CN102764250B - Composition composed of taurine and ginkgolide A and application thereof - Google Patents
Composition composed of taurine and ginkgolide A and application thereof Download PDFInfo
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- CN102764250B CN102764250B CN201110115955.8A CN201110115955A CN102764250B CN 102764250 B CN102764250 B CN 102764250B CN 201110115955 A CN201110115955 A CN 201110115955A CN 102764250 B CN102764250 B CN 102764250B
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- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 title claims abstract description 65
- 229960003080 taurine Drugs 0.000 title claims abstract description 30
- 239000000203 mixture Substances 0.000 title claims abstract description 17
- FPUXKXIZEIDQKW-MFJLLLFKSA-N ginkgolide A Natural products O=C1[C@H](C)[C@@]2(O)[C@@H](O1)C[C@]13[C@@H]4OC(=O)[C@]21O[C@@H]1OC(=O)[C@H](O)[C@]31[C@@H](C(C)(C)C)C4 FPUXKXIZEIDQKW-MFJLLLFKSA-N 0.000 title 1
- SQOJOAFXDQDRGF-WJHVHIKBSA-N ginkgolide B Natural products O=C1[C@@H](C)[C@@]2(O)[C@@H]([C@H](O)[C@]34[C@@H]5OC(=O)[C@]23O[C@H]2OC(=O)[C@H](O)[C@@]42[C@H](C(C)(C)C)C5)O1 SQOJOAFXDQDRGF-WJHVHIKBSA-N 0.000 title 1
- FPUXKXIZEIDQKW-VKMVSBOZSA-N ginkgolide-a Chemical compound O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13C[C@@H]1OC(=O)[C@@H](C)[C@]21O FPUXKXIZEIDQKW-VKMVSBOZSA-N 0.000 title 1
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
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- 239000011734 sodium Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- 241001659321 ANME-2 cluster Species 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
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- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
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- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A compound preparation for treating cardiovascular diseases in the invention is prepared from the following active components according to the following weight ratio with the assistance of routine pharmaceutic adjuvants through a routine technology: 100mg-400mg of taurine and 20-80mg of ginkgolide. The compound composition has a function of inhibiting platelet aggregation. By the use of the compound composition, rat myocardial infarction rate is reduced.
Description
Technical field
The present invention relates to a kind of compound capsules being formed by a certain percentage by taurine and ginkalide A and preparation method thereof.Belong to medical technical field.
Background technology
Cardiovascular disease is the first killer of harm humans life and health, according to updated statistics, within 2000, the whole world has 1,700 ten thousand people to die from cardiovascular disease, account for 1/3 of the total death toll of global a variety of causes, expect this numeral of the year two thousand twenty and will increase to 2,500 ten thousand, and wherein 80% all in developing country.
According to China's population analysis on cause of death in 1997, in the urban population cause of death, tumor held pride of place, and cerebrovascular accounts for second, and both numerical value is bordering on equal; In the rural population cause of death, respiratory system disease holds pride of place, and cerebrovascular accounts for second.Ischemic cerebrovascular accounts for 70% in whole cerebrovascular.Cardiovascular disease has quite high sickness rate and disability rate, can not be ignored.
Taurine (Taurine) chemical name is 2-aminoethyl sulfonic acid, is white or the oblique shape crystal of off-white color, and odorless, is dissolved in the organic solvents such as ether, is a kind of non-protein amino acid of sulfur-bearing.
Taurine can suppress platelet aggregation in blood circulation, reduces blood fat, keeps human normal blood pressure and prevents arteriosclerosis; Taurine can antagonism myocardial cell in calcium ion, maintain its balance, realize heart tonifying; Myocardial cell is had to protective effect, can arrhythmia; Taurine can increase the dissolubility of lipid and cholesterol, has special efficacy to reducing Blood Cholesterol content, can treat heart failure.
The people such as Benveniste have found the factor that can strongly cause platelet aggregation from rabbit basophil in 1972.This factor is named as platelet activating factor (hereafter is PAF).The physiological action of PAF was extensively examined or check, and known PAF is an important factor in multiple physiological reaction, comprises platelet aggregation, blood pressure lowering, anaphylactic type immunoreation, smooth muscle contraction, inflammatory reaction, pain, edema, and the adjusting of breathing and blood circulation.For example, thereby the compound with PAF antagonistic activity is very useful aspect the disease of the multiple PAF induction for the treatment of, inflammation disease, anaphylactic disease, anaphylactic shock, septic shock, angiopathy is as DIC, cardiomyopathy, asthma, pulmonary edema, and adult respiratory system disease.
Yet there are no with the compound preparation of taurine and ginkalide A compatibility separately; pertinent literature also do not report, both have definite curative effect to cardiovascular acute illness, after compound recipe, can bring into play synergism; particularly cardiovascular acute attack stage, rapidly onset and reach therapeutic purposes.
Summary of the invention
The object of the present invention is to provide a kind of soft capsule of the Cardiovarscular of preferably being made by a certain percentage by taurine and ginkalide A compositions warp.
Ginkalide A and taurine, both have quick acting effect to cardiovascular acute illness, after compound recipe, should be able to bring into play synergism, particularly cardiovascular acute attack stage, rapidly onset and reach the therapeutic effect of expection.Ginkalide A is PAF specific antagonists, and taurine can anticoagulant, again can antagonism myocardial cell in calcium ion, remove the cholesterol in blood vessel, vessel softening.The compatibility of this compositions uses, and major advantage is, ginkalide A and the potentiation of taurine compatibility, and this preparation is rapid-action, and curative effect is high.
This compositions is in order to various cardiovascular disease such as treatment, angina pectoris, myocardial ischemia.Pharmacodynamic experiment proves, with ginkalide A and taurine composition for qi depression to blood stasis cardiovascular diseases, evident in efficacy.Said composition medicine shows through toxicological experiment, and toxicity is minimum, and through the side's of tearing open research, our two medicines are combined adapted, obviously strengthen, and have Attenuation than alone wherein any not only drug effect.
Another object of the present invention is to provide the preparation method of this soft capsule.
The compound preparation of Cardiovarscular of the present invention is aided with conventional pharmaceutic adjuvant by following weight proportion active component and is prepared from by common process: taurine 100mg-400mg, ginkalide A 20-80mg.
The preparation method of the composite preparation of Cardiovarscular of the present invention contains taurine, ginkalide A, lytic agent, diluent, emulsifying solubilizing agent and opacifier.Lytic agent, diluent are specially vegetable and animals oils or the PEG400 such as Oleum Arachidis hypogaeae semen, Oleum Glycines, olive oil, fish oil, can be independent, also can mix by a certain percentage use, and addition is 30%-75%, is preferably 40%-60%.Contain emulsifying agent, be specially soybean phospholipid, lecithin, polyglycerin ester etc., its addition is 2%-10%, is preferably 5%-8%, and to increase the dissolubility of ginkalide A, taurine has good solubilization to ginkalide A.
Beneficial effect
Compound preparation of the present invention can be at cardiovascular acute attack stage performance synergism, and to the influence demonstration of ADP induction Platelet Aggregation in Rabbits, taurine and ginkalide A different proportion compositions all have the effect of anticoagulant.The result of the test that affects of rat coronary ligation Myocardial Ischemia shows: in taurine and ginkalide A, dosage group (10mg/kg, 2mg/ml) all has more significant curative effect for reduction rat myocardial infarction model rate higher dosage group, low dose group, single one-tenth grouping.
Specific embodiment party example
The impact of embodiment 1. on ADP induction Platelet Aggregation in Rabbits
A. group and dosage
(1) blank group: DMSO solution; (2) ginkalide A group, taurine group, taurine: ginkalide A different proportion compositions (I group 15: 1, II group 10: 1, III group 5: 1, IV group 2.5: 1, V group 1: 1, VI group 1: 2.5, VII group 1: 5, VIII group 1: 10) 8 groups: (3) troxerutin I, II, III, IV, V group: concentration be respectively 0.05mg/ml, 0.5mg/ml, 5mg/ml, 50mg/ml, 50mg/ml (administration volume be 20 μ l); When experiment, except troxerutin V group, try to please for each group and amass 10 μ l.
B. method
Get male new zealand rabbit, body weight 2.0-2.5kg.Dorsal position is fixed on operating table for rabbit, cuts off the cervical region rabbit hair, subcutaneous injection 1% procaine hydrochloride injection local infiltration anesthesia.Cut off the about 3cm of skin of neck, carry out blunt separation with mosquito forceps, isolate common carotid artery after exposing bronchus.Fine rule ligation common carotid artery distal end, then press from both sides and close proximal part with bulldog clamp, carry out fixing after vascular catheterization.After operation finishes, open bulldog clamp, blood is put into the test tube that contains 3.8% sodium citrate, making blood and the ratio of 3.8% sodium citrate volume is 9: 1.
After being mixed, the anticoagulated blood of above-mentioned preparation prepares PRP and PPP by different centrifugal speeds.After the centrifugal 10min of 800rpm, draw upper plasma and obtain PRP; Obtain PPP by drawing upper plasma after centrifugal residual blood 2500rpm 10min.
First get 250 μ l PPP and add in test cup, then put into instrument connection, press " PPP " key and calibrate.Then getting 250 μ l PRP adds in test cup, preheating 1min in 37 ℃ of pre-temperature grooves, put into the medicinal liquid (note: troxerutin V group adds 20 μ l medicinal liquids) that adds 10 μ l variable concentrations after instrument connection, while pressing " beginning " key, add immediately derivant 0.144mg/ml ADP 10 μ l, to measure maximum agglutination rate.4 passages of each mensuration, in the hope of average maximum agglutination rate.
Calculate platelet aggregation inhibition rate
Formula is as follows:
On the impact of ADP induction Platelet Aggregation in Rabbits
Result shows: 1. four dosage groups of troxerutin (18.6,186,1860,3720 μ g/ml) have inhibitory action to the Platelet Aggregation in Rabbits of ADP induction, wherein 3720 μ g/ml and blank group relatively have significant difference (P < 0.05), amount effect relation curve (the y=32.218x-30.634 that is proportionate, R=0.9957), IC50 is 388.36 μ g/ml.2. the drug effect of tested medicine is ginkalide A IC
50be 160 μ g/ml, taurine: ginkalide A compound recipe VIII organizes IC
50be 150 μ g/ml, VII organizes IC
50be 153 μ g/ml, VI organizes IC
50be 160 μ g/ml, IV organizes IC
50be 150, III group IC
50be 140 μ g/ml, II organizes IC
50be 160 μ g/ml, I organizes IC
50be 180 μ g/ml, taurine group IC
50be 260 μ g/ml.
Embodiment 2. on rat coronary ligation Myocardial Ischemia impact
Method: get male SD rat, body weight 250-300g, lumbar injection chloral hydrate 300mg/kg anesthesia, face upward position fixing, operative incision position is successively with iodine tincture and alcohol disinfecting, afterwards the 3rd, four root bones are opened breast, and practice artificial respiration, expose heart, with damage-free suture needle for medical use 5/0 ligation arteria coronaria left anterior descending branch, close rapidly thoracic cavity routine disinfection, operative process is no more than 30s, postoperative continuation artificial respiration 1～2min, intramuscular injection (i.m) 200,000 unit penicillin prevention infection, after 10min, record II lead electrocardiogram index J point and T ripple, whether successfully observe modeling.Another using 8 rats of not ligation of threading as puppet operation group.Postoperative 10min J point and T ripple are not obviously raised person for modeling success rat.
Get 32 of modeling success rats; be divided at random 4 groups by body weight; every group 8; be model control group, positive control drug nimodipine group (120mg/kg, 24mg/ml), taurine and ginkalide A compositions (20mg/kg, 4mg/ml), in (10mg/kg; 2mg/ml), low (5mg/kg; 1mg/ml) dosage group, administration volume is 0.5ml/100g, model control group gives isometric 0.5%CMC-Na.8 of not ligation of threading rats give isometric 0.5%CMC-Na as puppet operation group in addition.Respectively organize rat gastric infusion every day once, successive administration 3 days, after last administration, the blood-letting of 24h common carotid artery is for detection of biochemical indicator.Sample process: after experiment finishes, take out immediately heart, wash away blood with normal saline, cut off atrium and heart bottom blood vessel, claim ventricular weight, ventricle is on average cut into 5 along coronary sulcus and puts into 1%TTC solution, at 37 ℃ of water bath with thermostatic control dyeing 5min, after taking-up, first clap digital photograph, then separate the part (blocking part) weigh and calculate it and account for the percentage rate (myocardial infarction percentage rate) of whole ventricular weight of being unstained, and and ischemia model group organize between t check [2].Calculate infraction percentage rate formula as follows:
Infraction percentage rate (%)=pale district weight/(ventricular weight) × 100%.
As can be seen from Table 1: the experimental result of 6 group models is: (10mg/kg in of the present invention group; 2mg/ml) dosage group, taurine group, ginkalide A group, four groups of medicines of nimodipine group all have positive effect (P < 0.05) for reducing rat myocardial infarction model rate; especially (10mg/kg in of the present invention group; 2mg/ml) dosage group has extremely significant effect (P < 0.01), is better than other group.
Table 1 on rat coronary ligation Myocardial Ischemia impact (
) n=8
Note: with sham operated rats comparison,
##p < 0.01; With model group comparison,
*p < 0.05,
*p < 0.01.
Embodiment 3: prescription
Preparation method: 1. soft capsule content preparation: recipe quantity taurine is added in PEG400, soybean phospholipid mixed liquor, is stirred to dissolve.Add again the ginkalide A of recipe quantity, heat, be stirred to dissolve.2. the preparation of soft capsule shell: get gelatin 1.00kg, arabic gum 0.25kg, glycerol 0.75g, water 1.5L, the mixture of methyl parahydroxybenzoate for adding preservative agent (1.6%) and propyl p-hydroxybenzoate (0.04%) is appropriate, add again titanium dioxide 6g, stir evenly and be heated to 60 degree, be incubated for subsequent use.3. the rolling under 38 degree RH60% conditions of the preparation of soft capsule rotation rolling capsule machine dries up and washes capsule and get final product.
Embodiment 4: prescription
Preparation method preparation method: 1. soft capsule content preparation: recipe quantity taurine is added in PEG400, soybean phospholipid mixed liquor, is stirred to dissolve.Add again the ginkalide A of recipe quantity, heat, be stirred to dissolve.2. the preparation of soft capsule shell: get gelatin 1.00kg, arabic gum 0.25kg, glycerol 0.75g, water 1.5L, the mixture of methyl parahydroxybenzoate for adding preservative agent (1.6%) and propyl p-hydroxybenzoate (0.04%) is appropriate, ferrous oxide 6g again, stir evenly and be heated to 60 degree, be incubated for subsequent use.3. the rolling under 38 degree RH60% conditions of the preparation of soft capsule rotation rolling capsule machine dries up and washes capsule and get final product.
Embodiment 5: in prescription,, with the PEG400 in fish oil alternative embodiment 1, preparation method is with embodiment 1.
Embodiment 6: in prescription,, with the soybean oil in Oleum Arachidis hypogaeae semen alternative embodiment 2, preparation method is with embodiment 2.
Claims (4)
1. a compositions for the Cardiovarscular being made up of taurine and ginkalide A, is characterized in that taurine: the part by weight of ginkalide A is 5: 1.
2. compositions as claimed in claim 1, wherein taurine and ginkalide A are respectively 100mg and 20mg.
3. a soft capsule for Cardiovarscular, is characterized in that active component is that part by weight is taurine and the ginkalide A of 5: 1.
4. soft capsule as claimed in claim 3, wherein taurine and ginkalide A are respectively 100mg and 20mg.
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| 祁小燕.银杏苦内酯A、B心肌电生理效应观察及抗心肌缺血的实验研究.《万方数据库> * |
| 祁小燕.银杏苦内酯A、B心肌电生理效应观察及抗心肌缺血的实验研究.《万方数据库>》.2005,2、3、5、6、16、17. |
| 高福军.脂欣康胶囊治疗冠心病不稳定性劳力型心绞痛及其血管内皮保护作用的临床研究.《中国优秀博硕士学位论文全文数据库（硕士）医药卫生科技辑》.2002,(第1期),E056-233. * |
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