CN101152142A - Solid pharmaceutical composition containing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-5-thiazole methanoic acid - Google Patents
Solid pharmaceutical composition containing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-5-thiazole methanoic acid Download PDFInfo
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- CN101152142A CN101152142A CN 200610113474 CN200610113474A CN101152142A CN 101152142 A CN101152142 A CN 101152142A CN 200610113474 CN200610113474 CN 200610113474 CN 200610113474 A CN200610113474 A CN 200610113474A CN 101152142 A CN101152142 A CN 101152142A
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- polyethylene glycol
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- composite medicament
- febuxostat
- cyano
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Abstract
The present invention provides a solid medicine combination, which comprises 2 - (3 - cyano -4 - butyl rubber oxygen phenyl) -4 - methyl -5 - thiazole formic acid as active ingredients; and polyethylene glycol. In addition, the present invention is combined with one or a plurality of medicine excipients. The present is used for the curing of gout and hyperuricemia and reducing the outbreak of acute gout.
Description
Technical field
The present invention relates to a kind of solid composite medicament, it contains 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid or its pharmaceutically acceptable salt of pharmaceutically acceptable form.
Background technology
2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid (Febuxostat), structural formula is:
Febuxostat is a kind of non-purine selective depressant of new xanthine oxidase, can reduce uricopoiesis.The patient that Febuxostat suffers from gout and hyperuricemia to most acid is effective, can make serum uric acid level decline and be stabilized in below the 6.0mg/dl minimizing gouty attack,acute.
WO 9209279 discloses the Febuxostat chemical compound, and its chemical preparation process and be used for gout and the effect of the treatment of hyperuricemia is introduced the present invention as a reference in full at this.
CN 1642546 thinks that 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid has multiple crystal formation, in the formulation preparation process, also can't obtain medicine stripping curve zero deflection even be considered to the most stable crystal formation (WO9965885) in the test of use physical stability, have the solid composite medicament of good dissolving out capability.And CN 1642546 provides solid preparation stable and 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid that the stripping curve deviation is little.
Summary of the invention
The inventor is through a large amount of test, unexpectedly found a kind of pharmaceutical compositions, adopts open Febuxostat among the WO 9965885, obtains a kind of solid composite medicament stable and that have good dissolving out capability.
The invention provides a kind of Febuxostat of comprising as active component, and Polyethylene Glycol, and with the bonded solid composite medicament of one or more pharmaceutical excipients.
Solid composite medicament of the present invention, the relative gross weight of compositions contains the Febuxostat of 0.1% to 30% weight.
The molecular weight of high molecular polymer Polyethylene Glycol used in the present invention is 200-8000.
Preferred high molecular polymer Polyethylene Glycol can be mentioned polyethylene glycol 6000.
In solid composite medicament of the present invention, the mass ratio of Febuxosta and Polyethylene Glycol is 1: 0.2-8.
In solid composite medicament of the present invention, the mass ratio of Febuxosta and Polyethylene Glycol is 1: 0.4-4.
In solid composite medicament of the present invention, the mass ratio of Febuxosta and Polyethylene Glycol is 1: 0.8-2.
In solid composite medicament of the present invention, the mass ratio of Febuxosta and Polyethylene Glycol is preferably 1: 1.
Except the high molecular polymer Polyethylene Glycol, solid composite medicament of the present invention can also contain normally used known pharmaceutical excipient in the oral form medicine.
Pharmaceutical excipient used in the present invention comprises filler, disintegrating agent, binding agent, lubricant and fluidizer.
Solid composite medicament of the present invention, the relative gross weight of compositions contains the pharmaceutical excipient of 10% to 90% weight.
The mentioned filler of the present invention can be selected from: pregelatinized Starch, dextrin, sucrose, glucose, mannitol, sorbitol, microcrystalline Cellulose, carboxymethyl cellulose, methylcellulose, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate, one or more in the light magnesium oxide.
The mentioned disintegrating agent of the present invention can be selected from: low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose sodium, one or more in the carboxymethylstach sodium.
The mentioned binding agent of the present invention can be selected from: water, ethanol, starch slurry, polyvinylpyrrolidone rubber cement, carmethose rubber cement, gelatine size, one or more in the syrup.
The mentioned lubricant of the present invention can be selected from: magnesium stearate, calcium stearate, aluminium stearate, stearic acid, Polyethylene Glycol, one or more in Oleum Brassicae campestris, palmitoleoyl tristerin, hydrogenated vegetable oil, magnesium oxide, mineral oil, the magnesium laurylsulfate.
The mentioned fluidizer of the present invention can be selected from: Pulvis Talci, micropowder silica gel, one or more in the silicon dioxide.
In order to improve the bad mouthfeel of Febuxostat, improve patient's compliance, compositions of the present invention can also comprise one or more correctives known in the art, coloring agent and aromatic.
Pharmaceutical composition of the present invention can be that the form with tablet exists, do not exist with other clinical acceptable dosage forms but do not get rid of it, and as capsule, solution etc.
With preparation of pharmaceutical compositions of the present invention become tablet technical process can for: Febuxostat and Polyethylene Glycol with the ratio of quality 1: 1, are dissolved in fully and contain in the alcoholic acid aqueous solution of 50% (v/v); Spray drying obtains powder; Add filler, disintegrating agent, mix homogeneously; Add wetting agent or binding agent, granulate drying by a common wet granulation technology or a step prilling.Dried particles adds correctives, mix lubricant is even, is pressed into tablet.
With preparation of pharmaceutical compositions of the present invention become tablet technical process can for: Febuxostat and Polyethylene Glycol with the ratio of quality 1: 1, are dissolved in fully and contain in the alcoholic acid aqueous solution of 50% (v/v); Spray drying obtains powder; One or more of adding filler, disintegrating agent, binding agent, correctives, lubricant and fluidizer, mix homogeneously directly is pressed into tablet.
With preparation of pharmaceutical compositions of the present invention become tablet technical process can for: Febuxostat and Polyethylene Glycol with the ratio of quality 1: 1, are dissolved in fully and contain in the alcoholic acid aqueous solution of 50% (v/v); Spray drying obtains powder; Add filler, disintegrating agent and binding agent mix homogeneously; Dry granulation; Granule adds correctives, mix lubricant is even, is pressed into tablet.
The present invention is dissolved in Febuxostat and an amount of high molecular polymer Polyethylene Glycol mixing in the appropriate solvent, carries out spray drying, the gained powder further adds the other drug excipient, be prepared into conventional solid preparation,, can obviously reduce its dissolution in vitro deviation as tablet.
The specific embodiment
The present invention is further elaborated by following examples, but whether will limit the invention by any way with it.
Embodiment 1
| Composition | The mg/ sheet |
| Febuxostat | 20.00 |
| Polyethylene glycol 6000 | 20.00 |
| Microcrystalline Cellulose PH101 | 28.50 |
| Lactose | 30.00 |
| Polyvinylpolypyrrolidone xl | 1.00 |
| Magnesium stearate | 0.50 |
| 10% starch slurry | In right amount |
(1), is dissolved in and contains in the alcoholic acid aqueous solution of 50% (v/v) with Febuxostat and Polyethylene Glycol mix homogeneously;
(2) with (1) step gained solution, spray drying;
(3) with (2) step gained powder, add microcrystalline Cellulose PH101, lactose, polyvinylpolypyrrolidone xl, mix homogeneously; An amount of with 10% starch slurry, granulate, drying, granulate, dried granule adds magnesium stearate, and is total mixed, tabletting.
Embodiment 2
| Composition | The mg/ sheet |
| Febuxostat | 20.00 |
| Polyethylene glycol 6000 | 10.00 |
| Microcrystalline Cellulose PH101 | 33.50 |
| Lactose | 35.00 |
| Polyvinylpolypyrrolidone xl | 1.00 |
| Magnesium stearate | 0.50 |
| 10% starch slurry | In right amount |
(1), is dissolved in and contains in the alcoholic acid aqueous solution of 50% (v/v) with Febuxostat and Polyethylene Glycol mix homogeneously;
(2) with (1) step gained solution, spray drying;
(3) with (2) step gained powder, add microcrystalline Cellulose PH101, lactose, polyvinylpolypyrrolidone xl, mix homogeneously.An amount of with 10% starch slurry, granulate, drying, granulate, dried granule adds magnesium stearate, and is total mixed, tabletting.
Embodiment 3
| Composition | The mg/ sheet |
| Febuxostat | 20.00 |
| Polyethylene glycol 6000 | 80.00 |
| Microcrystalline Cellulose PH101 | 47.00 |
| Lactose | 50.00 |
| Polyvinylpolypyrrolidone xl | 2.00 |
| Magnesium stearate | 1.00 |
| 10% starch slurry | In right amount |
(1), is dissolved in and contains in the alcoholic acid aqueous solution of 50% (v/v) with Febuxostat and Polyethylene Glycol mix homogeneously;
(2) with (1) step gained solution, spray drying;
(3) with (2) step gained powder, add microcrystalline Cellulose PH101, lactose, polyvinylpolypyrrolidone xl, mix homogeneously.An amount of with 10% starch slurry, granulate, drying, granulate, dried granule adds magnesium stearate, and is total mixed, tabletting.
Embodiment 4
| Composition | The mg/ sheet |
| Febuxostat | 40.00 |
| Polyethylene glycol 6000 | 40.00 |
| Microcrystalline Cellulose PH101 | 57.00 |
| Lactose | 60.00 |
| Polyvinylpolypyrrolidone xl | 2.00 |
| Magnesium stearate | 1.00 |
| 10% starch slurry | In right amount |
(1), is dissolved in and contains in the alcoholic acid aqueous solution of 50% (v/v) with Febuxostat and Polyethylene Glycol mix homogeneously;
(2) with (1) step gained solution, spray drying;
(3) with (2) step gained powder, add microcrystalline Cellulose PH101, lactose, polyvinylpolypyrrolidone xl, mix homogeneously; An amount of with 10% starch slurry, granulate, drying, granulate, dried granule adds magnesium stearate, and is total mixed, tabletting.
Embodiment 5: the comparative example
| Composition | The mg/ sheet |
| Febuxostat | 20.00 |
| Microcrystalline Cellulose PH101 | 38.5 |
| Lactose | 40 |
| Polyvinylpolypyrrolidone xl | 1 |
| Magnesium stearate | 0.5 |
| 10% starch slurry | In right amount |
With Febuxostat and microcrystalline Cellulose PH101, lactose, polyvinylpolypyrrolidone xl, mix homogeneously.An amount of with 10% starch slurry, granulate, drying, granulate, dried granule adds magnesium stearate, and is total mixed, tabletting.
Embodiment 6 dissolution in vitro are measured
With reference to two appendix X of Chinese Pharmacopoeia version in 2000 C, second method, be dissolution medium with 900ml water, rotating speed is 50 rev/mins, temperature is 37 ℃ ± 1 ℃.Respectively at sampling in the 5th, 10,20,30,45,60 minute, press high effective liquid chromatography for measuring embodiment 1, embodiment 4 and comparative example's dissolution.
| Time (min) | Dissolution % | |||||
| Embodiment 1 | SD | Embodiment 4 | SD | The comparative example | SD | |
| 5 | 25.83 | 1.20 | 25.12 | 1.01 | 20.38 | 7.52 |
| 10 | 36.47 | 0.78 | 37.32 | 0.96 | 34.49 | 6.47 |
| 20 | 58.24 | 1.00 | 61.31 | 1.27 | 55.24 | 7.26 |
| 30 | 75.34 | 1.35 | 79.30 | 1.28 | 76.88 | 7.03 |
| 45 | 89.48 | 1.23 | 90.22 | 0.96 | 88.26 | 6.34 |
| 60 | 97.55 | 1.12 | 95.47 | 1.01 | 96.78 | 4.56 |
These results show by Febuxostat is mixed with Polyethylene Glycol, dissolving, and spray drying can significantly reduce the dissolution in vitro deviation of Febuxostat solid preparation, obtains to have the solid composite medicament of good dissolving out capability.
Claims (9)
1. a solid composite medicament is characterized in that comprising 0.1% to 30% (quality) 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid, Polyethylene Glycol and one or more pharmaceutical excipients.
2. solid composite medicament as claimed in claim 1, the molecular weight that it is characterized in that Polyethylene Glycol is 200-8000.
3. solid composite medicament as claimed in claim 2 is characterized in that described Polyethylene Glycol is a polyethylene glycol 6000.
4. as each described solid composite medicament of claim 1-3, it is characterized in that the mass ratio of 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid and Polyethylene Glycol is 1: 0.2-8, preferred 1: 1.
5. as each described solid composite medicament of claim 1-4, it is characterized in that it contains the pharmaceutical excipient of 10% to 90% quality, is selected from one or more that comprise filler, disintegrating agent, binding agent, correctives, lubricant and fluidizer.
6. solid composite medicament as claimed in claim 1 is characterized in that possessing following composition:
。
7. solid composite medicament as claimed in claim 1 is characterized in that possessing following composition:
。
8. solid composite medicament as claimed in claim 1 is characterized in that possessing following composition:
。
9. as the preparation method of each described solid composite medicament of claim 1-8, comprise the following steps:
(1) with 2-(3-cyano-4-isobutoxy phenyl)-4-methyl-5-thiazole formic acid and Polyethylene Glycol with suitable weight ratio, mix homogeneously is dissolved in and contains in the alcoholic acid aqueous solution of 50% (v/v);
(2) with (1) step gained solution, spray drying;
(3) with (2) step gained powder, add one or more of filler, disintegrating agent, binding agent, correctives, lubricant and fluidizer, be prepared into tablet or other solid preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610113474 CN101152142A (en) | 2006-09-29 | 2006-09-29 | Solid pharmaceutical composition containing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-5-thiazole methanoic acid |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200610113474 CN101152142A (en) | 2006-09-29 | 2006-09-29 | Solid pharmaceutical composition containing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-5-thiazole methanoic acid |
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| CN101152142A true CN101152142A (en) | 2008-04-02 |
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| CN 200610113474 Pending CN101152142A (en) | 2006-09-29 | 2006-09-29 | Solid pharmaceutical composition containing 2-(3-cyano-4- isobutoxy phenyl)-4-methyl-5-thiazole methanoic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102860991A (en) * | 2012-10-10 | 2013-01-09 | 杭州华东医药集团生物工程研究所有限公司 | Medicine composition containing febuxostat and preparation method thereof |
| CN112945954A (en) * | 2021-01-26 | 2021-06-11 | 山东省分析测试中心 | Preparation method of high-throughput liquid crystal detection platform for screening enzyme inhibitor by using enzyme catalysis to induce aptamer release |
-
2006
- 2006-09-29 CN CN 200610113474 patent/CN101152142A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102860991A (en) * | 2012-10-10 | 2013-01-09 | 杭州华东医药集团生物工程研究所有限公司 | Medicine composition containing febuxostat and preparation method thereof |
| CN112945954A (en) * | 2021-01-26 | 2021-06-11 | 山东省分析测试中心 | Preparation method of high-throughput liquid crystal detection platform for screening enzyme inhibitor by using enzyme catalysis to induce aptamer release |
| CN112945954B (en) * | 2021-01-26 | 2022-08-09 | 山东省分析测试中心 | Preparation method of high-throughput liquid crystal detection platform for screening enzyme inhibitor by using enzyme catalysis to induce aptamer release |
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