CN103550242B - Pharmaceutical composition for treating hepatic fibrosis and preparation method thereof - Google Patents
Pharmaceutical composition for treating hepatic fibrosis and preparation method thereof Download PDFInfo
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- CN103550242B CN103550242B CN201310593006.XA CN201310593006A CN103550242B CN 103550242 B CN103550242 B CN 103550242B CN 201310593006 A CN201310593006 A CN 201310593006A CN 103550242 B CN103550242 B CN 103550242B
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Abstract
The invention relates to a pharmaceutical composition for treating hepatic fibrosis and a preparation method thereof. The pharmaceutical composition is a formulation prepared from a main ingredient and pharmaceutically acceptable auxiliary materials, wherein the main ingredient comprises 100-300 parts of pirfenidone and 50-150 parts of inosine. The formulation of pirfenidone and inosine is stable in quality, controllable, safe and effective. In clinic, the formulation is mainly used for the treatment of diseases of hepatic fibrosis, cirrhosis, liver cancer, and the like.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition for the treatment of hepatic fibrosis and preparation method thereof, belong to medical art.
Background technology
The extracellular matrixs such as liver fiber refers to the liver chronic lesion that various disease factor causes, the collagen protein caused in its repair process synthesis and degraded dysequilibrium, cause the pathological process of ECM abnormal increase and over-deposit in liver.Hepatic fibrosis be further developed into liver cirrhosis must through approach, and liver cirrhosis is the important cause of death of chronic hepatopathy.Research thinks that hepatic fibrosis can reverse.The hepatic fibrosis cause of disease is complicated, is difficult to early discovery, for the medicine of hepatic fibrosis, as interferon, colchicine and Chinese medicine etc., they or have side effect, or uncertain therapeutic efficacy is cut, and does not also have medicine to be used for Strategies of Anti-fibrosis Therapy by U.S. food Drug Administration (FDA) approval at present.
Pirfenidone (Pirfenidone PFD) is that Abroad in Recent Years studies more a kind of pyridine compounds with spectrum anti-fibrosis effect newly, all has good effect to organ fibrosis such as lung, heart, livers.PFD is the micromolecular compound of synthesis in 1970, and original research finds that it has certain antiinflammatory action, find that PFD has anti-fibrosis effect afterwards, and untoward reaction is little.First nineteen ninety-five lyer etc. report that PFD can significantly stop bleomycin to induce hamster hepatic fibrosis to be formed, and PFD is all proved good anti-fibrosis effect in multiple organ fibrosis subsequently.But the untoward reaction of pirfenidone is more, comprise nauseating, dyspepsia, vomiting, anorexia, photaesthesia, erythra and dizzy.
Inosine directly can enter somatic cell through cell, activation pyruvate oxidation enzyme, thus the cell under making to be in mental retardation anaerobic condition continues to carry out metabolism smoothly, and participate in the synthesis of human energy metabolism and protein, clinical in illness such as cardiac disorder, central serous chorioretinopathy, optic atrophy such as leukocyte or thrombocytopenia, various acute and chronic liver disease, pulmonary heart disease at present.
Summary of the invention
The invention provides a kind of pharmaceutical composition for the treatment of hepatic fibrosis, it contains pirfenidone and inosine is the preparation that main component is prepared from.
Drug quality of the present invention is stablized, and pirfenidone and inosine compatibility use, and can play the drug effect of Synergistic, and clinical practice is convenient, provides a kind of selection newly for clinical.
The invention provides a kind of pharmaceutical composition for the treatment of hepatic fibrosis, it contains pirfenidone and inosine is the preparation that main component and pharmaceutically acceptable adjuvant are prepared from:
Pirfenidone 100 ~ 300 parts, inosine 50 ~ 150 parts.
Further preferably, it contains pirfenidone and inosine is the preparation that main component is prepared from:
Pirfenidone 200 parts, inosine 100 parts.
Wherein, described preparation is ordinary tablet, Film coated tablets, hard capsule, granule, enteric coatel tablets, effervescent tablet.
Pharmaceutically acceptable adjuvant can be filler, binding agent, disintegrating agent, lubricant and coating materials.
Further, described filler comprises and is not limited to lactose, sucrose, glucose, mannitol, sorbitol, microcrystalline Cellulose, pregelatinized Starch, carboxymethyl starch, hydroxypropyl cellulose.
Further, described binding agent includes but not limited to starch, gelatin, dextrin, polyvidone, maltodextrin, sucrose, methylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose.
Further, described disintegrating agent includes but not limited to pregelatinized Starch, microcrystalline Cellulose, alginic acid, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose or gas-producing disintegrant.
Detailed description of the invention:
The preparation of embodiment 1 medicinal tablet of the present invention
Prescription:
Pirfenidone 200 g
Inosine 100 g
Lactose 250 g
Microcrystalline Cellulose 50 g
Carboxymethyl starch sodium 30 g
PVP K30 20 g
Make 1000
Operation: take by recipe quantity pulverize, the 80 object pirfenidones that sieve, inosine, lactose, microcrystalline Cellulose, fully mix by equal increments mixing method after, then to pulverize and sieve.Get PVP K30, after the solution of 5% PVP K30 is made in adding distil water heating, add in mixed powder and make soft material, granulate with 20 mesh sieves, 60 DEG C of dryings 4 hours, receive grain, add carboxymethyl starch sodium, mix, with 18 mesh sieve granulate, make suitable preparation.
The preparation of embodiment 2 medicine capsule of the present invention
Prescription:
Pirfenidone 250 g
Inosine 80 g
Carboxymethyl starch sodium 25g
The starch slurry of 5% is appropriate
Magnesium stearate 3 g
Make 1000
Operation: take by recipe quantity pulverize, sieve 80 object pirfenidones, inosine; The starch slurry adding 5% makes suitable soft material, granulates with 24 mesh sieves, 60 DEG C of dryings 4 hours, granulate; Add carboxymethyl starch sodium, the abundant mix homogeneously of magnesium stearate, be packed into Capsules and get final product.
The preparation of embodiment 3 oral cavity disintegration tablet of the present invention
Prescription:
Pirfenidone 180 g
Inosine 120 g
Carboxymethyl starch sodium 15g
Cross-linking sodium carboxymethyl cellulose 15g
Microcrystalline Cellulose 30g
Pregelatinized Starch 26g
Sucralose 4g
Fructus Citri Limoniae essence 1g
Magnesium stearate 3 g
Make 1000
Pirfenidone and inosine raw material and adjuvant are pulverized respectively, crosses 80 mesh sieves.Getting pirfenidone and inosine is mixed homogeneously with pregelatinized Starch, microcrystalline Cellulose, carboxymethyl starch sodium, take water as binding agent soft material, and 24 mesh sieves are granulated, after drying, and 24 mesh sieve granulate.Add the abundant mix homogeneously of cross-linking sodium carboxymethyl cellulose, sucralose, Fructus Citri Limoniae essence and magnesium stearate, tabletting, to obtain final product.
Experimental example 1
1.1 material
1.1.1 animal 2 monthly age male Wister rat totally 75, quality 150 ~ 170g, purchased from West China Hospital animal experimental center.
1.1.2 reagent PFD is purchased from Zhejiang Huana Pharmaceutical Co., Ltd.; Inosine is purchased from Jinan Ming Xin Pharmacy stock Co., Ltd; DMN (molecular formula C2H6N20, relative molecular mass 74.08) is purchased from Tianjin chemical reagent institute; Laminin，LN (LN), hyaluronic acid (HA), III procollagen type (PC III), type Ⅳ collagen (IV-C) enzyme immunoassay determination box all grind medical biotechnology center purchased from Shang Haihai.Transforminggrowthfactor-β1 (TGF-β 1) test kit is purchased from biological gene engineering company limited of Zhejiang University.
1.2 method
1.2.1 the foundation of hepatic fibrosis rats model and grouping adopt DMN lumbar injection liquid to make hepatic fibrosis rats model.Rat normally feeds 1 week, is divided into 5 groups at random: normal group, model group, PFD group, inosine group, drug combination group.Wherein PFD group, inosine group, drug combination group and model group rats 3d continuous intraperitoneal injection 1%DMN 10mg/ (kg d) (normal saline dilution) weekly, totally 4 weeks.PFD group gives PFD 500 mg/ (kg d) simultaneously, inosine group gives inosine 200mg/ (kg d) simultaneously, drug combination group gives PFD 200 mg/ (kg d) simultaneously and inosine 100 mg/ (kg d) gavage, 1 time/d, totally 4 weeks, model group and normal group compared with isopyknic normal saline gavage.4 weekends, with 3% pentobarbital sodium 8mL intraperitoneal injection of anesthesia rat, Weighing body quality; Open abdominal cavity and observe the change of liver spleen, get cardiac blood, the centrifugal 3min of 15000g, go supernatant-20 DEG C preservation.
1.2..2 the complete liver of Liver Spleen assessment of indices clip, spleen, proposes fascia and connective tissue, cleans, drains bloodstain, take liver, spleen weight in wet base (g), calculates liver, spleen index, liver/spleen index=liver or spleen weight in wet base/weight (g/100g).
1.2.3 pathological study hepatic tissue specimen 10% neutral formalin is fixed, dehydration, specimens paraffin embedding slices 5 μm, conventional creep plate.Conventional H E dyeing is observed liver pathology and is changed, and Masson collagen staining method observes hepatic fibrosis.Liver tissues inflammatory mobility grader fibrosis is carried out by stages with the viral hepatitis control prece that parasitic disease credit meeting, hepatopathy credit can combine revision according to Chinese Medical Association's infectious disease in 2000.
1.2.4 ultrastructure is observed and is got about 1mm
3the hepatic tissue of size is fixed with 2.5% glutaraldehyde, conventional electron microscopyc sample preparation, observes liver Change of Ultrastructure under H-800 type projection electron microscope.
1.2.5 serological index detect HA, LN, PC III, IV-C and TCF-β 1 Concentration Testing illustrate that carrying out paddy ammonia transaminase (ALT), glutamic oxaloacetic transaminase, GOT (AST), total bilirubin (TBIL) and albumin (ALB) level is detected by automatic clinical chemistry analyzer by enzyme-linked immunoassay kit.
2.1 rat mode of appearance change in experimentation, and normal group hair color is pure white smooth, and gloss is naturally soft, is quick on the draw; Experiment starts latter 2 weeks, and model group hair color turns yellow gradually, and color and luster dims out, and appetite declines, and along with the prolongation of application DMN time, rat becomes thin gradually, and urine turns yellow, and defecates rare, lassitude, reaction dull; Compare with model group, PFD group, inosine group, the drug combination group mental status are better, and appetite is good, and hair color is pure whiter, glossy, but compared with normal group is poor, wherein drug combination group than PFD group and inosine group mode of appearance better.At the end of the course for the treatment of, 5 groups of mortality rate no difference of science of statistics.
2.2 each group rat weights, liver spleen weight in wet base and liver spleen index compare and compare with normal group, and PFD group, inosine group, drug combination group rat weight, liver spleen weight in wet base regulating liver-QI index have no significant change; Compare with model group, PFD group, inosine group, drug combination group rat weight obviously increase, and liver spleen index obviously reduces, in table 1.
Table 1 respectively organizes Rat mass, liver spleen weight in wet base and liver spleen index change (x ± s)
| Group | n | Weight (m/g) | Liver weight in wet base (m/g) | Liver index (g/100g) | Spleen weight in wet base (m/g) | Spleen index (g/100g) |
| Normal group | 15 | 324.61±13.90 | 12.17±0.51 | 3.75±0.05 | 0.92±0.07 | 0.28±0.02 |
| Model group | 13 | 271.30±14.00 | 11.42±0.93 | 4.20±0.18 | 1.14±0.09 | 0.42±0.03 |
| PFD group | 14 | 304.90±26.50 | 11.96±0.41 | 3.92±0.07 | 1.00±0.03 | 0.32±0.11 |
| Inosine group | 16 | 312.20±20.10 | 12.05±0.84 | 3.86±0.07 | 0.99±0.08 | 0.32±0.08 |
| Drug combination group | 17 | 322.49±18.20 | 12.12±0.63 | 3.77±0.05 | 0.93±0.02 | 0.29±0.03 |
2.3 respectively group rat blood serum HA, LN, PC III, IV-C and TCF-β 1 assay results model group rat blood serum HA, LN, PC III, IV-C and TCF-β 1 all compared with normal group obviously raise.PFD group, inosine group, drug combination group rat blood serum HA, LN, PC III, IV-C, PC III and TCF-β 1 all comparatively model group all have decline, drug combination group HA, LN, PC III, IV-C and TCF-β 1 assay result close with normal group, obvious decline is more all had, in table 2 with PFD group, inosine group.
Table 2 is group rat blood serum HA, LN, PC III, IV-C and TCF-β 1 assay result (x ± s) respectively
| Group | n | HA（ρ/μg·L -1） | LN(ρ/μg·L -1） | PCⅢ（ρ/μg·L -1） | Ⅳ-C（ρ/μg·L -1） | TCF-β1（ρ/ng·L -1） |
| Normal group | 15 | 98.40±8.93 | 72.10±12.28 | 21.30±4.20 | 37.40±3.65 | 3.45±0.24 |
| Model group | 13 | 178.90±20.46 | 124.10±19.82 | 40.40±3.23 | 82.50±10.56 | 11.90±1.50 |
| PFD group | 14 | 145.30±14.12 | 97.80±7.22 | 38.10±4.37 | 52.80±4.62 | 5.98±0.92 |
| Inosine group | 16 | 150.50±16.20 | 100.12±13.35 | 40.07±3.89 | 60.45±8.76 | 7..11±1.08 |
| Drug combination group | 17 | 110.10±9.27 | 80.07±10.23 | 30.27±2.78 | 39.17±2.45 | 3.89±0.46 |
2.4 respectively organize rat blood serum ALT, AST, TBLL and ALB testing result model group serum obviously declines; PFD group, inosine group, drug combination group rat blood serum ALS, AST and TBLL comparatively model group obviously decline, and ALB comparatively model group obviously raises, in table 3.
Table 3 respectively group rat blood serum ALS, AST, TBLL and ALB compares (x ± s)
| Group | n | ALT(U/L) | AST(U/L) | TBLL（c/μmol·L -1） | ALB（ρ/g·L -1） |
| Normal group | 15 | 60.24±7.68 | 76.27±13.60 | 1.86±0.67 | 35.10±2.27 |
| Model group | 13 | 210.83±50.95 | 262.61±67.35 | 3.33±0.78 | 28.83±2.73 |
| PFD group | 14 | 130.36±31.29 | 151.52±25.07 | 1.64±0.39 | 33.74±3.70 |
| Inosine group | 16 | 146.42±58.17 | 120.35±5.04 | 2.45±0.84 | 32.17±2.59 |
| Drug combination group | 17 | 65.10±12.11 | 83.43±10.38 | 1.92±0.64 | 34.25±3.04 |
2.5 MASSON coloration result normal rats lobules of liver clear in structure, collagen-free fibroplasia.Model group lobules of liver normal configuration disappears, and in liver, blood vessel structure is disorderly, stem cell degeneration, downright bad heavier, sees Piecemeal necrosis, bridging necrosis, a large amount of cell infiltration in portal area.PFD group and inosine group lobules of liver structure normal, slight hepatic cell swelling, the visible a small amount of inflammatory cell infiltration in portal area, hypertrophy that collagen fiber are slight.Drug combination group lobules of liver clear in structure, collagen fiber mild hyperplasia.
Claims (8)
1. treat a pharmaceutical composition for hepatic fibrosis, it is characterized in that: it contains pirfenidone and inosine is the preparation that main component and pharmaceutically acceptable adjuvant are prepared from:
Pirfenidone 100 ~ 300 parts, inosine 50 ~ 150 parts.
2.2. treat the pharmaceutical composition of hepatic fibrosis as claimed in claim 1, it is characterized in that: it contains pirfenidone and inosine is the preparation that main component is prepared from:
Pirfenidone 200 parts, inosine 100 parts.
3.3. treat the pharmaceutical composition of hepatic fibrosis as claimed in claim 1 or 2, it is characterized in that: described preparation is ordinary tablet, Film coated tablets, hard capsule, granule, enteric coatel tablets, effervescent tablet.
4.4. treat the pharmaceutical composition of hepatic fibrosis as claimed in claim 1, it is characterized in that: can be filler, binding agent, disintegrating agent, lubricant and coating materials with pharmaceutically acceptable adjuvant.
5.5. treat the pharmaceutical composition of hepatic fibrosis as claimed in claim 4, it is characterized in that: described filler is lactose, sucrose, glucose, mannitol, sorbitol, microcrystalline Cellulose, pregelatinized Starch, carboxymethyl starch, hydroxypropyl cellulose.
6.6. treat the pharmaceutical composition of capsula fibrosa as claimed in claim 4, it is characterized in that: described binding agent is starch, gelatin, dextrin, maltodextrin, sucrose, methylcellulose, carboxymethyl cellulose, hydroxypropyl cellulose.
7.7. treat the pharmaceutical composition of capsula fibrosa as claimed in claim 4, it is characterized in that: described disintegrating agent is pregelatinized Starch, microcrystalline Cellulose, alginic acid, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose or gas-producing disintegrant.
8.8. preparation according to claim 1, is characterized in that: this preparation is mainly used in the treatment of hepatic fibrosis, liver cirrhosis, liver cancer diseases clinically.
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| MX2007009796A (en) | 2007-08-14 | 2009-02-25 | Cell Therapy And Technology S | Gel containing pirfenidone. |
| MX346763B (en) | 2012-03-28 | 2017-03-31 | Cell Therapy And Tech S A De C V | Semi-solid topical composition which contains pirfenidone and modified diallyl disulphide oxide (m-ddo) for eliminating or preventing acne. |
| WO2016198698A2 (en) * | 2015-06-12 | 2016-12-15 | Cnic Fundación Centro Nacional De Investigaciones Cardiovasculares Carlos Iii | P38 inhibitors for the treatment and prophylaxis of liver cancer |
| TW202402283A (en) * | 2015-06-30 | 2024-01-16 | 美商伊格集團國際股份有限公司 | Use of clemizole compounds for prevention and treatment of liver cancer |
| MX364040B (en) * | 2016-11-11 | 2019-04-11 | Cell Therapy And Tech S A De C V | Pharmaceutical use of an extended-release composition containing pirfenidone for the treatment and reversal of human steatohepatitis (nafld/nash). |
| MX366086B (en) | 2017-08-15 | 2019-06-27 | Cell Therapy And Tech S A De C V | A semi-solid topical composition containing an antimicrobial agent and pirfenidone for the treatment of chronic skin damage. |
| CN109432431B (en) | 2018-12-14 | 2020-06-30 | 中国药科大学 | Composition containing SUMO inhibitor and application |
| US11491175B2 (en) | 2019-02-25 | 2022-11-08 | Celagenex Research (India) Pvt. Ltd. | Synergistic bioactive compositions for enhancing cellular energy |
| CN113750258A (en) * | 2020-06-02 | 2021-12-07 | 温州医科大学 | Novel method for treating hepatic fibrosis diseases by pirfenidone |
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| CN1611260A (en) * | 2003-11-01 | 2005-05-04 | 杨喜鸿 | Combined medicine of adefovir dipivoxil |
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| CN1611260A (en) * | 2003-11-01 | 2005-05-04 | 杨喜鸿 | Combined medicine of adefovir dipivoxil |
| CN1660432A (en) * | 2004-12-31 | 2005-08-31 | 北京阜康仁生物制药科技有限公司 | Preparation of compound Tatin class and hepatic protectant and applications |
Non-Patent Citations (1)
| Title |
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| 肝纤维化机制及最新治疗药物研究进展;陈海滨 等;《临床和实验医学杂志》;20080229;第7卷(第2期);164-165 * |
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Denomination of invention: Pharmaceutical composition for treating hepatic fibrosis and preparation method thereof Effective date of registration: 20160126 Granted publication date: 20150715 Pledgee: Agricultural Bank of China Limited by Share Ltd Chengdu Qingyang branch Pledgor: Sichuan Guokang Pharmaceutical Co., Ltd. Registration number: 2016990000074 |
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Date of cancellation: 20180130 Granted publication date: 20150715 Pledgee: Agricultural Bank of China Limited by Share Ltd Chengdu Qingyang branch Pledgor: Sichuan Guokang Pharmaceutical Co., Ltd. Registration number: 2016990000074 |
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Denomination of invention: Pharmaceutical composition for treating hepatic fibrosis and preparation method thereof Effective date of registration: 20180201 Granted publication date: 20150715 Pledgee: Agricultural Bank of China Limited by Share Ltd Chengdu Qingyang branch Pledgor: Sichuan Guokang Pharmaceutical Co., Ltd. Registration number: 2018510000010 |