CN102846569A - Drug composition containing pirfenidone, and preparation method thereof - Google Patents
Drug composition containing pirfenidone, and preparation method thereof Download PDFInfo
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- CN102846569A CN102846569A CN 201210326774 CN201210326774A CN102846569A CN 102846569 A CN102846569 A CN 102846569A CN 201210326774 CN201210326774 CN 201210326774 CN 201210326774 A CN201210326774 A CN 201210326774A CN 102846569 A CN102846569 A CN 102846569A
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- pirfenidone
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Abstract
The present invention belongs to the technical field of medicine, and particularly relates to a solid drug composition containing pirfenidone, and a preparation process thereof. The drug composition contains pirfenidone, a binder and a disintegrating agent, and can be prepared into tablets, granules and capsules.
Description
Technical field
The present invention relates to the preparation method of a kind of pirfenidone Pharmaceutical composition and this kind compositions, belong to medical technical field.
Background technology
Pirfenidone is a kind of synthetic molecules of non-peptide, and molecular weight is 185.23 dalton.Its chemical element is expressed as C12H11NO, and its structure is known.
Fibrotic disease such as pulmonary fibrosis, hepatic fibrosis, myocardial fibrosis etc. are the important diseases of a class serious harm human life health, and along with global industrialization and people live, the change of diet style, the sickness rate of fibrotic disease increases just gradually.Global commonly encountered diseases, nearly 10 annual morbidities and case fatality rate raise, and according to estimates, the U.S., Europe, Japanese three ground suffer patient's number that IPF torments greatly about about 220,000, and wherein just there are 90,000 IPF patients in the U.S..The popularity degree of IPF can be mentioned in the same breath with diseases such as chronic lymphocytic leukemias.Primary disease is a kind of sustainable development disease.Secondary cases pulmonary fibrosis development is then comparatively slow, can stop development by pulmonary fibrosis after the exopathogenic factor causer removal cause of disease.Pulmonary fibrosis is the disease of respiratory system, except between lungs itself fibrosis of matter disease, the disease injury interstitial lung of many other systems, all can form pulmonary fibrosis, such as rheumatism immunity class disease, Drug disease, radiation disease, occupation and environmental disease etc., these diseases are damaged lungs in evolution, injure interstitial lung, cause the damage of alveolar persistence, pulmonary fibrosis occurs.
Idiopathic pulmonary fibrosis is a kind of agnogenic, chronic, carrying out property interstitial lung sexually transmitted disease (STD) change.Modern medicine thinks to be autoimmune disease.Sickness rate and case fatality rate constantly rise in recent years, and its cause of disease and pathogenesis are indefinite so far.Clinical manifestation be dry cough, uncomfortable in chest, pant and carrying out property dyspnea is feature, dead because of respiratory failure at last.The primary disease prognosis mala, clinical shortage specific short.Treatment IPF choice drug is glucocorticoid at present, secondly be immunosuppressant and Chinese herbal medicine, and prolonged application glucocorticoid and immunosuppressant can cause serious untoward reaction, even accelerates dead.Along with the aging of population and the improvement of diagnostic techniques, estimate that patient's number of suffering from IPF will increase considerably.Patient's IPF 5 annual survival rates only are 20%, and this ratio will be lower than the many neoplastic diseases that comprise non Hodgkin's disaese, colorectal carcinoma, carcinoma of prostate and breast carcinoma.At present, the medicine that also is not specifically designed to treatment IPF on the market is sold.
Through continuous research and probe, find that at present pyridine compounds is having preferably performance aspect fibrosis, a kind of new fibrosis chemical compound 5-methyl-1-phenyl-2(1H)-pyridone (pirfenidone) goes on the market in Japan.Chinese patent CN101267810A discloses the capsule preparations of a kind of pirfenidone and the acceptable excipient of medicine, and this capsule preparations can be kept hope in the patient body pharmacokinetics is corresponding.US Patent No. 2006/0167064A1 discloses a kind of pirfenidone liquid preparation, contains at least 25% pirfenidone in this liquid preparation.
The present domestic pirfenidone list marketing that still has no.
Summary of the invention
The object of the present invention is to provide the preparation method of a kind of pirfenidone Pharmaceutical composition and compositions thereof.
The solid composite that the present invention relates to, per unit contain pirfenidone 0.2g, need the pirfenidone raw material is carried out Ordinary pulverization.
The solid composite that the present invention relates to, its filler are one or more the mixture in lactose, microcrystalline Cellulose, mannitol, the starch etc., and are preferably lactose and microcrystalline Cellulose, and addition is the heavy 20%-50% of total sheet.
The solid composite that the present invention relates to, disintegrating agent is low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, and is preferably cross-linking sodium carboxymethyl cellulose, consumption is the heavy 3%-15% of total sheet.
The solid composite that the present invention relates to, it is characterized in that described lubricant can be one or more the mixture in stearic acid and its metallic salt, Pulvis Talci, micropowder silica gel, the sucrose fatty acid ester etc., and being preferably magnesium stearate, consumption is the heavy 0.5%-1.5% of total sheet.
The solid composite that the present invention relates to is characterized in that described coating weightening finish 2%-4%.
This solid composite that the present invention relates to, be that pirfenidone is carried out Ordinary pulverization, with lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose mix homogeneously, wherein the lactose consumption is 15%-30%, the crystallite consumption is 10%-30%, and the cross-linking sodium carboxymethyl cellulose consumption is 3%-10%;
The present invention prepares 5% hydroxypropyl cellulose solution as binding agent, and with said mixture soft material processed, wherein binder dosage is 2%-5%, and binding agent adding mode is that gradation adds, the non-once adding, and 18 mesh sieves are granulated behind the soft material processed; With dry granule under the 50-60 ℃ of condition, 24 mesh sieve granulate;
This compositions that the present invention relates to, with above-mentioned granule and magnesium stearate mix homogeneously tabletting and get final product, wherein the consumption of magnesium stearate is 0.5%-1.5%.
A kind of compositions that contains pirfenidone that the present invention relates to, its preparation technology was for to pulverize 100 mesh sieves with pirfenidone, and all the other adjuvants are crossed 80 mesh sieves; Take by weighing pirfenidone, lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose by recipe quantity and place dry grinding cup, mix homogeneously; With 5% hydroxypropyl cellulose solution soft material processed, 18 mesh sieves are granulated; 50 ℃ of oven dryings; 24 mesh sieve granulate; Add magnesium stearate, mix homogeneously; Tabletting, coating and get final product.
The tablet of this compositions preparation of the present invention sets high respectively to carry out under temperature, high humidity, the illumination condition investigating in 5 days, 10 days and mixes rear related substance and changes of contents, compares with 0 day measurement result, the results are shown in Table:
| Investigate item | 0 day | 5 days | 10 days |
| Appearance character | Off-white powder | Off-white powder | Off-white powder |
| Related substance | 0.00% | 0.01% | 0.01% |
| Content | 100.1% | 99.08% | 98.91% |
| Dissolution | 100.0% | 99.27% | 98.27% |
The result shows that related substance is without significant change, and pirfenidone content does not reduce.Show that pirfenidone and each adjuvant have good stability.
4, the specific embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following examples.
The Pirfenidone tablet of the present invention's preparation, per 1 preparation unit's pirfenidone content is 0.2g.Specific embodiment is as follows:
The preparation of embodiment 1 Pirfenidone tablet (1000)
| Supplementary material forms | Part by weight (%) |
| Pirfenidone | 50.00 |
| Lactose | 20 |
| Microcrystalline Cellulose | 21 |
| Cross-linking sodium carboxymethyl cellulose | 3.00 |
| Hydroxypropyl cellulose | 4.50 |
| Magnesium stearate | 1.50 |
| Total | 100.00 |
Take by weighing recipe quantity and take by weighing pirfenidone and cross 100 mesh sieves, with lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, mix homogeneously is for subsequent use; With 5% hydroxypropyl cellulose solution soft material processed, 18 mesh sieves are granulated; 50 ℃ of oven dryings; Cross 24 sieve granulate, add magnesium stearate, mix homogeneously, tabletting, the coating weightening finish is about 2%-4%.
The preparation of embodiment 2 Pirfenidone tablets (1000)
| Supplementary material forms | Part by weight (%) |
| Pirfenidone | 66.67 |
| Lactose | 13.83 |
| Microcrystalline Cellulose | 10.00 |
| Cross-linking sodium carboxymethyl cellulose | 5.00 |
| Hydroxypropyl cellulose | 4.00 |
| Magnesium stearate | 0.50 |
| Total | 100.00 |
Take by weighing recipe quantity and take by weighing pirfenidone and cross 100 mesh sieves, with lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, mix homogeneously is for subsequent use; With 5% hydroxypropyl cellulose solution soft material processed, 18 mesh sieves are granulated; 50 ℃ of oven dryings; Cross 24 sieve granulate, add magnesium stearate, mix homogeneously, tabletting, the coating weightening finish is about 2%-4%.
The preparation of embodiment 3 Pirfenidone tablets (1000)
| Supplementary material forms | Part by weight (%) |
| Pirfenidone | 50 |
| Lactose | 14.00 |
| Microcrystalline Cellulose | 20.00 |
| Cross-linking sodium carboxymethyl cellulose | 10.00 |
| Hydroxypropyl cellulose | 5.00 |
| Magnesium stearate | 1.00 |
| Total | 100.00 |
Take by weighing recipe quantity and take by weighing pirfenidone and cross 100 mesh sieves, with lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, mix homogeneously is for subsequent use; With 5% hydroxypropyl cellulose solution soft material processed, 18 mesh sieves are granulated; 50 ℃ of oven dryings; Cross 24 sieve granulate, add magnesium stearate, mix homogeneously, tabletting, the coating weightening finish is about 2%-4%.
The preparation of embodiment 4 Pirfenidone tablets (1000)
| Supplementary material forms | Part by weight (%) |
| Pirfenidone | 66.67 |
| Lactose | 4.83 |
| Microcrystalline Cellulose | 10.00 |
| Cross-linking sodium carboxymethyl cellulose | 15.00 |
| Hydroxypropyl cellulose | 3.00 |
| Magnesium stearate | 0.50 |
| Total | 100.00 |
Take by weighing recipe quantity and take by weighing pirfenidone and cross 100 mesh sieves, with lactose, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, mix homogeneously is for subsequent use; With 5% hydroxypropyl cellulose solution soft material processed, 18 mesh sieves are granulated; 50 ℃ of oven dryings; Cross 24 sieve granulate, add magnesium stearate, mix homogeneously, tabletting, the coating weightening finish is about 2%-4%.
Embodiment 5 Pirfenidone tablet stability tests are investigated
According to the listed investigation project of stability test in 2010 editions two appendix of Chinese Pharmacopoeia " medicine stability test guideline ", Pirfenidone tablet of the present invention is carried out factors influencing.
Getting 100826 batches in sample of listing packing and putting intensity of illumination 4500Lx ± 500Lx, 60 ℃ of high temperature and 25 ℃ of RH92.5% of high humidity ± 5% and transfer and deposit 10 days, the 5th day and sampling detection in the 10th day, the results are shown in following table:
Conclusion: this product is through factors influencing, and it is all qualified that indices was compared with 0 day, illustrates that this compositions and the stable preparation process that the present invention relates to are feasible.
Claims (7)
1. a solid composite is characterized in that containing pirfenidone, filler, binding agent and disintegrating agent, lubricant, coating powder.
2. solid composite according to claim 1 is characterized in that described preparation per unit contains pirfenidone 0.2g.
3. solid composite according to claim 1 is characterized in that described filler is one or more the mixture in lactose, microcrystalline Cellulose, mannitol, the starch etc., and is preferably lactose and microcrystalline Cellulose that addition is the heavy 20%-50% of total sheet.
4. solid composite according to claim 1, it is characterized in that described disintegrating agent is low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, and being preferably cross-linking sodium carboxymethyl cellulose, consumption is the heavy 3%-15% of total sheet.
5. solid composite according to claim 1, it is characterized in that described lubricant can be one or more the mixture in stearic acid and its metallic salt, Pulvis Talci, micropowder silica gel, the sucrose fatty acid ester etc., and being preferably magnesium stearate, consumption is the heavy 0.5%-1.5% of total sheet.
6. solid composite according to claim 1 is characterized in that described coating weightening finish 2%-4%.
7. described a kind of compositions that contains pirfenidone according to claim 1, its preparation technology was for to pulverize 100 mesh sieves with pirfenidone, and all the other adjuvants are crossed 80 mesh sieves; Take by weighing pirfenidone, lactose, MCC, cross-linking sodium carboxymethyl cellulose by recipe quantity and place dry grinding cup, mix homogeneously; With 5% hydroxypropyl cellulose solution soft material processed, 18 mesh sieves are granulated; 50 ℃ of oven dryings (90 ℃, 5min); 24 mesh sieve granulate; Add magnesium stearate, mix homogeneously, tabletting, coating and get final product.
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| CN 201210326774 CN102846569A (en) | 2012-09-06 | 2012-09-06 | Drug composition containing pirfenidone, and preparation method thereof |
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| CN 201210326774 CN102846569A (en) | 2012-09-06 | 2012-09-06 | Drug composition containing pirfenidone, and preparation method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10188637B2 (en) | 2016-03-29 | 2019-01-29 | Hoffmann-La Roche Inc. | Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same |
| EP3511001A1 (en) * | 2018-01-12 | 2019-07-17 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Pirfenidone-containing tablet and capsule formulation |
| CN110430871A (en) * | 2017-03-02 | 2019-11-08 | 永进药品工业株式会社 | The pharmaceutical composition of pirfenidone of grain-size controlled and preparation method thereof that compressibility improves |
| CN112409246A (en) * | 2019-08-21 | 2021-02-26 | 北京凯因科技股份有限公司 | Novel pirfenidone crystal form and preparation method thereof |
| CN114053242A (en) * | 2021-11-19 | 2022-02-18 | 苏州天马医药集团天吉生物制药有限公司 | Rebamipide tablet and preparation method thereof |
| CN115666533A (en) * | 2020-04-22 | 2023-01-31 | 永进药品工业株式会社 | Enteric coated formulation containing pirfenidone with improved safety and stability and method of making the same |
-
2012
- 2012-09-06 CN CN 201210326774 patent/CN102846569A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10188637B2 (en) | 2016-03-29 | 2019-01-29 | Hoffmann-La Roche Inc. | Granulate formulation of 5-methyl-1-phenyl-2-(1H)-pyridone and method of making the same |
| CN110430871A (en) * | 2017-03-02 | 2019-11-08 | 永进药品工业株式会社 | The pharmaceutical composition of pirfenidone of grain-size controlled and preparation method thereof that compressibility improves |
| EP3511001A1 (en) * | 2018-01-12 | 2019-07-17 | Alfred E. Tiefenbacher (GmbH & Co. KG) | Pirfenidone-containing tablet and capsule formulation |
| US20190216738A1 (en) * | 2018-01-12 | 2019-07-18 | Laurus Labs Ltd | Pirfenidone-containing tablet and capsule formulation |
| CN112409246A (en) * | 2019-08-21 | 2021-02-26 | 北京凯因科技股份有限公司 | Novel pirfenidone crystal form and preparation method thereof |
| CN112409246B (en) * | 2019-08-21 | 2023-04-07 | 北京凯因科技股份有限公司 | Crystal form of pirfenidone and preparation method thereof |
| CN115666533A (en) * | 2020-04-22 | 2023-01-31 | 永进药品工业株式会社 | Enteric coated formulation containing pirfenidone with improved safety and stability and method of making the same |
| CN114053242A (en) * | 2021-11-19 | 2022-02-18 | 苏州天马医药集团天吉生物制药有限公司 | Rebamipide tablet and preparation method thereof |
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| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130102 |
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| DD01 | Delivery of document by public notice |
Addressee: Song Xuemei Document name: Notification of Approving Refund |