Pharmaceutical composition for treating cardiovascular diseases and preparation method thereof

Abstract

The invention provides a pharmaceutical composition for treating cardiovascular diseases. The active ingredients of the pharmaceutical composition comprise bepidolic acid and salvia miltiorrhiza and hawthorn extracts. The weight ratio of the beidelic acid to the salvia miltiorrhiza and hawthorn extract is 1: (1.3-1.5); the pharmaceutical composition can be used for preparing drugs for increasing high-density lipoprotein.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a cardiovascular therapeutic drug composition and a preparation method thereof. Background Art

[0002] With the changes in dietary structure and lifestyle, human diseases are also constantly evolving. In recent years, the incidence of hyperlipidemia (dyslipidemia), coronary heart disease and related diseases has increased year by year. Dyslipidemia is one of the important risk factors for cardiovascular disease. Hyperlipidemia is an independent risk factor for coronary heart disease. Dyslipidemia plays a major role in the whole process of the occurrence, development and deterioration of atherosclerosis. It is related to the onset of coronary heart disease, the stability or progression of lesions, and seriously threatens the life and quality of life of patients. There are many items for testing blood lipids in clinical practice. The basic test items for blood lipids are TC, TG, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C).

[0003] High-density lipoprotein (HDL-C) is a complex lipoprotein composed of lipids, proteins and the regulatory factors they carry, also known as a1 lipoprotein. It is relatively rich in phospholipids, and its content in serum is about 200 mg / dl. Its protein part, A-Ⅰ is about 75%, A-Ⅱ is about 20%. Because it can export cholesterol and promote cholesterol metabolism, it is valued as a preventive factor for atherosclerosis. High-density lipoprotein carries cholesterol in the surrounding tissues, and then converts it into bile acid or directly excretes it from the intestines through bile. Arterial angiography has shown that the content of high-density lipoprotein cholesterol is significantly negatively correlated with the degree of arterial lumen stenosis. Therefore, high-density lipoprotein is a plasma lipoprotein that resists atherosclerosis and is a protective factor for coronary heart disease. It is commonly known as the "vascular scavenger."

[0004] Bepedoic acid (also known as Bempedoic acid: ETC-1002) is the first ACL inhibitor developed by Nasdaq-based Esperion Therapeutics. After oral administration, it is rapidly absorbed in the small intestine and enters the liver, where it is metabolized into an active form (ETC-1002-CoA) under the action of acyl-CoA synthetase-1 (ASCVL1). This active form can competitively inhibit the activity of ACL, thereby reducing the synthesis of cholesterol and fatty acids, and then upregulating the level of LDL-C receptors, promoting the liver's absorption of LDL-C, and achieving the purpose of reducing LDL-C. Existing technologies show that bepedoic acid can significantly reduce low-density lipoprotein, but can only slightly increase high-density lipoprotein.

[0005] Formula 1 Danshen is bitter and slightly cold; it has the effects of promoting blood circulation and removing blood stasis, relieving pain, clearing the heart and eliminating vexation, cooling blood and eliminating carbuncle. It is used for chest pain, abdominal pain, flank pain, accumulation of lumps, pain caused by heat, restlessness and insomnia, irregular menstruation, dysmenorrhea, amenorrhea, sores and swelling Hawthorn is sour, sweet and slightly warm in nature. It enters the spleen, stomach and liver meridians. It has the effects of eliminating food accumulation and removing stagnation and blood stasis. It is mainly used to treat food stagnation, abdominal distension and pain, diarrhea and dysentery, dysmenorrhea due to blood stasis, amenorrhea, postpartum abdominal pain, lochia retention, hernia or testicular swelling and pain, and hyperlipidemia.

[0006] There is no report on the combined use of bepedrucic acid and salvia miltiorrhiza and hawthorn extract in the prior art. Summary of the invention

[0007] The purpose of the present invention is to provide a pharmaceutical composition, the active ingredients of which are composed of bepedonic acid and salvia miltiorrhiza and hawthorn extract, and the pharmaceutical composition has a synergistic effect and can significantly increase high-density lipoprotein.

[0008] To achieve the above object, the present invention adopts the following technical solution: A pharmaceutical composition for treating cardiovascular diseases, wherein the active ingredients are composed of bepedrucic acid and salvia miltiorrhiza and hawthorn extract, wherein the weight ratio of bepedrucic acid to salvia miltiorrhiza and hawthorn extract is 1:1.3-1.5, more preferably 1:1.4.

[0009] Furthermore, in the above-mentioned pharmaceutical composition, the weight ratio of bepedrucic acid to the salvia miltiorrhiza and hawthorn extract is 1:1.3-1.4 by weight.

[0010] In the above composition, in the Salvia miltiorrhiza and hawthorn extract, the weight ratio of Salvia miltiorrhiza to hawthorn is 1:3-4, preferably 1:3.5.

[0011] Another aspect of the present invention is to provide a method for preparing the salvia miltiorrhiza and hawthorn extract.

[0012] A method for preparing a salvia miltiorrhiza and hawthorn extract comprises the following steps: Step (1): Wash and dry Danshen and Hawthorn respectively, grind into coarse powder, and dry the coarse powder at 50-60° C. for 24-48 hours; Step (2): taking salvia miltiorrhiza and hawthorn in a weight ratio of 1:3-4, adding water in a weight ratio of 5-6 times, controlling the temperature at 85-90°C, performing a microwave extraction for 20-30 minutes and a stirring extraction for 20-30 minutes as one cycle, extracting for 3-4 hours, after the extraction is completed, separating the solid and the liquid, and freeze-drying the extract to obtain a salvia miltiorrhiza and hawthorn water extract, and the filter residue is a salvia miltiorrhiza and hawthorn extract powder 1.

[0013] Step (3): Take 1% of the Danshen and Hawthorn extract powder of step (2), add 1-3 times of n-heptane, control the temperature to 80-85°C, stir for 2-3 hours, let stand for 5-6 hours, separate the solid and liquid, and freeze-dry the extract to obtain the Danshen and Hawthorn n-heptane extract.

[0014] Step (4): combining the Salvia miltiorrhiza and Crataegus pinnatifida water extract of step (2) and the Salvia miltiorrhiza and Crataegus pinnatifida n-heptane extract of step (3) to obtain a Salvia miltiorrhiza and Crataegus pinnatifida extract.

[0015] In the above preparation method, in the step (1), the drying is preferably performed for 30-40 hours, and more preferably for 34-36 hours.

[0016] In the above preparation method, in the step (2), the weight ratio of Salvia miltiorrhiza to Crataegus pinnatifida is 1:3.5.

[0017] The "times" mentioned in step (2) and step (3) are based on the sum of the weights of Danshen and Hawthorn. For example, in step (2), the sum of the weights of Danshen and Hawthorn is 1 kg, and "adding 5-6 times the weight of water" in step (2) means "adding 5-6 kg of water"; and "adding 1-3 times the weight of n-heptane" in step (3) means "adding 1-3 kg of n-heptane".

[0018] In the above step (2), preferably, microwave extraction for 24-26 minutes and stirring extraction for 24-26 minutes constitute one cycle of cyclic extraction.

[0019] Furthermore, the above-mentioned pharmaceutical composition also contains pharmaceutically acceptable excipients and is prepared into oral preparations or injections; the oral preparations include but are not limited to capsules, tablets, granules, and oral liquids; the injections include but are not limited to sterile powder for injection, water injection, sodium chloride or glucose intravenous infusion.

[0020] In the above-mentioned pharmaceutical composition, the oral preparation includes additives, and the additives are selected from at least one of fillers, diluents, disintegrants, binders, lubricants, glidants, surfactants, solvents, flavoring agents, stabilizers, colorants, and preservatives.

[0021] The fillers or diluents include sugars such as lactose, sucrose, glucose, mannitol, sorbitol, and dextrin; starches such as starch, pregelatinized starch, α-starch, and dextrin; celluloses such as microcrystalline cellulose, gum arabic, fenugreek gum, and dextran; and inorganic salts such as calcium sulfate, calcium hydrogen phosphate, medicinal calcium carbonate, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium aluminosilicate.

[0022] The lubricant, glidant or anti-adhesive agent includes stearic acid; metal stearate such as calcium stearate or magnesium stearate; talc; colloidal silica; micro powder silica gel, hydrogenated vegetable oil; polyethylene glycol, lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; silicate such as silicic anhydride or silicate hydrate, etc.

[0023] The adhesive comprises distilled water, ethanol of different concentrations, starch slurry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, polyvinyl pyrrolidone, polyethylene glycol and compounds similar to the above excipients.

[0024] The disintegrants include cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium or cross-linked carboxymethyl cellulose sodium; cross-linked polyvinyl pyrrolidone; and chemically modified starch / cellulose, such as carboxymethyl starch or carboxymethyl starch sodium.

[0025] The surfactant includes Tween-80, sodium lauryl sulfate, sodium stearate sulfonate and the like.

[0026] The antioxidants include sodium bisulfite, sodium pyrosulfite, sodium sulfite, dried sodium sulfite, sodium thiosulfate, ascorbic acid, methionine (methionine), thiourea, phosphoric acid, citric acid and the like.

[0027] The preservatives or antibacterial agents include benzoic acid and sodium benzoate, sorbic acid, ethanol, parabens (parabens), benzalkonium bromide, o-phenylphenol, benzyl alcohol, phenylethyl alcohol, sodium propionate, sorbic acid, eucalyptus oil, cinnamon oil and peppermint oil.

[0028] The flavoring agents include sweeteners such as saccharin sodium, aspartame, syrup, stevioside, mannitol, sorbitol, mannose, galactose, maltose, fructose, glucose, sucrose, etc.; sour flavoring agents such as citric acid, malic acid or tartaric acid; and aromatics such as fennel oil, peppermint oil, menthol, peppermint water, cinnamon oil, lemon essence, lemon oil and spices of various flavors.

[0029] The pharmaceutical composition of the present invention can be prepared into various dosage forms suitable for clinical administration by using appropriate auxiliary materials according to any commonly used method known in the field of pharmacy.

[0030] Another object of the present invention is to provide an application of the above pharmaceutical composition, that is, an application of the pharmaceutical composition in the preparation of a drug for increasing high-density lipoprotein.

[0031] Compared with the prior art, the present invention has the following beneficial effects: The present invention discovers for the first time that a combination of bepedrucic acid in a specific dosage ratio and a salvia miltiorrhiza and hawthorn extract obtained by a specific preparation method can not only significantly reduce the concentration of low-density lipoprotein, but also significantly increase the concentration of high-density lipoprotein, and the effect is significantly better than the same dose of bepedrucic acid or salvia miltiorrhiza and hawthorn extract, which indicates that the combination of bepedrucic acid or salvia miltiorrhiza and hawthorn extract has a significant synergistic effect.

[0032] The pharmaceutical composition of the present invention can be developed into a pharmaceutical composition for treating cardiovascular diseases, and is expected to have good social and economic benefits. DETAILED DESCRIPTION

[0033] The present invention discloses a pharmaceutical composition and a method for preparing the same. Those skilled in the art can refer to the contents of the present invention, combine the relevant principles of traditional Chinese medicine and pharmaceutics, and appropriately improve the process parameters to achieve the same. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included within the scope of the present invention. The application of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and apply the technology of the present invention.

[0034] In order to better understand the present invention but not to limit the scope of the present invention, all the numbers expressing the amount, percentage, and other numerical values ​​used in this application should be understood to be modified by the word "about" in all cases. Each numerical parameter should at least be considered to be obtained based on the reported significant figures and by conventional rounding methods.

[0035] Preparation Example 1: Preparation of Danshen Hawthorn Extract Step (1): Wash and dry Danshen and Hawthorn respectively, grind into coarse powder, and dry the coarse powder at 54-56°C for 36 hours; Step (2): Take 1 kg of salvia miltiorrhiza and hawthorn in a weight ratio of 1:3.5, add 5.5 kg of water in a weight ratio, control the temperature at 85-90°C, perform microwave extraction for 25 minutes and stirring extraction for 25 minutes as one cycle, extract for 250 minutes, separate the solid and liquid after the extraction, freeze-dry the extract to obtain the salvia miltiorrhiza and hawthorn water extract, and the filter residue is the salvia miltiorrhiza and hawthorn extract powder 1.

[0036] Step (3): Take the Danshen Hawthorn extract powder 1 prepared in step (2), add 2 kg of n-heptane, control the temperature at 80-85° C., stir for 2.5 hours, let stand for 5 hours, separate the solid and liquid, and freeze-dry the extract to obtain the Danshen Hawthorn n-heptane extract.

[0037] Step (4): combining the Salvia miltiorrhiza and Crataegus pinnatifida water extract of step (2) and the Salvia miltiorrhiza and Crataegus pinnatifida n-heptane extract of step (3) to obtain a Salvia miltiorrhiza and Crataegus pinnatifida extract.

[0038] Preparation Example 2: Preparation of Danshen Hawthorn Extract Step (1): Wash and dry Danshen and Hawthorn respectively, grind into coarse powder, and dry the coarse powder at 50-52°C for 48 hours; Step (2): Take 1 kg of salvia miltiorrhiza and hawthorn in a weight ratio of 1:3.5, add 5.5 kg of water in a weight ratio, control the temperature at 85-90°C, perform microwave extraction for 24 minutes and stirring extraction for 26 minutes as one cycle, extract for 250 minutes, separate the solid and liquid after the extraction, freeze-dry the extract to obtain the salvia miltiorrhiza and hawthorn water extract, and the filter residue is the salvia miltiorrhiza and hawthorn extract powder 1.

[0039] Step (3): Take the Danshen Hawthorn extract powder 1 prepared in step (2), add 2 kg of n-heptane, control the temperature at 80-85° C., stir for 2.5 hours, let stand for 5 hours, separate the solid and liquid, and freeze-dry the extract to obtain the Danshen Hawthorn n-heptane extract.

[0040] Step (4): combining the Salvia miltiorrhiza and Crataegus pinnatifida water extract of step (2) and the Salvia miltiorrhiza and Crataegus pinnatifida n-heptane extract of step (3) to obtain a Salvia miltiorrhiza and Crataegus pinnatifida extract.

[0041] Preparation Example 3: Preparation of Danshen Hawthorn Extract Step (1): Wash and dry Danshen and Hawthorn respectively, grind into coarse powder, and dry the coarse powder at 55-58°C for 30 hours; Step (2): Take 1 kg of Danshen and Hawthorn in a weight ratio of 1:3, add 6 kg of water in a weight ratio, control the temperature at 85-90°C, perform microwave extraction for 25 minutes and stirring extraction for 25 minutes as one cycle, extract for 250 minutes, separate the solid and liquid after the extraction, freeze-dry the extract to obtain Danshen Hawthorn water extract, and the filter residue is Danshen Hawthorn extract powder 1.

[0042] Step (3): Take the Danshen Hawthorn extract powder 1 of step (2), add 1.5 kg of n-heptane, control the temperature to 80-85° C., stir for 2 hours, let stand for 5 hours, separate the solid and liquid, and freeze-dry the extract to obtain the Danshen Hawthorn n-heptane extract.

[0043] Step (4): combining the Salvia miltiorrhiza and Crataegus pinnatifida water extract of step (2) and the Salvia miltiorrhiza and Crataegus pinnatifida n-heptane extract of step (3) to obtain a Salvia miltiorrhiza and Crataegus pinnatifida extract.

[0044] Preparation Example 4: Preparation of Danshen Hawthorn Extract Step (1): Wash and dry Danshen and Hawthorn respectively, grind into coarse powder, and dry the coarse powder at 58-60°C for 24 hours; Step (2): Take 1 kg of Danshen and Hawthorn in a weight ratio of 1:4, add 5 kg of water in a weight ratio, control the temperature at 85-90°C, perform microwave extraction for 25 minutes and stirring extraction for 25 minutes as one cycle, extract for 250 minutes, separate the solid and liquid after the extraction, freeze-dry the extract to obtain Danshen Hawthorn water extract, and the residue is Danshen Hawthorn extract powder 1.

[0045] Step (3): Take the Danshen Hawthorn extract powder 1 prepared in step (2), add 3 kg of n-heptane, control the temperature at 80-85° C., stir for 3 hours, let stand for 6 hours, separate the solid and liquid, and freeze-dry the extract to obtain the Danshen Hawthorn n-heptane extract.

[0046] Step (4): combining the Salvia miltiorrhiza and Crataegus pinnatifida water extract of step (2) and the Salvia miltiorrhiza and Crataegus pinnatifida n-heptane extract of step (3) to obtain a Salvia miltiorrhiza and Crataegus pinnatifida extract.

[0047] Preparation Example 5: Preparation of Salvia miltiorrhiza extract Step (1): clean the salvia miltiorrhiza, dry it, and grind it into coarse powder, and dry the coarse powder at 54-56°C for 36 hours; Step (2): Take 1 kg of salvia miltiorrhiza, add 5.5 kg of water by weight, control the temperature at 85-90°C, perform microwave extraction for 25 minutes and stirring extraction for 25 minutes as one cycle, extract for 250 minutes, separate the solid and liquid after the extraction, freeze-dry the extract to obtain the salvia miltiorrhiza water extract, and the filter residue is the salvia miltiorrhiza extract powder 1.

[0048] Step (3): Take the Danshen extract powder 1 prepared in step (2), add 2 kg of n-heptane, control the temperature at 80-85° C., stir for 2.5 hours, let stand for 5 hours, separate the solid and liquid, and freeze-dry the extract to obtain the Danshen n-heptane extract.

[0049] Step (4): combining the Salvia miltiorrhiza water extract of step (2) and the Salvia miltiorrhiza n-heptane extract of step (3) to obtain a Salvia miltiorrhiza extract.

[0050] Preparation Example 6: Preparation of Hawthorn Extract Step (1): clean the hawthorn, dry it, and grind it into coarse powder, and dry the coarse powder at 54-56°C for 36 hours; Step (2): Take 1 kg of hawthorn, add 5.5 kg of water by weight, control the temperature to 85-90°C, perform microwave extraction for 25 minutes and stirring extraction for 25 minutes as one cycle, extract for 250 minutes, separate the solid and liquid after the extraction, freeze-dry the extract to obtain the hawthorn water extract, and the filter residue is the hawthorn extract powder 1.

[0051] Step (3): Take the hawthorn extract powder 1 prepared in step (2), add 2 kg of n-heptane, control the temperature at 80-85° C., stir for 2.5 hours, let stand for 5 hours, separate the solid and liquid, and freeze-dry the extract to obtain the hawthorn n-heptane extract.

[0052] Step (4): combining the hawthorn water extract of step (2) and the hawthorn n-heptane extract of step (3) to obtain a hawthorn extract.

[0053] Preparation Example 7: Preparation of Danshen Hawthorn Extract Step (1), step (3) and step (4) are the same as those in Preparation Example 1, and step (2) is as follows: Step (2): Take 1 kg of salvia miltiorrhiza and hawthorn in a weight ratio of 1:1, add 5.5 kg of water in a weight ratio, control the temperature at 85-90°C, perform microwave extraction for 25 minutes and stirring extraction for 25 minutes as one cycle, extract for 250 minutes, separate the solid and liquid after the extraction, freeze-dry the extract to obtain the salvia miltiorrhiza and hawthorn water extract, and the filter residue is the salvia miltiorrhiza and hawthorn extract powder 1.

[0054] Preparation Example 8: Preparation of Danshen Hawthorn Extract Step (1), step (3) and step (4) are the same as those in Preparation Example 1, and step (2) is as follows: Step (2): Take 1 kg of salvia miltiorrhiza and hawthorn in a weight ratio of 1:6, add 5.5 kg of water in a weight ratio, control the temperature to 85-90°C, perform microwave extraction for 25 minutes and stirring extraction for 25 minutes as one cycle, extract for 250 minutes, separate the solid and liquid after the extraction, freeze-dry the extract to obtain the salvia miltiorrhiza and hawthorn water extract, and the filter residue is the salvia miltiorrhiza and hawthorn extract powder 1.

[0055] Preparation Example 9: Preparation of Danshen Hawthorn Extract Steps (1) and (3) are the same as those in Preparation Example 1, and step (2) is as follows: Step (3): Take 1 danshen hawthorn extract powder from step (2), add 2 kg of ethyl acetate, control the temperature to 80-85°C, stir for 2.5 hours, let stand for 5 hours, separate the solid and liquid, and freeze-dry the extract to obtain danshen hawthorn ethyl acetate extract.

[0056] Step (4): combining the Salvia miltiorrhiza and Crataegus pinnatifida water extract of step (2) and the Salvia miltiorrhiza and Crataegus pinnatifida ethyl acetate extract of step (3) to obtain a Salvia miltiorrhiza and Crataegus pinnatifida extract.

[0057] Preparation Example 10: Preparation of Danshen Hawthorn Extract Step (2), step (3) and step (4) are the same as those in Preparation Example 1, and step (1) is as follows: Step (1): Wash and dry Danshen and Hawthorn respectively, and grind them into coarse powder; Examples 1-14: Preparation of pharmaceutical compositions (1) Composition (2) Preparation method S1. Add bepedonic acid and Danshen hawthorn extract into water for injection, add 60g of sulfobutyl-β-cyclodextrin sodium, stir for 2-3 hours, and filter through 1.0μm, 0.45μm, and 0.22μm filters into a freeze dryer.

[0058] S2. Freeze drying.

[0059] Test example: Effect evaluation test 1.1 Drugs: The tested drugs were: the drug compositions of Examples 1 to 14, and the model control was 0.9% saline.

[0060] 1.2 Experimental animals and groups C57BL / 6 mice, male, 6 weeks old, were adaptively housed for one week under a standard feeding environment (free access to food and water, alternating day and night, 12 hours each).

[0061] Ten rats were not treated and served as a normal control group. The rest were fed a high-fat diet. After 4 weeks, the rats developed hyperlipidemia and the high-density lipoprotein concentration was tested. If the high-density lipoprotein concentration was lower than 0.6mmol / L and the low-density lipoprotein concentration was higher than 2.0mmol / L, they could be included in the group and then randomly divided into 15 groups, with 10 rats in each group.

[0062] After grouping, gavage administration was started. Before the gavage experiment every day, the mice in each group were weighed and the dosage was calculated according to the body weight. The groups of Example 1 to Example 14 were gavaged with 10 mg·kg-1 of active ingredient or drug composition, and the normal control group and the model control group were gavaged with 10 ml·kg-1 of purified water. Once a day for 16 consecutive weeks.

[0063] After the administration, the concentrations of low-density lipoprotein and high-density lipoprotein were measured.

[0064] 2. Test results Note: #P<0.05; ##P<0.01; compared with the blank control group *P<0.05; **P<0.01; compared with the model group ★P<0.05; ★★P<0.01; compared with Example 1 group (1) The pharmaceutical compositions prepared in Examples 1-4 can not only reduce the concentration of low-density lipoprotein, but also significantly increase the concentration of high-density lipoprotein.

[0065] Compared with the model control group, the pharmaceutical composition prepared in Examples 1-4 significantly reduced the LDL-C content in blood lipids and increased the HDL-C content in blood lipids, both with very significant differences (P < 0.01), indicating that the pharmaceutical composition prepared in Examples 1-4 can reduce blood lipid content.

[0066] (2) The salvia miltiorrhiza and hawthorn extract obtained by a specific extraction method works synergistically with bepadocalic acid to achieve a better effect in increasing high-density lipoprotein.

[0067] ① The only difference between Example 1 and Examples 5-10 is that the Danshen and Hawthorn extracts are different. Example 1 adopts the specific extraction method of the present invention to obtain Danshen and Hawthorn water extract and Danshen and Hawthorn n-heptane extract. Example 5 obtains Danshen extract (without Hawthorn component); Example 6 obtains Hawthorn extract (without Danshen component); the weight ratios of Danshen and Hawthorn in the extracts of Examples 7-8 are different, Example 9 uses ethyl acetate instead of n-heptane, and in Step (1) of Example 10, Danshen and Hawthorn are not dried for a long time.

[0068] ② The pharmaceutical composition prepared in Example 1 can significantly reduce the LDL-C content in blood lipids and increase the HDL-C content, both of which are very significantly different from those in the model control group (P < 0.01).

[0069] ③ The pharmaceutical composition prepared in Examples 5-6 can significantly reduce the LDL-C content in blood lipids, and there is a very significant difference compared with the model control group (P < 0.01); it can slightly increase the HDL-C content in blood lipids, and there is no significant difference compared with the model control group (P > 0.05), and there is a significant difference compared with Example 1 (P < 0.05), indicating that the pharmaceutical composition prepared in Examples 5-6 cannot increase the HDL-C content, and the effect is significantly worse than that of Example 1.

[0070] ④ The pharmaceutical composition prepared in Examples 7-10 can significantly reduce the LDL-C content in blood lipids, and there is a very significant difference compared with the model control group (P < 0.01); it can increase the HDL-C content in blood lipids, and there is a significant difference compared with the model control group (P < 0.05). Compared with Example 1, the effect is slightly worse, indicating that the pharmaceutical composition prepared in Examples 7-10 can increase the HDL-C content, but the effect is worse than that in Example 1.

[0071] Therefore, the salvia miltiorrhiza and hawthorn extract obtained by the specific extraction method of the present invention acts synergistically with bepedrucic acid, and the effect is better.

[0072] (3) The specific weight ratio of Salvia miltiorrhiza extract and bepaedic acid works synergistically, resulting in a better effect.

[0073] ① The difference between Example 1 and Examples 11-14 is only whether they contain different components or different weight ratios of the components. Example 1 is bepedic acid and salvia miltiorrhiza hawthorn extract in a weight ratio of 1:1.4; Example 11 is bepedic acid alone without salvia miltiorrhiza hawthorn extract; Example 12 is bepedic acid alone with salvia miltiorrhiza hawthorn extract without bepedic acid; Example 13 is bepedic acid and salvia miltiorrhiza hawthorn extract in a weight ratio of 2:1; Example 14 is bepedic acid and salvia miltiorrhiza hawthorn extract in a weight ratio of 1:5.

[0074] ② The pharmaceutical composition prepared in Example 1 can significantly reduce the LDL-C content in blood lipids and increase the HDL-C content. Compared with the model control group, there are very significant differences (P < 0.01), and the synergistic effect is significant.

[0075] ③ The pharmaceutical composition prepared in Examples 11-12 can significantly reduce the LDL-C content in blood lipids, and has a significant difference (P < 0.05) or a very significant difference (P < 0.01) compared with the model control group; it can slightly increase the HDL-C content in blood lipids, and has no significant difference (P > 0.05) compared with the model control group, and has a significant difference (P < 0.05) or a very significant difference (P < 0.01) compared with Example 1, indicating that neither bepedonic acid alone nor Danshen hawthorn extract alone can increase the HDL-C content.

[0076] ④ The pharmaceutical composition prepared in Examples 13-14 can significantly reduce the content of LDL-C in blood lipids, which is significantly different from the model control group (P < 0.01); it can increase the content of HDL-C in blood lipids, which is significantly different from the model control group (P < 0.05). Compared with Example 1, the effect is slightly worse, indicating that the pharmaceutical composition prepared in Examples 13-14 can increase the content of HDL-C, but the effect is worse than that of Example 1. Therefore, when the weight ratio of bepedrucic acid to Danshen hawthorn extract is 1:1.3-1.5, the effect is better.

Claims

1. A pharmaceutical composition for treating cardiovascular diseases, the active ingredients of which are composed of bepedrucic acid and salvia miltiorrhiza and hawthorn extract; by weight, the weight ratio of bepedrucic acid to salvia miltiorrhiza and hawthorn extract is 1:1.3-1.

5.

2. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of bepedrucic acid to salvia miltiorrhiza and hawthorn extract is 1:1.

4.

3. The pharmaceutical composition according to claim 1, characterized in that In the salvia miltiorrhiza and hawthorn extract, the weight ratio of salvia miltiorrhiza to hawthorn is 1:3-4.

4. The pharmaceutical composition according to claim 3, characterized in that In the salvia miltiorrhiza and hawthorn extract, the weight ratio of salvia miltiorrhiza to hawthorn is 1:3.

5.

5. The pharmaceutical composition according to claim 1, characterized in that The preparation method of the salvia miltiorrhiza and hawthorn extract comprises the following steps: Step (1): Wash and dry Danshen and Hawthorn respectively, grind into coarse powder, and dry the coarse powder at 50-60° C. for 24-48 hours; Step (2): taking salvia miltiorrhiza and hawthorn in a weight ratio of 1:3-4, adding water in a weight ratio of 5-6 times, controlling the temperature at 85-90°C, performing microwave extraction for 20-30 minutes and stirring extraction for 20-30 minutes as one cycle, extracting for 3-4 hours, after the extraction, performing solid-liquid separation, freeze-drying the extract to obtain salvia miltiorrhiza and hawthorn water extract, and the filter residue is salvia miltiorrhiza and hawthorn extract powder 1; Step (3): taking the Danshen Hawthorn extract powder 1 of step (2), adding 1-3 times of n-heptane, controlling the temperature at 80-85°C, stirring for 2-3 hours, standing for 5-6 hours, separating the solid and liquid, and freeze-drying the extract to obtain the Danshen Hawthorn n-heptane extract; Step (4): combining the Salvia miltiorrhiza and Crataegus pinnatifida water extract of step (2) and the Salvia miltiorrhiza and Crataegus pinnatifida n-heptane extract of step (3) to obtain a Salvia miltiorrhiza and Crataegus pinnatifida extract.

6. The pharmaceutical composition according to claim 5, characterized in that In the step (2), the weight ratio of Salvia miltiorrhiza to Crataegus pinnatifida is 1:3.

5.

7. The pharmaceutical composition according to claim 5, characterized in that In step (1), drying is performed for 34-36 hours.

8. The pharmaceutical composition according to claim 5, characterized in that In step (2), microwave extraction for 24-26 minutes and stirring extraction for 24-26 minutes constitute one cycle of cyclic extraction.

9. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable excipient.

10. Use of any pharmaceutical composition according to claims 1 to 9 in the preparation of a drug for increasing high-density lipoprotein.

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