CN111000806A - Ibrutinib tablet composition - Google Patents
Ibrutinib tablet composition Download PDFInfo
- Publication number
- CN111000806A CN111000806A CN201811164727.8A CN201811164727A CN111000806A CN 111000806 A CN111000806 A CN 111000806A CN 201811164727 A CN201811164727 A CN 201811164727A CN 111000806 A CN111000806 A CN 111000806A
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- CN
- China
- Prior art keywords
- ibrutinib
- sodium
- tablet composition
- sieving
- microcrystalline cellulose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to an ibrutinib tablet composition, and belongs to the technical field of pharmacy. Each thousand tablets of the ibrutinib tablet composition contain 140g of ibrutinib, 26-40g of microcrystalline cellulose, 12-22g of croscarmellose sodium, 0.8-1.5g of sodium dodecyl sulfate, 60007-12 g of polyethylene glycol, 0.8-1.8g of soybean lecithin, 7-15g of sodium alginate, 0.8-1.8g of magnesium stearate and 4-8g of superfine silica gel powder. The invention provides a tablet composition with stable quality.
Description
Technical Field
The invention relates to an ibrutinib tablet composition, and belongs to the technical field of pharmacy.
Background
Ibrutinib (irutinib) is a new targeted anticancer drug developed by Johnson and pharmaceuticals in cooperation, is approved by the Food and Drug Administration (FDA) to be marketed at 11/13 of 2013 under the trade name of Imbruvica, and is used for treating Mantle Cell Lymphoma (MCL). The Chinese cultural name of ibrutinib: 1- [3(R) - [ 4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl ] piperidin-1-yl ] -2-propen-1-one.
Ibrutinib is sold in the market as a capsule, and the specification is 140 mg. The bulk drug of ibrutinib belongs to BCSII class, the solubility in water is only 0.003mg/ml, the bulk drug is almost insoluble in water, and how to improve the dissolution rate of the main drug in the preparation needs to be considered in the preparation process of the preparation. Because the main medicine has larger specification, the original ibrutinib is sold on the market in the form of capsules, and the No. 0 capsules are adopted.
The capsule is not suitable for some people to swallow, so that the market popularization of the capsule is influenced. Therefore, preparing ibrutinib tablets is a matter that formulation researchers should do. However, since ibrutinib is insoluble in water, and has a large specification and a small amount of auxiliary materials, tablet preparation needs to take into consideration indexes such as tablet weight and dissolution rate.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide an ibrutinib tablet composition which can expand the adaptive population.
The technical scheme is as follows:
in the preparation process of the tablet, the problem that the bulk drug of ibrutinib needs to be crushed to increase the dissolution of the tablet, the crushed bulk drug has low specific gravity and is in a loose powder state, and the problems of top fracture and unstable dissolution rate are easily caused in the tabletting process.
Through many studies, the applicant invented the following technical scheme.
The technical scheme of the invention is as follows: an ibrutinib tablet composition is characterized in that each thousand tablets of the composition contain 140g of ibrutinib, 26-40g of microcrystalline cellulose, 12-22g of croscarmellose sodium, 0.8-1.5g of sodium dodecyl sulfate, 60007-12 g of polyethylene glycol, 0.8-1.8g of soybean lecithin, 7-15g of sodium alginate, 0.8-1.8g of magnesium stearate and 4-8g of aerosil.
The preferred technical scheme of the invention is as follows: an ibrutinib tablet composition is characterized in that each thousand tablets of the composition contain 140g of ibrutinib, 28-36g of microcrystalline cellulose, 15-20g of croscarmellose sodium, 0.8-1.5g of sodium dodecyl sulfate, 60008-10 g of polyethylene glycol, 0.9-1.6g of soybean lecithin, 8-13g of sodium alginate, 1.0-1.5g of magnesium stearate and 5-7g of superfine silica gel powder.
The preferred technical scheme of the invention is as follows: an ibrutinib tablet composition is characterized in that each thousand tablets of the composition contain 140g of ibrutinib, 32g of microcrystalline cellulose, 18g of croscarmellose sodium, 1.3g of sodium dodecyl sulfate, 60009 g of polyethylene glycol, 1.4g of soybean lecithin, 12g of sodium alginate, 1.3g of magnesium stearate and 6g of superfine silica gel powder.
The preparation method of the tablet of the invention comprises the following steps:
firstly, sieving ibrutinib with a 120-mesh sieve, and sieving other auxiliary materials with a 80-mesh sieve;
uniformly mixing the ibrutinib with the sodium dodecyl sulfate, the superfine silica gel powder and the soybean lecithin; moistening with 55% ethanol water solution for softening; drying at 60 ℃, granulating and sieving by a 60-mesh sieve;
step three, evenly mixing the obtained product with the microcrystalline cellulose, the croscarmellose sodium, the polyethylene glycol 6000 and the alginic acid according to the prescription amount, and wetting by 55% ethanol water solution to prepare soft materials; drying at 60 ℃, granulating and sieving by a 40-mesh sieve;
and step four, adding magnesium stearate with the prescription amount, uniformly mixing and tabletting.
Has the advantages that: the invention provides a qualified ibrutinib tablet composition, and provides a replacement option for clinic. Solves the problems of top crack and dissolution in the preparation process of the tablet.
Example 1, 140g of ibrutinib, 28-36g of microcrystalline cellulose, 15-20g of croscarmellose sodium, 0.8-1.5g of sodium lauryl sulfate, 60008-10 g of polyethylene glycol, 0.9-1.6g of soybean lecithin, 8-13g of sodium alginate, 1.0-1.5g of magnesium stearate and 5-7g of aerosil, and 1000 tablets are prepared according to the preparation method described in the technical scheme of the specification.
Example 3, 140g of ibrutinib, 28-36g of microcrystalline cellulose, 15-20g of croscarmellose sodium, 0.8-1.5g of sodium lauryl sulfate, 60008-10 g of polyethylene glycol, 0.9-1.6g of soybean lecithin, 8-13g of sodium alginate, 1.0-1.5g of magnesium stearate and 5-7g of aerosil, and 1000 tablets are prepared according to the preparation method described in the technical scheme of the specification.
Example 3, 140g of ibrutinib, 32g of microcrystalline cellulose, 18g of croscarmellose sodium, 1.3g of sodium lauryl sulfate, 60009 g of polyethylene glycol, 1.4g of soybean lecithin, 12g of sodium alginate, 1.3g of magnesium stearate and 6g of aerosil, and 1000 tablets are prepared by the preparation method according to the technical scheme in the specification.
Comparative example 1 referring to the formulation of example 3, the corresponding amount was supplemented with microcrystalline cellulose without addition of soybean lecithin and sodium alginate. The method comprises the following specific steps:
prescription: 140g of ibrutinib, 45g of microcrystalline cellulose, 18g of croscarmellose sodium, 1.3g of sodium dodecyl sulfate, 60009 g of polyethylene glycol, 1.3g of magnesium stearate and 6g of aerosil, and 1000 tablets are prepared according to the following preparation method.
Firstly, sieving ibrutinib with a 120-mesh sieve, and sieving other auxiliary materials with a 80-mesh sieve;
uniformly mixing the ibrutinib with the prescription amount, the sodium dodecyl sulfate and the micropowder silica gel; moistening with 55% ethanol water solution for softening; drying at 60 ℃, granulating and sieving by a 60-mesh sieve;
the third step, the second step, the obtained material is moistened with the microcrystalline cellulose, the croscarmellose sodium, the polyethylene glycol 6000 and 55 percent ethanol water solution according to the prescription dose to prepare soft materials; drying at 60 ℃, granulating and sieving by a 40-mesh sieve;
and step four, adding magnesium stearate with the prescription amount, uniformly mixing and tabletting.
Comparative example 2 referring to the formulation of example 3, polyethylene glycol 6000 and sodium alginate were not added and the corresponding amount was supplemented with microcrystalline cellulose. The method comprises the following specific steps:
prescription: 140g of ibrutinib, 53g of microcrystalline cellulose, 18g of croscarmellose sodium, 1.3g of sodium lauryl sulfate, 1.4g of soybean lecithin, 1.3g of magnesium stearate and 6g of aerosil, and 1000 tablets are prepared by the following preparation method.
Firstly, sieving ibrutinib with a 120-mesh sieve, and sieving other auxiliary materials with a 80-mesh sieve;
uniformly mixing the ibrutinib with the sodium dodecyl sulfate, the superfine silica gel powder and the soybean lecithin; moistening with 55% ethanol water solution for softening; drying at 60 ℃, granulating and sieving by a 60-mesh sieve;
step three, evenly mixing the mixture obtained in the step two with the microcrystalline cellulose and the croscarmellose sodium in the prescription amount, and wetting by 55% ethanol water solution to prepare soft cellulose; drying at 60 ℃, granulating and sieving by a 40-mesh sieve;
and step four, adding magnesium stearate with the prescription amount, uniformly mixing and tabletting.
In comparison with the formulation of example 3 and example 3, 1000 tablets were prepared by the following preparation method.
Firstly, sieving ibrutinib with a 120-mesh sieve, and sieving other auxiliary materials with a 80-mesh sieve;
secondly, weighing 53g of ibrutinib and microcrystalline cellulose, 18g of croscarmellose sodium, 1.3g of sodium dodecyl sulfate, 1.4g of soybean lecithin and 6g of superfine silica powder according to the formula amount, uniformly mixing, and moistening with 55% ethanol water solution to prepare soft capsules; drying and granulating at 60 ℃, and sieving with a 40-mesh sieve;
and step three, mixing the mixture obtained in the step two with magnesium stearate in a prescription amount, and tabletting.
Test example 1 50 pieces of the products of examples 1 to 3 and comparative examples 1 to 3 were taken, respectively, and the appearance of the pieces was observed and recorded in Table 1.
| Example 1 product | EXAMPLE 2 product | EXAMPLE 3 product | Comparative example 1 product | Comparative example 2 product | Comparative example 3 product | |
| Appearance of the product | Is smooth and smooth | Is smooth and smooth | Is smooth and smooth | 18 pieces topCrack (crack) | Top crack of 27 pieces | Is smooth and smooth |
The data in Table 1 show that the product pieces of the invention are smooth in appearance.
Experimental example 2 100 tablets of the products of examples 1 to 3 and comparative examples 1 to 3 were stored in a constant temperature and humidity chamber at 30 ℃ and 65% relative humidity for 4 months, and the dissolution rate and related substances were measured at the end of 0 day and 4 th month, respectively, at 60 th minute. The dissolution rate is measured according to a rotating basket method specified by pharmacopoeia, and 0.1mol/l hydrochloric acid medium; the related substances are measured by an HLPC method. Data are recorded in table 2.
The data in Table 2 show that the product of the invention has stable indexes during long-term storage.
Claims (4)
1. An ibrutinib tablet composition is characterized in that each thousand tablets contain 140g of ibrutinib, 26-40g of microcrystalline cellulose, 12-22g of croscarmellose sodium, 0.8-1.5g of sodium dodecyl sulfate, 60007-12 g of polyethylene glycol, 0.8-1.8g of soybean lecithin, 7-15g of sodium alginate, 0.8-1.8g of magnesium stearate and 4-8g of aerosil.
2. The ibrutinib tablet composition of claim 1, wherein each thousand tablets contain 140g of ibrutinib, 28-36g of microcrystalline cellulose, 15-20g of croscarmellose sodium, 0.8-1.5g of sodium lauryl sulfate, 60008-10 g of polyethylene glycol, 0.9-1.6g of soybean lecithin, 8-13g of sodium alginate, 1.0-1.5g of magnesium stearate and 5-7g of aerosil.
3. The ibrutinib tablet composition of claim 1, wherein each thousand tablets contain 140g of ibrutinib, 32g of microcrystalline cellulose, 18g of croscarmellose sodium, 1.3g of sodium lauryl sulfate, 60009 g of polyethylene glycol, 1.4g of soybean lecithin, 12g of sodium alginate, 1.3g of magnesium stearate and 6g of aerosil.
4. A process for preparing an ibrutinib tablet composition of claim 1 comprising the steps of:
firstly, sieving ibrutinib with a 120-mesh sieve, and sieving other auxiliary materials with a 80-mesh sieve;
uniformly mixing the ibrutinib with the sodium dodecyl sulfate, the superfine silica gel powder and the soybean lecithin; moistening with 55% ethanol water solution for softening; drying at 60 ℃, granulating and sieving by a 60-mesh sieve;
step three, evenly mixing the obtained product with the microcrystalline cellulose, the croscarmellose sodium, the polyethylene glycol 6000 and the alginic acid according to the prescription amount, and wetting by 55% ethanol water solution to prepare soft materials; drying at 60 ℃, granulating and sieving by a 40-mesh sieve;
and step four, adding magnesium stearate with the prescription amount, uniformly mixing and tabletting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811164727.8A CN111000806A (en) | 2018-10-07 | 2018-10-07 | Ibrutinib tablet composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811164727.8A CN111000806A (en) | 2018-10-07 | 2018-10-07 | Ibrutinib tablet composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111000806A true CN111000806A (en) | 2020-04-14 |
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ID=70110546
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811164727.8A Withdrawn CN111000806A (en) | 2018-10-07 | 2018-10-07 | Ibrutinib tablet composition |
Country Status (1)
| Country | Link |
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| CN (1) | CN111000806A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111617028A (en) * | 2020-07-14 | 2020-09-04 | 扬子江药业集团江苏紫龙药业有限公司 | Oral preparation containing ibrutinib and preparation method |
| US11433072B1 (en) | 2021-06-10 | 2022-09-06 | Hikma Pharmaceuticals USA, Inc. | Oral dosage forms of ibrutinib |
| WO2022260667A1 (en) * | 2021-06-10 | 2022-12-15 | Hikma Pharmaceuticals Usa Inc. | Oral dosage forms of ibrutinib |
-
2018
- 2018-10-07 CN CN201811164727.8A patent/CN111000806A/en not_active Withdrawn
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111617028A (en) * | 2020-07-14 | 2020-09-04 | 扬子江药业集团江苏紫龙药业有限公司 | Oral preparation containing ibrutinib and preparation method |
| US11433072B1 (en) | 2021-06-10 | 2022-09-06 | Hikma Pharmaceuticals USA, Inc. | Oral dosage forms of ibrutinib |
| WO2022260667A1 (en) * | 2021-06-10 | 2022-12-15 | Hikma Pharmaceuticals Usa Inc. | Oral dosage forms of ibrutinib |
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Legal Events
| Date | Code | Title | Description |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20200414 |