Pharmaceutical composition preparation as well as preparation method and application thereof

Abstract

The invention discloses a pharmaceutical composition preparation and a preparation method and application thereof.The pharmaceutical composition preparation is prepared from tanshinone, eriochin and crocetin according to the mass ratio of 0.4-0.8: 1: 0.3-0.6. The preparation method of the pharmaceutical composition preparation comprises the steps that the tanshinone, the eriochin and the crocetin are mixed with hydroxypropyl-beta-cyclodextrin and polyvinylpyrrolidone, water is added for grinding, then heating and stirring are conducted, finally centrifugation is conducted, supernatant is taken, and the pharmaceutical composition preparation is obtained. And obtaining the pharmaceutical composition preparation. The pharmaceutical composition is a preparation of tanshinone, eriolaryngogenin and crocetin, and has an excellent cardiac hypertrophy treatment effect, the preparation method is simple and convenient, no organic solvent is needed, the preparation process is green and environment-friendly, and the cost is controllable.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to a drug combination preparation and a preparation method and application thereof. Background Art

[0002] Myocardial hypertrophy, especially hypertrophic cardiomyopathy (HCM), is a common hereditary heart disease, the main feature of which is the significant hypertrophy of the left ventricle. Globally, there are a large number of HCM patients, estimated to be about 20 million, of which the number of adult patients in China may have exceeded 1 million. This disease not only seriously affects the prognosis and quality of life of patients, but also brings heavy disease and economic burdens. Therefore, the development of effective drugs for the treatment of myocardial hypertrophy has always been an important research direction in the medical community.

[0003] At present, the commonly used drugs for the treatment of myocardial hypertrophy in clinical practice mainly include the following categories: beta-blockers, non-dihydropyridine calcium channel blockers, antiarrhythmic drugs, etc. In recent years, with the in-depth study of the pathophysiological mechanism of HCM, scientists have begun to explore new therapeutic drugs that can directly solve myocardial excessive contraction and energy changes. Among them, the most representative drug is Mavacamten (MKY-461). Mavacamten (MKY-461) is a small molecule cardiac myosin allosteric inhibitor that can inhibit the excessive formation of myosin-actin cross-bridges at the sarcomere level, thereby reducing myocardial hypertrophy. The drug has shown good safety and efficacy in multiple clinical trials, especially in reducing left ventricular outflow tract obstruction, improving exercise capacity and symptoms in patients with obstructive HCM. In 2022, the U.S. Food and Drug Administration (FDA) approved the listing of Mavacamten, but its long-term efficacy and safety need to be further verified.

[0004] In recent years, the therapeutic effects of active ingredients of traditional Chinese medicine on myocardial hypertrophy have received increasing attention. These ingredients have a positive effect on myocardial hypertrophy through multiple targets and multiple pathways. However, the therapeutic effect of a single active ingredient of traditional Chinese medicine is limited. How to develop an effective combination of active ingredients of traditional Chinese medicine and its preparations to effectively improve myocardial hypertrophy remains a key technical problem to be solved.

[0005] Therefore, it is necessary to provide a drug combination preparation and a preparation method and application thereof to solve the above technical problems. Summary of the invention

[0006] The present invention overcomes the deficiencies of the prior art and provides a drug combination preparation and a preparation method and application thereof.

[0007] To achieve the above object, the technical solution adopted by the present invention is: a drug combination preparation, comprising: tanshinone, forskolin and crocetin.

[0008] In a preferred embodiment of the present invention, the preparation method of the drug combination preparation comprises: mixing tanshinone, forskolin and crocetin with hydroxypropyl-β-cyclodextrin and polyvinylpyrrolidone, grinding with water, then heating and stirring, and finally centrifuging to obtain the supernatant to obtain the drug combination preparation.

[0009] In a preferred embodiment of the present invention, the mass ratio of tanshinone, forskolin and crocetin is 0.4-0.8:1:0.3-0.6.

[0010] In a preferred embodiment of the present invention, the mass ratio of the drug combination to hydroxypropyl-β-cyclodextrin is 1.7-2.4:50.

[0011] In a preferred embodiment of the present invention, the mass ratio of hydroxypropyl-β-cyclodextrin to polyvinyl pyrrolidone is 20:20-40.

[0012] In a preferred embodiment of the present invention, the heating and stirring temperature is 55-65° C. and the time is 1 hour.

[0013] In a preferred embodiment of the present invention, the centrifugal speed is 4000-5500 rpm, and the centrifugal time is 20 minutes.

[0014] Based on the use of a drug combination preparation described in any one of the above items, the drug combination preparation is used to prepare a medicament for treating myocardial hypertrophy disease.

[0015] In a preferred embodiment of the present invention, the drug combination preparation has a good therapeutic effect on a mouse myocardial hypertrophy model.

[0016] The present invention solves the defects existing in the background technology and has the following beneficial effects:

[0017] (1) The present invention provides a drug combination preparation and a preparation method thereof. The drug combination preparation of tanshinone, forskolin and crocetin has excellent therapeutic effect on myocardial hypertrophy, and the preparation method is simple, does not require the use of organic solvents, and the preparation process is green and environmentally friendly with controllable costs.

[0018] (2) In the pharmaceutical composition of the present invention, when an appropriate amount of forskolin is added and the mass ratio of tanshinone, forskolin and crocetin is ensured to be within the range of 0.4-0.8:1:0.3-0.6, the activation of adenylate cyclase in forskolin can increase the intracellular cAMP level, thereby promoting cell signal transduction, and enhancing the anticoagulant and anti-inflammatory effects of tanshinone, and can inhibit the increase in calcium ion concentration in myocardial cells induced by angiotensin II, thereby inhibiting myocardial cell hypertrophy and the proliferation of myocardial fibroblasts. Further, tanshinone and crocetin regulate vascular tension by regulating the target genes of the hypoxia-inducible factor 1 (HIF-1) signaling pathway, while forskolin increases the cAMP level, further regulates the HIF-1 signaling pathway, and achieves myocardial protection, which helps to improve the therapeutic effect and alleviate the symptoms of myocardial hypertrophy. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art are briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those of ordinary skill in the art, other drawings can be obtained based on these drawings without creative work.

[0020] Figure 1 A flow chart of a method for preparing a pharmaceutical combination preparation according to a preferred embodiment of the present invention;

[0021] Figure 2 H&E staining images of heart sections of normal rats given phosphate buffer;

[0022] Figure 3 H&E staining images of heart sections of model rats given phosphate buffer;

[0023] Figure 4 H&E staining images of heart sections of model rats administered MYK-461;

[0024] Figure 5 This is an H&E staining image of a heart section of a model rat administered with Example 4;

[0025] Figure 6 This is an H&E staining image of a heart section of a model rat administered with Example 5;

[0026] Figure 7 This is an H&E staining image of a heart section of a model rat administered with Example 1;

[0027] Figure 8The WGA staining images are of heart sections of normal rats (a), model rats (b), and model rats (c), Example 4 (d), Example 5 (e), and Example 1 (f) administered with phosphate buffer. DETAILED DESCRIPTION

[0028] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein. Therefore, the protection scope of the present invention is not limited to the specific embodiments disclosed below.

[0030] like Figure 1 As shown, the present invention provides a method for preparing a drug combination preparation, the steps of which are as follows: mixing tanshinone, forskolin and crocetin with hydroxypropyl-β-cyclodextrin and polyvinylpyrrolidone, grinding with water, then heating and stirring, and finally centrifuging to obtain a supernatant to obtain a drug combination preparation.

[0031] In the pharmaceutical composition of the present invention, when an appropriate amount of forskolin is added and the mass ratio of tanshinone, forskolin and crocetin is ensured to be within the range of 0.4 to 0.8:1:0.3 to 0.6, the activation of adenylate cyclase in forskolin can increase the intracellular cAMP level, thereby promoting cell signal transduction, and enhancing the anticoagulant and anti-inflammatory effects of tanshinone, and can inhibit the increase in calcium ion concentration in myocardial cells induced by angiotensin II, thereby inhibiting myocardial cell hypertrophy and the proliferation of myocardial fibroblasts. Further, tanshinone and crocetin regulate the target genes of the hypoxia-inducible factor 1 (HIF-1) signaling pathway to achieve the regulation of vascular tension, while forskolin increases the cAMP level, further regulates the HIF-1 signaling pathway, achieves myocardial protection, helps to improve the therapeutic effect, and alleviates the symptoms of myocardial hypertrophy.

[0032] In the preparation method of the drug combination preparation, the mass ratio of tanshinone, forskolin and crocetin is 0.4-0.8:1:0.3-0.6; the mass ratio of the drug combination to hydroxypropyl-β-cyclodextrin is 1.7-2.4:50; the mass ratio of hydroxypropyl-β-cyclodextrin to polyvinylpyrrolidone is 50:50-80; the heating and stirring temperature is 55-65°C, and the time is 1 hour; the centrifugal speed is 4000-5500rpm, and the centrifugal time is 20 minutes.

[0033] Hereinafter, each step of the method for preparing the pharmaceutical combination preparation is described in detail.

[0034] Danshen powder (crushed through a 40-mesh sieve) is first soaked with 70% ethanol for 1 hour at a temperature of 30-35°C, and then placed in a sealed container to allow the powder to be evenly moistened and expanded. After being placed in a percolation cylinder and soaked in an ethanol aqueous solution containing 70% alcohol for 5-10 hours, the percolation is performed at a rate of 2-4 mL / min×kg, and 6-8 times the amount of percolation liquid is collected. The ethanol is removed by decompression and recovery, and water is added to dilute to 0.5 g / mL, the pH value is adjusted to 3 (preferably with hydrochloric acid), and the solution is allowed to stand for precipitation, filtered or centrifuged to obtain a tanshinone extract. The forskolin extract and crocetin extract are purchased from the market, and the purity of forskolin is ≥97%, and the purity of crocetin is ≥98%.

[0035] Tanshinone powder, forskolin powder and crocetin powder are mixed in a mass ratio of 0.4 to 0.8:1:0.3 to 0.6. Hydroxypropyl-β-cyclodextrin and polyvinyl pyrrolidone are then added to the drug combination, wherein the mass ratio of the drug combination to hydroxypropyl-β-cyclodextrin is 1.7 to 2.4:50, and the mass ratio of hydroxypropyl-β-cyclodextrin to polyvinyl pyrrolidone is 50:50 to 80. Hydroxypropyl-β-cyclodextrin and polyvinyl pyrrolidone are added as excipients to play auxiliary roles such as solubilization and stability improvement.

[0036] 30 ml of water was added to the mixture and the mixture was ground for 30 minutes. Grinding with water can increase the surface area of ​​the drug, improve solubility and bioavailability, and further promote uniform mixing of the drug combination and excipients.

[0037] After the mixture is ground, add 400 ml of water and heat to 55-65°C. Stir while heating for 1 hour to promote the interaction between the drug and the excipients, which helps encapsulate the drug and form a stable preparation.

[0038] The mixed solvent after heating and stirring is centrifuged at a speed of 4000-5500 rpm for 20 minutes. The unencapsulated drug and excipient particles can be removed by centrifugation, thereby obtaining a relatively pure drug combination preparation. The supernatant after centrifugation contains a drug combination preparation with a high encapsulation rate, which can improve the quality and efficacy of the preparation.

[0039] Through the above steps, the present invention provides a drug combination preparation and a preparation method thereof. The drug combination preparation of tanshinone, forskolin and crocetin has excellent therapeutic effect on myocardial hypertrophy, and the preparation method is simple, does not require the use of organic solvents, and the preparation process is green and environmentally friendly with controllable costs.

[0040] Example 1

[0041] 0.6 g of tanshinone, 1 g of forskolin and 0.5 g of crocetin were mixed with 50 g of hydroxypropyl-β-cyclodextrin and 70 g of polyvinylpyrrolidone, and ground with 30 mL of water for 30 minutes. Then 400 mL of water was added, heated to 60°C and stirred for 1 hour. Finally, the mixture was centrifuged at 5000 rpm for 20 minutes, and the supernatant was taken to obtain a drug combination preparation.

[0042] The encapsulation rates of tanshinone, forskolin and crocetin in the prepared drug combination preparation were determined by high performance liquid chromatography to be 68%, 59% and 74%, respectively. The drug mass ratio in the preparation was tanshinone:forskolin:crocetin=0.69:1:0.63.

[0043] Example 2

[0044] 0.6 g of tanshinone, 1 g of forskolin and 0.5 g of crocetin were mixed with 50 g of hydroxypropyl-β-cyclodextrin and 50 g of polyvinylpyrrolidone, and ground with 30 mL of water for 30 minutes. Then 400 mL of water was added, heated to 60°C and stirred for 1 hour. Finally, the mixture was centrifuged at 5000 rpm for 20 minutes, and the supernatant was taken to obtain a drug combination preparation.

[0045] The encapsulation rates of tanshinone, forskolin and crocetin in the prepared drug combination preparation were determined by high performance liquid chromatography to be 57%, 46% and 62% respectively. The drug mass ratio in the preparation was tanshinone: forskolin: crocetin = 0.74:1:0.67.

[0046] Example 3

[0047] 0.6 g of tanshinone, 1 g of forskolin and 0.5 g of crocetin were mixed with 50 g of hydroxypropyl-β-cyclodextrin and 80 g of polyvinylpyrrolidone, and ground with 30 mL of water for 30 minutes. Then 400 mL of water was added, heated to 60°C and stirred for 1 hour. Finally, the mixture was centrifuged at 5000 rpm for 20 minutes, and the supernatant was taken to obtain a drug combination preparation.

[0048] The encapsulation rates of tanshinone, forskolin and crocetin in the prepared drug combination preparation were determined by high performance liquid chromatography to be 70%, 60% and 76% respectively. The drug mass ratio in the preparation was tanshinone: forskolin: crocetin = 0.70:1:0.63.

[0049] Example 4

[0050] 0.4 g of tanshinone, 1 g of forskolin and 0.3 g of crocetin were mixed with 50 g of hydroxypropyl-β-cyclodextrin and 70 g of polyvinylpyrrolidone, and ground with 30 mL of water for 30 minutes. Then 400 mL of water was added, heated to 60°C and stirred for 1 hour. Finally, the mixture was centrifuged at 5000 rpm for 20 minutes, and the supernatant was taken to obtain a drug combination preparation.

[0051] The encapsulation rates of tanshinone, forskolin and crocetin in the prepared drug combination preparation were determined by high performance liquid chromatography to be 74%, 63% and 81% respectively. The drug mass ratio in the preparation was tanshinone: forskolin: crocetin = 0.47:1:0.39.

[0052] Example 5

[0053] 0.8 g of tanshinone, 1 g of forskolin and 0.6 g of crocetin were mixed with 50 g of hydroxypropyl-β-cyclodextrin and 70 g of polyvinylpyrrolidone, and ground with 30 mL of water for 30 minutes. Then 400 mL of water was added, heated to 60°C and stirred for 1 hour. Finally, the mixture was centrifuged at 5000 rpm for 20 minutes, and the supernatant was taken to obtain a drug combination preparation.

[0054] The encapsulation rates of tanshinone, forskolin and crocetin in the prepared drug combination preparation were determined by high performance liquid chromatography to be 53%, 51% and 66% respectively. The drug mass ratio in the preparation was tanshinone: forskolin: crocetin = 0.83:1:0.78.

[0055] Example 6

[0056] 0.6 g of tanshinone and 0.5 g of crocetin were mixed with 50 g of hydroxypropyl-β-cyclodextrin and 70 g of polyvinylpyrrolidone, and 30 mL of water was added for grinding for 30 minutes. Then 400 mL of water was added, and the mixture was heated to 60°C and stirred for 1 hour. Finally, the mixture was centrifuged at 5000 rpm for 20 minutes, and the supernatant was taken to obtain a drug combination preparation.

[0057] The encapsulation rates of tanshinone and crocetin in the prepared drug combination preparation were determined by high performance liquid chromatography to be 68% and 74%, respectively, and the drug mass ratio in the preparation was tanshinone:crocetin=0.69:0.64.

[0058] Example 7

[0059] 0.3 g of tanshinone, 1 g of forskolin and 0.5 g of crocetin were mixed with 50 g of hydroxypropyl-β-cyclodextrin and 70 g of polyvinylpyrrolidone, and ground with 30 mL of water for 30 minutes. Then 400 mL of water was added, heated to 60°C and stirred for 1 hour. Finally, the mixture was centrifuged at 5000 rpm for 20 minutes, and the supernatant was taken to obtain a drug combination preparation.

[0060] The encapsulation rates of tanshinone, forskolin and crocetin in the prepared drug combination preparation were determined by high performance liquid chromatography to be 70%, 58% and 74%, respectively. The drug mass ratio in the preparation was tanshinone:forskolin:crocetin=0.39:1:0.61.

[0061] Example 8

[0062] 1 g of tanshinone, 1 g of forskolin and 0.5 g of crocetin were mixed with 50 g of hydroxypropyl-β-cyclodextrin and 70 g of polyvinylpyrrolidone, and ground with 30 mL of water for 30 minutes. Then 400 mL of water was added, and the mixture was heated to 60°C and stirred for 1 hour. Finally, the mixture was centrifuged at 5000 rpm for 20 minutes, and the supernatant was taken to obtain a drug combination preparation.

[0063] The encapsulation rates of tanshinone, forskolin and crocetin in the prepared drug combination preparation were determined by high performance liquid chromatography to be 72%, 59% and 75%, respectively, and the drug mass ratio in the preparation was tanshinone:forskolin:crocetin=1.02:1:0.59.

[0064] Example 9

[0065] 0.6 g of tanshinone, 0.6 g of forskolin and 0.5 g of crocetin were mixed with 50 g of hydroxypropyl-β-cyclodextrin and 70 g of polyvinylpyrrolidone, and ground with 30 mL of water for 30 minutes. Then 400 mL of water was added, heated to 60°C and stirred for 1 hour. Finally, the mixture was centrifuged at 5000 rpm for 20 minutes, and the supernatant was taken to obtain a drug combination preparation.

[0066] The encapsulation rates of tanshinone, forskolin and crocetin in the prepared drug combination preparation were determined by high performance liquid chromatography to be 68%, 62% and 74%, respectively. The drug mass ratio in the preparation was tanshinone: forskolin: crocetin = 0.69:0.62:0.64.

[0067] Example 10

[0068] 0.6 g of tanshinone, 1.2 g of forskolin and 0.5 g of crocetin were mixed with 50 g of hydroxypropyl-β-cyclodextrin and 70 g of polyvinylpyrrolidone, and ground with 30 mL of water for 30 minutes. Then 400 mL of water was added, heated to 60°C and stirred for 1 hour. Finally, the mixture was centrifuged at 5000 rpm for 20 minutes, and the supernatant was taken to obtain a drug combination preparation.

[0069] The encapsulation rates of tanshinone, forskolin and crocetin in the prepared drug combination preparation were determined by high performance liquid chromatography to be 68%, 57% and 74%, respectively. The drug mass ratio in the preparation was tanshinone: forskolin: crocetin = 0.69:1.2:0.63.

[0070] Comparative Examples 1 and 2 show that when the mass ratio of hydroxypropyl-β-cyclodextrin to polyvinyl pyrrolidone increases from 50:50 to 50:70, the encapsulation efficiency of each drug increases. Comparative Examples 1 and 3 show that when the mass ratio of hydroxypropyl-β-cyclodextrin to polyvinyl pyrrolidone increases from 50:70 to 50:80, the encapsulation efficiency of each drug does not increase significantly. Therefore, a mass ratio of hydroxypropyl-β-cyclodextrin to polyvinyl pyrrolidone of 50:70 is selected to prepare preparations with different drug ratios, i.e., Examples 4 and 5. The increase in encapsulation efficiency reduces the release of tanshinone, forskolin and crocetin in the drug combination at non-target sites, more effectively reaches the target site and exerts its pharmacological effects, and achieves precise drug delivery.

[0071] The drug combination preparations prepared in Examples 1 to 5 above were used to conduct a rat myocardial hypertrophy treatment experiment.

[0072] Model establishment: Rats were purchased and adaptively raised for 7 days; rats were pre-anesthetized, the abdomen was prepared, and an incision was made in the left upper abdomen to fully expose the abdominal aorta. A No. 7 needle was ligated together with the abdominal aorta 0.5 cm above the bilateral renal arteries, and the needle was removed, causing a 50% to 60% annular narrowing of the abdominal aorta lumen. Penicillin 50,000 U / rat was injected intramuscularly for 1 week after surgery to prevent infection. Ventricular hypertrophy was observed 4 weeks later, and the rats were in a depressed state and had frizzy hair.

[0073] Administration: Half of the model rats were divided into 5 groups and administered by gavage, and phosphate buffer, MYK-461 (40 mg / kg), Example 1 (tanshinone + forskolin + crocetin total 40 mg / kg), Example 4 (tanshinone + forskolin + crocetin total 40 mg / kg), Example 5 (tanshinone + forskolin + crocetin total 40 mg / kg), normal rats were gavaged with phosphate buffer as a control, and the drug was given once every three days for a total of 30 days. After 30 days, the rats were killed, and the hearts were removed for sectioning and HE and WGA staining for histopathological analysis.

[0074] Compare Figure 2 and Figure 3 It can be seen that the myocardial cells of the model rats were significantly disordered, showing obvious symptoms of myocardial hypertrophy. After MYK-461 treatment, the disorder of myocardial cells was significantly improved. Figure 4 After treatment in Examples 4 and 5, the disorder of myocardial cells was improved. Figure 5 and Figure 6 After treatment in Example 1, the disorder of myocardial cells was significantly improved. Figure 7 , and is superior to MYK-461.

[0075] Compare Figure 8As shown in a and b, the volume of myocardial cells in the model rats increased significantly. After MYK-461 treatment, the increase in myocardial cell volume was significantly improved. Figure 8 c. After treatment in Examples 4 and 5, the volume increase of myocardial cells was also significantly improved. Figure 8 d and e. After the treatment of Example 1, the increase in the volume of myocardial cells was basically completely alleviated, as shown in Figure 8 f.

[0076] The above results show that Examples 4 and 5 have therapeutic effects comparable to MYK-461, while Example 1 has the best therapeutic effect for myocardial hypertrophy, indicating that the drug combination preparation prepared when the mass ratio of tanshinone, forskolin and crocetin is 0.4-0.8:1:0.3-0.6 can effectively treat myocardial hypertrophy, and when the ratio of the drug combination of tanshinone, forskolin and crocetin is optimized to 0.6:1:0.5, the best therapeutic effect can be exerted.

[0077] Further, the other half of the model rats were divided into 7 groups, and MYK-461 (40 mg / kg), Example 1 (tanshinone + forskolin + crocetin total 40 mg / kg), Example 6 (tanshinone + crocetin total 40 mg / kg), Example 7 (tanshinone + forskolin + crocetin total 40 mg / kg), Example 8 (tanshinone + forskolin + crocetin total 40 mg / kg), Example 9 (tanshinone + forskolin + crocetin total 40 mg / kg), Example 10 (tanshinone + forskolin + crocetin total 40 mg / kg) were administered by gavage with phosphate buffer as a control group, and the drug was administered once every three days for a total of 30 days. After 30 days, the rats were killed, the hearts were removed for sectioning and HE and WGA staining, and the cell diameters were observed and measured under an optical microscope, as shown in Table 1.

[0078] Table 1 Effects of various drug administration regimens on the diameter of myocardial cells in model rats

[0079] Group Diameter of cardiomyocytes (um) Control group 12.5±1.03 MYK-461 10.78±0.66 Example 1 9.69±0.5 Example 6 11.4±1.03 Example 7 10.9±0.78 Example 8 11.1±1.2 Example 9 10.77±0.8 Example 10 11±0.5

[0080] The morphological observation results show that the diameter of the cardiomyocytes in the control group is significantly thickened, showing obvious symptoms of myocardial hypertrophy. The specific data of measuring the cell diameter show that the diameter of the cardiomyocytes of the model rats after drug administration is reduced to varying degrees, wherein the reduction trend of the five drug combinations of Examples 6 to 10 is close to or lower than the reduction trend of MYK-461, further verifying that when the ratio of the drug combination of tanshinone, forskolin and crocetin is 0.6:1:0.5, the best therapeutic effect can be exerted, and the drug combination lacking forskolin in Example 6, although there is still a certain therapeutic effect on myocardial hypertrophy, the synergistic effect of forskolin between tanshinone and crocetin is lacking, and the myocardial protection effect is poor, resulting in insufficient reduction of the cardiomyocyte diameter of the model rats.

[0081] The above is based on the ideal embodiment of the present invention. Through the above description, relevant personnel can make various changes and modifications without departing from the technical concept of the present invention. The technical scope of the present invention is not limited to the content in the specification, and the technical scope must be determined according to the scope of the claims.

Claims

1. A pharmaceutical combination preparation, characterized in that: The drug combination comprises: tanshinone, forskolin and crocetin.

2. A pharmaceutical combination preparation according to claim 1, characterized in that: The preparation method of the drug combination preparation comprises: mixing tanshinone, forskolin and crocetin with hydroxypropyl-β-cyclodextrin and polyvinyl pyrrolidone, grinding with water, heating and stirring, and finally centrifuging to obtain a supernatant to obtain the drug combination preparation.

3. A pharmaceutical combination preparation according to claim 2, characterized in that: The mass ratio of tanshinone, forskolin and crocetin is 0.4-0.8:1:0.3-0.

6.

4. A pharmaceutical combination preparation according to claim 2, characterized in that: The mass ratio of the drug combination to hydroxypropyl-β-cyclodextrin is 1.7-2.4:

50.

5. A pharmaceutical combination preparation according to claim 2, characterized in that: The mass ratio of the hydroxypropyl-β-cyclodextrin to polyvinyl pyrrolidone is 50:50-80.

6. A pharmaceutical combination preparation according to claim 1, characterized in that: The heating and stirring temperature is 55-65° C. and the time is 1 hour.

7. A pharmaceutical combination preparation according to claim 1, characterized in that: The centrifugal speed is 4000-5500 rpm, and the centrifugal time is 20 minutes.

8. The use of a pharmaceutical combination preparation according to any one of claims 1 to 7, characterized in that: The drug combination preparation is used for preparing a medicament for treating myocardial hypertrophy.

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