CN103239444A - Dextroindobufen and clopidogrel compound drug composition - Google Patents
Dextroindobufen and clopidogrel compound drug composition Download PDFInfo
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- CN103239444A CN103239444A CN2012105716201A CN201210571620A CN103239444A CN 103239444 A CN103239444 A CN 103239444A CN 2012105716201 A CN2012105716201 A CN 2012105716201A CN 201210571620 A CN201210571620 A CN 201210571620A CN 103239444 A CN103239444 A CN 103239444A
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- clopidogrel
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Abstract
The invention relates to an antithrombotic drug composition which comprises the following active components: dextroindobufen and clopidogrel or pharmaceutically acceptable salts thereof. The invention also relates to a preparation method and application of the compound preparation of the drug composition, and the compound preparation is a tablet and an injection preparation. The drug composite disclosed by the invention is used for preventing or curing cardiovascular and cerebrovascular diseases and thrombotic diseases which are caused by thrombi or embolism, can reduce the usage dosage under the precondition of ensuring and even enhancing the curative effect, reduces the irritation of drugs on gastrointestinal tracts, reduces the hemorrhage probability, reduces the cost, alleviates the burden of a patient and has good clinical use value.
Description
Technical field
The present invention relates to a kind of antithrombotic pharmaceutical composition, be specifically related to comprise active component clopidogrel and right-handed indobufen or its in compound preparation preparation and the purposes of pharmaceutically acceptable salt.
Background technology
In recent years, the cerebrovascular thrombotic disease is the common disease that threatens human health, and platelet aggregation has pivotal role in hemostasis and thrombosis, and platelet aggregation causes that thrombosis is the major reason that cardiovascular and cerebrovascular disease takes place.At present, using more widely, antithrombotic reagent mainly contains aspirin, clopidogrel, ticlopidine, indobufen etc.
In patent WO9729753 (1997-8-21), a kind of pharmaceutical preparations composition that contains clopidogrel and aspirin is disclosed, for collagen-induced platelet aggregation, said composition has produced remarkable role in synergy, and the mechanism of the two synergistic function that underdrawed is in order to be combined in the advantage that platelet aggregation inhibitor is imitated, aspirin associating ticlopidine has abroad been arranged, the medication of aspirin associating clopidogrel prevents in-stent restenosis and thrombotic complications after the intracoronary stent implantation, the report of the treatment aspects such as thrombosis after the percutaneous transluminal coronary angioplasty (PTCA) has also been obtained curative effect preferably, and clopidogrel share aspirin and share aspirin surely with respect to thiophene chlorine pyrrole significant superiority is being arranged aspect safety and the toleration.
Although the compositions of clopidogrel and aspirin has the synergistic function of significant antiplatelet aggregation, but said composition does not still solve the TTP of clopidogrel merging merges the risk of the easier recurrence of TTP and the problem that the two is relevant to the gastrointestinal side reaction than ticlopidine, therefore this method is not optimum, can not be as basic solution.And discovery such as McQuaid, aspirin (75mg) and clopidogrel (75mg) therapeutic alliance have further increased the probability of severe haemorrhage.Severe haemorrhage danger is significantly higher than arbitrary medicine list usefulness due to the two medicine couplings, and the advantages outweigh the disadvantages with the patient who inserts coronary artery bracket (especially bracket for eluting medicament) to acute coronary syndrome, then more harm than good in cardiovascular diseases's primary prevention.More than all these have all limited the application of the compositions compound preparation of clopidogrel and aspirin.
Indobufen (Indobufen) is the same with aspirin, be all antiplatelet drug, it can selectively act on the platelet of circulation, blocking-up thrombosis, by influencing arachidonic acid metabolic, suppress platelet factor (as adenosine diphosphate (ADP), the 5-hydroxytryptamine, platelet factor 3,4 and β-thromoboglobulin etc.) release reaction that causes and bring into play antiplatelet aggregative activity, this inhibition is reversible, do not change plasma parameters, do not change the prostacyclin blood concentration, harmless platelet function, and make the normal platelet function of variation recover normal, and also make endotheliocyte produce the blood vessel dilating effect simultaneously, be unique reversible, many target spots of selectivity antithrombotic new drug.Indobufen can be brought into play than the more strong antiplatelet effects of aspirin, on auxiliary thromboembolism treatment, also more have superiority than aspirin, case fatality rate is more effective than aspirin in hospital improving urokinase fibrinolytic effect, the emerging ischemic event of prevention and minimizing for indobufen, and indobufen is with respect to aspirin, more can alleviating pain, the gastrointestinal stimulation is also reduced greatly.
In patent CN 101352436 B in order to solve GI irritation, the gastric mucosa infringement that aspirin produces in taking with process for a long time, reduce the compositions of ticlopidine and aspirin and reduce the severe haemorrhage probability that pharmaceutical composition that chlorine adjoins Gray and aspirin occurs in application, particularly reduce the gastrointestinal hemorrhage incidence rate, improve the compliance of patient's medication, improve clinical drug safety.This patent provides the pharmaceutical composition of indobufen and clopidogrel pharmaceutical composition and indobufen and ticlopidine.
The CN101270027A patent disclosure right-handed indobufen and for the preparation of the purposes of medicine, relate to the effect of right-handed indobufen aspect antithrombotic.Research for the drug regimen of right-handed indobufen and clopidogrel in this patent provides reference.
The indobufen that existing market is used is raceme, the clinical using dosage of indobufen is 200-400mg/ day, be used for prevention thrombosis, be applicable to ischemic cerebrovascular, heart disease, peripheral blood vessel, phlebothrombosis, disorders of lipid metabolism, diabetes and the extracorporeal circulation patients such as (hemodialysis) that atherosclerosis causes.
The medical value of its single dextrorotation optical isomer of indobufen does not also obtain paying attention to, and studies have shown that to compare indobufen by right-handed indobufen to suppress the effect of platelet aggregation more obvious, can effectively block thrombosis.
Summary of the invention
Purpose of the present invention just provides a kind of antithrombotic pharmaceutical composition, and it comprises active component is right-handed indobufen and clopidogrel and at pharmaceutically acceptable salt.
The present invention uses the single dextrorotation optical isomer of indobufen, and it is more obvious to experimental results show that right-handed indobufen is compared its anti-platelet aggregation effect of indobufen raceme, and has reduced dosage when can keep identical drug effect, alleviates side effect.
Pharmaceutical composition of the present invention has further improved antithrombotic acitivity, has alleviated the gastrointestinal side effect.
Drug regimen of the present invention is right-handed indobufen and clopidogrel or it is at pharmaceutically acceptable salt, according to the present invention, can use right-handed indobufen and clopidogrel with the form of pharmaceutically-acceptable salts, these salt can be selected from salt benzoate, acetate, citrate, benzene sulfonate, maleate, fumarate, tartrate, mesylate pharmaceutically commonly used.
The molar ratio of right-handed indobufen and clopidogrel is that the mol ratio of two kinds of active component right-handed indobufens and clopidogrel is that 1 ~ 4:1 exists in the compound preparation of the present invention, and the preferred molar ratio example is 2 ~ 3:1, and more preferably mol ratio is 3:1.
The present invention's technical scheme preferably is that the clopidogrel of effective dose is 20 ~ 400mg, and preferred dose is 20 ~ 80mg; The right-handed indobufen that comprises effective dose is 40 ~ 500mg, and preferred dose is 75 ~ 200mg.
Compound preparation of the present invention can be oral formulations or ejection preparation, and oral formulations can be tablet, capsule, slow releasing agent, and the preferred oral dosage form is tablet; Ejection preparation is preferably the intravenous fluid dosage form.
Acceptable carrier comprises filler, binding agent, diluent, lubricant and coating material on its tablet Chinese materia medica.Filler can be selected from pregelatinized Starch, lactose; Binding agent optional in polyvidone, hydroxypropyl methylcellulose, carmethose, ethyl cellulose, microcrystalline Cellulose one or more, preferably microcrystalline cellulose, hydroxypropyl methylcellulose.Lubricant is selected from magnesium stearate, Pulvis Talci.
Its ejection preparation also comprises 0.0001% ~ 1% metal chelating agent, 0.65% ~ 0.95% sodium chloride, needle-use activated carbon and water for injection.Metal chelating agent can be calcium disodium edetate, disodium edetate, edetic acid, preferred calcium disodium edetate.
Characteristics of the present invention provide a kind of antithrombotic pharmaceutical composition that contains right-handed indobufen and clopidogrel, this drug regimen suppresses platelet aggregation by the synergism of right-handed indobufen and clopidogrel, the cardiovascular and cerebrovascular vessel thrombotic disease that prevention or curative are caused by thrombosis or thromboembolism, under the prerequisite that improves curative effect, reduced using dosage, reduced medicine to the gastrointestinal zest, reduce hemorrhage probability, reduced cost, alleviate patient's burden, had good clinical use value.
Specific implementation method
By the following examples the present invention is further described, following examples do not limit the scope of the invention in any form.
The preparation of embodiment 1 right-handed indobufen and clopidogrel compound tablet
Prescription:
Technology:
Preparation method is direct compression process.With 25g clopidogrel, 50g pregelatinized Starch, right-handed indobufen 75g, microcrystalline Cellulose 25g, magnesium stearate 1g mix homogeneously, it is an amount of to add Pulvis Talci, fully behind the mixing, after 12 order nylon mesh granulate, granule is through after the assay was approved, with particle powder with 12mm towards direct compression, namely.
Embodiment 2 right-handed indobufens and clopidogrel compound tablet
Prescription:
Technology:
Preparation method is direct compression process.With 25g clopidogrel, 50g pregelatinized Starch, right-handed indobufen 100g, microcrystalline Cellulose 25g, magnesium stearate 1g mix homogeneously, it is an amount of to add Pulvis Talci, fully behind the mixing, after 12 order nylon mesh granulate, granule is through after the assay was approved, with particle powder with 12mm towards direct compression, namely.
Embodiment 3 indobufens and clopidogrel compound tablet
Prescription:
Technology:
Preparation method is direct compression process.With 25g clopidogrel, 50g pregelatinized Starch, indobufen 100g, microcrystalline Cellulose 25g, magnesium stearate 1g mix homogeneously, the adding Pulvis Talci is an amount of, fully behind the mixing, after 12 order nylon mesh granulate, granule is through after the assay was approved, with particle powder with 12mm towards direct compression, namely.
The preparation of the compound injection of embodiment 4 right-handed indobufens and clopidogrel
Prescription:
Technology:
Get right-handed indobufen 75g, clopidogrel 25g, disodium edetate 0.1g joins in the 800ml water for injection, is heated to 70 ℃, stirs to make dissolving, adds 1g injection active carbon, insulation absorption 30min, filtered while hot, decarburization.On filter, add water to 1000ml, carry out active component content and detect, qualified back 0.22um filtering with microporous membrane, the quantitative embedding of 1ml in ampoule bottle, 115 ℃ of autoclaving 50min, namely.Be used with a certain proportion of sodium-chloride water solution before the injecting drug use.
Embodiment 5 zooperies
The antagonism that pharmaceutical composition of the present invention is assembled mouse platelets
Laboratory animal: 50 of healthy Kunming mouses, body weight 24 ~ 26g;
Reagent: SJAMP is sashimi acid mucopolysaccharide potassium salt preparation, and white powder becomes the aqueous solution that concentration is 2.5mg/ml with the distilled water preparation, and fresh preparation is for the mouse peritoneal injection;
Medicine among medicine: the embodiment 1,2,3,4.Embodiment 1,2, and the tablet in 3 all is mixed with the suspension of desired concn with distilled water, and 4 ℃ of preservations now fit over distilled water before the injection injection among the embodiment 4 and are mixed with desired concn;
Test method: mice is divided into 5 groups at random, and embodiment 1,2,3,4 prepared medicine groups and SJAMP group, 1,2,3,5 group of gastric infusion, 4 groups of tail vein administrations, 1,2,3,4 group of administration every day 2 times, successive administration 4 days; Lumbar injection SJAMP is 1 time in 1,2,3,4 administrations administration on the 2nd, in addition, and 5 groups of normal saline that give same solvent.Then 1,24 and 48 hour mouse orbit rear vein beard after the SJAMP administration is got the hematometry clotting time, the promoting the circulation of blood platelet number of going forward side by side.Glass capillary method is adopted in coagulation time test, observe 300 seconds still can not blood coagulation person, clotting time calculated by 300 seconds, platelet count employing microscope direct counting method.
Experimental data is as follows:
The influence that the compound medicament composition of table 1 embodiment 1,2,3,4 reduces SJAMP induced mice platelet counts (
S)
The compound medicament composition of table 2 embodiment 1,2,3,4 to the influence of SJAMP induced mice cruor time extending (
S)
SJAMP itself has platelet aggregation effect and blood coagulation resisting function because of it, and the platelet counts of animal reduces behind the lumbar injection SJAMP, cruor time extending, and the platelet counts minimizing may persist to 48 hours behind the single administration, and clotting time can prolong 28 hours.
Its effect of combination that the combination of right-handed indobufen and clopidogrel is compared indobufen and clopidogrel to the effect of platelet aggregation due to the SJAMP is more outstanding, gives its platelet counts of SJAMP behind the filling stomach that right-handed indobufen and clopidogrel are made up and the drug administration by injection again and can keep level before the administration substantially.
Experimental result also shows, when right-handed indobufen and clopidogrel are combined in due to the antagonism SJAMP animal platelet aggregation, cruor time extending due to the SJAMP do not had obvious influence, only cruor time extending after 48 hours.Prove by above experimental data, compare the combination of indobufen and clopidogrel, right-handed indobufen and the effect of clopidogrel compound medicine combination anticoagulant are more remarkable, can effectively block thrombosis.
Claims (9)
1. antithrombotic pharmaceutical composition, wherein active component is the right-handed indobufen of effective dose and clopidogrel and at pharmaceutically acceptable salt.
2. a kind of pharmaceutical composition according to claim 1, wherein active component right-handed indobufen and clopidogrel are that 1 ~ 4:1 exists with the mol ratio of right-handed indobufen/clopidogrel.
3. according to the described described a kind of pharmaceutical composition of claim 2, it is characterized in that active component right-handed indobufen and clopidogrel are that 2 ~ 3:1 exists with the mol ratio of right-handed indobufen/clopidogrel.
4. according to the described described a kind of pharmaceutical composition of claim 3, it is characterized in that active component right-handed indobufen and clopidogrel with the mol ratio of right-handed indobufen/clopidogrel for being 3:1.
5. pharmaceutical composition according to claim 1, wherein said pharmaceutically acceptable salt is: benzoate, acetate, citrate, benzene sulfonate, maleate, fumarate, tartrate, mesylate.
6. a kind of pharmaceutical composition according to claim 1, the right-handed indobufen of contained effect dosage is 40 ~ 500mg in its unit dose, the clopidogrel of effective dose is 20 ~ 400mg.
7. a kind of pharmaceutical composition according to claim 6, the right-handed indobufen of contained effect dosage is for being 75 ~ 200mg in its unit dose; The clopidogrel of effective dose is 20 ~ 80mg.
8. pharmaceutical composition according to claim 1, its compound medicine dosage form is peroral dosage form or injection type, and peroral dosage form is tablet, and ejection preparation is the intravenous fluid dosage form.
9. the described compound medicament composition of claim 1, its application in the cardiovascular and cerebrovascular vessel thrombotic disease that prevention or treatment are caused by thrombosis or thromboembolism.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012105716201A CN103239444A (en) | 2012-12-26 | 2012-12-26 | Dextroindobufen and clopidogrel compound drug composition |
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| CN2012105716201A CN103239444A (en) | 2012-12-26 | 2012-12-26 | Dextroindobufen and clopidogrel compound drug composition |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105853364A (en) * | 2016-04-29 | 2016-08-17 | 济南康和医药科技有限公司 | Indobufen solid preparation and preparing method |
| CN116297908A (en) * | 2023-02-03 | 2023-06-23 | 湖南九典制药股份有限公司 | Analysis method of indobufen isomer impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101270072A (en) * | 2008-02-25 | 2008-09-24 | 北京阜康仁生物制药科技有限公司 | Right-handed indobufen and use for preparing medicament |
| CN101352436A (en) * | 2008-08-21 | 2009-01-28 | 武汉远大制药集团有限公司 | Novel medicament composition for resisting thrombosis |
-
2012
- 2012-12-26 CN CN2012105716201A patent/CN103239444A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101270072A (en) * | 2008-02-25 | 2008-09-24 | 北京阜康仁生物制药科技有限公司 | Right-handed indobufen and use for preparing medicament |
| CN101352436A (en) * | 2008-08-21 | 2009-01-28 | 武汉远大制药集团有限公司 | Novel medicament composition for resisting thrombosis |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105853364A (en) * | 2016-04-29 | 2016-08-17 | 济南康和医药科技有限公司 | Indobufen solid preparation and preparing method |
| CN105853364B (en) * | 2016-04-29 | 2018-10-26 | 济南康和医药科技有限公司 | A kind of Indobufen solid pharmaceutical preparation and preparation method |
| CN116297908A (en) * | 2023-02-03 | 2023-06-23 | 湖南九典制药股份有限公司 | Analysis method of indobufen isomer impurity |
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Application publication date: 20130814 |