CN1915250A - Medicinal composition, preparation method and quality control method - Google Patents
Medicinal composition, preparation method and quality control method Download PDFInfo
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- CN1915250A CN1915250A CN 200510093114 CN200510093114A CN1915250A CN 1915250 A CN1915250 A CN 1915250A CN 200510093114 CN200510093114 CN 200510093114 CN 200510093114 A CN200510093114 A CN 200510093114A CN 1915250 A CN1915250 A CN 1915250A
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- angelicae sinensis
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Abstract
A composite medicine in the form of injection or orally taken medicine for treating cardiovascular and cerebrovascular diseases, such as coronary heart disease, angina pectoris, apoplexy sequelae, cerebral thrombus, etc, is prepared from Chinese angelica root or its extract and ozagrel. Its preparing process and quality control method are also disclosed.
Description
Technical field
The invention provides a kind of pharmaceutical composition that is used for the treatment of cardiovascular and cerebrovascular disease, the preparation method and the method for quality control of said composition is provided simultaneously, belong to technical field of medicaments.
Technical background
At present, cardiovascular and cerebrovascular disease has become the topmost disease that influences the residents ' health level, becomes the No.1 killer of harm humans health, is worldwide distribution.In China, annual nearly 2,600,000 people, every day, nearly 7000 people died from cardiovascular and cerebrovascular disease.Modern society is from the pressure of aspects such as work, society, life, add not science and do not get enough athletic exercise etc. of irregular, the diet of life, impel the sickness rate of cardiovascular and cerebrovascular disease in 30 years old to 40 years old young and middle-aged people also constantly to rise, the morbidity crowd has the trend of continuous rejuvenation, and the age span of morbidity is in continuous expansion.And hypertension, hypercholesterolemia, diabetes, obesity and smoking etc. these influence the most important risk factor of cardiovascular and cerebrovascular disease will long-term existence and progressively increase the weight of, still be continuous growth trend.And the drug main for the treatment of cardiovascular and cerebrovascular disease at present will concentrate on pure Chinese medicinal preparation and Western medicine preparation, yet Western medicine preparation is not as the absolute advantages of antibiotic, and side effect is bigger, although pure Chinese medicinal preparation shows certain advantage, but, influence therapeutic effect because onset is slow.In the prior art, Chinese patent application 200410008757.1 discloses a kind of Chinese medicine and western medicine pharmaceutical composition and preparation method thereof, in this invention, form by Folium Ginkgo extract, Radix Angelicae Sinensis, rutin, Radix Polygoni Multiflori, vitamin C, major function is blood circulation promoting and blood stasis dispelling, blood lipid regulation, prevent atherosclerosis, right prescription complexity, Radix Polygoni Multiflori has hepatic injury, upper gastrointestinal hemorrhage, skin hypersensitivity pathological changes in the side.Untoward reaction such as eye melanin pigmentation, anthraquinone derivatives such as the chrysophanic acid in the while Radix Polygoni Multiflori, emodin, can stimulate intestinal to cause the congested inflammation of intestinal, stomachache, diarrhoea, overdose, can promote neural excitation, muscular paralysis, cause nervous, tachycardia, dyspnea, symptoms such as spasm tic, circulatory failure.Chinese patent application 200410040845.X discloses compound recipe and has returned astragalus injection liquid and preparation method thereof, this product is made up of Radix Notoginseng total arasaponins, Radix Angelicae Sinensis, the Radix Astragali, treatment syndrome of deficiency of blood, chest arthralgia precordial pain syndrome, apoplexy and apoplexy sequela and blood stasis disease, right this invention dosage form is single, the selectivity of doctors and patients' medication is little, this medicine is pure Chinese prescription simultaneously, and drug treatment is long, and is not ideal to emergency and severe disease patient's effect.In view of such circumstances, the searching compatibility is better, therapeutic effect is better, and the medicine of the treatment cardiovascular and cerebrovascular disease that toxic and side effects is littler has just become urgent problem.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical composition for the treatment of cardiovascular and cerebrovascular disease, adopt the preparation that Radix Angelicae Sinensis or Radix Angelicae Sinensis extract and ozagrel compatibility are made to be needed, when the dry root that is classified as umbelliferae angelica.Sweet in the mouth, suffering, warm in nature.Can enrich blood and invigorate blood circulation, menstruction regulating and pain relieving is moisturized laxation.Pharmacological action shows: Radix Angelicae Sinensis has stronger anticoagulation and anti thrombotic action; antioxidation, anti-aging effects are arranged, the protective effect of pair brain, renal ischaemia damage is arranged, study of anti-atherogenic effect; energy is anticoagulant obviously; antitumor is arranged, anti-damage, pulmonary fibrosis resistant; hepatoprotective effect; the central nervous system there is sleep effect due to analgesia, anticonvulsant action, the prolongation pentobarbital, alleviates effect such as amnesia, suppress smooth muscle effect, effects such as antiinflammatory and enhance immunity.Ozagrel is a thromboxane synthetase inhibitor, suppresses TXA
2Generate, thereby have antiplatelet accumulation and blood vessel dilating effect; The zoopery performance, intravenously administrable can reduce blood plasma TXB
2Level, Keto-PGF
12/ TXB
2Ratio descends, and platelet aggregation due to the different derivants is all had inhibitory action, and the cerebral infarction that the rat mesencephalic arteries is caused is plugged with preventive effect.Discover that by pharmacological effect the two share, have for treatment cardiovascular and cerebrovascular disease such as coronary heart disease, angina pectoris, cerebral thrombosis, apoplexy etc. to have obvious synergistic function, determined curative effect.Effectively avoided using separately at present the drawback of Chinese medicine or Western medicine, the risk of having avoided clinical interim compatibility to use simultaneously; Another object of the present invention is the method for Chinese medicinal of this treatment cardiovascular and cerebrovascular disease of open preparation, comprise multiple injection type and peroral dosage form, effectively avoid the single inconvenience that brings of dosage form of present doctors and patients' medication, satisfied the selection of clinician and extensive patients to a greater degree; The present invention also aims to provide its method of quality control,, and then overcome the variety of issue that prior art exists with assurance stability of formulation, safety and effectiveness.
Preparation of the present invention is to constitute like this: calculate according to components by weight percent, it by 1～50 part of 10～10000 parts of Radix Angelicae Sinensis and ozagrel through extracting refining forming; Or the Radix Angelicae Sinensis extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made.The pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease is characterized in that: calculate according to components by weight percent, it by 1～30 part of 100～5000 parts of Radix Angelicae Sinensis and ozagrel through extracting refining forming; Or the Radix Angelicae Sinensis extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made.Say exactly: calculate according to parts by weight, it by 1～20 part of 100～3000 parts of Radix Angelicae Sinensis and ozagrel through extracting refining forming; Or the Radix Angelicae Sinensis extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made.
The pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease, dosage form are injection and oral formulations.Wherein injection comprises: liquid drugs injection, powder pin or infusion solutions; Oral formulations comprises: all acceptable dosage forms on the pharmaceuticss such as tablet, dispersible tablet, effervescent tablet, oral cavity disintegration tablet, capsule, soft capsule, microcapsule, granule, pill, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, soft extract, extractum, gel, membrane.Preferably liquid drugs injection, powder pin, infusion solutions, oral liquid, drop pill, capsule, soft capsule, oral cavity disintegration tablet, tablet, dispersible tablet, buccal tablet, oral gel or granule.
The pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease: count by weight percentage: content of ferulic acid be not less than in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 0.002%; The component content sum that derives from the Radix Angelicae Sinensis medical material that all can be surveyed in the injection be not less than in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 20%; Ozagrel content should be 90.0%～110.0% of preparation labelled amount.
The preparation of drug combination method of described treatment cardiovascular and cerebrovascular disease is: get Radix Angelicae Sinensis, add entry or ethanol extraction, the extracting solution concentrate drying gets the Radix Angelicae Sinensis crude extract, also can further adopt in precipitate with ethanol, organic solvent extraction, flocculent precipitation, the column chromatography one or more to unite to use carry out suitably refining, get the Radix Angelicae Sinensis extract, with Radix Angelicae Sinensis crude extract or Radix Angelicae Sinensis extract and ozagrel mixing, be prepared into the preparation that needs with diverse ways.
Radix Angelicae Sinensis extract can also be commercially available or adopt other preparation methoies to prepare in the preparation of drug combination method of described treatment cardiovascular and cerebrovascular disease.
The pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease has atherosclerosis, platelet aggregation, and antithrombotic, blood vessel dilating reduces myocardial oxygen consumption, protection cardiac muscle, reduces functions such as vascular resistance, blood flow increasing; Be used for the treatment of coronary heart disease, angina pectoris, apoplexy, the acute thrombotic cerebral infarction dyskinesia that cardiovascular and cerebrovascular disease and cerebral infarction follow of waiting indefinitely.
Its assay is to adopt in high performance liquid chromatography, spectrophotography, thin layer chromatography scanning, the titrimetry one or more to record in the method for quality control of the pharmaceutical composition of described treatment cardiovascular and cerebrovascular disease.
In the prior art, Radix Angelicae Sinensis or Radix Angelicae Sinensis extract and ozagrel all are active drugs of treatment cardiovascular and cerebrovascular disease, because its effective ingredient purity is higher, and the intravenous administrations that adopt in the emergency and severe disease treatment more.But do not have the preparation report of the two prescription, with both combinations, though can obtain potentiation, its preparation stability and safety can't guarantee clinically.So, the applicant is combined into novel formulation with Radix Angelicae Sinensis extract and ozagrel and develops research, bring into play the cooperative compensating effect that both wait indefinitely at angina pectoris, cerebral thrombosis, apoplexy, acute thrombotic cerebral infarction by compatibility, for new medication of treatment increase of cardiovascular and cerebrovascular disease is selected.Simultaneously, can system further investigate Radix Angelicae Sinensis or the safety of Radix Angelicae Sinensis extract and ozagrel compatibility and the controllability of quality, for data for clinical drug use is given security.By antiplatelet aggregation test, inhibition mouse tail thrombotest, to these two kinds of medicines (Radix Angelicae Sinensis extract: ozagrel) carried out the prescription screening test of system, found that with Radix Angelicae Sinensis extract: the prescription pharmacological action of ozagrel=8: 1 is strong and consumption is lower, preparations shaping and having good stability, and both compatibilities can reach potentiation antidotal effect.The result shows; after the two herbal medicine use in conjunction; the obvious synergistic effect is arranged aspect blood circulation promoting and blood stasis dispelling; aspect the treatment cerebral ischemia obvious synergistic effect is being arranged also; can obviously increase simultaneously blood flow coronarius, reduce myocardial oxygen consumption; reduce vascular resistance, thus the better protection ischemic myocardium.
Pharmaceutical preparation of the present invention, with respect to the independent preparation of Radix Angelicae Sinensis, ozagrel better efficacy not only, and use is carried all very convenient, the preparation method of multiple different oral formulations is provided, being suitable for different crowd uses, heart disease and hyperpietic also can take for a long time, avoided dosage form single to hospitalized patients bring unfavorable.
The applicant has also carried out following experiment, to prove effective effect of medicine provided by the invention.
(1) the prescription screening experimental study conclusion of drug regimen compatibility
We are by antiplatelet aggregation test, inhibition mouse tail thrombotest, the prescription screening test that the Radix Angelicae Sinensis extract and the ozagrel of different content carried out system in varing proportions, found that with Radix Angelicae Sinensis extract: ozagrel=combination in 8: 1, the prescription pharmacological action is strong and consumption is lower, is best prescription so determine this ratio prescription.
Table: prescription research conclusion
| Formula number | Prescription is formed and the ratio Radix Angelicae Sinensis extract: ozagrel | The screening and assessment index | |
| Platelet suppression ratio (%) | Thrombosis suppression ratio (%) | ||
| 1 2 3 4 5 6 7 8 9 10 | 1∶10 1∶5 1∶1 2∶1 5∶1 8∶1 10∶1 20∶1 50∶1 80∶1 | 87.2％ 82.5％ 81.7％ 80.8％ 78.4％ 79.2％ 70.7％ 65.8％ 50.2％ 45.8％ | 58.4％ 52.8％ 49.5％ 48.3％ 55.5％ 57.5％ 58.1％ 47.1％ 35.4％ 22.7％ |
From above-mentioned prescription screening result as can be seen, the Radix Angelicae Sinensis extract of different purity and ozagrel compatibility all can produce certain curative effect, but through system thinking, determine to reach potentiation antidotal effect with Radix Angelicae Sinensis extract and ozagrel by force and consumption is lower, preparations shaping and having good stability with 8: 1 ratio compatibility pharmacological action.
(2) Radix Angelicae Sinensis extract: affirmation and the side's of tearing open research conclusion of ozagrel=8: 1 combination prescription effectiveness
Drug efficacy study through system shows; after two medication combined application; aspect blood circulation promoting and blood stasis dispelling, has the obvious synergistic effect; at aspects such as treatment cerebral thrombosis, apoplexy the obvious synergistic effect is arranged also; simultaneously; can obviously increase the increase of the blood flow of arteria coronaria, the afterload that reduces Ischemic Heart, antagonism myocardial oxygen consumption, thus the better protection ischemic myocardium.
The prescription research conclusion
| Pilot project | Prescription of the present invention | The Radix Angelicae Sinensis extract group | The ozagrel group |
| Myocardial infarction model test platelet aggregation-against is tested the test promoting blood circulation and removing blood stasis of anti-mouse tail thrombotest rat ICA injection thrombus local cerebral ischemia model test due to the dog CAL method | Effect is remarkable, the effect reinforced effects is remarkable, the effect reinforced effects is remarkable, and effect reinforced effects remarkable result is remarkable | The general successful of the general successful effect of successful effect | The general successful successful of effect successful successful |
Concrete embodiment
Embodiment 1: the preparation Radix Angelicae Sinensis extract: get 10 parts of Radix Angelicae Sinensis (part is: kilogram or gram)
Get Radix Angelicae Sinensis, be ground into the coarse powder of 10 mesh sieves, add 8 times of decoctings and boil 3 times, collecting decoction filters, measuring relative density when filtrate is concentrated into 60 ℃ is 1.05～1.15, add ethanol and make and contain the alcohol amount and reach 70%, cold preservation is spent the night, and filters, measuring relative density during filtrate recycling ethanol to 60 ℃ is 1.05～1.15, the water dissolution that adds 2 times of medical material bulking values filters, and filtrate is crossed the ZTC-1 macroporous adsorptive resins, with 5 times of resinite hydrops flushing resin columns, use 25% alcohol desorption then, collect 25% ethanolysis imbibition, reclaim ethanol, drying gets Radix Angelicae Sinensis extract.
Embodiment 2: the preparation Radix Angelicae Sinensis extract: 1000 parts of Radix Angelicae Sinensis (kilogram or gram)
Get Radix Angelicae Sinensis, be ground into the coarse powder of 10 mesh sieves, extract secondary with 70% alcohol heating reflux that is equivalent to 8 times of amounts of medical material, each 1.5 hours, merge extractive liquid, filtered, and filtrate recycling ethanol also is condensed into thick paste, gets the Radix Angelicae Sinensis crude extract.
Embodiment 3: the preparation Radix Angelicae Sinensis extract: 5000 parts of Radix Angelicae Sinensis (kilogram or gram)
Get Radix Angelicae Sinensis, be ground into coarse powder, add 8 times of water gagings and decoct 3 times, preceding secondary 1 hour 0.5 hour for the third time, filters, it is 1.15～1.20 (65 ℃) that filtrate is concentrated into relative density, puts coldly, adds ethanol and makes that to contain alcohol amount be 70%, leave standstill, cold preservation is spent the night, filter, I is standby for precipitation, filtrate recycling ethanol and to be concentrated into relative density be 1.16 (65 ℃), put coldly, add ethanol and make and contain alcohol amount and reach 85%, cold preservation, spend the night, filter, II is standby for precipitation, filtrate recycling ethanol, the drying I that gets dry extract, precipitation I, II is dissolved in water, water liquid adds clarifier and gets clear liquor, 70 ℃ of insulations, and supernatant concentration gets thick paste II, dried cream I and II promptly get Radix Angelicae Sinensis extract.
Embodiment 4: the preparation Radix Angelicae Sinensis extract: 10000 parts of Radix Angelicae Sinensis (kilogram or gram)
Get Radix Angelicae Sinensis, be ground into coarse powder, add 8 times of decoctings and boil 3 times, 2 hours for the first time, 1.5 hours for the second time, 0.5 hour for the third time, merge extractive liquid,, relative density is about 1.18 clear paste when being concentrated into 70 ℃, adds ethanol, makes to contain the alcohol amount and reach 30%, supernatant adds ethanol to be made and contains alcohol amount and reach 50%, supernatant adds ethanol to be made and contains alcohol amount and reach 70%, and the supernatant concentration drying promptly gets Radix Angelicae Sinensis extract.
Embodiment 5: the preparation Radix Angelicae Sinensis extract: 100 parts of Radix Angelicae Sinensis (kilogram or gram)
Get Radix Angelicae Sinensis powder and be broken into coarse powder,, make solvent, flood after 48 hours slowly percolation with 70% ethanol according to percolation under fluid extract and the extractum item, the collection liquid of filtering, recovery ethanol, being concentrated into relative density is the thick paste of 1.15～1.20 (70 ℃), promptly gets Radix Angelicae Sinensis extract.
Embodiment 6: the preparation Radix Angelicae Sinensis extract: 500 parts of Radix Angelicae Sinensis (kilogram or gram)
Get Radix Angelicae Sinensis, be ground into the coarse powder of 10 mesh sieves, extract secondary with 70% alcohol heating reflux that is equivalent to 8 times of amounts of medical material, 2 hours for the first time, 1.5 hours for the second time, merge extractive liquid,, filter, filtrate is put 70 ℃ of water bath methods, and residue adds the dissolving of 5% aqueous sodium carbonate, puts in the separatory funnel, wash with ether, water is used extracted with diethyl ether after using the hydrochloric acid adjust pH, and water adds the water dissolution of 2 times of medical material bulking values, filter, filtrate is crossed the ZTC-1 macroporous adsorptive resins, with 5 times of resinite hydrops flushing resin columns, uses 25% alcohol desorption then, collect 25% ethanolysis imbibition, reclaim ethanol, drying gets Radix Angelicae Sinensis extract.
Embodiment 7: 100 parts of Radix Angelicae Sinensis, 10 parts of ozagrels (part is: kilogram or gram)
Get Radix Angelicae Sinensis, be ground into the coarse powder of 10 mesh sieves, and added 8 times of decoctings and boil collecting decoction 3 times, filter, measuring relative density when filtrate is concentrated into 60 ℃ is 1.05～1.15, adds ethanol and makes and contain the alcohol amount and reach 70%, and cold preservation is spent the night, filter, measuring relative density during filtrate recycling ethanol to 60 ℃ is 1.05～1.15, adds the water dissolution of 2 times of medical material bulking values, filters, filtrate is crossed the ZTC-1 macroporous adsorptive resins, with 5 times of resinite hydrops flushing resin columns, use 25% alcohol desorption then, collect 25% ethanolysis imbibition, reclaim ethanol and get thick paste, add water for injection,, stir and make it dissolving; Other gets ozagrel, adds water for injection, stirs to make it dissolving; With above-mentioned two parts of solution mix homogeneously, add 0.3% active carbon again, heated and boiled, keep little and boiled 15 minutes, cooling, coarse filtration, fine straining, regulate pH about 7.0, add bisulfites, benzyl alcohol, poloxamer, add the injection water and transfer to full dose, divide to install to ampoule bottle, seal, the low temperature discontinuous sterilization, promptly get aqueous injection.
Embodiment 8: 5000 parts of ozagrels of Radix Angelicae Sinensis: 50 parts (part is: kilogram or gram)
Get Radix Angelicae Sinensis, be ground into the coarse powder of 10 mesh sieves, add 8 times of decoctings and boil 3 times, collecting decoction filters, measuring relative density when filtrate is concentrated into 60 ℃ is 1.05～1.15, add ethanol and make and contain the alcohol amount and reach 70%, cold preservation is spent the night, and filters, measuring relative density during filtrate recycling ethanol to 60 ℃ is 1.05～1.15, the water dissolution that adds 2 times of medical material bulking values filters, and filtrate is crossed the ZTC-1 macroporous adsorptive resins, with 5 times of resinite hydrops flushing resin columns, use 25% alcohol desorption then, collect 25% ethanolysis imbibition, reclaim ethanol and get thick paste, add water for injection, stir and make it dissolving; Other gets ozagrel, adds water for injection, stirs to make it dissolving; With above-mentioned two parts of solution and mannitol mix homogeneously, add 0.3% active carbon again, heated and boiled, keep little and boiled 15 minutes, fine straining, cooling, filter, filtrate adds to the full amount of water for injection, and regulates PH about 7.0, the intermediate sampling, to be detected qualified after, quantitatively be sub-packed in the cillin bottle lyophilization: pre-freeze temperature-45～-40 ℃, pre-freeze time 6～8h;-40～-35 ℃ of evacuation keep 6～8h; Be warming up to-30～-25 ℃ again, keep 6～8h; Be warming up to-20～-15 ℃, keep 6～8h; Be warming up to-10～-5 ℃, keep 3～5h; Be warming up to 0 ℃, keep 3～5h; Be warming up to 15～20 ℃, keep 1～3h; Be warming up to 25～30 ℃, keep 1～3h, be warming up to 35～40 ℃, keep 1～3h, packing promptly gets lyophilized injectable powder.The content of ozagrel is 102.7% of labelled amount.
Embodiment 9: Radix Angelicae Sinensis: 10 parts, and ozagrel: 1 part (part is: kilogram or gram)
Get Radix Angelicae Sinensis, be ground into coarse powder, add 8 times of decoctings and boil 3 times, 2 hours for the first time, 1.5 hours for the second time, 0.5 hour for the third time, merge extractive liquid,, relative density is about 1.18 clear paste when being concentrated into 70 ℃, adds ethanol, make and contain alcohol amount and reach 30%, supernatant adds ethanol to be made and contains alcohol amount and reach 50%, and supernatant adds ethanol to be made and contain the alcohol amount and reach 70%, the supernatant concentration drying, add water for injection, stir and make it dissolving; Other gets ozagrel, adds water for injection, stirs to make it dissolving; Above-mentioned two parts of solution are mixed and the mannitol mix homogeneously, add 0.3% active carbon, heated and boiled keeps little and boiled 15 minutes, cooling, coarse filtration, fine straining add in an amount of process glucose solution that boils, and are diluted to full dose with water for injection, embedding, the low temperature discontinuous sterilization promptly gets glucose injection.
Embodiment 10: Radix Angelicae Sinensis: 10000 parts, and ozagrel: 10 parts (part is: kilogram or gram)
Get Radix Angelicae Sinensis, be ground into the coarse powder of 10 mesh sieves, add 8 times of decoctings and boil 3 times, collecting decoction filters, measuring relative density when filtrate is concentrated into 60 ℃ is 1.05～1.15, add ethanol and make and contain the alcohol amount and reach 70%, cold preservation is spent the night, and filters, measuring relative density during filtrate recycling ethanol to 60 ℃ is 1.05～1.15, the water dissolution that adds 2 times of medical material bulking values filters, and filtrate is crossed the ZTC-1 macroporous adsorptive resins, with 5 times of resinite hydrops flushing resin columns, use 25% alcohol desorption then, collect 25% ethanolysis imbibition, reclaim ethanol and get thick paste, add water for injection, stir and make it dissolving; Other gets ozagrel, adds water for injection, stirs to make it dissolving; With above-mentioned two parts of solution and mannitol mix homogeneously, add 0.3% active carbon again, heated and boiled, keeping little boiled 15 minutes, fine straining, cooling, coarse filtration, fine straining, add in an amount of process sodium chloride solution that boils, be diluted to full dose with water for injection, embedding, the low temperature discontinuous sterilization promptly gets sodium chloride injection.
Embodiment 11: Radix Angelicae Sinensis extract: 3000 parts of ozagrels: 40 parts (part is: kilogram or gram)
Get Radix Angelicae Sinensis extract, add water for injection,, stir and make it dissolving; Other gets ozagrel, adds water for injection, stirs to make it dissolving; With above-mentioned two parts of solution mix homogeneously, add 0.3% active carbon again, heated and boiled, keep little and boiled 15 minutes, cooling, coarse filtration, fine straining, regulate pH about 7.0, add bisulfites, benzyl alcohol, poloxamer, add the injection water and transfer to full dose, divide to install to ampoule bottle, seal, the low temperature discontinuous sterilization, promptly get aqueous injection.Content of ferulic acid be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 0.003%; The component content sum that derives from the Radix Angelicae Sinensis medical material that all can be surveyed in the injection be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 23%.
Embodiment 12: Radix Angelicae Sinensis extract: 500 parts of ozagrels: 20 parts (part is: kilogram or gram)
Get Radix Angelicae Sinensis extract, add water for injection, stir and make it dissolving; Other gets ozagrel, adds water for injection, stirs to make it dissolving; With above-mentioned two parts of solution and mannitol mix homogeneously, add 0.3% active carbon again, heated and boiled, keep little and boiled 15 minutes, fine straining, cooling, filter, filtrate adds to the full amount of water for injection, and regulates PH about 7.0, the intermediate sampling, to be detected qualified after, quantitatively be sub-packed in the cillin bottle lyophilization: pre-freeze temperature-45～-40 ℃, pre-freeze time 6～8h;-40～-35 ℃ of evacuation keep 6～8h; Be warming up to-30～-25 ℃ again, keep 6～8h; Be warming up to-20～-15 ℃, keep 6～8h; Be warming up to-10～-5 ℃, keep 3～5h; Be warming up to 0 ℃, keep 3～5h; Be warming up to 15～20 ℃, keep 1～3h; Be warming up to 25～30 ℃, keep 1～3h, be warming up to 35～40 ℃, keep 1～3h, packing promptly gets lyophilized injectable powder.Content of ferulic acid be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 32%; The component content sum that derives from the Radix Angelicae Sinensis medical material that all can be surveyed in the injection be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 49%.
Embodiment 13: Radix Angelicae Sinensis extract: 80 parts of ozagrels: 8 parts (part is: kilogram or gram)
Get Radix Angelicae Sinensis extract, add water for injection, stir and make it dissolving; Other gets ozagrel, adds water for injection, stirs to make it dissolving; Above-mentioned two parts of solution are mixed and the mannitol mix homogeneously, add 0.3% active carbon, heated and boiled keeps little and boiled 15 minutes, cooling, coarse filtration, fine straining add in an amount of process glucose solution that boils, and are diluted to full dose with water for injection, embedding, the low temperature discontinuous sterilization promptly gets glucose injection.Content of ferulic acid be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 89%; The component content sum that derives from the Radix Angelicae Sinensis medical material that all can be surveyed in the injection be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 97%.
Embodiment 14: Radix Angelicae Sinensis extract: 6 parts of ozagrels: 3 parts (part is: kilogram or gram)
Get Radix Angelicae Sinensis extract, add water for injection, stir and make it dissolving; Other gets ozagrel, adds water for injection, stirs to make it dissolving; With above-mentioned two parts of solution and mannitol mix homogeneously, add 0.3% active carbon again, heated and boiled keeps little and boiled fine straining 15 minutes, cooling, coarse filtration, fine straining adds an amount of through in the sodium chloride solution that boils, be diluted to full dose with water for injection, embedding, sterilization promptly gets sodium chloride injection.The content of ozagrel is 103.5% of preparation labelled amount.
Embodiment 15: 10000 parts of Radix Angelicae Sinensis, 50 parts of ozagrels (part is: kilogram or gram)
Get Radix Angelicae Sinensis, be ground into the coarse powder of 10 mesh sieves, extract secondary with 70% alcohol heating reflux that is equivalent to 8 times of amounts of medical material, 2 hours for the first time, 1.5 hours for the second time, merge extractive liquid,, filter, filtrate is put 70 ℃ of water bath methods, and residue adds the dissolving of 5% aqueous sodium carbonate, puts in the separatory funnel, wash with ether, water is used extracted with diethyl ether after using the hydrochloric acid adjust pH, and water adds the water dissolution of 2 times of medical material bulking values, filter, filtrate is crossed the ZTC-1 macroporous adsorptive resins, with 5 times of resinite hydrops flushing resin columns, uses 25% alcohol desorption then, collect 25% ethanolysis imbibition, reclaim ethanol, drying gets Radix Angelicae Sinensis extract; Add ozagrel, mixing is standby; Get PEG4000 and polyoxyethylene monostearate S-40 portion, mix homogeneously, water-bath is melted, and stirs evenly, add Radix Angelicae Sinensis extract and ozagrel and be stirred to thawing, transfer to reservoir, airtight and insulation is regulated the dropping liquid quantitative valve at 70 ℃, splash in the liquid Paraffin about 10 ℃, with the drop pill drop that is shaped to the greatest extent and wipe liquid Paraffin, drying promptly gets drop pill.
Embodiment 16: 100 parts of Radix Angelicae Sinensis extracts, 50 parts of ozagrels (part is: kilogram or gram)
Get Radix Angelicae Sinensis extract, ozagrel mix homogeneously, press medication amount: substrate amount=1: 1.2 adding soybean oil, mixing; The prescription of rubber is a gelatin: glycerol: water: titanium dioxide=100g: 40g: 100g: 1g, batchingization adhesive tape part is: weigh batching, in the inputization glue jar, merceration is warming up to 60 ~ 70 ℃ gradually after 30 minutes, stir 5 hours whiles evacuation and remove bubble, treat evenly back blowing of sizing material, incapsulate after the filtration in the sizing material bucket of machine; The debugging pellet press, 65 ℃ of gelatin box temperature controls, film rotating speed 2.0 is rolled in 45 ℃ of sprinkler body temperature controls, rubber thickness 0.8mm, 18～25 ℃ of indoor temperatures, relative humidity 40%, pelleting; The dry typing drying of rolling that adopts combined with two steps of tray dried, rolled qualitative dry 2 hours, and 22 ℃ of baking temperatures, dry relative humidity should be lower than 65%, and promptly got soft capsule at 24～48 hours drying time.
Embodiment 17: 50 parts of Radix Angelicae Sinensis extracts, 25 parts of ozagrels (part is: kilogram or gram)
Get Radix Angelicae Sinensis extract, ozagrel mix homogeneously, add 7% polyvinylpolypyrrolidone PVPP and 2% mannitol, compacting promptly gets oral cavity disintegration tablet in flakes.
Embodiment 18: 500 parts of Radix Angelicae Sinensis, 36 parts of ozagrels (part is: kilogram or gram)
Get Radix Angelicae Sinensis, be ground into the coarse powder of 10 mesh sieves, extract secondary with 70% alcohol heating reflux that is equivalent to 8 times of amounts of medical material, 2 hours for the first time, 1.5 hours for the second time, merge extractive liquid,, filter, filtrate is put 70 ℃ of water bath methods, and residue adds the dissolving of 5% aqueous sodium carbonate, put in the separatory funnel, with the ether washing, after water is used the hydrochloric acid adjust pH, use extracted with diethyl ether, water adds the water dissolution of 2 times of medical material bulking values, filters, filtrate is crossed the ZTC-1 macroporous adsorptive resins, with 5 times of resinite hydrops flushing resin columns, uses 25% alcohol desorption then, collect 25% ethanolysis imbibition, reclaim ethanol, drying gets Radix Angelicae Sinensis extract, pulverize, add ozagrel, starch is an amount of, and oven dry is ground into fine powder, mixing, granulate, compacting promptly gets tablet in flakes.
Embodiment 19: 5000 parts of Radix Angelicae Sinensis, 48 parts of ozagrels (part is: kilogram or gram)
Get Radix Angelicae Sinensis powder and be broken into coarse powder,, make solvent with 70% ethanol according to percolation under fluid extract and the extractum item, flood after 48 hours slowly percolation, collect the liquid of filtering, reclaim ethanol, being concentrated into relative density is the thick paste of 1.15～1.20 (70 ℃), adds ozagrel, 4% carboxymethyl starch sodium, mix, drying is granulated granulate, incapsulate, promptly get capsule.
Embodiment 20: 10 parts of Radix Angelicae Sinensis extracts, 20 parts of ozagrels (part is: kilogram or gram)
Get Radix Angelicae Sinensis extract, the ozagrel mix homogeneously, standby; Get polyvinylpolypyrrolidone PVPP, CMC-Na, an amount of and lemon yellow mixing, get half and medicated powder mixing, make binding agent with 1.5% K30 anhydrous alcohol solution, 40 order system material, granulate remain half and are added in the particle that makes, and tabletting promptly gets dispersible tablet.Content of ferulic acid be deduction adjuvant amount, water quantities and ozagrel amount in the preparation total solid 17%.
Embodiment 21: 1000 parts of Radix Angelicae Sinensis, 30 parts of ozagrels (part is: kilogram or gram)
Get Radix Angelicae Sinensis, be ground into the coarse powder of 10 mesh sieves, add 8 times of decoctings and boil 3 times, collecting decoction filters, and measuring relative density when filtrate is concentrated into 60 ℃ is 1.05～1.15, add ethanol and make and contain the alcohol amount and reach 70%, cold preservation is spent the night, and filters, measuring relative density during filtrate recycling ethanol to 60 ℃ is 1.05～1.15, adds ozagrel, mixing, dry, add magnesium stearate, steviosin is an amount of, tabletting promptly gets buccal tablet.
Embodiment 22: 300 parts of Radix Angelicae Sinensis extracts, 10 parts of ozagrels (part is: kilogram or gram)
Get an amount of K-carrageenan, locust bean gum makes swelling with low amounts of water, and slight fever makes dissolving, slowly adds Radix Angelicae Sinensis extract and ozagrel, mix homogeneously, and warm macerating is 2 hours under 40 ℃ temperature; Other gets lactose, citric acid and potassium sorbate, with an amount of water dissolution, filters, and adds in the above-mentioned colloid solution, adds water to ormal weight, and mix homogeneously is crossed colloid mill, packing.Promptly get oral gel.
Embodiment 23: 100 parts of Radix Angelicae Sinensis, 18 parts of ozagrels (part is: kilogram or gram)
Get Radix Angelicae Sinensis, be ground into coarse powder, add 8 times of decoctings and boil 3 times, 2 hours for the first time, 1.5 hours for the second time, 0.5 hour for the third time, merge extractive liquid,, relative density is about 1.18 clear paste when being concentrated into 70 ℃, adds ethanol, makes to contain the alcohol amount and reach 30%, supernatant adds ethanol to be made and contains alcohol amount and reach 50%, supernatant adds ethanol to be made and contains alcohol amount and reach 70%, the supernatant concentration drying, Radix Angelicae Sinensis extract; Add ozagrel, 15% lactose mixing, granulate, sieve, promptly get granule.
Claims (11)
1, a kind of pharmaceutical composition that is used for the treatment of cardiovascular and cerebrovascular disease is characterized in that: calculate according to components by weight percent, it by 1～50 part of 10～10000 parts of Radix Angelicae Sinensis and ozagrel through extracting refining forming; Or the Radix Angelicae Sinensis extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made.
2, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 1, it is characterized in that: calculate according to components by weight percent, it by 1～30 part of 100～5000 parts of Radix Angelicae Sinensis and ozagrel through extracting refining forming; Or the Radix Angelicae Sinensis extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made.
3, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 2, it is characterized in that: calculate according to parts by weight, it by 1～20 part of 100～3000 parts of Radix Angelicae Sinensis and ozagrel through extracting refining forming; Or the Radix Angelicae Sinensis extract and the corresponding weight portion ozagrel that are obtained after extracting by corresponding weight portion medical material are made.
4, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease among the claim 1-3, it is characterized in that: preparation of the present invention is injection and oral formulations; Injection comprises: little liquid drugs injection, powder pin or infusion solutions; Oral formulations comprises: all acceptable dosage forms on tablet, dispersible tablet, effervescent tablet, oral cavity disintegration tablet, capsule, soft capsule, microcapsule, granule, pill, powder, drop pill, slow releasing preparation, controlled release preparation, oral liquid, soft extract, extractum, gel, membrane and other pharmaceuticss.
5, according to the pharmaceutical composition of the described treatment cardiovascular and cerebrovascular disease of claim 4, it is characterized in that: preparation of the present invention is liquid drugs injection, powder pin, infusion solutions, oral liquid, drop pill, capsule, soft capsule, oral cavity disintegration tablet, tablet, capsule, dispersible tablet, buccal tablet, oral gel or granule.
6, according to the pharmaceutical composition of claim 4 or 5 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: content of ferulic acid be not less than in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 0.002%; The component content sum that derives from the Radix Angelicae Sinensis medical material that all can be surveyed in the injection be not less than in the preparation deduction adjuvant amount, water quantities and ozagrel amount total solid 20%; Ozagrel content should be 90.0%～110.0% of preparation labelled amount.
7, according to the preparation of drug combination method of claim 4 or 5 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: get Radix Angelicae Sinensis, add entry or ethanol extraction, the extracting solution concentrate drying gets the Radix Angelicae Sinensis crude extract, one or more that also can further adopt precipitate with ethanol, organic solvent extraction, flocculent precipitation, column chromatography unite use carry out suitably refining, get the Radix Angelicae Sinensis extract,, be prepared into the preparation that needs with diverse ways Radix Angelicae Sinensis crude extract or Radix Angelicae Sinensis extract and ozagrel mixing.
8, according to the preparation of drug combination method of the described treatment cardiovascular and cerebrovascular disease of claim 7, it is characterized in that: Radix Angelicae Sinensis extract can also be commercially available or adopt other preparation methoies to prepare.
9, according to the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease among the claim 1-3; it is characterized in that: the present invention has atherosclerosis; platelet aggregation; antithrombotic; blood vessel dilating reduces myocardial oxygen consumption, protection cardiac muscle, reduces functions such as vascular resistance, blood flow increasing.
10, as the application in preparation treatment coronary heart disease, angina pectoris, apoplexy, acute thrombotic cerebral infarction are waited indefinitely the dyskinesia medicine that cardiovascular and cerebrovascular disease and cerebral infarction follow of the pharmaceutical composition of any described treatment cardiovascular and cerebrovascular disease among the claim 1-3.
11, according to the method for quality control of the pharmaceutical composition of claim 4 or 5 described treatment cardiovascular and cerebrovascular diseases, it is characterized in that: assay is to adopt in high performance liquid chromatography, spectrophotography, thin layer chromatography scanning, the titrimetry one or more to record.
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| CN 200510093114 CN1915250A (en) | 2005-08-19 | 2005-08-19 | Medicinal composition, preparation method and quality control method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110025758A (en) * | 2019-05-23 | 2019-07-19 | 无锡济民可信山禾药业股份有限公司 | A kind of Xingnaojing oral gel preparation and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110025758A (en) * | 2019-05-23 | 2019-07-19 | 无锡济民可信山禾药业股份有限公司 | A kind of Xingnaojing oral gel preparation and preparation method thereof |
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