CN1666739A - Application of Silibinin or its salts in preparation of medicine for treating coronary heart disease or strengthening the effect of coronary heart disease treatment - Google Patents
Application of Silibinin or its salts in preparation of medicine for treating coronary heart disease or strengthening the effect of coronary heart disease treatment Download PDFInfo
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- CN1666739A CN1666739A CN 200410023675 CN200410023675A CN1666739A CN 1666739 A CN1666739 A CN 1666739A CN 200410023675 CN200410023675 CN 200410023675 CN 200410023675 A CN200410023675 A CN 200410023675A CN 1666739 A CN1666739 A CN 1666739A
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Abstract
The invention discloses the use of silibinin or its salt in preparing medicament for treating coronary disease and the use in enhancing the curative effect of medicaments for treating coronary heart diseases. The salts provided by the invention can be inorganic alkaline salt, organic base salt or basic amino acidic salt.
Description
Technical field
The present invention relates to silibinin or its salt treats coronary heart disease or is used for strengthening the application for the treatment of the medicaments for coronary disease curative effect in preparation.
Background technology
Along with the acceleration of aged tendency of population process and the change of life style, coronary heart disease has become one and has had a strong impact on people's disease of quality of life, and mortality rate is high, and the drug development of novel and effective treatment coronary heart disease is very urgent.
Control to coronary heart disease people myocardial damage can be divided into prevention and treat two aspects, prevents to treat to be (as serious angina pectoris and myocardial infarction) medication behind the myocardial damage into preceding medication takes place myocardial damage, and is all significant to coronary disease patient prevention and treatment.
Silibinin is the active component of extraction separation from Herba Silybi mariani, has free radical resisting, stabilizing cell membrane and anti-liver injury effect.Bibliographical information silibinin 20,50,80mg/kg intravenously administrable before coronary artery ligation; rat heart muscle infarction size after the remarkable reduction ligation; 20mg/kg can prevent the generation [Chen Hong of reperfusion arrhythmia; Su Dingfeng; Zhang Tonghua etc. silibinin is to the protective effect of anesthetized rat acute myocardial infarction and reperfusion injury. Acta Pharmacologica Sinica .1992; 13 (1): 69～71.], promptly silibinin has certain preventive effect to ischemia myocardial damage.But give silibinin behind the heart and injury again, whether have therapeutical effect and do not appear in the newspapers.We discover silybin-N-methylglucamine in the posterior vein administration of coronary artery ligation a period of time, can significantly reduce rat heart muscle infarction size after the ligation, force down raising that J is ordered in the electrocardiogram, and promptly silibinin has therapeutical effect to myocardial damage.We find that also it has very obvious synergistic effect to the treatment medicaments for coronary disease simultaneously.Based on this, it is medicine or its medical usage in the curative effect of treatment coronary heart disease and enhancing treatment medicaments for coronary disease of effective ingredient with silibinin or its salt that the inventor has invented a kind of.
Summary of the invention
The invention provides the application in the medicine of preparation treatment coronary heart disease or enhancing treatment coronary heart disease of silibinin or its salt.
The invention provides with silibinin or its salt is effective ingredient, is used for the treatment of coronary heart disease, strengthens the medicine for the treatment of the medicaments for coronary disease curative effect.
Silibinin salt of the present invention can be silibinin inorganic base salts, the organic alkali salt of silibinin, silibinin alkaline amino acid salt, and the silibinin inorganic base salts can be silibinin sodium salt, silibinin potassium salt; The organic alkali salt of silibinin can be silybin-N-methylglucamine, silibinin diethyl amine salt; The silibinin alkaline amino acid salt can be silibinin arginine salt, silibinin lysinate.
Silibinin salt preferred water Silybin meglumine of the present invention, silibinin arginine salt, silibinin lysinate.
Provided by the invention is effective ingredient with silibinin or its salt, and the medicine that be used for the treatment of coronary heart disease, strengthens treatment medicaments for coronary disease curative effect is made up of silibinin or its salt and pharmaceutically acceptable carrier.This medicine can oral or injection administration, and drug administration by injection can be intravenous injection or intramuscular injection.Medicine can exist with the form of tablet, pill, granule, capsule, suspension, solution, syrup, injection, the preferred freeze-dried powder of injection preparation, injection vein emulsion.Various pharmaceutical dosage form provided by the present invention all can be prepared from the pharmacy conventional method.
Silibinin of the present invention or its salt are when being used for above-mentioned arbitrary purposes, and its using dosage scope is 50-5000mg, and the preferred dose scope is 200-1000mg.
The inventor is that representative has confirmed that by following test silibinin or its salt have the effect of treatment coronary heart disease with the silybin-N-methylglucamine, strengthen the effect in the treatment medicaments for coronary disease curative effect, but effect is not limited thereto test.Testing used silybin-N-methylglucamine is provided by natural drug Engineering Technical Research Centre preparation research chamber, Shandong Province.
The specific embodiment:
Preparation embodiment 1: the preparation of injection silybin meglumine freeze-dried powder
Take by weighing the 100g silybin meglumine, add water for injection 1000ml, 85 ℃ of insulations of the needle-use activated carbon of adding 0.1% 30 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um; Filtrate is sub-packed in the 10ml cillin bottle, and every loading amount 2ml makes freeze-dried powder through the freeze dryer lyophilizing.
Preparation embodiment 2: the preparation of injection silibinin arginine salt freeze-dried powder
Take by weighing silibinin 482g, add arginine 179g, add 5000ml water, shake up, after question response was complete, rotary evaporator was flung to most of water, and 60 ℃ of drying under reduced pressure are ground into fine powder, promptly get the silibinin arginine salt.
Take by weighing 100g silibinin arginine salt, add water for injection 1000ml, 85 ℃ of insulations of the needle-use activated carbon of adding 0.1% 30 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um; Filtrate is sub-packed in the 10ml cillin bottle, and every loading amount 2ml makes freeze-dried powder through the freeze dryer lyophilizing.
Preparation embodiment 3: the preparation of injection silibinin lysinate freeze-dried powder
Take by weighing silibinin 482g, add lysine 79g, add 5000ml water, shake up, after question response was complete, rotary evaporator was flung to most of water, and 60 ℃ of drying under reduced pressure are ground into fine powder, promptly get the silibinin lysinate.
Take by weighing 100g silibinin lysinate, add water for injection 1000ml, 85 ℃ of insulations of the needle-use activated carbon of adding 0.1% 30 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um; Filtrate is sub-packed in the 10ml cillin bottle, and every loading amount 2ml makes freeze-dried powder through the freeze dryer lyophilizing.
Preparation embodiment 4: the preparation of injection silibinin sodium salt freeze-dried powder
Take by weighing silibinin 482g, add sodium hydroxide 40g, add 2000ml water, shake up, after question response was complete, rotary evaporator was flung to most of water, and 60 ℃ of drying under reduced pressure are ground into fine powder, promptly get the silibinin sodium salt.
Take by weighing 100g silibinin sodium salt, add water for injection 1000ml, 85 ℃ of insulations of the needle-use activated carbon of adding 0.1% 30 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um; Filtrate is sub-packed in the 10ml cillin bottle, and every loading amount 2ml makes freeze-dried powder through the freeze dryer lyophilizing.
Preparation embodiment 5: the preparation of injection silibinin potassium salt freeze-dried powder
Take by weighing silibinin 482g, add lysine 56g, add 2000ml water, shake up, after question response was complete, rotary evaporator was flung to most of water, and 60 ℃ of drying under reduced pressure are ground into fine powder, promptly get silibinin potassium salt.
Take by weighing 100g silibinin potassium salt, add water for injection 1000ml, 85 ℃ of insulations of the needle-use activated carbon of adding 0.1% 30 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um; Filtrate is sub-packed in the 10ml cillin bottle, and every loading amount 2ml makes freeze-dried powder through the freeze dryer lyophilizing.
Preparation embodiment 6: the preparation of injection silibinin diethyl amine salt freeze-dried powder
Take by weighing silibinin 482g, add diethylamine 30g, add 5000ml water, shake up, after question response was complete, rotary evaporator was flung to most of water, and 60 ℃ of drying under reduced pressure are ground into fine powder, promptly get silibinin diethyl amine salt.
Take by weighing 100g silibinin diethyl amine salt, add water for injection 1000ml, 85 ℃ of insulations of the needle-use activated carbon of adding 0.1% 30 minutes, G
3Sintered glass funnel filters, the filtering with microporous membrane of 0.22um; Filtrate is sub-packed in the 10ml cillin bottle, and every loading amount 2ml makes freeze-dried powder through the freeze dryer lyophilizing.
Preparation embodiment 7: the preparation of injection silibinin Emulsion
Silibinin 200mg
Refined soybean oil 10g
Refining soybean phospholipid 2.0g
Poloxamer 1.0g
Glycerol 2.5g
Cholesterol 0.5g
Water for injection adds to 100ml
Silibinin, fabaceous lecithin, cholesterol are joined in the refined soybean oil after with dissolve with ethanol, be mixed to clear and brightly, and by rotary evaporation or feed vaporized nitrogen and remove alcohol, obtain containing the soybean oil solution of silibinin 20mg/ml and 50mg/ml cholesterol.Poloxamer, glycerol are dispersed in the water for injection, and under the high-speed stirred condition, the oil solution that slowly drips the phospholipid contain silibinin, cholesterol is made thick Emulsion in dispersion.Under the condition of pressure 100Mpa, by the further emulsifying of dispersing emulsification machine, emulsifying finishes the back in 115 ℃ with resulting thick Emulsion, the 30min sterilization, and packing is promptly.
Preparation embodiment 8: the preparation of silybin-N-methylglucamine tablet
Take by weighing the 100g silybin meglumine, add starch 100g, mixing, 75% ethanol water is made binding agent, the suitable soft material of system, 18 mesh sieves are granulated, 60 ℃ of oven dryings 2 hours, 16 order nylon mesh granulate add magnesium stearate, mixing, tabletting, the heavy 100mg/ sheet of sheet.
Preparation embodiment 9: the preparation of silibinin lysinate tablet
Take by weighing 100g silibinin lysine, add starch 100g, mixing, 75% ethanol water is made binding agent, the suitable soft material of system, 18 mesh sieves are granulated, 60 ℃ of oven dryings 2 hours, 16 order nylon mesh granulate add magnesium stearate, mixing, tabletting, the heavy 100mg/ sheet of sheet.
Preparation embodiment 10: the preparation of silibinin arginine salt tablet
Take by weighing 100g silibinin arginine, add starch 100g, mixing, 75% ethanol water is made binding agent, the suitable soft material of system, 18 mesh sieves are granulated, 60 ℃ of oven dryings 2 hours, 16 order nylon mesh granulate add magnesium stearate, mixing, tabletting, the heavy 100mg/ sheet of sheet.
Preparation embodiment 11: the preparation of silibinin tablet
Take by weighing the 100g silibinin, add starch 100g, mixing, 75% ethanol water is made binding agent, the suitable soft material of system, 18 mesh sieves are granulated, 60 ℃ of oven dryings 2 hours, 16 order nylon mesh granulate add magnesium stearate, mixing, tabletting, the heavy 100mg/ sheet of sheet.
Test example 1: silybin-N-methylglucamine treatment administration is to the influence test of rat heart muscle ischemia
(1) material:
Silybin-N-methylglucamine (SB): provide by natural drug Engineering Technical Research Centre preparation research chamber, Shandong Province.
Chlorination nitro blue tetrazolium (N-BT) is provided by Military Medical Science Institute medical supply station.
Laboratory animal: regular grade Wistar rat, male, body weight 280g-350g, natural drug Engineering Technical Research Centre zoopery center, Shandong Province provides.The quality certification number: No. 200106005, Shandong kinoplaszm word.
(2) method and result:
After the rat fasting 12 hours,, ip urethane (1.2g/kg) anesthesia, limbs II lead electrocardiogram is surveyed in anesthesia immediately after the Nifedipine group rat oral gavage administration (6mg/kg).Cut off left front fur, iodine tincture and alcohol disinfecting, along left border of sternum 1cm place, cut off thoracic wall muscle and two ribs, open the thoracic cavity rapidly, expose heart, the ligation left coronary artery is put back to heart immediately between arterial cone and left auricle, squeezes the thoracic cavity air, use the mosquito forceps closed-chest, cause Model Rats with Acute Myocardial Ischemia.After the modeling 2 hours, silybin-N-methylglucamine gastric infusion group (500mg/kg) gastric infusion, all the other respectively organize after the rat modeling 2 hours, be divided into model control group (waiting the capacity solvent) at random, silybin-N-methylglucamine small dose group (20mg/kg), silybin-N-methylglucamine is heavy dose of group (100mg/kg), the heavy dose of group of silybin-N-methylglucamine (200mg/kg), every group 10, each treated animal intravenous injection relative medicine, the electrocardiogram of record postoperative 2,3,4,6h takes out heart subsequently, after cleaning with cold saline ,-20 ℃ of refrigerator freeze overnight.Next day, refrigerated heart is cut into 5 by ligation place to apex uniform thickness, immerse in the freshly prepared 0.25%N-BT phosphate buffer (pH 7.4).37 ℃ of water-bath jolting 10～15min.Blot the dyeing liquor of slice surface with filter paper, separate the coloured portions and the part of being unstained, weigh the compute infarct size.Infarct size (%)=infarction part weight/(non-infarction part weight+infarction part weight) * 100%.
The result is as shown in table 1, behind the ligation coronary artery 2 hours, the silybin-N-methylglucamine that gives various dose obviously reduces the myocardial infarction area that Acute Myocardial Ischemia in Rats causes due to the ligation coronary artery, and can reduce the rising that the limbs II lead electrocardiogram J that caused by myocardial ischemia is ordered.
Table 1 silybin-N-methylglucamine is to the influence of rat heart muscle ischemic injuries (n=10, X ± s)
| Group | Infarct size (%) | Postoperative J point rising (mV) | |||
| 2h | 3h | 4h | 6h | ||
| Model group | 26.2±5.5 | 0.375±0.071 | 0.368±0.096 | 0.373±0.108 | 0.373±0.085 |
| Nifedipine group | 18.5±4.5 ** | 0.298±0.067 * | 0.283±0.073 * | 0.340±0.092 | 0.363±0.068 |
| The SB small dose group | 21.2±4.2 * | 0.371±0.097 | 0.313±0.063 | 0.286±0.069 * | 0.341±0.079 |
| The heavy dose of group of SB | 19.6±4.5 ** | 0.383±0.085 | 0.275±0.084 * | 0.251±0.052 ** | 0.310±0.061 * |
| The heavy dose of group of SB | 19.3±4.3 ** | 0.379±0.084 | 0.270±0.097 * | 0.245±0.056 ** | 0.304±0.068 * |
| SB gastric infusion group | 20.0±4.2 * | 0.379±0.078 | 0.338±0.091 | 0.276±0.074 * | 0.250±0.051 ** |
Compare with model control group:
*, P＜0.05;
*, P＜0.01
Test example 2: silybin-N-methylglucamine is to the synergism test of treatment medicaments for coronary disease
1. material:
Silybin-N-methylglucamine: provide by natural drug Engineering Technical Research Centre preparation research chamber, Shandong Province.
Chlorination nitro blue tetrazolium (N-BT) is provided by Military Medical Science Institute medical supply station.
Laboratory animal: regular grade Wistar rat, male, body weight 280g-350g, natural drug Engineering Technical Research Centre zoopery center, Shandong Province provides.The quality certification number: No. 200106005, Shandong kinoplaszm word.
2. method and result:
2.1 grouping
Solvent control group: the normal saline solution that gives equivalent
Nifedipine group small dose group: give nifedipine 1.5mg/kg
Nifedipine group low dose+silybin-N-methylglucamine small dose group: give Nifedipine group 1.5mg/kg+ silibinin 5mg/kg
The heavy dose of group of Nifedipine group low dose+silybin-N-methylglucamine: give Nifedipine group 1.5mg/kg+ silibinin 40mg/kg
The heavy dose of group of Nifedipine group: give Nifedipine group 6mg/kg
Nifedipine group heavy dose+silybin-N-methylglucamine small dose group: give Nifedipine group 6mg/kg+ silibinin 5mg/kg
The heavy dose of group of silybin-N-methylglucamine: give silibinin 40mg/kg
2.2 method and result
Rat is divided into the solvent control group at random, the Nifedipine group small dose group, Nifedipine group low dose+silybin-N-methylglucamine small dose group, the heavy dose of group of Nifedipine group low dose+silybin-N-methylglucamine, the heavy dose of group of Nifedipine group, Nifedipine group heavy dose+silybin-N-methylglucamine small dose group, the heavy dose of group of silybin-N-methylglucamine.Every group 10, fasting is after 12 hours, the nifedipine gastric infusion, and the silybin-N-methylglucamine intravenously administrable, limbs II lead electrocardiogram is surveyed in ip urethane (1.2g/kg) anesthesia after the administration.Cut off left front fur, iodine tincture and alcohol disinfecting are along left border of sternum 1cm place, cut off thoracic wall muscle and two ribs, open the thoracic cavity rapidly, expose heart, the ligation left coronary artery is put back to heart immediately between arterial cone and left auricle, squeezes the thoracic cavity air, use the mosquito forceps closed-chest, cause Model Rats with Acute Myocardial Ischemia, the electrocardiogram of record postoperative 1,2,4h takes out heart subsequently, after cleaning with cold saline ,-20 ℃ of refrigerator freeze overnight.Next day, refrigerated heart is cut into 5 by ligation place to apex uniform thickness, immerse in the freshly prepared 0.25%N-BT phosphate buffer (pH7.4).37 ℃ of water-bath jolting 10～15min.Blot the dyeing liquor of slice surface with filter paper, separate the coloured portions and the part of being unstained, weigh the compute infarct size.Infarct size (%)=infarction part weight/(non-infarction part weight+infarction part weight) * 100%.
The result is as shown in table 2, the silybin-N-methylglucamine coupling nifedipine of various dose obviously reduces the myocardial infarction area that Acute Myocardial Ischemia in Rats causes due to the ligation coronary artery, and can reduce the rising that the limbs II lead electrocardiogram J that caused by myocardial ischemia is ordered.
Table 2 silybin-N-methylglucamine is to the synergic influence of rat heart muscle ischemic injuries (n=10, X ± s)
| Group | Dosage (mg/kg) | Infarct size (%) | Postoperative J point rising (mV) | ||
| 1h | 2h | 4h | |||
| Model group | --- | 26.0±5.6 | 0.374±0.081 | 0.346±0.075 | 0.330±0.092 |
| The nifedipine small dose group | 1.5 | 23.7±4.9 | 0.336±0.037 | 0.306±0.065 | 0.305±0.063 |
| The silibinin small dose group | 5 | 23.9±5.1 | 0.324±0.094 | 0.293±0.085 | 0.303±0.092 |
| The heavy dose of group of nifedipine | 6 | 18.3±4.2 ** | 0.266±0.070 ** | 0.258±0.057 ** | 0.251±0.061 * |
| Nifedipine+silibinin | 1.5+5 | 20.5±4.0 * | 0.294±0.063 * | 0.266±0.059 * | 0.279±0.080 |
| 1.5+40 | 19.0±4.3 ** | 0.279±0.079 * | 0.249±0.057 ** | 0.245±0.065 * | |
| 6+5 | 17.3±4.0 ** | 0.275±0.064 * | 0.256±0.051 ** | 0.234±0.061 * | |
| The heavy dose of group of silibinin | 40 | 19.4±4.5 ** | 0.281±0107 * | 0.263±0.086 * | 0.250±0.066 * |
Compare with model control group:
*, P＜0.05;
*, P＜0.01
Experimental example three silybin-N-methylglucamine intravenously administrable toxicity tests
1. material:
Silybin-N-methylglucamine: provide by natural drug Engineering Technical Research Centre preparation research chamber, Shandong Province.
Laboratory animal: the secondary Kunming mouse, male and female half and half, body weight 18g-22g, natural drug Engineering Technical Research Centre zoopery center, Shandong Province provides.The quality certification number: No. 200106003, Shandong kinoplaszm word.
2. method and result:
30 of mices are divided into 3 groups at random, and 10 every group, the situation of mice after observing a vein and giving silybin-N-methylglucamine 500mg/kg, 250mg/kg and once irritate stomach silybin-N-methylglucamine 1000mg/kg.
It is all normal that the result respectively organizes mice hair color, body weight, activity, the mental status, untoward reaction do not occur.
Claims (10)
1. silibinin or its salt are treated coronary heart disease or are used for strengthening the application for the treatment of medicaments for coronary disease in preparation.
2. application according to claim 1, silibinin salt can be silibinin inorganic base salts, the organic alkali salt of silibinin, silibinin alkaline amino acid salt; The silibinin inorganic base salts can be silibinin sodium salt, silibinin potassium salt; The organic alkali salt of silibinin can be silybin-N-methylglucamine, silibinin diethyl amine salt; The silibinin alkaline amino acid salt can be silibinin arginine salt, silibinin lysinate.
3. application according to claim 2, the preferred meglumine of its salt, arginine, lysine.
4. according to the arbitrary described application of claim 1-3, the using dosage scope of silibinin or its salt is 50-2000mg.
5. application according to claim 4, the using dosage scope of silibinin or its salt is preferably 200-1000mg.
6. be effective ingredient with silibinin or its salt, be used for the treatment of coronary heart disease, strengthen the medicine for the treatment of the medicaments for coronary disease curative effect.
7. medicine according to claim 6, it is made up of silibinin or its salt and pharmaceutically acceptable carrier.
8. medicine according to claim 7, it can be with oral or injection administration, and drug administration by injection can be intravenous injection or intramuscular injection.
9. medicine according to claim 8, oral formulations can be tablet, capsule, pill, granule, drop pill, soft capsule, suspension, solution, syrup, capsule, granule, drop pill; Injection preparation can be freeze-dried powder, injection vein emulsion, injection, transfusion.
10. medicine according to claim 9, oral formulations is preferably tablet, capsule, granule; The preferred freeze-dried powder of injection preparation, injection vein emulsion.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009155887A1 (en) * | 2008-06-26 | 2009-12-30 | Agra Group, A.S. | Composition of flavanolignan and amino acid with improved water solubility |
| WO2011104667A1 (en) * | 2010-02-25 | 2011-09-01 | Anthem Biosciences Private Limited | Basic aminoacid salts of polyphenols |
| CN102614121A (en) * | 2011-11-10 | 2012-08-01 | 上海天氏利医药科技有限公司 | Silibinin injection composition and preparation process |
-
2004
- 2004-03-08 CN CN 200410023675 patent/CN1666739A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009155887A1 (en) * | 2008-06-26 | 2009-12-30 | Agra Group, A.S. | Composition of flavanolignan and amino acid with improved water solubility |
| CN102066364A (en) * | 2008-06-26 | 2011-05-18 | 阿格拉集团公司 | Composition of flavanolignan and amino acid with improved water solubility |
| EA016903B1 (en) * | 2008-06-26 | 2012-08-30 | Агра Груп, А.С. | Composition of flavanolignans and method of preparation thereof |
| WO2011104667A1 (en) * | 2010-02-25 | 2011-09-01 | Anthem Biosciences Private Limited | Basic aminoacid salts of polyphenols |
| CN102614121A (en) * | 2011-11-10 | 2012-08-01 | 上海天氏利医药科技有限公司 | Silibinin injection composition and preparation process |
| CN102614121B (en) * | 2011-11-10 | 2013-12-11 | 上海天氏利医药科技有限公司 | Silibinin injection composition and preparation process |
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