the production process, so that the defects of no moisture absorption in the mixing and tabletting process and slow dissolution after long-term storage can be ensured.

Patent CN117653609a adopts a matrix tablet technology, but it is known that the technology has the disadvantages that the release rule is different in different media, the release phenomenon is easily caused by the influence of pH and food in the body and the outside, the osmotic pump is easy to absorb moisture in the storage process, the osmotic pump takes osmotic pressure as a slow release mechanism, the osmotic pump is less influenced by the peristaltic motion in the stomach in the body, the matrix tablet takes diffusion and corrosion as slow release mechanisms, and the matrix tablet may be more influenced by the peristaltic motion in the stomach in the body.

The patent CN113712932A mainly adopts a single-layer osmotic pump tablet design, which is easy to cause incomplete drug release, and the patent claims to adopt an osmotic pump technology, but does not have laser drilling and even adopts HPMC as a slow-release coating material, which obviously does not conform to the principle of an osmotic pump, and does not disclose in-vitro dissolution data, so that the research is insufficient.

In addition, the patent requires a layer of isolation coating to influence the drug release and increase the complexity of the process, and the slow-release coating liquid adopts hydroxypropyl cellulose as a pore-forming agent and acetone as a coating solvent, which is very easy to cause incomplete dissolution of the pore-forming agent in the acetone, thereby causing the defect that the coating film is uneven due to sedimentation of the coating liquid, and further causing larger difference in dissolution batch.

Therefore, the problem to be solved by the skilled person is to provide a tofacitinib citrate sustained-release tablet preparation with complete release and simple preparation process.

Disclosure of Invention

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

In order to achieve the above purpose, the present invention adopts the following technical scheme:

The slow-release tablet comprises a double-layer tablet core and a coating layer, wherein 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 glidant and a lubricant;

The pushing layer comprises mannitol, a binder, red ferric oxide, polyoxyethylene, a glidant and a lubricant;

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

Preferably, the mass ratio of tofacitinib citrate, the adhesive, the polyoxyethylene, the silicon dioxide and the magnesium stearate in the drug-containing layer is 11:8-12:130-170:1.7:1.7.

Preferably, the mass ratio of mannitol, binder, red ferric oxide, polyoxyethylene, silicon dioxide and magnesium stearate in the pushing layer is 20-40:12-18:1:80-120:1.3:1.3.

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

Preferably, the mass ratio of the tofacitinib citrate to the mannitol to the cellulose acetate is 11:20-40:30.

Preferably, the binder is hydroxypropyl cellulose;

the glidant is silicon dioxide;

The lubricant is magnesium stearate;

The pore-forming agent is lactose;

The plasticizer is polyethylene glycol.

Preferably, the sustained release tablet is a round tablet, and holes are formed in the side of the drug-containing layer.

The preparation method of the tofacitinib citrate sustained-release tablet preparation comprises the following specific steps:

(1) Weighing the raw materials according to the mass ratio:

The medicine-containing layer comprises tofacitinib citrate, an adhesive, polyoxyethylene, a glidant and a lubricant, the pushing layer comprises mannitol, an adhesive, red ferric oxide, polyoxyethylene, a glidant and a lubricant, and the coating layer comprises cellulose acetate, a pore-forming agent, a plasticizer, water and acetone;

(2) After the raw materials of the medicine-containing layer and the pushing layer are respectively and uniformly mixed, preparing a double-layer tablet core through a tablet press;

(3) Adding the cellulose acetate, the pore-forming agent and the plasticizer into the mixed solution of the water and the acetone to obtain coating liquid;

(4) Spraying the coating liquid onto the double-layer tablet core to obtain coated tablet, perforating the side of the drug-containing layer of the coated tablet, and curing by a coating machine to obtain the tofacitinib citrate sustained-release tablet.

Preferably, the curing time is 2-4 hours.

The preparation process of the prior tofacitinib citrate sustained-release tablet mainly comprises the procedures of crushing, mixing, tabletting, sustained-release coating, laser drilling, curing, color coating and the like, and preparation equipment required to be used comprises an airflow crusher, a mixer, a tabletting machine, a coating machine, a special-shaped tablet laser drilling machine, a drying oven and the like.

Compared with the prior art, the invention has the following beneficial effects:

(1) The drug-containing layer and the pushing layer of the sustained-release tablet are directly tableted, so that the production process and the energy consumption are simplified, the curing process is cured by a coating machine, the time is obviously shortened, the use of equipment is reduced, and the use cost of the equipment is reduced;

(2) The slow release tablet adopts the middle of the round tablet for punching, and can meet the requirement of a common punching machine, thereby improving the production efficiency;

(3) The sustained release tablet adopts a double-layer osmotic pump design, avoids the defect of incomplete release of a single-layer preparation dissolution end point, adopts materials such as mannitol which are not hygroscopic, avoids the influence of humidity in the production process, avoids the increase of moisture in the storage process and the slow dissolution phenomenon in the long-term storage process, does not use methanol for preparing a sustained release coating layer, reduces the solvent residue and the damage to human bodies, and reduces the use of coating pore-foaming agent and the use of coating materials and the coating time.

Drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.

FIG. 1 is a front view of an example preparation product;

Fig. 2 is a side view of an example article of manufacture.

Detailed Description

The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

The invention provides a preparation method of a tofacitinib citrate sustained-release tablet preparation, which comprises the following specific steps:

(1) Weighing raw materials of a medicine-containing layer according to mass ratio, namely tofacitinib citrate, an adhesive, polyoxyethylene, a glidant and a lubricant, wherein the raw materials of a pushing layer comprise mannitol, the adhesive, red ferric oxide, polyoxyethylene, the glidant and the lubricant, and the raw materials of a coating layer comprise cellulose acetate, a pore-forming agent, a plasticizer, water and acetone;

(2) The raw materials and the auxiliary materials of the medicine-containing layer and the pushing layer are respectively and uniformly mixed and then added into a double-layer tablet press, and a round punch is adopted to press the double-layer tablet core;

(3) Adding cellulose acetate, a pore-forming agent and a plasticizer into a mixed solution of water and acetone, and uniformly stirring to obtain a coating solution;

(4) Uniformly spraying the coating solution onto the double-layer tablet core by a coating machine to obtain coated tablet, punching the side of the drug-containing layer of the coated tablet by a laser punching machine, and then placing into the coating machine to be cured for 2-4h to obtain the tofacitinib citrate sustained-release tablet, wherein the related products are shown in figures 1 and 2.

Examples 1-3 and comparative examples 1-2

By adopting the preparation method, the relevant proportion of the raw materials and the auxiliary materials of the examples 1-3 and the comparative examples 1-2 is shown in the table 1,

TABLE 1 relevant proportions of raw materials and auxiliary materials for examples 1-3 and comparative examples 1-2

Comparative example 3

The tofacitinib citrate double-layer sustained-release tablet sample prepared by adopting the patent CN117653609A and the example 2 is adopted.

Comparative example 4

A sample of 11mg tablets was prepared using patent CN105101952B, example 2.

The sustained release tablets prepared in examples 1-3 and comparative examples 1-2, comparative examples 3-4 and the as-ground formulation (Shang Jie ^R mg lot: FN 6775) were subjected to the following performance tests:

Dissolution detection

Taking the product, adding a sedimentation basket, measuring according to a dissolution rate and release rate measuring method (a second method of the four general rules 0931 of Chinese pharmacopoeia 2020 edition), taking 900ml of phosphate buffer solution (40.8 g of monopotassium phosphate is weighed, water is added for dissolution and dilution to 6000ml, 3mol/L potassium hydroxide is used for regulating pH to 6.8+/-0.05) as a dissolution medium, the rotating speed is 50 revolutions per minute, taking 10ml of dissolution liquid after 1h, 2.5h and 6h according to the normal operation, filtering, discarding 3ml of primary filtrate, taking the continuous filtrate as a solution of a sample, and timely supplementing the dissolution medium with the same temperature and the same volume;

Taking about 18mg of tofacitinib citrate reference substance, precisely weighing, putting into a 100ml measuring flask, adding a solvent for dissolution and quantitatively diluting to a scale, shaking uniformly, precisely weighing 5ml, putting into a 50ml measuring flask, adding a dissolution medium for dilution to the scale, shaking uniformly, and taking as a reference substance solution;

The test solution and the reference solution were taken, and the elution amounts at different times were measured by the chromatographic method under the content measurement item, and the results are shown in tables 2 and 3.

TABLE 2 dissolution test results for products of examples 1-3 and comparative examples 1-2

TABLE 3 comparative examples 3-4 and results of the dissolution test of the original developer products

As is clear from the results in Table 2 and Table 3, the release rate of the products of examples 1 to 3 can reach more than 90% in 6 hours, the release rate of the original grinding preparation is about 85%, the release rate is obviously more complete than that of the original grinding preparation, the drug effect is improved, in addition, the dissolution RSD of the examples is obviously superior to that of the original grinding preparation, the release rate of comparative example 1 is slower, the release rate of comparative example 2 is not complete, the release rate of comparative example 2 is obviously faster, the release effect is not obvious, the release rate of comparative example 3 is at risk of sudden release in 1 hour, the release rate of comparative example 4 is 85% in 6 hours, and the release is incomplete.

Residual solvent detection

The residual solvent is measured according to a residual solvent measurement method (a second method of the fourth rule 0861 of the Chinese pharmacopoeia 2020 edition);

taking 5 pieces of sample solution, precisely weighing, placing into a 100ml measuring flask, adding a proper amount of N, N-dimethylacetamide, oscillating for about 60 minutes on a reciprocating/oscillating oscillator at a speed of 200 times per minute, diluting to a scale with the N, N-dimethylacetamide, shaking uniformly, centrifuging, precisely weighing 5ml of supernatant, placing into a 20ml headspace flask, and sealing;

taking a proper amount of methanol and acetone, precisely weighing, dissolving with N, N-dimethylacetamide, diluting to obtain a mixed solution containing 34 mug of methanol and 56 mug of acetone in each 1ml, precisely weighing 5ml, placing into a 20ml headspace bottle, and sealing;

The chromatographic conditions were a capillary column with 6% cyanopropylphenyl-94% dimethylsiloxane (or similar polarity) as the fixing liquid as the chromatographic column, nitrogen as the carrier gas at a flow rate of 1.6ml per minute, a starting temperature of 40 ℃ for 5 minutes, then rising to 90 ℃ at a rate of 2 ℃ per minute, then rising to 225 ℃ at a rate of 30 ℃ per minute, and holding for 2 minutes. The detector is a hydrogen Flame Ionization Detector (FID) with the temperature of 260 ℃, the temperature of a sample inlet of 180 ℃, the balance temperature of a headspace bottle of 105 ℃, the temperature of a sample loop of 110 ℃, the temperature of a transmission pipeline of 115 ℃, the balance time of 30 minutes and the split ratio of 30:1;

Taking sample solution and reference solution, respectively taking headspace sample, recording chromatogram, and the result is shown in Table 4.

TABLE 4 residual solvent detection results

As is clear from the results of the residual solvent detection in Table 4, the methanol was not used in the examples, and thus was not detected, and both the crude preparation and the comparative example 4 preparation samples contained methanol residues.

Dose dumping test

The dissolution behavior of the example preparation and the original preparation is evaluated according to the guidelines of the pharmaceutical study technology of the ethanol dose dumping test of the chemical simulated pharmaceutical oral modified release preparation, and the results are shown in table 5;

TABLE 5 results of dose dumping test

As can be seen from the data relating to 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 preparation, the risk of dose dumping after the patient drinks the medicine is reduced, the dose dumping of comparative example 3 is significantly worse than that of the original preparation, and the dose dumping of comparative example 2 is basically the same as that of comparative example 4.

Open bottle test study-moisture

Referring to the instruction book, according to the fact that bottle opening and medicine taking are simulated in the morning every day, each time lasts for 10 minutes, the change of moisture indexes is examined, and the related results are shown in Table 6;

TABLE 6 results of stability to opening bottles

As can be seen from the data in Table 6, examples 1-3 and comparative examples 1-2 showed slower moisture growth than the original formulation, indicating that the original formulation was more hygroscopic, whereas comparative example 3 showed the fastest moisture growth and the most hygroscopic, and comparative example 4 was substantially identical to the original formulation.

The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (8)

1. The tofacitinib citrate sustained-release tablet preparation is characterized by comprising a double-layer tablet core and a coating layer, wherein 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 glidant and a lubricant;

The pushing layer comprises mannitol, a binder, red ferric oxide, polyoxyethylene, a glidant and a lubricant;

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

2. The tofacitinib citrate sustained-release tablet preparation according to claim 1, wherein the mass ratio of tofacitinib citrate, adhesive, polyoxyethylene, 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 formulation according to claim 1, wherein the mass ratio of mannitol, binder, red ferric oxide, polyoxyethylene, 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 formulation according to claim 1, wherein 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 formulation according to claim 1, wherein the mass ratio of tofacitinib citrate, mannitol and cellulose acetate is 11:20-40:30.

6. A tofacitinib citrate sustained-release tablet formulation according to claim 1, wherein the binder is hydroxypropyl cellulose;

the glidant is silicon dioxide;

The lubricant is magnesium stearate;

The pore-forming agent is lactose;

The plasticizer is polyethylene glycol.

7. The tofacitinib citrate sustained-release tablet formulation according to claim 1, wherein the sustained-release tablet is a round tablet and is perforated at the drug-containing layer side.

8. The method for preparing a tofacitinib citrate sustained-release tablet formulation according to any one of claims 1-7, comprising the specific steps of:

(1) Weighing the raw materials according to the mass ratio:

The medicine-containing layer comprises tofacitinib citrate, an adhesive, polyoxyethylene, a glidant and a lubricant, the pushing layer comprises mannitol, an adhesive, red ferric oxide, polyoxyethylene, a glidant and a lubricant, and the coating layer comprises cellulose acetate, a pore-forming agent, a plasticizer, water and acetone;

(2) After the raw materials of the medicine-containing layer and the pushing layer are respectively and uniformly mixed, preparing a double-layer tablet core through a tablet press;

(3) Adding the cellulose acetate, the pore-forming agent and the plasticizer into the mixed solution of the water and the acetone to obtain coating liquid;

(4) Spraying the coating liquid onto the double-layer tablet core to obtain coated tablet, perforating the side of the drug-containing layer of the coated tablet, and curing by a coating machine to obtain the tofacitinib citrate sustained-release tablet.