CN1762341B - Salvianolic acid compound for treating cardiovascular and cerebrovascular disease and liver disease, and application thereof - Google Patents
Salvianolic acid compound for treating cardiovascular and cerebrovascular disease and liver disease, and application thereof Download PDFInfo
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Abstract
The invention relates to a salvianolic acid compound and its use in preparing medicament for treating cardiovascular and cerebrovascular diseases, liver diseases. The compound comprises salvianolic acid and alkaline amino acid, or alkaline glucose derivatives. The compound can be prepared into various preparations.
Description
Technical field
The present invention relates to a kind of the treat salvianolic acid compound of cardiovascular and cerebrovascular disease, hepatic disease and the application in pharmacy thereof.
Background technology
The salvianolic acid compounds is the phenolic acid compound that is present in Radix Salviae Miltiorrhizae or its congener.The salvianolic acid compounds has protective effect for cardiovascular and cerebrovascular vessel.Can anti-hepatic fibrosis, anti-liver injury.Can treat peptic ulcer.Can also kill and wound cancerous cell, strengthen the curative effect of cancer therapy drug, and toxicity that can corresponding increase cancer therapy drug.The salvianolic acid compounds does not have obvious toxic and side effects.
1993, Liu's equality, Chinese Medicine journal, the magnesium-Fibrotic effect of salviol property acid B Chinese People's Anti-Japanese Military and Political College's Hepar Mus, 8 (supplementary issues): in 65, disclose the effect of Mus carbon tetrachloride institute of salvianolic acid B Chinese People's Anti-Japanese Military and Political College liver fibrosis due.
1997; Journal of Chinese Pharmaceutical Sciences; Water soluble activecomponents of Salvia miltiorrhiza and related plants, 6 (2): the structural identification of having reported salvianolic acid among the 57-64.
1998, Shanghai Pharmaceutical Inst., Chinese Academy of Sciences also applied for the patent of " Salvia polyphenol salts admixture and its preparation method and its usage ", and the applying date is on JIUYUE 11st, 1998, and is authorized to, and the patent No. is 98111076.2.
1999; The patent of Shanghai Univ. of Traditional Chinese Medicine and Shanghai Pharmaceutical Inst., Chinese Academy of Sciences's co-applications " application of salvianolic acid B magnesium in preparation treatment chronic hepatopathy medicament "; The applying date is on April 19th, 1999, and is authorized to, and the patent No. is 99113644.6.
1999, China Medicine University's journal, salvia-soluble The Chemical Constituents, 30 (6): separation and the structural identification of having reported salvianolic acid in 411～416.
Calendar year 2001, Yunnan University of Traditional Chinese Medicine's journal, Yunnan salvianolic acid composition water alcohol method preparation technology's preliminary study, reported the water alcohol method preparation technology of salvianolic acid at 24 (4): 6～8.
2003, pharmacy practice magazine, macroreticular resin absorbing method extracted the applied research of salvianolic acid B, had reported that macroreticular resin absorbing method extracts the method for salvianolic acid B in 21 (6), 339～341.
2003; The time precious traditional Chinese medical science traditional Chinese medicines; The progress of salvianolic acid, 14 (6): reported in 371～373 that the salvianolic acid compounds is to the protective effect of heart, cerebral protection, effect of anti hepatic fibrosis, to therapeutical effect and the antitumor action of peptic ulcer.
Aminoacid is one of base substance that constitutes human body, is the material base of life, in food nutrition, has consequence and effect, in medical treatment, also has very high value.Some of them have certain curative effect for cardiovascular and cerebrovascular disease, hepatic disease, like arginine, lysine, histidine etc.The L-arginine can reduce the atherosclerosis degree and improve vascular endothelial function, has certain curative effect for hepatopathy and the heart, brain, angiopathy.Because these aminoacid are the necessary nutrient substance of human body, therefore has good safety.D-glucosamine is a kind of monosaccharide micromolecule of biologically active, Chinese hepatopathy magazine, and 2004, the 12nd volume o. 11th was delivered " research of the derivative induced hepatoma cell apoptosis of D-glucosamine " for 697 pages.Salvianolic acid and arginine, lysine, histidine, glucosamine, meglumine are processed complex, have synergism, can improve curative effect with respect to existing salvianolic acid B magnesium salt for the treatment of cardiovascular and cerebrovascular disease, hepatic disease.Comprise the pharmaceutical composition that salvianolic acid and other Chinese medicine are formed in the prior art; Applied for the patent of " a kind of active ingredient of Chinese herbs composition and method of making the same of preventing and treating cardiovascular and cerebrovascular disease " like the gentle Lu Bo of Xu Jiang; Application number is 200410026913.7; Wherein disclose the combination of total salvianolic acid and Rhizoma Chuanxiong total phenols, be used for the treatment of cardiovascular and cerebrovascular disease.But, salvianolic acid and the combination of other Chinese medicine ingredients, composition is more complicated, and wherein some unknown composition possibly have safety hidden danger, and the Chinese medicine differences between batches are bigger, brings very big difficulty to quality control.And among the present invention; Salvianolic acid and arginine, lysine, histidine, glucosamine, meglumine are processed complex; Above-mentioned raw materials is the known single component of molecular structure; And side effect is little, and therefore some or even pharmaceutical necessities commonly used can solve the shortcoming of above-mentioned safety and quality control aspect.Simultaneously, because synergism, under the situation that reaches identical or close curative effect, available above-mentioned raw material cheap and easy to get is to practice thrift cost.Still there is not at present the report that salvianolic acid and above-mentioned raw materials form complex.
Summary of the invention
The objective of the invention is to, a kind of the treat salvianolic acid compound of cardiovascular and cerebrovascular disease, hepatic disease and the application in pharmacy thereof are provided.
The present invention relates to a kind of salvianolic acid and basic amino acid; Or the complex of alkaline glucose derivant composition; Said salvianolic acid is meant and is present in Radix Salviae Miltiorrhizae or its congener; Through extraction separation or the synthetic phenolic acid compound that obtains, comprise the arbitrary monomer component in DA Sal-A, B, C, D, E, F, G, H, I, J, caffeic acid or the danshensu, with above-mentioned any or appoint several kinds of effective sites that composition is the master.
Said basic amino acid is selected from arginine, lysine or histidine.Said alkaline glucose derivant is selected from meglumine or glucosamine.
Salvianolic acid and basic amino acid, or the mol ratio of alkaline glucose derivant is 1: (0.1～10); Preferred 1: (0.5～5); More preferably 1: 2.
The method for preparing of complex of the present invention does; Said salvianolic acid and arginine, lysine, histidine, glucosamine or meglumine are reacted in water and/or alcoholic solvent; With methods such as the conventional evaporated under reduced pressure of pharmaceutical field, lyophilizations, remove solvent, obtain salvianolic acid double salt solid.Salvianolic acid is 1 with other mol ratio that forms the medicine of double salt with it: (0.1～10); Preferred 1: (0.5～5); More preferably 1: 2.
The invention still further relates to the pharmaceutical preparation of processing with described salvianolic acid compound; Contain the ingredient of treating effective dose; And pharmaceutically acceptable pharmaceutical carrier; Its dosage form is said any dosage form on the pharmaceutics, includes but not limited to tablet, capsule, spray, gel, inhalant, oral agents, solution, Emulsion, suspensoid, electuary, patch, ointment, pill, powder, granule, injection, infusion solution, freeze dried injection, suppository, slow releasing preparation or controlled release preparation.
Pharmaceutical carrier in the said pharmaceutical preparation is for solid preparation; Include but not limited to filler, disintegrating agent, binding agent, wetting agent, lubricant; Said filler comprises starch, dextrin, lactose, sucrose, Icing Sugar, microcrystalline Cellulose, glucose, meglumine, glucosamine, mannitol, calcium sulfate, calcium hydrogen phosphate; Disintegrating agent comprises hyprolose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, crosslinked hydroxypropyl methylcellulose; Binding agent comprises hydroxypropyl methylcellulose, polyvidone, and wetting agent comprises water, ethanol, and lubricant comprises magnesium stearate, Pulvis Talci; For liquid preparation; Include but not limited to solvent, solubilizing agent, cosolvent, emulsifying agent, pH regulator agent; Said solvent comprises water, glycerol, ethanol, Polyethylene Glycol, fatty oil, liquid paraffin; Solubilizing agent comprises the polyoxyethylene ether Oleum Ricini; Tween, pluronic F-68, cosolvent comprise arginine or lysine, meglumine or glucosamine, diethylamine, ethylenediamine, carbamide, carnitine, ligustrazine, nicotiamide, proline, glucose, citric acid and sodium salt thereof, and isoosmotic adjusting agent comprises glucose, sodium chloride; The pH regulator agent comprises arginine, lysine, meglumine, glucosamine, diethylamine, ethylenediamine, and various mineral acids, alkali and organic acid, alkali and buffer thereof; For semi-solid preparation, suppository or drop pill, include but not limited to substrate, substrate comprises carbomer, paraffin, vegetable oil, soap class, high fatty alcohol, Polyethylene Glycol.
Described pharmaceutical preparation, the preferred freeze dried injection of its dosage form, used carrier includes but not limited to sodium chloride, glucose, mannitol, poloxamer, dextran, glucosamine, meglumine.
Technical problem to be solved by this invention can also further realize through following technical scheme.Above-described medicinal composition preparation can be salvianolic acid compounds and salvianolic acid compounds and the medicinal composites of different bases formation and the preparation of suitable adjuvant formation.For example, tablet or capsule that the medicinal composites that can be salvianolic acid compounds and salvianolic acid compounds form with different bases and filler, disintegrating agent are filled a prescription; Or the medicinal composites that forms of salvianolic acid compounds and salvianolic acid compounds and different bases and filler, the hypromellose slow releasing tablet or the capsule of filling a prescription; Or the medicinal composites that forms of salvianolic acid compounds and salvianolic acid compounds and different bases, the lyophilized formulations that forms with adjuvants such as sodium chloride, glucose, mannitol, dextran, glucosamine, meglumines.
The method for preparing of pharmaceutical preparation according to the invention is the pharmaceutics conventional method.
Complex according to the invention can be used for preparation treatment hepatopathy, reaches the medicine of the heart, brain, angiopathy.The amount of application of medicine is the treatment effective dose; Can be according to variations such as the type of route of administration, patient's age, body weight, the disease of treating and the orders of severity; Its daily dose can be 0.01～100mg/kg by salvianolic acid, preferred 0.1～100mg/kg, but one or many uses.
The various medicine materials that the present invention is used are the known material of prior art, can directly buy from market.Also available prior art is extracted or is synthetic.
Creativeness of the present invention is, with salvianolic acid and basic amino acid, forms complex like arginine, lysine, histidine; Or form complex with glucosan derivatives such as meglumine, glucosamine, and have synergism for the treatment of cardiovascular and cerebrovascular disease, hepatic disease, can improve curative effect with respect to existing salvianolic acid B magnesium salt.Comprise the pharmaceutical composition that salvianolic acid and other Chinese medicine are formed in the prior art, be used for the treatment of cardiovascular and cerebrovascular disease.But, salvianolic acid and the combination of other Chinese medicine ingredients, composition is more complicated, and wherein some unknown composition possibly have safety hidden danger, and the Chinese medicine differences between batches are bigger, brings very big difficulty to quality control.And among the present invention, the raw material that forms complex with salvianolic acid is the known single component of molecular structure, and side effect is little, and therefore some or even pharmaceutical necessities commonly used can solve the shortcoming of above-mentioned safety and quality control aspect.Simultaneously, because synergism, under the situation that reaches identical or close curative effect, available above-mentioned raw material cheap and easy to get is to practice thrift cost.
Embodiment 1: the preparation of salvianolic acid B or total salvianolic acid arginine complex
In reaction bulb, add salvianolic acid B or total salvianolic acid 7.19g successively, arginine 1.74g, distilled water 300ml, stirring reaction are to clear liquor, and the evaporated under reduced pressure solvent promptly gets.
Embodiment 2: the preparation of salvianolic acid B or total salvianolic acid histidine complex
In reaction bulb, add salvianolic acid B or total salvianolic acid 7.19g successively, histidine 1.55g, distilled water 300ml, stirring reaction are to clear liquor, and the evaporated under reduced pressure solvent promptly gets.
Embodiment 3: the preparation of salvianolic acid B or total salvianolic acid lysine complex
In reaction bulb, add salvianolic acid B or total salvianolic acid 7.19g successively, lysine 1.46g, distilled water 300ml, stirring reaction are to clear liquor, and the evaporated under reduced pressure solvent promptly gets.
Embodiment 4: the preparation of salvianolic acid B or total salvianolic acid glucosamine complex
In reaction bulb, add salvianolic acid B or total salvianolic acid 7.19g successively, glucosamine 1.79g, distilled water 300ml, stirring reaction are to clear liquor, and the evaporated under reduced pressure solvent promptly gets.
Embodiment 5: the preparation (1000) of salvianolic acid B or total salvianolic acid amino acid complex capsule
Salvianolic acid B or total salvianolic acid arginine complex 15g
Microcrystalline Cellulose 60g
Lactose 100g
Carboxymethyl starch sodium 14g
2%HPMC solution is an amount of
Magnesium stearate 2g
Salvianolic acid B or total salvianolic acid arginine complex, microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 100 mesh sieve mix homogeneously respectively, are binding agent system soft material with 2%HPMC solution, cross 20 mesh sieve system granules, and wet granular is in 50-60 ℃ of baking oven forced air drying; Dried granule is crossed 20 mesh sieve granulate, and with the magnesium stearate mixing, fill is in capsule.
Embodiment 6: the preparation (1000) of salvianolic acid B or total salvianolic acid lysine complex tablet
Salvianolic acid B or total salvianolic acid lysine complex 20g
Microcrystalline Cellulose 30g
Lactose 40g
Carboxymethyl starch sodium 7g
2%HPMC solution is an amount of
Magnesium stearate 1g
Salvianolic acid B or total salvianolic acid lysine complex, microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 100 mesh sieve mix homogeneously respectively; HPMC solution with 2% is binding agent system soft material; Cross 20 mesh sieve system granules, wet granular is in 50-60 ℃ of baking oven forced air drying; Dried granule is crossed 20 mesh sieve granulate, with magnesium stearate mixing, tabletting.
Embodiment 7: salvianolic acid B or total salvianolic acid arginine complex, salvianolic acid B or total salvianolic acid lysine complex, or the preparation (1000 bottles) of salvianolic acid B or total salvianolic acid histidine complex injectable powder
Salvianolic acid B arginine complex, salvianolic acid B
Lysine complex or salvianolic acid B histidine complex 10.0g
Mannitol 20.0g
Water for injection is to 1000ml
Get salvianolic acid B arginine complex, salvianolic acid B lysine complex or salvianolic acid B histidine complex and put in the appropriate vessel, add injection water 900ml, stir, ultrasonic to dissolving, add the mannitol stirring and make dissolving; Add needle-use activated carbon by 0.1%, stirred 30 minutes, through titanium core decarburization sucking filtration in the container of cleaning; Add water for injection to 1000ml, solution stirring was made evenly in 5 minutes, again through 0.22 μ m filtering with microporous membrane; Filtrate fill in the 7ml cillin bottle, every bottle of 2ml, partly butyl rubber match beyond the Great Wall then; Deliver on the flaggy in the freeze drying box, insert temperature probe, close chamber door.Press the freeze-drying curve lyophilization, the final drying temperature is more than 35 ℃ and kept 2 hours.Close plug, venting, outlet rolls lid.
Embodiment 8: salvianolic acid B or total salvianolic acid glucosamine complex slow releasing capsule (1000)
Salvianolic acid B or total salvianolic acid glucosamine complex 80g
Microcrystalline Cellulose 15g
Hypromellose K4M 100g
3% hypromellose (E5) aqueous solution is an amount of
Pulvis Talci 2g
Salvianolic acid B or total salvianolic acid glucosamine complex, microcrystalline Cellulose, hypromellose K4M are crossed 60 mesh sieves mix all, add 3% hypromellose (E5) aqueous solution and make soft material in right amount, cross 20 mesh sieves and granulate.40-50 ℃ of baking oven forced air drying.Dried granule is crossed 20 mesh sieve granulate, adds the Pulvis Talci of recipe quantity, mix homogeneously.Press the recipe quantity fill in capsule.
Embodiment 9: salvianolic acid glucosamine complex oral liquid (50 bottles)
Get salvianolic acid extract (effective site) 10.2 grams (containing total salvianolic acid 80%), glucosamine 2.1g, distilled water 300ml, stirring reaction is to clear liquor; The evaporated under reduced pressure solvent gets salvianolic acid (effective site) glucosamine complex, gets this complex 1.0g and is dissolved in the 1000ml purified water, stirs and makes abundant dissolving; Add 85% simple syrup, regulate pH value 3.5～7.0, add 0.3% sodium benzoate again and make antiseptic; Heated and boiled 30 minutes, with the filtering with microporous membrane of 0.8 μ m, embedding is in the brown oral vial of 20ml; 100 ℃, sterilization in 30 minutes gets salvianolic acid glucosamine complex oral liquid.
Embodiment 10: salvianolic acid B and complex thereof protect the liver and cardiovascular aspect drug efficacy study, test method and result are following:
One, trial drug: salvianolic acid B (No. 1, medicine), salvianolic acid B arginine complex (No. 2, medicine), salvianolic acid B and glucosamine complex (No. 3, medicine)
Two, test method:
1. get the mice that body weight is 20g ± 2g, male, be divided into 5 groups at random, normal control group, model control group and medicine 1-3 number group.Gastric infusion, dosage (in salvianolic acid B) 25mg/kg, normal control group and model control group give the equivalent distilled water, successive administration 7 days, after administration in the 6th day 6 hours, except that the normal control group, equal lumbar injection 0.1%CCl
410ml/kg after the last administration 24 hours; Eye socket is got blood (get blood before fasting 16 hours), surveys Serum ALT, AST and LPO (MDA), cuts open to get same position fritter liver and claim quality; Process 10% liver tissue homogenate with normal saline, survey wherein malonaldehyde (MDA) level.
2. male rat is 20; Be divided into 4 groups; Inject phosphate buffer and medicine 1-3 number by the tongue vein respectively, dosage (in salvianolic acid B) 10mg/kg, 10min prepares PRP (being rich in platelet blood plasma) and PPP (platelet poor plasma) by abdominal aortic blood after the administration; Use platelet count, and transfer among the PRP platelet count to 2.5-3.5 * 10 with PPP
8/ ml.On platelet aggregation instrument, survey and add behind the derivant hematoblastic PAR in the 5min, inductive final concentration is respectively 5 ' adenosine diphosphate (ADP) 5 μ mol/L, arachidonic acid (AA) 0.6mmol/L, collagen 25ml/L.
3. rat is tapped the head and causes dusk, takes out heart rapidly, and preparation Langendorff isolated heart is with 95%O
2± 5%CO
2The K-H buffer that mist is saturated (37 ℃ ± 0.5 ℃), reverse constant speed perfusion, speed 6-8ml/min, perfusion pressure 7.0～7.5kPa contains (mmol/L) Nacl 118 in the K-H buffer, and Kcl 0.8, Mgcl
21.2 Cacl
21.27, KH
2PO
41.2, NaHCO
3.25, Glucose 10, treat that heart recovers to stablize 30min after the normal rhythm activity, and the ligation LADCA is blocked its blood flow fully then.Ischemia 15min cuts off ligature, recovers blood flow and pours into 10min again, leads with standard I I and writes down different time electrocardio-activity situation.Ventricular fibrillation (VF) to occur is that arrhythmia is positive, asks the incidence rate of respectively organizing VF.
LDH and GOT assay in the perfusate: respectively at 15min before the ligation, after the ligation with pour into 10min again, get the arteria coronaria effluent and measure LDH and GOT.
The mensuration of lipid peroxidation product MDA in the cardiac muscular tissue: after perfusion finishes, clip ischemic region cardiac muscular tissue, homogenate is processed with 100mmol/L phosphate buffer (pH7.4) in the back of weighing, and measures MDA content.
Each administration group adds respectively in buffer medicine 1-3 number, and concentration is 1.0 μ mol/L (in salvianolic acid B).
Three, result of the test:
1, salvianolic acid B class medicine is to CCl
4Cause the protective effect of hepatic injury mice: see table 1.The concentration of the glutamate pyruvate transaminase of model control group (ALT), glutamic oxaloacetic transaminase, GOT (AST), serum lipid peroxide (LPO) and liver homogenate malonaldehyde (MDA) explains that all apparently higher than the normal control group model is successful.And the These parameters of each administration group all is starkly lower than model group, explains medicine 1-3 number to CCl
4Causing mouse liver injury has the significant protection effect, and medicine 2-3 number effect is better than medicine No. 1.
Table 1 salvianolic acid B class medicine is to CCl
4Cause the protective effect of hepatic injury mice
X ± SD, compare with model group:
*P＜0.01
2, antiplatelet aggregative activity in the salvianolic acid B class medicine halfbody: see table 2.' adenosine diphosphate (ADP), arachidonic acid (AA) and collagen-induced platelet aggregation all have the obvious suppression effect to salvianolic acid B class medicine to 5; And medicine 2-3 number effect is better than medicine No. 1.
Table 2 salvianolic acid B class medicine is to the influence
by ADP, collagen, the inductive rat platelet aggregation of AA
X ± SD, compare with normal group:
*P＜0.05
*P＜0.01
3, salvianolic acid B class medicine is to the protective effect of rat myocardial ischemia and reperfusion property damage
3.1 the influence that salvianolic acid B class medicine quivers to rat heart muscle ischemic chamber: see table 3.Matched group recovers perfusion again behind ligation arteria coronaria 15min; It is thus clear that electrocardiogram typical ventricular fibrillation occurs or/and performances such as arrhythmia such as ventricular tachycardias; The chamber incidence rate of quivering is 78.6%, and the obvious chamber of the administration group rate of quivering obviously descends, and medicine 2-3 number effect is better than medicine No. 1.
The influence that table 3 salvianolic acid B class medicine quivers to rat heart muscle ischemic chamber
Compare with normal group:
*P＜0.05
*P＜0.01
3.2 salvianolic acid B class medicine is to the influence of the MDA in the rat ischemia property heart homogenate: see table 4.The malonaldehyde (MDA) that also contains trace in the normal myocardium tissue, ischemia-reperfusion can make in the cardiac muscular tissue MDA content higher by 43.6% than normal myocardium content, and with pastille perfusate perfusion heart, the MDA content in the ischemia-reperfusion district cardiac muscular tissue does not have obvious increase.
Table 4 salvianolic acid B class medicine is to the influence
of the MDA in the rat ischemia property heart homogenate
X ± SD, compare with matched group:
*P＜0.05
*P＜0.01
3.3 salvianolic acid B class medicine is to the influence of the LDH in the rat arteria coronaria perfusate: see table 5.Respectively at before the ischemia, ischemia 15min and get arteria coronaria effluent 0.1ml when pouring into 10min again and measure that wherein LDH is active.Increase 60% before the LDH specific activity is poured into again behind the ischemia-reperfusion; And after pouring into again with the pastille perfusate, in the perfusate LDH active do not have obviously raise, explain that having reduced LDH for medicine 1-3 number spills in born of the same parents; Cardiac muscle is had protective effect, and medicine 2-3 number effect is better than medicine No. 1.
Table 5 salvianolic acid B class medicine is to the influence (U/100ml)
of the LDH in the rat arteria coronaria perfusate
X ± SD, compare with matched group:
*P＜0.05
*P＜0.01
Claims (13)
1. salvianolic acid and basic amino acid; Or the complex of alkaline glucose derivant composition; Said salvianolic acid is meant and is present in Radix Salviae Miltiorrhizae or its congener; Through extraction separation or the synthetic salvianolic acid B chemical compound that obtains, wherein basic amino acid is an arginine, and the alkaline glucose derivant is a glucosamine.
2. the described complex of claim 1, wherein salvianolic acid B and basic amino acid, or the mol ratio of alkaline glucose derivant is 1: (0.1～10).
3. the described complex of claim 1, wherein salvianolic acid B and basic amino acid, or the mol ratio of alkaline glucose derivant is 1: (0.5～5).
4. the described complex of claim 1, wherein salvianolic acid B and basic amino acid, or the mol ratio of alkaline glucose derivant is 1: 2.
5. the method for preparing of the described complex of claim 1 is reacted salvianolic acid B and basic amino acid or alkaline glucose derivant in water and/or alcoholic solvent, remove solvent with the pharmaceutical field conventional method, obtains salvianolic acid B complex solid.
6. the pharmaceutical preparation of processing with each described complex in the claim 1 to 4 contains the ingredient of treating effective dose, and pharmaceutically acceptable pharmaceutical carrier, and its dosage form is said any dosage form on the pharmaceutics.
7. the described pharmaceutical preparation of claim 6, its dosage form are oral agents or injection.
8. the described pharmaceutical preparation of claim 6, its dosage form is for being tablet, capsule, Emulsion, suspensoid, pill, powder, granule, slow releasing preparation or controlled release preparation.
9. the described pharmaceutical preparation of claim 6, its dosage form are infusion solution or freeze dried injection.
10. the described pharmaceutical preparation of claim 6, its dosage form are patch, suppository or ointment.
11. the described pharmaceutical preparation of claim 6, its dosage form are gel.
12. the application of each said complex in the medicine of preparation treatment hepatopathy in the claim 1 to 4.
13. the application of each said complex in the medicine of preparation treatment cardiovascular and cerebrovascular disease in the claim 1 to 4.
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| CN101376628B (en) * | 2007-08-30 | 2013-02-20 | 山东绿叶天然药物研究开发有限公司 | Novel phenolic acid compound, preparation and pharmaceutical composition thereof and use |
| CN101564388B (en) * | 2008-04-21 | 2012-03-14 | 北京环京弘方生物科技有限公司 | Composition for Danshensu and danshinolic acid B and use thereof |
| CN102335146A (en) * | 2010-07-19 | 2012-02-01 | 上海医药工业研究院 | Injectable drug combination and preparation method thereof |
| CN105617355A (en) | 2016-01-29 | 2016-06-01 | 徐宝贞 | Medicine for treating cardiovascular and cerebrovascular diseases |
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