CN112007004A - Tofacitinib citrate tablet and preparation method thereof - Google Patents
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Abstract
The invention provides tofacitinib citrate tablets and a preparation method thereof, belonging to the technical field of pharmaceutical preparations and comprising 2-8 parts of tofacitinib citrate and 92-98 parts of pharmaceutic adjuvant; the pharmaceutical excipients comprise a filler, a binder, a disintegrating agent, a lubricant and a coating material, wherein the mass ratio of the filler, the binder, the disintegrating agent, the lubricant and the coating material is 60-90: 1-5: 2-6: 0.1-5: 1-4. The tofacitinib citrate tablet provided by the invention can be quickly dissolved out in a short time. The preparation method can achieve the dissolution rate consistent with that of a reference preparation without adding a surfactant or carrying out micronization and sieving treatment on raw materials, and simultaneously improves the content uniformity of the tablet; the process is beneficial to enhancing oral absorption and improving bioavailability; the prescription process is simple and easy for industrial production; solves the problems that tofacitinib citrate has poor water solubility and low permeability and limits the oral bioavailability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to tofacitinib citrate tablets and a preparation method thereof.
Background
Tofacitinib citrate, chemical name: (3R,4R) -4-methyl-3- (methyl-7H-pyrrolo [2, 3-d)]Pyrimidin-4-ylamino) -beta-oxo-1-piperidinepropanitrile citrate of formula C16H20N6O·C6H8O7Relative molecular weight 504.5. The structural formula is as follows:
tofacitinib citrate, also called tofacitinib citrate, is a drug developed by the American pflug pharmaceutical company for treating rheumatoid arthritis, is used for adult patients with moderate to severe active Rheumatoid Arthritis (RA) with insufficient or intolerant response to methotrexate treatment, and is a Janus kinase inhibitor. Unlike most other RA therapeutics that act primarily on extracellular targets at present, tofacitinib acts on the core of the cytokine network with intracellular signaling pathways as targets. Tofacitinib inhibits JAK3 5-100 times stronger than JAK1 and JAK 2. Tofacitinib is the pioneer drug for developing rheumatoid arthritis treatment, and the FDA approved a JAK inhibitor for treating adult active stages and moderate to severe rheumatoid arthritis patients who do not respond well to methotrexate on day 11, 6 of 2012.
As is known, the gastrointestinal tract is the most ideal administration way for the medicine to enter the body to play the therapeutic role, and the route has the characteristics of safest administration, most convenient use, accurate dosage, simple process, good stability and the like, and is always the most popular and advocated dosage form in clinic. Therefore, how to design and produce tablets with optimal therapeutic effect is always the focus of attention in the pharmaceutical manufacturing industry.
Disclosure of Invention
In view of the above, the invention aims to provide a tofacitinib citrate tablet and a preparation method thereof, and the tofacitinib citrate tablet provided by the invention can be quickly dissolved out in a short time.
In order to achieve the above purpose, the invention provides the following technical scheme:
the invention provides tofacitinib citrate tablets which comprise the following components in parts by weight: 2-8 parts of tofacitinib citrate and 92-98 parts of pharmaceutic adjuvant;
the pharmaceutical auxiliary materials comprise a filling agent, a binding agent, a disintegrating agent, a lubricating agent and a coating material, wherein the mass ratio of the filling agent to the binding agent to the disintegrating agent to the lubricating agent to the coating material is 60-90: 1-5: 2-6: 0.1-5: 1-4.
Preferably, the filler comprises one or more of dextrin, lactose, microcrystalline cellulose, starch and mannitol.
Preferably, the binder comprises one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, carboxymethyl cellulose and corn starch.
Preferably, the disintegrant comprises one or more of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch.
Preferably, the lubricant comprises one or more of magnesium stearate, talcum powder, polyethylene glycol and aerosil.
The invention provides a preparation method of tofacitinib citrate tablets, which comprises the following steps:
1) homogenizing the tofacitinib citrate, purified water and 30% of the total mass of the adhesive under high pressure to obtain a lubricating solution;
2) mixing 70% of the total mass of the filler and the adhesive with a disintegrating agent to obtain a premixed auxiliary material;
3) mixing and granulating the lubricating solution obtained in the step 1) and the premixed auxiliary material obtained in the step 2) to obtain granules, mixing the granules with a lubricant, and tabletting to obtain tabletting materials;
4) coating the tabletting material obtained in the step 3) with a coating material to obtain tofacitinib citrate tablets.
Preferably, the mass ratio of the tofacitinib citrate in the step 1) to the purified water and the adhesive is 1: 5-15: 0.5-1.5.
Preferably, the conditions for high-pressure homogenization in step 1) include: adding tofacitinib citrate and an adhesive into purified water, carrying out ultrasonic treatment for 5-10min, shearing at the rotating speed of 5000-20000 rpm for 5-10min, and homogenizing under high pressure at the pressure of 1000-2000 bar for 3-5 times.
Preferably, the mixing time in the step 2) is 10-20 min.
Preferably, the mixing time in the step 3) is 3-8 min.
The invention provides tofacitinib citrate tablets which comprise the following components in parts by weight: 2-8 parts of tofacitinib citrate and 92-98 parts of pharmaceutic adjuvant; the pharmaceutical auxiliary materials comprise a filling agent, a binding agent, a disintegrating agent, a lubricating agent and a coating material, wherein the mass ratio of the filling agent to the binding agent to the disintegrating agent to the lubricating agent to the coating material is 60-90: 1-5: 2-6: 0.1-5: 1-4. The tofacitinib citrate tablet provided by the invention can realize the rapid dissolution of tofacitinib citrate in a short time.
The invention also provides a preparation method of the tofacitinib citrate tablet, which can achieve the dissolution rate consistent with that of a reference preparation without adding a surfactant or micronizing and sieving raw materials, and simultaneously improve the content uniformity of the tablet; the process is beneficial to enhancing oral absorption and improving bioavailability; the prescription process is simple and easy for industrial production; solves the problems that tofacitinib citrate has poor water solubility and low permeability and limits the oral bioavailability.
Drawings
FIG. 1 shows the dissolution profiles of commercial, example and comparative examples.
Detailed Description
The invention provides tofacitinib citrate tablets which comprise the following components in parts by weight: 2-8 parts of tofacitinib citrate and 92-98 parts of pharmaceutic adjuvant; the pharmaceutical auxiliary materials comprise a filling agent, a binding agent, a disintegrating agent, a lubricating agent and a coating material, wherein the mass ratio of the filling agent to the binding agent to the disintegrating agent to the lubricating agent to the coating material is 60-90: 1-5: 2-6: 0.1-5: 1-4.
The source of the tofacitinib citrate is not specially limited, and the tofacitinib citrate is obtained by adopting conventional market selling.
In the present invention, the filler preferably includes one or more of dextrin, lactose, microcrystalline cellulose, starch, and mannitol. In the invention, the filler preferably accounts for 60-90% of the total weight of the tofacitinib citrate tablet.
In the present invention, the binder preferably includes one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, carboxymethyl cellulose and corn starch. In the invention, the binder preferably accounts for 1-5% of the total weight of the tofacitinib citrate tablet, and more preferably accounts for 2-4%.
In the present invention, the disintegrant preferably comprises one or more of croscarmellose sodium, crospovidone, and sodium carboxymethyl starch. In the invention, the disintegrant preferably accounts for 2-6% of the total weight of the tofacitinib citrate tablet.
In the present invention, the lubricant preferably includes one or more of magnesium stearate, talc, polyethylene glycol and aerosil. In the invention, the lubricant preferably accounts for 0.5-5% of the total weight of the tofacitinib citrate tablet, and more preferably accounts for 0.2-2%.
The invention also provides a preparation method of the tofacitinib citrate tablet, which comprises the following steps:
1) homogenizing the tofacitinib citrate, purified water and 30% of the total mass of the adhesive under high pressure to obtain a lubricating solution;
2) mixing 70% of the total mass of the filler and the adhesive with a disintegrating agent to obtain a premixed auxiliary material;
3) mixing and granulating the lubricating solution obtained in the step 1) and the premixed auxiliary material obtained in the step 2) to obtain granules, mixing the granules with a lubricant, and tabletting to obtain tabletting materials;
4) coating the tabletting material obtained in the step 3) with a coating material to obtain tofacitinib citrate tablets.
The preparation method comprises the step of homogenizing tofacitinib citrate, purified water and 30% of total mass of an adhesive under high pressure to obtain a lubricating solution.
In the invention, the mass ratio of the tofacitinib citrate to the purified water to the adhesive is preferably 1: 5-15: 0.5-1.5. In the present invention, the conditions for the high-pressure homogenization preferably include: adding tofacitinib citrate and an adhesive into purified water, carrying out ultrasonic treatment for 5-10min, shearing at the rotating speed of 5000-20000 rpm for 5-10min, and homogenizing under high pressure at the pressure of 1000-2000 bar for 3-5 times. In the present invention, the sonication allows the drug to be well dispersed in the purified water. The shearing is preferably carried out using a high-speed disperser, and the homogenization is preferably carried out using a high-pressure homogenizer.
The invention mixes 70 percent of the total mass of the filler and the adhesive with the disintegrating agent to obtain the premixed auxiliary material. The invention preferably mixes the filling agent, the adhesive and the disintegrating agent in a mixer for 10-20 min.
The obtained lubricating solution and the obtained premixed auxiliary material are mixed and granulated to obtain granules, and the granules are mixed with the lubricating agent and tabletted to obtain the tabletted material. Preferably, the premixed auxiliary materials are placed in a fluidized bed, the preheating is carried out for 5-15 min, the obtained wetting solution is uniformly added into a fluidized bed spray gun through a peristaltic pump, the temperature is set to be 50 ℃, the lubricating agent is added after the granulation is finished, and the total mixing is carried out for 3-8 min. The invention preferably uses a shallow concave die with the diameter of 8mm to carry out tabletting on the total mixed materials.
The tablet pressing material is coated by a coating material to obtain tofacitinib citrate tablets. The invention preferentially prepares the coating material into a film coating premix solution, the solid content is 10-20%, the air inlet temperature is 50-60 ℃, the rotating speed of a host is 5-8rpm, and the coating is carried out on the tabletting material.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
The prescription of the tofacitinib citrate tablet comprises the following components:
the preparation method comprises the following steps:
(1) adding tofacitinib citrate and hydroxypropyl cellulose into purified water under stirring, and performing ultrasonic treatment for 8min to disperse the medicine in water; shearing with high speed disperser at 10000rpm for 8min to obtain suspension; then the high-pressure homogenizer is circulated for 4 times under the pressure of 1500 bar;
(2) premixing: mixing microcrystalline cellulose, lactose, and croscarmellose sodium in a mixer for 25 min;
(3) and (3) granulating: placing the mixed materials in a fluidized bed, preheating for 5min, pumping the wetting agent solution into a spray gun of the fluidized bed by a peristaltic pump, wherein the atomization pressure of the spray gun is 0.2Mpa, and the granulation temperature is 50 ℃;
(4) total mixing: mixing the obtained granules with magnesium stearate for 5 min;
(5) tabletting: use of
The shallow concave punching die is used for tabletting the total mixed materials;
(6) coating: preparing coating liquid with solid content of 10%, wherein the inlet air temperature is 50-60 ℃, the host rotating speed is 5-8rpm, and the coating weight is increased by 2.6%.
Example 2
The prescription of the tofacitinib citrate tablet comprises the following components:
the preparation method comprises the following steps:
1) adding tofacitinib citrate and hydroxypropyl cellulose into purified water under stirring, and performing ultrasonic treatment for 8min to disperse the medicine in water; shearing with high speed disperser at 10000rpm for 8min to obtain suspension; then the high-pressure homogenizer is circulated for 4 times under the pressure of 1500 bar;
(2) premixing: mixing microcrystalline cellulose, lactose, and croscarmellose sodium in a mixer for 25 min;
(3) and (3) granulating: placing the mixed materials in a fluidized bed, preheating for 5min, pumping the wetting agent solution into a spray gun of the fluidized bed by a peristaltic pump, wherein the atomization pressure of the spray gun is 0.2Mpa, and the granulation temperature is 50 ℃;
(4) total mixing: mixing the obtained granules with magnesium stearate for 5 min;
(5) tabletting: use of
The shallow concave punching die is used for tabletting the total mixed materials;
(6) coating: preparing coating liquid with solid content of 10%, wherein the inlet air temperature is 50-60 ℃, the host rotating speed is 5-8rpm, and the coating weight is increased by 2.4%.
Example 3
The prescription of the tofacitinib citrate tablet comprises the following components:
the preparation method comprises the following steps:
(1) adding tofacitinib citrate and hydroxypropyl cellulose into purified water under stirring, and performing ultrasonic treatment for 8min to disperse the medicine in water; shearing with high speed disperser at 10000rpm for 8min to obtain suspension; then the high-pressure homogenizer is circulated for 4 times under the pressure of 1500 bar;
(2) premixing: mixing microcrystalline cellulose, lactose, and croscarmellose sodium in a mixer for 25 min;
(3) and (3) granulating: placing the mixed materials in a fluidized bed, preheating for 5min, pumping the wetting agent solution into a spray gun of the fluidized bed by a peristaltic pump, wherein the atomization pressure of the spray gun is 0.2Mpa, and the granulation temperature is 50 ℃;
(4) total mixing: mixing the obtained granules with magnesium stearate for 5 min;
(5) tabletting: use of
The shallow concave punching die is used for tabletting the total mixed materials;
(6) coating: preparing coating liquid with solid content of 10%, wherein the inlet air temperature is 50-60 ℃, the host rotating speed is 5-8rpm, and the coating weight is increased by 2.7%.
Example 4
The prescription of the tofacitinib citrate tablet comprises the following components:
the preparation method comprises the following steps:
(1) adding tofacitinib citrate and hydroxypropyl cellulose into purified water under stirring, and performing ultrasonic treatment for 8min to disperse the medicine in water; shearing with high speed disperser at 10000rpm for 8min to obtain suspension; then the high-pressure homogenizer is circulated for 4 times under the pressure of 1500 bar;
(2) premixing: mixing microcrystalline cellulose, lactose, and croscarmellose sodium in a mixer for 25 min;
(3) and (3) granulating: placing the mixed materials in a fluidized bed, preheating for 5min, pumping the wetting agent solution into a spray gun of the fluidized bed by a peristaltic pump, wherein the atomization pressure of the spray gun is 0.2Mpa, and the granulation temperature is 50 ℃;
(4) total mixing: mixing the obtained granules with magnesium stearate for 5 min;
(5) tabletting: use of
The shallow concave punching die is used for tabletting the total mixed materials;
(6) coating: preparing coating liquid with solid content of 10%, wherein the inlet air temperature is 50-60 ℃, the host rotating speed is 5-8rpm, and the coating weight is increased by 2.8%.
Comparative example 1
Prescription:
the preparation method comprises the following steps:
(1) premixing: mixing tofacitinib citrate, microcrystalline cellulose, lactose, croscarmellose sodium and sodium lauryl sulfate in a mixer for 25 min;
(2) total mixing: adding magnesium stearate, and mixing for 5 min;
(3) tabletting: use of
The shallow concave punching die is used for tabletting the total mixed materials;
(4) coating: preparing coating liquid with solid content of 10%, wherein the inlet air temperature is 50-60 ℃, the host rotating speed is 5-8rpm, and the coating weight is increased by 2.7%.
Formulation testing
The content uniformity, in vitro release results and release curves of the tofacitinib citrate tablets prepared in the above examples 1-4 and comparative example 1 were determined.
The content uniformity a +2.2S of each example was less than 3.0, and the content uniformity a +2.2S of the comparative example was 11.12, and the results are shown in table 1.
Table 1 results for content uniformity of examples and comparative examples
Tofacitinib citrate tablet, a commercially available product from pfpristmc.v., was used as a reference formulation, trade name: shangjie, manufacturer's place of production: pfizermafacturing deutschlandgmbh, specification: 5mg as reference; the tofacitinib citrate tablets of the self-made samples of examples 1-4 and comparative example 1 were also set to 5 mg.
The dissolution curve detection method comprises the following steps: according to the first method of 0931 in the four general guidelines of the "Chinese pharmacopoeia" 2015 edition: the basket method is carried out. Taking the product, taking 900ml of 0.1mol/L hydrochloric acid solution as a dissolution medium, wherein the rotating speed is 50 r/min per minute, and the sampling time is as follows: 5. 10, 15, 20, 30 and 45 min. Respectively taking the sample as a test solution at a sampling time point, preparing a tofacitinib citrate reference solution, and measuring a sample by adopting an HPLC method, wherein the chromatographic conditions are as follows: a chromatographic column: aiger venusil c18plus (4.6mm 150mm, 3.0 μm) or performance equivalent chromatography column, detection wavelength: 287nm, flow rate: 1.0ml/min, column temperature: 40 ℃, mobile phase: 0.01mol/L potassium dihydrogen phosphate solution (pH 3.0 adjusted with phosphoric acid) -acetonitrile (80: 20). The amount of elution was calculated as peak area by external standard method. The results are shown in Table 2 and FIG. 1.
TABLE 2 measurement results of dissolution curves
| Time of day | Is commercially available | Example 1 | Example 2 | Example 3 | Example 4 | |
| 0min | ||||||
| 0 | 0 | 0 | 0 | 0 | 0 | |
| 5min | 72.0％ | 71.1％ | 72.8％ | 73.1％ | 75.5％ | 23.6％ |
| 10min | 87.9％ | 88.9％ | 91.2％ | 87.7％ | 92.0％ | 48.3％ |
| 15min | 93.8％ | 93.1％ | 96.5％ | 94.3％ | 97.8％ | 64.2％ |
| 20min | 96.0％ | 94.9％ | 98.4％ | 97.1％ | 98.1％ | 78.5％ |
| 30min | 97.5％ | 95.9％ | 99.6％ | 98.3％ | 98.4％ | 89.7％ |
| 45min | 97.6％ | 96.5％ | 99.8％ | 98.4％ | 98.7％ | 97.1％ |
As can be seen from tables 1 and 2 and fig. 1, the present invention provides a method for preparing tofacitinib citrate tablets, which can achieve a dissolution rate consistent with that of a reference preparation without adding a surfactant or micronizing and sieving raw materials, and simultaneously improve the content uniformity of the tablets.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. The tofacitinib citrate tablet is characterized by comprising the following components in parts by weight: 2-8 parts of tofacitinib citrate and 92-98 parts of pharmaceutic adjuvant;
the pharmaceutical auxiliary materials comprise a filling agent, a binding agent, a disintegrating agent, a lubricating agent and a coating material, wherein the mass ratio of the filling agent to the binding agent to the disintegrating agent to the lubricating agent to the coating material is 60-90: 1-5: 2-6: 0.1-5: 1-4.
2. The tofacitinib citrate tablet according to claim 1, wherein the filler comprises one or more of dextrin, lactose, microcrystalline cellulose, starch and mannitol.
3. The tofacitinib citrate tablet according to claim 1, wherein the binder comprises one or more of hydroxypropyl cellulose, hypromellose, povidone, carboxymethyl cellulose and corn starch.
4. The tofacitinib citrate tablet according to claim 1, wherein the disintegrant comprises one or more of croscarmellose sodium, crospovidone and sodium carboxymethyl starch.
5. The tofacitinib citrate tablet according to claim 1, wherein the lubricant comprises one or more of magnesium stearate, talc, polyethylene glycol and aerosil.
6. The preparation method of tofacitinib citrate tablet as claimed in any one of claims 1 to 5, characterized by comprising the following steps:
1) homogenizing the tofacitinib citrate, purified water and 30% of the total mass of the adhesive under high pressure to obtain a lubricating solution;
2) mixing 70% of the total mass of the filler and the adhesive with a disintegrating agent to obtain a premixed auxiliary material;
3) mixing and granulating the lubricating solution obtained in the step 1) and the premixed auxiliary material obtained in the step 2) to obtain granules, mixing the granules with a lubricant, and tabletting to obtain tabletting materials;
4) coating the tabletting material obtained in the step 3) with a coating material to obtain tofacitinib citrate tablets.
7. The preparation method according to claim 6, wherein the mass ratio of the tofacitinib citrate in the step 1) to the purified water and the adhesive is 1: 5-15: 0.5-1.5.
8. The method according to claim 6, wherein the step 1) of high-pressure homogenization comprises: adding tofacitinib citrate and an adhesive into purified water, carrying out ultrasonic treatment for 5-10min, shearing at the rotating speed of 5000-20000 rpm for 5-10min, and homogenizing under high pressure at the pressure of 1000-2000 bar for 3-5 times.
9. The preparation method of claim 6, wherein the mixing time in the step 2) is 10-20 min.
10. The preparation method of claim 6, wherein the mixing time in the step 3) is 3-8 min.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115068432A (en) * | 2022-08-02 | 2022-09-20 | 沈阳信康药物研究有限公司 | Tofacitinib citrate pressed coating sustained release tablet and preparation method thereof |
| CN115381788A (en) * | 2022-09-19 | 2022-11-25 | 苏州弘森药业股份有限公司 | Tofacitinib citrate preparation and preparation method thereof |
| CN115887408A (en) * | 2022-11-29 | 2023-04-04 | 江苏慧聚药业股份有限公司 | Pharmaceutical composition and pharmaceutical preparation comprising tofacitinib |
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| CN115887408A (en) * | 2022-11-29 | 2023-04-04 | 江苏慧聚药业股份有限公司 | Pharmaceutical composition and pharmaceutical preparation comprising tofacitinib |
| CN115887408B (en) * | 2022-11-29 | 2024-05-24 | 江苏慧聚药业股份有限公司 | Pharmaceutical compositions and pharmaceutical formulations comprising tofacitinib |
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