CN113081992B - JAK kinase inhibitor tablet and preparation method thereof - Google Patents

JAK kinase inhibitor tablet and preparation method thereof Download PDF

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CN113081992B
CN113081992B CN202010020109.7A CN202010020109A CN113081992B CN 113081992 B CN113081992 B CN 113081992B CN 202010020109 A CN202010020109 A CN 202010020109A CN 113081992 B CN113081992 B CN 113081992B
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tablet
coating
tofacitinib citrate
mixing
lubricant
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CN113081992A (en
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阚红亮
丁思远
章晓骅
徐丹
朱春霞
田舟山
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Nanjing Chia Tai Tianqing Pharmaceutical Co Ltd
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
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    • A61K9/2813—Inorganic compounds
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
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    • A—HUMAN NECESSITIES
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    • A61K9/2826—Sugars or sugar alcohols, e.g. sucrose; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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  • Orthopedic Medicine & Surgery (AREA)
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Abstract

The invention relates to a JAK kinase inhibitor tablet and a preparation method thereof, wherein the JAK kinase inhibitor tablet comprises an active ingredient tofacitinib citrate, a filling agent consisting of lactose and microcrystalline cellulose PH200, a disintegrating agent, a lubricant and a coating agent. The tofacitinib citrate tablet has high stability, small tablet weight difference and high content uniformity, and the production efficiency can be improved by adopting a direct powder tabletting process.

Description

JAK kinase inhibitor tablet and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a JAK kinase inhibitor tablet and a preparation method thereof.
Background
Tofacitinib (Tofacitinib), also known as Tofacitinib, is an oral small molecule Janus Kinase (JAK) inhibitor developed by pfeiri. The drug is approved to be marketed by the FDA in 2012 and has the trade name of
Figure BDA0002360411140000012
Can be used for treating rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. The medicine is approved to be on the market in 2017 in China, and the trade name is
Figure BDA0002360411140000013
(Tofacitinib citrate tablet, 5 mg) is suitable for the moderate-to-severe active Rheumatoid Arthritis (RA) adult patients with insufficient treatment effect or intolerance to methotrexate, and can be used together with methotrexate or other non-biological disease-improving antirheumatic drugs (DMARDs).
Primarily ground tofacitinib citrate tablet
Figure BDA0002360411140000014
The FDA approved marketed prescription of 5mg size is: the active component tofacitinib citrate comprises the following auxiliary materials: croscarmellose sodium, HPMC 2910/hypromellose (6 cP), lactose monohydrate, polyethylene glycol/PEG 3350, magnesium stearate, microcrystalline cellulose, titanium dioxide and triacetin.
In patent CN106420648A, dry granulation is adopted in the original research, which is tedious in process, poor in operability and high in equipment requirement. In actual production, the tofacitinib citrate belongs to a high-solubility medicine, is easy to migrate during granulation and drying to cause uneven product content, and has the problems of stability and the like.
Further improvements in their formulation and preparation are therefore desirable.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the tofacitinib citrate tablet which is stable in chemical property and uniform in content.
The tofacitinib citrate tablet consists of active ingredients of tofacitinib citrate, lactose, microcrystalline cellulose PH200, a disintegrating agent, a lubricant and a coating agent.
In some embodiments, the weight percentages of tofacitinib citrate, lactose, microcrystalline cellulose PH200, disintegrant, and lubricant are as follows:
Figure BDA0002360411140000011
the weight percentage is the proportion of each component in the plain tablets.
In some exemplary embodiments, the weight percentages of tofacitinib citrate, lactose, microcrystalline cellulose PH200, disintegrant, and lubricant are as follows:
Figure BDA0002360411140000021
the weight percentage is the proportion of each component in the plain tablets.
In some embodiments, the disintegrant is selected from sodium carboxymethyl starch, croscarmellose sodium, low substituted hydroxypropyl cellulose, or crospovidone; in some typical embodiments, the disintegrant is croscarmellose sodium.
In some embodiments, the lubricant is selected from magnesium stearate, talc, or sodium stearyl fumarate; in some typical embodiments, the lubricant is magnesium stearate.
In some embodiments, the coating agent is opadry; in some exemplary embodiments, the coating agent is
Figure BDA0002360411140000024
Figure BDA0002360411140000023
33G28523-CN, the main components are lactose, titanium dioxide, triethyl glycerolate, hydroxypropyl methylcellulose and polyethylene glycol.
In some embodiments, the coating weight gain is from 2.0% to 4.0%.
On the other hand, the invention also provides a preparation method of the tofacitinib citrate tablet, which comprises the steps of primary mixing, sieving, total mixing, tabletting and coating.
Specifically, the preparation method comprises the following steps:
1) Primary mixing: mixing the tofacitinib citrate, lactose, microcrystalline cellulose PH200 and croscarmellose sodium in feeding amount;
2) Sieving: sieving the materials after primary mixing, wherein the aperture of a sieve is phi 0.6mm;
3) Total mixing: adding magnesium stearate with a feeding amount into the sieved materials for total mixing;
4) Tabletting: directly tabletting the totally mixed materials, and controlling the hardness of the tablets to be between 50N and 90N;
5) Coating: preparing a coating solution, wherein the solvent is purified water, slowly adding the Opadry with the prescription amount into the purified water, fully stirring for 45min to disperse, and then coating, wherein the weight gain of the coating is 2.0-4.0%.
Detailed Description
The following examples are provided to further illustrate the technical solutions of the present invention, but not to limit the present invention.
Example 1
Preparing 1000 tablets of prescription composition:
Figure BDA0002360411140000022
Figure BDA0002360411140000031
the preparation process comprises the following steps:
mixing tofacitinib citrate, lactose, microcrystalline cellulose PH200 and croscarmellose sodium, and adding magnesium stearate for total mixing; directly tabletting after mixing, wherein the tablet hardness is 50N-90N (punching: 8.0mm shallow concave punching); preparing a coating solution, adding purified water into a stirring barrel, starting a stirring paddle, slowly adding the Opadry with the prescription amount into the stirring barrel, fully stirring for 45min to disperse, and then coating.
Example 2
1000 tablets are prepared according to the prescription composition:
Figure BDA0002360411140000032
the preparation process comprises the following steps:
mixing tofacitinib citrate, lactose, microcrystalline cellulose PH200 and croscarmellose sodium, and adding magnesium stearate for total mixing; directly tabletting after mixing, wherein the tablet hardness is 50N-90N (punching: 8.0mm shallow concave punching); preparing a coating solution, adding purified water into a stirring barrel, starting a stirring paddle, slowly adding the Opadry with the prescription amount into the stirring barrel, fully stirring for 45min to disperse, and then coating.
Example 3
1000 tablets are prepared according to the prescription composition:
Figure BDA0002360411140000033
Figure BDA0002360411140000041
the preparation process comprises the following steps:
mixing tofacitinib citrate, lactose, microcrystalline cellulose PH200 and croscarmellose sodium, and adding magnesium stearate for total mixing; directly tabletting after mixing, wherein the tablet hardness is 50N-90N (punching: 8.0mm shallow concave punching); preparing a coating solution, adding purified water into a stirring barrel, starting a stirring paddle, slowly adding the Opadry with the prescription amount into the stirring barrel, fully stirring for 45min to disperse, and then coating.
Comparative example 1
1000 tablets are prepared according to the prescription composition:
Figure BDA0002360411140000042
the preparation process comprises the following steps:
mixing tofacitinib citrate, lactose, microcrystalline cellulose PH102 and croscarmellose sodium, and adding magnesium stearate for total mixing; directly tabletting after mixing, wherein the tablet hardness is 50N-90N (punching: 8.0mm shallow concave punching); preparing a coating solution, adding purified water into a stirring barrel, starting a stirring paddle, slowly adding the Opadry with the prescription amount into the stirring barrel, fully stirring for 45min to disperse, and then coating.
Comparative example 2
1000 tablets are prepared according to the prescription composition:
Figure BDA0002360411140000043
the preparation process comprises the following steps:
mixing tofacitinib citrate, lactose, microcrystalline cellulose PH112 and croscarmellose sodium, and adding magnesium stearate for total mixing; directly tabletting after mixing, wherein the tablet hardness is 50N-90N (punching: 8.0mm shallow concave punching); preparing a coating solution, adding purified water into a stirring barrel, starting a stirring paddle, slowly adding the Opadry with the prescription amount into the stirring barrel, fully stirring for 45min to disperse, and then coating.
Example 4 determination of intermediate angle of repose, carr coefficient and tablet hardness, tablet weight variation and content uniformity
Angle of repose measurement method: and (3) taking a totally mixed sample, putting the totally mixed sample into a sample tank of a powder fluidity tester, setting a detection parameter, starting a button, and reading the numerical value of the repose angle displayed by the tester after the measurement is finished.
Karl coefficient determination method: and (3) placing the totally mixed sample into a measuring cylinder, vibrating the sample for a certain number of times by using a vibration meter, respectively recording the weight of the sample, the volume before and after vibration, and calculating the Carl coefficient.
Tablet hardness determination method: and (5) taking 10 samples, measuring the hardness by using a hardness tester, and recording the hardness range.
The method for measuring the difference of tablet weights comprises the following steps: the piece weight was measured using an electronic balance for 20 samples and the average piece weight and standard deviation were calculated.
The content uniformity determination method comprises the following steps: taking 1 piece of sample, placing in a 100ml measuring flask, diluting properly and filtering, and taking the subsequent filtrate as the sample solution; and taking a proper amount of tofacitinib citrate as a reference substance solution, and properly diluting the tofacitinib citrate. The content is measured by a high performance liquid chromatograph, and the sum of the absolute value A of the difference between the average content of 10 tablets and the marked amount and the standard deviation S of 2.2 times is less than 15.0.
Table 1 examination results
Figure BDA0002360411140000051
The results show that the tablets prepared by the method of the invention in the examples 1-3 have better intermediate fluidity and compressibility, and the hardness, the weight difference and the content uniformity of the tablets meet the requirements, which are obviously better than other examples.
Example 5 stability study
The samples of the examples and the samples of the comparative examples were left at a high temperature (60 ℃ C. + -2 ℃ C.) for 30 days to measure the growth of the substances involved, and the results are shown in Table 2.
The related substance determination method comprises the following steps: the related substances are detected by a high performance liquid chromatograph, a Waters Xterra MS C18 column (4.6 mm multiplied by 250mm,5 mu m) or a chromatographic column with equivalent efficiency is selected as a chromatographic column, and the mobile phase is a mobile phase A: phosphate buffer (pH to 3.5); mobile phase B: acetonitrile, the method is gradient elution, and the elution conditions are as follows:
Figure BDA0002360411140000052
Figure BDA0002360411140000061
table 2 stability test results
Figure BDA0002360411140000062
The results show that the sample prepared by the method has good stability and is obviously superior to other examples.

Claims (11)

1. The tofacitinib citrate tablet is characterized by comprising active ingredients of tofacitinib citrate, lactose, microcrystalline cellulose PH200, a disintegrating agent, a lubricant and a coating agent, wherein the weight percentages of the tofacitinib citrate, the lactose, the microcrystalline cellulose PH200, the disintegrating agent and the lubricant are as follows:
Figure FDA0003781656310000011
the weight percentage is the proportion of each component in the plain tablets.
2. The tablet of claim 1, wherein the tofacitinib citrate, the lactose, the microcrystalline cellulose PH200, the disintegrant, and the lubricant are in the following weight percentages:
Figure FDA0003781656310000012
the weight percentage is the proportion of each component in the plain tablets.
3. The tablet according to claim 1, wherein the disintegrant is selected from the group consisting of sodium carboxymethyl starch, croscarmellose sodium, low substituted hydroxypropyl cellulose, and crospovidone.
4. The tablet according to claim 1, characterized in that the disintegrant is selected from croscarmellose sodium.
5. Tablet according to claim 1, wherein the lubricant is selected from magnesium stearate, talc or sodium stearyl fumarate.
6. The tablet according to claim 1, wherein the lubricant is selected from magnesium stearate.
7. The tablet of claim 1, wherein the coating agent is opadry.
8. The tablet of claim 1, wherein the coating agent is
Figure FDA0003781656310000013
33G28523-CN。
9. The tablet of claim 7, wherein the coating weight gain is from 2.0% to 4.0%.
10. A process for preparing tofacitinib citrate tablets as claimed in any one of claims 1 to 9, comprising primary mixing, sieving, total mixing, tabletting and coating.
11. The method of claim 10, comprising the steps of:
1) Primary mixing: mixing the tofacitinib citrate, lactose, microcrystalline cellulose PH200 and croscarmellose sodium in feeding amount;
2) Sieving: sieving the materials after primary mixing, wherein the aperture of a sieve is phi 0.6mm;
3) Total mixing: adding magnesium stearate with a feeding amount into the sieved materials for total mixing;
4) Tabletting: directly tabletting the totally mixed materials, and controlling the hardness of the tablets to be between 50N and 90N;
5) Coating: preparing a coating solution, wherein the solvent is purified water, slowly adding the Opadry with the prescription amount into the purified water, fully stirring for 45min to disperse, and then coating, wherein the weight gain of the coating is 2.0-4.0%.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105878202A (en) * 2016-05-27 2016-08-24 湖北丽益医药科技有限公司 Tofacitinib citrate tablet and preparation method thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105878202A (en) * 2016-05-27 2016-08-24 湖北丽益医药科技有限公司 Tofacitinib citrate tablet and preparation method thereof

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* Cited by examiner, † Cited by third party
Title
物理性质对微晶纤维素可压缩性和成型性的影响;李晓海等;《中国药学杂志》;20130131;第48卷(第2期);第116-122页，尤其是第116页摘要，第119页左栏第1段，右栏倒数第2段，第120页左栏第1段 *

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