Pharmaceutical composition for treating and preventing heart disease as well as preparation method and application of pharmaceutical composition

Abstract

The invention relates to the technical field of pharmaceutical compositions, in particular to a pharmaceutical composition for treating and preventing heart diseases and a preparation method and application thereof, and the pharmaceutical composition comprises the following components: modified tanshinone IIA, modified puerarin and auxiliary materials; the modified tanshinone IIA is prepared by adopting a process of combining sulfonation modification with composite cyclodextrin inclusion, and sulfonation modification introduces a sulfonic acid group into a molecular structure of the tanshinone IIA, so that the water solubility of the tanshinone IIA is remarkably enhanced, and the problems that natural tanshinone IIA is high in fat solubility and difficult to dissolve and absorb in vivo are solved; the compound cyclodextrin is composed of hydroxypropyl-beta-cyclodextrin and beta-cyclodextrin according to a specific proportion, the unique cavity structure of the compound cyclodextrin can form a stable inclusion compound with sulfonated tanshinone IIA, the solubility of the tanshinone IIA is improved, the tanshinone IIA can be prevented from being degraded by in-vivo enzyme, the action time is prolonged, the bioavailability of the tanshinone IIA is improved, and the bioavailability of the tanshinone IIA is improved. And the effects of expanding coronary artery, improving myocardial microcirculation and resisting oxidative damage are fully exerted.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical composition technology, specifically to a pharmaceutical composition for treating and preventing heart disease, its preparation method, and its application. Background Technology

[0002] Heart disease, a serious cardiovascular disease that threatens human life and health, encompasses various types such as coronary heart disease, heart failure, and arrhythmia, and its incidence and mortality rates remain high worldwide. Currently, there are many types of drugs used clinically to treat and prevent heart disease, but most of them have certain limitations.

[0003] While traditional chemical drugs are effective in relieving symptoms quickly, long-term use can lead to drug resistance and may cause side effects such as gastrointestinal discomfort and liver and kidney damage, raising concerns about their safety. Natural medicines, on the other hand, are gaining increasing attention in the treatment of cardiovascular diseases due to their wide availability and fewer side effects. Tanshinone IIA and puerarin are two common natural active ingredients. Studies have confirmed that tanshinone IIA has effects such as dilating coronary arteries, improving myocardial blood supply, and anti-oxidation, while puerarin can regulate lipid metabolism, inhibit platelet aggregation, and protect cardiomyocytes. Both have shown potential in the treatment of heart disease.

[0004] However, tanshinone IIA is highly lipid-soluble and poorly water-soluble, resulting in low bioavailability in the body and limiting its full efficacy. Puerarin is easily metabolized and decomposed in the body, with a short half-life, making it difficult to maintain a stable blood drug concentration and affecting the sustainability of the therapeutic effect.

[0005] Therefore, developing a drug composition that is effective, safe, and has a reasonable preparation process for the treatment and prevention of heart disease has become an urgent technical problem to be solved in this field. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and to propose a pharmaceutical composition for treating and preventing heart disease and a method for preparing the same.

[0007] The specific technical solution is as follows: A pharmaceutical composition for treating and preventing heart disease, comprising the following components by weight: 5-20 parts of modified tanshinone IIA, 10-30 parts of modified puerarin, and 40-85 parts of excipients; the modified tanshinone IIA is prepared by a process of sulfonation modification combined with complex cyclodextrin inclusion, wherein the complex cyclodextrin is composed of hydroxypropyl-β-cyclodextrin and β-cyclodextrin in a weight ratio of 1:2-3; the modified puerarin is prepared by a polyethylene glycol grafting modification process, wherein the grafting modification uses a composite catalytic system of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide.

[0008] As a further technical solution, the preparation steps of the modified tanshinone IIA include:

[0009] (1) Sulfonation modification: Take tanshinone IIA powder, add it to anhydrous ethanol and sonicate to dissolve it to form a solution with a concentration of 5-15 mg / mL. Place it in an ice bath at 0-5℃ and stir at 200-300 r / min. Slowly add a mixture of chlorosulfonic acid and anhydrous ethanol with a volume ratio of chlorosulfonic acid to anhydrous ethanol of 1:3-5. After the addition is complete, continue stirring for 2-4 h. Adjust the pH of the system to 6.5-7.5, centrifuge to collect the precipitate, wash until there are no chloride ions left, and vacuum dry to obtain sulfonated tanshinone IIA.

[0010] (2) Complex cyclodextrin inclusion: Hydroxypropyl-β-cyclodextrin and β-cyclodextrin were mixed at a weight ratio of 1:2-3, and deionized water was added. The mixture was heated to 60-70℃ and stirred at 400-500r / min to dissolve and form a complex cyclodextrin solution with a concentration of 10-20mg / mL. Sulfonated tanshinone IIA was slowly added. The weight ratio of sulfonated tanshinone IIA to complex cyclodextrin was 1:4-8. The mixture was stirred at a constant temperature for 3-6h. After cooling to room temperature, it was refrigerated and allowed to stand for 12-24h. The inclusion mixture was collected by centrifugation, dried under vacuum, and pulverized through an 80-100 mesh sieve to obtain modified tanshinone IIA.

[0011] As a further technical solution, the preparation steps of the modified puerarin include:

[0012] (1) Pretreatment: Take puerarin powder, add it to dimethyl sulfoxide and sonicate to dissolve it to form a solution with a concentration of 8-20 mg / mL. Add anhydrous magnesium sulfate to dry and remove water. Filter to remove the desiccant to obtain puerarin dimethyl sulfoxide solution.

[0013] (2) Grafting reaction: Add polyethylene glycol, the molar ratio of puerarin to polyethylene glycol is 1:0.8-1.2, add a composite catalyst, the composite catalyst is composed of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide in a molar ratio of 1:2, heat to 50-60℃ and stir for 8-12h, then cool to room temperature;

[0014] (3) Purification: Add the reaction liquid droplets to acetone to precipitate the precipitate, let it stand for 2-4 hours, centrifuge to collect the precipitate, wash it with acetone 2-3 times, dry it under vacuum, and then pulverize it through an 80-100 mesh sieve to obtain modified puerarin; the molecular weight of the polyethylene glycol is 2000-6000.

[0015] As a further technical solution, the excipients include fillers and lubricants, wherein the fillers are starch, lactose, and microcrystalline cellulose, and the lubricant is magnesium stearate.

[0016] As a further technical solution, the mass ratio of each auxiliary material is as follows: starch, lactose, microcrystalline cellulose, and magnesium stearate are 10-20: 5-15: 20-40: 0.5-2.

[0017] The method for preparing the pharmaceutical composition includes the following steps:

[0018] (1) Mixing: Weigh the modified tanshinone IIA, modified puerarin and excipients according to the weight parts, put them into the mixer and stir at a low speed of 150-200r / min for 15-25min until they are evenly mixed;

[0019] (2) Granulation: Add 5% binder, stir to form soft material, granulate through 18-24 mesh sieve, place wet granules in a drying oven at 60-70℃ for 2-3 hours, and then granulate through 16-20 mesh sieve after drying.

[0020] (3) Tableting: The raw materials obtained in step (2) are tableted, and the tablet hardness is controlled to be 3-5 kg, with a tablet weight difference within ±5%.

[0021] (4) Packaging: After passing the inspection, sterilize and package.

[0022] As a further technical solution, the adhesive in step (2) is a 4% (w / w) polyvinyl ketone K30 ethanol solution.

[0023] As a further technical solution, step (3) sterilization adopts radiation sterilization.

[0024] The pharmaceutical composition is used for the treatment and prevention of heart disease, including coronary heart disease, heart failure, arrhythmia, and hyperlipidemia-related heart disease.

[0025] As a further technical solution, the drug is an oral preparation, taken 3 times a day, 1-2 tablets each time.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The modified tanshinone IIA of this invention is prepared by a process combining sulfonation modification and complex cyclodextrin inclusion complexation. Sulfonation modification introduces sulfonic acid groups into the molecular structure of tanshinone IIA, significantly enhancing its water solubility and solving the problem that natural tanshinone IIA is highly lipid-soluble and difficult to dissolve and absorb in vivo. The complex cyclodextrin is composed of hydroxypropyl-β-cyclodextrin and β-cyclodextrin in a specific ratio. Its unique cavity structure can form a stable inclusion complex with sulfonated tanshinone IIA, which not only further improves the solubility of tanshinone IIA, but also protects it from degradation by enzymes in vivo, prolonging the duration of action, thereby improving the bioavailability of tanshinone IIA and allowing its effects of dilating coronary arteries, improving myocardial microcirculation, and resisting oxidative damage to be fully realized.

[0028] Modified puerarin was prepared via polyethylene glycol (PEG) grafting modification. A composite catalytic system of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide was used to efficiently catalyze the grafting reaction between puerarin and PEG. PEG molecules possess excellent hydrophilicity and biocompatibility; grafting them onto puerarin molecules significantly improves puerarin's water solubility and in vivo circulation stability, reduces its metabolic loss in vivo, and prolongs its half-life. This results in a more sustained and efficient effect of puerarin in regulating lipid metabolism, inhibiting platelet aggregation, and protecting cardiomyocytes.

[0029] The excipients selected are starch, lactose, and microcrystalline cellulose as fillers. The three are combined in a certain proportion to ensure the formability and flowability of the drug formulation, ensuring the smooth progress of the tableting process, and improving the stability of the tablets. Magnesium stearate is used as a lubricant to reduce the friction between particles and between particles and equipment, further improving the feasibility of the formulation process and the uniformity of product quality. The binder uses povidone K30 ethanol solution, which can effectively promote particle formation, enhance particle strength, and avoid problems such as tablet cracking and disintegration after compression.

[0030] Modified tanshinone IIA and modified puerarin exhibit synergistic effects in the pharmaceutical composition. Modified tanshinone IIA primarily focuses on dilating coronary arteries, improving myocardial blood supply, and combating oxidative damage, while modified puerarin's core functions are regulating blood lipids and inhibiting platelet aggregation. Their targets are complementary, working together to address the pathological mechanisms of heart disease. Modified tanshinone IIA improves local myocardial blood circulation, providing sufficient oxygen and nutrients to myocardial cells and reducing oxidative stress damage; modified puerarin regulates systemic lipid metabolism, reduces blood viscosity, and decreases the risk of thrombosis. Thus, they synergistically improve cardiac function at both local and systemic levels, significantly enhancing the overall efficacy of drug treatment and prevention of heart disease. Attached Figure Description

[0031] Figure 1 This is a flowchart of a pharmaceutical composition preparation method for treating and preventing heart disease. Detailed Implementation

[0032] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0033] This invention provides a pharmaceutical composition for treating and preventing heart disease, its preparation method, and its application. The pharmaceutical composition comprises the following components in parts by weight: 5-20 parts of modified tanshinone IIA, 10-30 parts of modified puerarin, and 40-85 parts of excipients. This pharmaceutical composition can effectively treat and prevent heart disease.

[0034] All raw materials used in this invention are commercially available conventional products. Among them, the purity of tanshinone IIA powder and puerarin powder is ≥98%; hydroxypropyl-β-cyclodextrin and β-cyclodextrin meet pharmaceutical grade standards; polyethylene glycol has a molecular weight range of 2000-6000 and a purity of ≥99%; 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide are chemically pure reagents; starch, lactose, and microcrystalline cellulose in the excipients are all pharmaceutical grade fillers, and magnesium stearate is a pharmaceutical grade lubricant.

[0035] Preparation of modified tanshinone IIA:

[0036] Modified tanshinone IIA was prepared using a process combining sulfonation modification and complex cyclodextrin inclusion. The specific steps are as follows:

[0037] Sulfonation modification: Take tanshinone IIA powder, add it to anhydrous ethanol and sonicate to dissolve it to form a solution with a concentration of 5-15 mg / mL. Place it in an ice bath at 0-5℃ and stir at 200-300 r / min. Slowly add a mixture of chlorosulfonic acid and anhydrous ethanol, with a volume ratio of chlorosulfonic acid to anhydrous ethanol of 1:3-5. After the addition is complete, continue stirring for 2-4 h. Adjust the pH of the system to 6.5-7.5 with sodium hydroxide solution. Centrifuge to collect the precipitate, wash it with deionized water until no chloride ion residue is found (no white precipitate is formed when tested with silver nitrate solution), and vacuum dry to obtain sulfonated tanshinone IIA.

[0038] Complex cyclodextrin inclusion: Hydroxypropyl-β-cyclodextrin and β-cyclodextrin were mixed at a weight ratio of 1:2-3, and deionized water was added. The mixture was heated to 60-70℃ and stirred at 400-500 r / min to dissolve and form a complex cyclodextrin solution with a concentration of 10-20 mg / mL. Sulfonated tanshinone IIA was slowly added at a weight ratio of 1:4-8 to the complex cyclodextrin. The mixture was stirred at a constant temperature for 3-6 h, cooled to room temperature, and then refrigerated for 12-24 h. The inclusion mixture was collected by centrifugation, vacuum dried, and then pulverized through an 80-100 mesh sieve to obtain modified tanshinone IIA.

[0039] Preparation of modified puerarin:

[0040] Modified puerarin was prepared using a polyethylene glycol grafting modification process, the specific steps of which are as follows:

[0041] Pretreatment: Take puerarin powder, add it to dimethyl sulfoxide and sonicate to dissolve it to form a solution with a concentration of 8-20 mg / mL. Add anhydrous magnesium sulfate to dry and remove water (the amount of anhydrous magnesium sulfate added is 1 / 10 of the solution volume). After standing for 2 hours, filter to remove the desiccant to obtain puerarin dimethyl sulfoxide solution.

[0042] Grafting reaction: Polyethylene glycol was added to a puerarin dimethyl sulfoxide solution, with a molar ratio of puerarin to polyethylene glycol of 1:0.8-1.2. A composite catalyst was added, which consisted of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide in a molar ratio of 1:2. The amount of composite catalyst added was 5% of the mass of puerarin. The temperature was raised to 50-60℃ and the reaction was stirred for 8-12 hours. The mixture was then cooled to room temperature.

[0043] Purification: The reaction solution was slowly added dropwise to acetone (the volume of acetone was 5 times the volume of the reaction solution) to precipitate the precipitate. After standing for 2-4 hours, the precipitate was collected by centrifugation, washed 2-3 times with acetone, dried under vacuum, and then pulverized through an 80-100 mesh sieve to obtain modified puerarin.

[0044] Preparation of pharmaceutical compositions:

[0045] The preparation method of the pharmaceutical composition includes the following steps:

[0046] Mixing: Weigh the modified tanshinone IIA, modified puerarin and excipients according to the weight parts. The mass ratio of starch, lactose, microcrystalline cellulose and magnesium stearate in the excipients is 10-20:5-15:20-40:0.5-2. Put all raw materials into a mixer and stir at a low speed of 150-200r / min for 15-25min until they are evenly mixed.

[0047] Granulation: Add 5% binder to the uniformly mixed raw materials. The binder is a 4% (w / w) polyvinyl ketone K30 ethanol solution. Stir to form a soft material, granulate through an 18-24 mesh sieve, and dry the wet granules in a drying oven at 60-70℃ for 2-3 hours. After drying, granulate through a 16-20 mesh sieve.

[0048] Tableting: The granulated granules are compressed into tablets, and the tablet hardness is controlled to be 3-5 kg, with a tablet weight difference within ±5%.

[0049] Packaging: After passing inspection, the product is sterilized by radiation and then packaged.

[0050] In the pharmaceutical composition provided by this invention, modified tanshinone IIA and modified puerarin work synergistically, and with the addition of excipients in a specific ratio, effectively improving the bioavailability of the drug in vivo and enhancing its therapeutic and preventative effects on heart disease. Furthermore, the preparation method is stable, easily scalable for industrial production, and ensures controllable product quality.

[0051] To further illustrate the present invention, detailed descriptions are provided below through examples, comparative examples, and experimental data.

[0052] Example 1:

[0053] Preparation of modified tanshinone IIA:

[0054] Sulfonation modification: Take tanshinone IIA powder, add it to anhydrous ethanol and sonicate to dissolve it to form a solution with a concentration of 5 mg / mL. Place it in an ice bath at 0℃ and stir at 200 r / min. Slowly add a mixture of chlorosulfonic acid and anhydrous ethanol with a volume ratio of 1:3. After the addition is complete, continue stirring for 2 h. Adjust the pH of the system to 6.5 with sodium hydroxide solution. Centrifuge to collect the precipitate, wash it with deionized water until no chloride ion residue remains, and vacuum dry to obtain sulfonated tanshinone IIA.

[0055] Complex cyclodextrin inclusion: Hydroxypropyl-β-cyclodextrin and β-cyclodextrin were mixed at a weight ratio of 1:2, and deionized water was added. The mixture was heated to 60°C and stirred at 400 r / min to dissolve the cyclodextrin to form a complex cyclodextrin solution with a concentration of 10 mg / mL. Sulfonated tanshinone IIA was slowly added at a weight ratio of 1:4 to the complex cyclodextrin. The mixture was stirred at a constant temperature for 3 h, cooled to room temperature, and then refrigerated for 12 h. The inclusion complex was collected by centrifugation, vacuum dried, and then pulverized through an 80-mesh sieve to obtain modified tanshinone IIA.

[0056] Preparation of modified puerarin:

[0057] Pretreatment: Take puerarin powder, add it to dimethyl sulfoxide and sonicate to dissolve it to form a solution with a concentration of 8 mg / mL. Add anhydrous magnesium sulfate to dry and remove water. After standing for 2 hours, filter to remove the desiccant to obtain puerarin dimethyl sulfoxide solution.

[0058] Grafting reaction: Polyethylene glycol with a molecular weight of 2000 was added to a puerarin dimethyl sulfoxide solution. The molar ratio of puerarin to polyethylene glycol was 1:0.8. A composite catalyst was added, which consisted of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide in a molar ratio of 1:2. The amount of composite catalyst added was 5% of the mass of puerarin. The mixture was heated to 50°C and stirred for 8 hours, then cooled to room temperature.

[0059] Purification: The reaction solution was slowly added dropwise to acetone to precipitate the precipitate. After standing for 2 hours, the precipitate was collected by centrifugation, washed twice with acetone, dried under vacuum, and then pulverized through an 80-mesh sieve to obtain modified puerarin.

[0060] Preparation of pharmaceutical compositions:

[0061] Mixing: Weigh out 5 parts of modified tanshinone IIA, 10 parts of modified puerarin and 40 parts of excipients by weight. The excipients include 10 parts of starch, 5 parts of lactose, 20 parts of microcrystalline cellulose and 0.5 parts of magnesium stearate. Put all the raw materials into a mixer and stir at a low speed of 150r / min for 15min until they are evenly mixed.

[0062] Granulation: Add 5% binder to the uniformly mixed raw materials. The binder is a 4% (w / w) polyvinyl ketone K30 ethanol solution. Stir to form a soft material, granulate through an 18-mesh sieve, place the wet granules in a 60℃ drying oven for 2 hours, and then granulate through a 16-mesh sieve.

[0063] Tableting: The granulated granules are compressed into tablets, and the tablet hardness is controlled to be within 3 kg, with a tablet weight difference within ±5%.

[0064] Packaging: After passing inspection, the product is sterilized by radiation and then packaged.

[0065] Example 2:

[0066] Preparation of modified tanshinone IIA:

[0067] Sulfonation modification: Take tanshinone IIA powder, add it to anhydrous ethanol and sonicate to dissolve it to form a solution with a concentration of 15 mg / mL. Place it in an ice bath at 5℃ and stir at 300 r / min. Slowly add a mixture of chlorosulfonic acid and anhydrous ethanol with a volume ratio of 1:5. After the addition is complete, continue stirring for 4 h. Adjust the pH of the system to 7.5 with sodium hydroxide solution. Centrifuge to collect the precipitate, wash it with deionized water until no chloride ion residue remains, and vacuum dry to obtain sulfonated tanshinone IIA.

[0068] Complex cyclodextrin inclusion: Hydroxypropyl-β-cyclodextrin and β-cyclodextrin were mixed at a weight ratio of 1:3, and deionized water was added. The mixture was heated to 70°C and stirred at 500 r / min to dissolve the cyclodextrin to form a complex cyclodextrin solution with a concentration of 20 mg / mL. Sulfonated tanshinone IIA was slowly added at a weight ratio of 1:8 to the complex cyclodextrin. The mixture was stirred at a constant temperature for 6 h, cooled to room temperature, and then refrigerated for 24 h. The inclusion complex was collected by centrifugation, vacuum dried, and then pulverized through a 100-mesh sieve to obtain modified tanshinone IIA.

[0069] Preparation of modified puerarin:

[0070] Pretreatment: Take puerarin powder, add it to dimethyl sulfoxide and sonicate to dissolve it to form a solution with a concentration of 20 mg / mL. Add anhydrous magnesium sulfate to dry and remove water. After standing for 2 hours, filter to remove the desiccant to obtain puerarin dimethyl sulfoxide solution.

[0071] Grafting reaction: Polyethylene glycol with a molecular weight of 6000 was added to a puerarin dimethyl sulfoxide solution. The molar ratio of puerarin to polyethylene glycol was 1:1.2. A composite catalyst was added, which consisted of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide in a molar ratio of 1:2. The amount of composite catalyst added was 5% of the mass of puerarin. The mixture was heated to 60°C and stirred for 12 hours, then cooled to room temperature.

[0072] Purification: The reaction solution was slowly added dropwise to acetone to precipitate the precipitate. After standing for 4 hours, the precipitate was collected by centrifugation, washed three times with acetone, dried under vacuum, and then pulverized through a 100-mesh sieve to obtain modified puerarin.

[0073] Preparation of pharmaceutical compositions:

[0074] Mixing: Weigh 20 parts of modified tanshinone IIA, 30 parts of modified puerarin, and 85 parts of excipients according to the weight. Among the excipients, there are 20 parts of starch, 15 parts of lactose, 40 parts of microcrystalline cellulose, and 2 parts of magnesium stearate. Put all the raw materials into a mixer and stir at a low speed of 200r / min for 25min until they are evenly mixed.

[0075] Granulation: Add 5% binder to the uniformly mixed raw materials. The binder is a 4% (w / w) polyvinyl ketone K30 ethanol solution. Stir to form a soft material, granulate through a 24-mesh sieve, place the wet granules in a 70℃ drying oven to dry for 3 hours, and then granulate through a 20-mesh sieve.

[0076] Tableting: The granulated granules are compressed into tablets, and the tablet hardness is controlled to be within 5 kg, with a tablet weight difference within ±5%.

[0077] Packaging: After passing inspection, the product is sterilized by radiation and then packaged.

[0078] Example 3:

[0079] Preparation of modified tanshinone IIA:

[0080] Sulfonation modification: Take tanshinone IIA powder, add it to anhydrous ethanol and sonicate to dissolve it to form a solution with a concentration of 10 mg / mL. Place it in an ice bath at 3℃ and stir at 250 r / min. Slowly add a mixture of chlorosulfonic acid and anhydrous ethanol with a volume ratio of 1:4. After the addition is complete, continue stirring for 3 h. Adjust the pH of the system to 7.0 with sodium hydroxide solution. Centrifuge to collect the precipitate, wash it with deionized water until no chloride ions remain, and vacuum dry to obtain sulfonated tanshinone IIA.

[0081] Complex cyclodextrin inclusion: Hydroxypropyl-β-cyclodextrin and β-cyclodextrin were mixed at a weight ratio of 1:2.5, and deionized water was added. The mixture was heated to 65°C and stirred at 450 r / min to dissolve the cyclodextrin to form a complex cyclodextrin solution with a concentration of 15 mg / mL. Sulfonated tanshinone IIA was slowly added at a weight ratio of 1:6 to the complex cyclodextrin. The mixture was stirred at a constant temperature for 4.5 h, cooled to room temperature, and then refrigerated for 18 h. The inclusion complex was collected by centrifugation, vacuum dried, and then pulverized through a 90-mesh sieve to obtain modified tanshinone IIA.

[0082] Preparation of modified puerarin:

[0083] Pretreatment: Take puerarin powder, add it to dimethyl sulfoxide and sonicate to dissolve it to form a solution with a concentration of 14 mg / mL. Add anhydrous magnesium sulfate to dry and remove water. After standing for 2 hours, filter to remove the desiccant to obtain puerarin dimethyl sulfoxide solution.

[0084] Grafting reaction: Polyethylene glycol with a molecular weight of 4000 was added to a puerarin dimethyl sulfoxide solution. The molar ratio of puerarin to polyethylene glycol was 1:1.0. A composite catalyst was added, which consisted of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide in a molar ratio of 1:2. The amount of composite catalyst added was 5% of the mass of puerarin. The mixture was heated to 55°C and stirred for 10 hours, then cooled to room temperature.

[0085] Purification: The reaction solution was slowly added dropwise to acetone to precipitate the precipitate. After standing for 3 hours, the precipitate was collected by centrifugation, washed twice with acetone, dried under vacuum, and then pulverized through a 90-mesh sieve to obtain modified puerarin.

[0086] Preparation of pharmaceutical compositions:

[0087] Mixing: Weigh 12 parts of modified tanshinone IIA, 20 parts of modified puerarin, and 62 parts of excipients according to weight. The excipients include 15 parts of starch, 10 parts of lactose, 30 parts of microcrystalline cellulose, and 1.2 parts of magnesium stearate. Put all raw materials into a mixer and stir at a low speed of 180 r / min for 20 min until they are evenly mixed.

[0088] Granulation: Add 5% binder to the uniformly mixed raw materials. The binder is a 4% (w / w) polyvinyl ketone K30 ethanol solution. Stir to form a soft material, granulate through a 20-mesh sieve, place the wet granules in a 65℃ drying oven and dry for 2.5 hours. After drying, granulate through an 18-mesh sieve.

[0089] Tableting: The granulated granules are compressed into tablets, and the tablet hardness is controlled to be 4 kg, with a tablet weight difference within ±5%.

[0090] Packaging: After passing inspection, the product is sterilized by radiation and then packaged.

[0091] Comparative Example 1:

[0092] Raw material preparation:

[0093] Unmodified tanshinone IIA powder was used directly as a raw material; the preparation method of modified puerarin was the same as in Example 3.

[0094] Preparation of pharmaceutical compositions:

[0095] Mixing: Weigh out 12 parts of unmodified tanshinone IIA, 20 parts of modified puerarin and 62 parts of excipients by weight. The excipients include 15 parts of starch, 10 parts of lactose, 30 parts of microcrystalline cellulose and 1.2 parts of magnesium stearate. Put all the raw materials into a mixer and stir at a low speed of 180 r / min for 20 min until they are evenly mixed.

[0096] Granulation: Add 5% binder to the uniformly mixed raw materials. The binder is a 4% (w / w) polyvinyl ketone K30 ethanol solution. Stir to form a soft material, granulate through a 20-mesh sieve, place the wet granules in a 65℃ drying oven and dry for 2.5 hours. After drying, granulate through an 18-mesh sieve.

[0097] Tableting: The granulated granules are compressed into tablets, and the tablet hardness is controlled to be 4 kg, with a tablet weight difference within ±5%.

[0098] Packaging: After passing inspection, the product is sterilized by radiation and then packaged.

[0099] Comparative Example 2:

[0100] Raw material preparation:

[0101] Unmodified puerarin powder was used directly as raw material; the preparation method of modified tanshinone IIA was the same as in Example 3.

[0102] Preparation of pharmaceutical compositions:

[0103] Mixing: Weigh 12 parts of modified tanshinone IIA, 20 parts of unmodified puerarin and 62 parts of excipients by weight. The excipients include 15 parts of starch, 10 parts of lactose, 30 parts of microcrystalline cellulose and 1.2 parts of magnesium stearate. Put all the raw materials into a mixer and stir at a low speed of 180 r / min for 20 min until they are evenly mixed.

[0104] Granulation: Add 5% binder to the uniformly mixed raw materials. The binder is a 4% (w / w) polyvinyl ketone K30 ethanol solution. Stir to form a soft material, granulate through a 20-mesh sieve, place the wet granules in a 65℃ drying oven and dry for 2.5 hours. After drying, granulate through an 18-mesh sieve.

[0105] Tableting: The granulated granules are compressed into tablets, and the tablet hardness is controlled to be 4 kg, with a tablet weight difference within ±5%.

[0106] Packaging: After passing inspection, the product is sterilized by radiation and then packaged.

[0107] Therapeutic effect test on rat model of coronary heart disease:

[0108] Test method:

[0109] Animal model establishment: Seventy healthy SD rats, weighing 200-250g, were randomly divided into seven groups of ten rats each: blank control group, model control group, Example 1 group, Example 2 group, Example 3 group, Comparative Example 1 group, and Comparative Example 2 group. Except for the blank control group, the rats in the other groups were fed a high-fat diet and intraperitoneally injected with vasopressin to establish a coronary heart disease model. After four weeks of high-fat diet feeding, vasopressin 0.5U / kg was injected intraperitoneally for three consecutive days to establish the coronary heart disease model.

[0110] Dosage regimen: After the model was successfully established, rats in Examples 1-3 and Comparative Examples 1-2 were administered the corresponding drug suspension (the drug tablets were ground and dissolved in physiological saline to a concentration of 10 mg / mL) by gavage once a day, with each gavage volume being 1 mL / 100 g body weight, for 4 consecutive weeks; rats in the blank control group and the model control group were administered an equal volume of physiological saline by gavage.

[0111] Detection indicators: After 4 weeks of drug administration, rats were fasted for 12 hours, anesthetized by intraperitoneal injection of 10% chloral hydrate, and blood was collected from the abdominal aorta. Serum was separated by centrifugation, and the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in the serum were determined using a fully automated biochemical analyzer. The levels of nitric oxide (NO), superoxide dismutase (SOD), and malondialdehyde (MDA) in the serum were determined using enzyme-linked immunosorbent assay (ELISA).

[0112] Statistical analysis: Data analysis was performed using statistical software. Quantitative data were expressed as mean ± standard deviation (x ± s). The t-test was used for comparisons between groups, and p < 0.05 was considered statistically significant. The experimental results are as follows:

[0113] Table 1

[0114] Group TC (mmol / L) TG (mmol / L) LDL-C (mmol / L) HDL-C (mmol / L) NO (μmol / L) SOD (U / mL) MDA (nmol / mL) Blank control group 3.21±0.35 1.12±0.21 1.56±0.23 1.32±0.18 65.32±5.21 128.56±8.45 5.21±0.63 Model control group 6.85±0.72 2.86±0.35 4.32±0.41 0.78±0.12 32.15±4.32 65.32±7.21 12.86±1.35 Example 1 Group 4.12±0.42 1.56±0.28 2.15±0.28 1.05±0.15 52.36±4.87 98.65±8.12 7.85±0.87 Example 2 group 3.85±0.38 1.42±0.25 1.98±0.25 1.12±0.16 56.89±5.12 105.32±8.56 7.21±0.78 Example 3 Group 3.56±0.32 1.28±0.22 1.75±0.21 1.21±0.17 60.23±5.36 112.87±9.21 6.58±0.72 Comparative Example 1 5.32±0.51 2.15±0.32 3.21±0.35 0.92±0.13 41.56±4.58 82.36±7.89 9.65±1.02 Comparative Example 2 5.18±0.48 2.03±0.29 3.05±0.32 0.95±0.14 43.21±4.65 85.69±8.01 9.23±0.98

[0115] Compared with the blank control group, the serum levels of TC, TG, LDL-C, and MDA in the model control group were significantly increased (P<0.05), while the levels of HDL-C, NO, and SOD were significantly decreased (P<0.05), indicating that the rat model of coronary heart disease was successfully established and the rats showed obvious lipid metabolism disorders and oxidative stress damage.

[0116] Compared with the model control group, the serum levels of TC, TG, LDL-C, and MDA in groups 1-3 were significantly reduced (P<0.05), while the levels of HDL-C, NO, and SOD were significantly increased (P<0.05). This indicates that the pharmaceutical composition of the present invention can effectively improve lipid metabolism disorders and reduce oxidative stress damage in rats with coronary heart disease, and has a good therapeutic effect on coronary heart disease.

[0117] The preferred embodiments of the present invention disclosed above are merely illustrative of the invention. These preferred embodiments do not describe all details exhaustively, nor do they limit the invention to the specific implementations described. Clearly, many modifications and variations can be made based on the content of this specification.

Claims

1. A pharmaceutical composition for treating and preventing heart disease, characterized in that, It is made from the following ingredients in parts by weight: 5-20 parts of modified tanshinone IIA, 10-30 parts of modified puerarin, and 40-85 parts of excipients; The modified tanshinone IIA was prepared by a process of sulfonation modification combined with complex cyclodextrin inclusion, wherein the complex cyclodextrin is composed of hydroxypropyl-β-cyclodextrin and β-cyclodextrin in a weight ratio of 1:2-3; the modified puerarin was prepared by a polyethylene glycol grafting modification process, wherein the grafting modification was carried out using a composite catalytic system of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide.

2. The pharmaceutical composition according to claim 1, characterized in that, The preparation steps of the modified tanshinone IIA include: (1) Sulfonation modification: Take tanshinone IIA powder, add it to anhydrous ethanol and sonicate to dissolve it to form a solution with a concentration of 5-15 mg / mL. Place it in an ice bath at 0-5℃ and stir at 200-300 r / min. Slowly add a mixture of chlorosulfonic acid and anhydrous ethanol with a volume ratio of chlorosulfonic acid to anhydrous ethanol of 1:3-5. After the addition is complete, continue stirring for 2-4 h. Adjust the pH of the system to 6.5-7.5, centrifuge to collect the precipitate, wash until there are no chloride ions left, and vacuum dry to obtain sulfonated tanshinone IIA. (2) Complex cyclodextrin inclusion: Hydroxypropyl-β-cyclodextrin and β-cyclodextrin were mixed at a weight ratio of 1:2-3, and deionized water was added. The mixture was heated to 60-70℃ and stirred at 400-500r / min to dissolve and form a complex cyclodextrin solution with a concentration of 10-20mg / mL. Sulfonated tanshinone IIA was slowly added. The weight ratio of sulfonated tanshinone IIA to complex cyclodextrin was 1:4-8. The mixture was stirred at a constant temperature for 3-6h. After cooling to room temperature, it was refrigerated and allowed to stand for 12-24h. The inclusion mixture was collected by centrifugation, dried under vacuum, and pulverized through an 80-100 mesh sieve to obtain modified tanshinone IIA.

3. The pharmaceutical composition according to claim 1, characterized in that, The preparation steps of the modified puerarin include: (1) Pretreatment: Take puerarin powder, add it to dimethyl sulfoxide and sonicate to dissolve it to form a solution with a concentration of 8-20 mg / mL. Add anhydrous magnesium sulfate to dry and remove water. Filter to remove the desiccant to obtain puerarin dimethyl sulfoxide solution. (2) Grafting reaction: Add polyethylene glycol, the molar ratio of puerarin to polyethylene glycol is 1:0.8-1.2, add a composite catalyst, the composite catalyst is composed of 4-dimethylaminopyridine and N,N'-dicyclohexylcarbodiimide in a molar ratio of 1:2, heat to 50-60℃ and stir for 8-12h, then cool to room temperature; (3) Purification: Add the reaction liquid droplets to acetone to precipitate the precipitate, let it stand for 2-4 hours, centrifuge to collect the precipitate, wash it with acetone 2-3 times, dry it under vacuum, and then pulverize it through an 80-100 mesh sieve to obtain modified puerarin; the molecular weight of the polyethylene glycol is 2000-6000.

4. The pharmaceutical composition according to claim 1, characterized in that, The excipients include fillers and lubricants. The fillers are starch, lactose, and microcrystalline cellulose, and the lubricant is magnesium stearate.

5. The pharmaceutical composition according to claim 4, characterized in that, The mass ratio of each auxiliary material is as follows: starch, lactose, microcrystalline cellulose, and magnesium stearate are 10-20: 5-15: 20-40: 0.5-2.

6. A method for preparing a pharmaceutical composition according to any one of claims 1-5, characterized in that, Includes the following steps: (1) Mixing: Weigh the modified tanshinone IIA, modified puerarin and excipients according to the weight parts, put them into the mixer and stir at a low speed of 150-200r / min for 15-25min until they are evenly mixed; (2) Granulation: Add 5% binder, stir to form soft material, granulate through 18-24 mesh sieve, place wet granules in a drying oven at 60-70℃ for 2-3 hours, and then granulate through 16-20 mesh sieve after drying. (3) Tableting: The raw materials obtained in step (2) are tableted, and the tablet hardness is controlled to be 3-5 kg, with a tablet weight difference within ±5%. (4) Packaging: After passing the inspection, sterilize and package.

7. The preparation method according to claim 6, characterized in that, In step (2), the adhesive is a 4% (w / w) polyvinyl ketone K30 ethanol solution.

8. The preparation method according to claim 6, characterized in that, Step (3) Sterilization is performed by radiation sterilization.

9. The use of a pharmaceutical composition according to any one of claims 1-5 in the treatment and prevention of heart disease, characterized in that, The heart diseases mentioned include coronary heart disease, heart failure, arrhythmia, and hyperlipidemia-related heart disease.

10. The application according to claim 9, characterized in that, The medication is an oral preparation, taken 3 times daily, 1-2 tablets each time.

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