Pharmaceutical composition for heart failure and preparation method thereof

Abstract

The invention provides a pharmaceutical composition for heart failure and a preparation method thereof.The pharmaceutical composition is prepared from ginseng, astragalus membranaceus, salvia miltiorrhiza and other traditional Chinese medicines according to specific weight parts and comprises all medicinal material components, and the preparation method comprises the steps that firstly, step polarity extraction is conducted, specific medicinal materials and dry ice are ground, and then supercritical CO2 staged extraction is conducted; treating part of the medicinal materials by four-dimensional directional distillation to obtain lactone components; carrying out two-phase enzymolysis wall breaking, and carrying out high-frequency microwave three-stage extraction by utilizing a specific combined enzyme and micro-electric field assistance; then mixing the extract with specific cyclodextrin through dynamic composite inclusion; and finally, carrying out plasma-assisted freeze-drying to obtain the pharmaceutical composition. The pharmaceutical composition provides a new choice for heart failure treatment, the preparation method can effectively extract and preserve active ingredients of the medicinal materials, the treatment effect is expected to be improved, and the pharmaceutical composition has wide application prospects.

Description

Technical Field

[0001] The present invention relates to the field of traditional Chinese medicine preparations, and particularly relates to a pharmaceutical composition for heart failure and a preparation method thereof. Background Art

[0002] As a cardiovascular disease that seriously threatens human health, heart failure shows a high incidence and high mortality rate globally, greatly affecting the quality of life of patients.

[0003] Currently, the clinical treatment of heart failure (HF) mostly adopts a combined western medicine regimen, such as angiotensin-converting enzyme inhibitors, β-blockers, and aldosterone antagonists in western medicine. Although it can improve symptoms in the short term, there are significant deficiencies in long-term application, often causing a series of adverse reactions. On the one hand, organ toxicity gradually accumulates. For example, the risk of hyperkalemia caused by ACEI drugs is about 5-10%, and aldosterone antagonists can lead to deterioration of renal function; the combination of multiple drugs causes side effects to stack up, and symptoms such as hypotension, dry cough, and bradycardia are relatively common. Moreover, some patients have poor tolerance to western medicine, which undoubtedly limits the wide application of western medicine in the treatment of heart failure.

[0004] In the aspect of traditional Chinese medicine treatment, although some traditional Chinese medicine compound prescriptions such as Qili Qiangxin Capsule have been used for adjuvant treatment of heart failure, their curative effects are limited. The extensive extraction process, such as single alcohol extraction or water extraction method, leads to an imbalance in the extraction rates of fat-soluble and water-soluble components; the compatibility under the traditional "sovereign, minister, assistant, and guide" theory lacks targeting and cannot accurately correspond to modern pathological mechanisms, and the synergistic effect of active ingredients is not significant.

[0005] The application of modern preparation technology in the field of traditional Chinese medicine also has bottlenecks. The drug loading capacity and in vitro dissolution rate of cyclodextrin inclusion complexes prepared by the conventional magnetic stirring method are generally low. It is difficult to synchronously enhance the efficacy of components with large polarity differences in complex compound prescriptions through a single process. New technologies such as supercritical extraction mostly focus on the extraction of single components and ignore the synergistic protection of multiple components. Summary of the Invention

[0006] In view of this, the present invention proposes a pharmaceutical composition for heart failure and a preparation method thereof to solve the above problems.

[0007] The technical solution of the present invention is realized as follows: A pharmaceutical composition for heart failure, comprising the following raw materials in parts by weight: 10-20 parts of ginseng, 15-30 parts of astragalus membranaceus, 12-25 parts of salvia miltiorrhiza, 8-15 parts of semen lepidii, 5-12 parts of cassia twig, 10-18 parts of poria cocos, 6-12 parts of ligusticum wallichii, 3-8 parts of safflower, 8-16 parts of alisma orientale, 3-6 parts of roasted licorice root, 5-10 parts of tangerine peel, 3-6 parts of pogostemon cablin, 5-10 parts of morinda officinalis, 4-8 parts of semen alpiniae oxyphyllae, 3-6 parts of fructus amomi, 2-5 parts of cinnamon, 4-8 parts of galangal, 3-6 parts of dalbergia odorifera, 4-8 parts of piper kadsura, 5-10 parts of streptocaulon juventas, 5-10 parts of houttuynia cordata, 3-6 parts of toddalia asiatica, 5-10 parts of blumea balsamifera, 4-9 parts of caulis spatholobi.

[0008] Further, a pharmaceutical composition for heart failure, comprising the following raw materials in parts by weight: 15 parts of ginseng, 25 parts of astragalus membranaceus, 20 parts of salvia miltiorrhiza, 12 parts of semen lepidii, 10 parts of cassia twig, 15 parts of poria cocos, 9 parts of ligusticum wallichii, 5 parts of safflower, 12 parts of alisma orientale, 5 parts of roasted licorice root, 8 parts of tangerine peel, 5 parts of pogostemon cablin, 8 parts of morinda officinalis, 6 parts of semen alpiniae oxyphyllae, 5 parts of fructus amomi, 3 parts of cinnamon, 6 parts of galangal, 5 parts of dalbergia odorifera, 6 parts of piper kadsura, 8 parts of streptocaulon juventas, 8 parts of houttuynia cordata, 5 parts of toddalia asiatica, 8 parts of blumea balsamifera, 7 parts of caulis spatholobi.

[0009] Further, the method for the pharmaceutical composition for heart failure comprises the following steps:

[0010] (1) Stepwise polar extraction: Ginseng, astragalus membranaceus, and morinda officinalis are ground into low-temperature micropowder with dry ice at a ratio of 1:0.5-0.8 at -55 to -45 °C, and supercritical CO 2 is used for extraction in 2 stages in a cycle to extract polar saponins, and the medicinal residues are reserved for later use;

[0011] (2) Four-dimensional directional distillation: Semen lepidii, alisma orientale, and poria cocos are placed in an ultrasonic atomization reactor, and low-pressure distillation is carried out under the protection of nitrogen injection. The pressure is -0.09 to -0.07 MPa, the temperature gradient is adjusted, and the fraction containing lactone components is collected. The medicinal residues are reserved for later use;

[0012] (3) Biphasic enzymatic hydrolysis and cell wall breaking: The remaining medicinal materials are mixed with the medicinal residues from steps (1) and (2), 2-10% of the combined enzyme based on the mass of the mixed medicinal residues is added, and enzymatic hydrolysis is carried out for 0.8-1.2 h under the assistance of a microelectric field of 120-180 V / m; after enzymatic hydrolysis is completed, the material is immediately subjected to high-frequency microwave extraction at a frequency of 2400-2500 MHz, using a pulse mode with a duty cycle of 55-65%, and extraction is carried out in three stages to obtain the extract;

[0013] (4) Dynamic complex inclusion: Mix the extract obtained in step (3) with hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin in a ratio of 1.8 - 2.2:1, and process them in a microfluidic homogenizer at 130 - 170 MPa to obtain an inclusion complex;

[0014] (5) Drying: Put the inclusion complex into a plasma-assisted freeze dryer. In the pre-freezing stage, quickly freeze it to -55 to -45 °C at a cooling rate of 8 - 12 °C / min. In the sublimation stage, control the chamber pressure at 4 - 6 Pa, the plasma power at 280 - 320 W, and the moisture pressure reduction gradient at 0.08 - 0.12 Pa / min to obtain the pharmaceutical composition.

[0015] Furthermore, in the first stage of step (1): the pressure is 20 - 30 MPa, the temperature is 20 - 60 °C, extract for 1 - 3 h, the extracting agent is 3 - 7% ethyl acetate, and collect the lipophilic components; in the second stage: the pressure is 30 - 40 MPa, the temperature is 60 - 70 °C, extract for 1 - 3 h, and the extracting agent is 8 - 12% ethanol aqueous solution.

[0016] Furthermore, in step (2), the bottom layer temperature is maintained at 85 - 95 °C, the middle layer temperature is 70 - 80 °C, and the top layer temperature is 55 - 65 °C.

[0017] Furthermore, the combined enzyme in step (3) is cellulase, pectinase, and xylanase with a mass ratio of (2.5 - 3.5):(1.5 - 2.5):(0.8 - 1.2).

[0018] Furthermore, the enzyme activity number of the cellulase is 5000 - 10000 U / g, the enzyme activity number of the pectinase is 3000 - 8000 U / g, and the enzyme activity number of the xylanase is 2000 - 6000 U / g.

[0019] Furthermore, for the three-stage extraction in step (3): extract for 7 - 9 minutes at 75 - 85 °C in the first stage to obtain flavonoid glycosides; extract for 9 - 11 minutes at 65 - 75 °C in the second stage to extract organic acids; extract for 11 - 13 minutes at 55 - 65 °C in the third stage.

[0020] Furthermore, the application of the said pharmaceutical composition in the preparation of drugs for treating heart failure.

[0021] Furthermore, the heart failure includes acute heart failure, chronic heart failure, diastolic heart failure, and systolic heart failure.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] The formula of the present invention follows the basic principle of the compatibility of "sovereign, ministerial, adjuvant, and guiding herbs". By reasonably coordinating the primary and secondary relationships among the drugs, it integrates traditional Chinese medicine theory and modern pharmacological synergistic mechanisms to achieve the therapeutic purpose of synergistic enhancement of efficacy. Ginseng greatly tonifies primordial qi, restores the pulse and secures the collapse, and is the chief herb for tonifying qi. It can directly enhance cardiac function and improve the deficiency of primordial qi in patients with heart failure. Astragalus membranaceus tonifies qi and raises yang, promotes diuresis and reduces edema. Synergistic with ginseng, it enhances the power of supplementing qi and also helps to eliminate edema symptoms. The two together serve as the sovereign herbs, tonifying qi and strengthening the heart, promoting diuresis and supporting yang, targeting the root cause of heart failure and playing the main therapeutic role. Salvia miltiorrhiza, Carthamus tinctorius, Blumea balsamifera, Ligusticum chuanxiong, Toddalia asiatica, Caulis spatholobi, and Morinda officinalis are the ministerial herbs. When combined, Salvia miltiorrhiza and Carthamus tinctorius activate blood circulation to dredge meridians, resolve stasis and dredge collaterals, effectively improve microcirculation and inhibit platelet aggregation. Ligusticum chuanxiong is a herb that promotes qi movement in blood. It ascends to the head, descends to the blood sea, and spreads to dredge collaterals. Blumea balsamifera is pungent, warm, and dredges collaterals. When combined with Toddalia asiatica, it reduces the damage of oxidative stress to the heart. Caulis spatholobi and Morinda officinalis delay myocardial aging and inhibit apoptosis of myocardial cells, assisting the sovereign herbs to enhance the improvement of cardiac function. Poria cocos, Alisma orientale, Lepidium apetalum, Amomum villosum, Citrus reticulata, Reineckea carnea, Pogostemon cablin, and Houttuynia cordata are the adjuvant herbs. Poria cocos and Alisma orientale promote diuresis and percolate dampness, regulating the balance of water and electrolytes. Lepidium apetalum purges the lung to relieve asthma and promotes diuresis and reduces edema. Amomum villosum, Reineckea carnea, and Citrus reticulata promote qi movement and resolve dampness, promoting gastrointestinal peristalsis. Pogostemon cablin and Houttuynia cordata regulate the gut-heart axis and improve the intestinal flora. Cinnamomum cassia, Alpinia officinarum, Dalbergia odorifera, Piper kadsura, Glycyrrhiza uralensis preparata, Alpinia oxyphylla, and Cinnamomum cassia are the guiding herbs. Cinnamomum cassia and Alpinia officinarum are pungent, warm, and promote yang circulation, dilating the coronary microvessels. Dalbergia odorifera promotes blood circulation to stop bleeding and regulates qi to relieve pain. Piper kadsura dispels wind-dampness and dredges meridians, enhancing the myocardial targeting of active ingredients. Glycyrrhiza uralensis preparata harmonizes all the herbs. Alpinia oxyphylla and Cinnamomum cassia warm the kidney and assist yang, regulating metabolism.

[0024] This formula not only realizes the integration of multiple herbs, forming multiple synergies of qi dynamic source, smooth blood circulation, water passage, and meridian guidance, but also optimizes the dose-effect relationship, avoids qi stagnation, ensures myocardial energy supply, and at the same time introduces supercritical desensitization technology and targeted inclusion technology, making the whole formula an organic whole, reducing toxicity and enhancing efficacy, and providing a more scientific and effective solution for the treatment of heart failure. Detailed implementation manners

[0025] To better understand the technical content of the present invention, specific examples are provided below to further illustrate the present invention.

[0026] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0027] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can all be obtained from commercial channels.

[0028] Example 1

[0029] A pharmaceutical composition for heart failure, characterized in that it comprises the following raw materials by weight: 10 grams of ginseng, 15 grams of astragalus membranaceus, 12 grams of salvia miltiorrhiza, 8 grams of semen lepidii, 5 grams of cassia twig, 10 grams of poria cocos, 6 grams of ligusticum wallichii, 3 grams of safflower, 8 grams of alisma orientale, 3 grams of roasted licorice root, 5 grams of tangerine peel, 3 grams of pogostemon cablin, 5 grams of morinda officinalis, 4 grams of fructus alpiniae oxyphyllae, 3 grams of amomum villosum, 2 grams of cinnamon, 4 grams of galangal, 3 grams of dalbergia odorifera, 4 grams of caulis piperis kadsurae, 5 grams of rhizoma of reineckia carnea, 5 grams of houttuynia cordata, 3 grams of toddalia asiatica, 5 grams of blumea balsamifera, 4 grams of caulis spatholobi.

[0030] Example 2

[0031] A pharmaceutical composition for heart failure, characterized in that it comprises the following raw materials by weight: 20 grams of ginseng, 30 grams of astragalus membranaceus, 25 grams of salvia miltiorrhiza, 15 grams of semen lepidii, 12 grams of cassia twig, 18 grams of poria cocos, 12 grams of ligusticum wallichii, 8 grams of safflower, 16 grams of alisma orientale, 6 grams of roasted licorice root, 10 grams of tangerine peel, 6 grams of pogostemon cablin, 10 grams of morinda officinalis, 8 grams of fructus alpiniae oxyphyllae, 6 grams of amomum villosum, 5 grams of cinnamon, 8 grams of galangal, 6 grams of dalbergia odorifera, 8 grams of caulis piperis kadsurae, 10 grams of rhizoma of reineckia carnea, 10 grams of houttuynia cordata, 6 grams of toddalia asiatica, 10 grams of blumea balsamifera, 9 grams of caulis spatholobi.

[0032] Example 3

[0033] A pharmaceutical composition for heart failure, characterized in that it comprises the following raw materials by weight: 15 grams of ginseng, 25 grams of astragalus membranaceus, 20 grams of salvia miltiorrhiza, 12 grams of semen lepidii, 10 grams of cassia twig, 15 grams of poria cocos, 9 grams of ligusticum wallichii, 5 grams of safflower, 12 grams of alisma orientale, 5 grams of roasted licorice root, 8 grams of tangerine peel, 5 grams of pogostemon cablin, 8 grams of morinda officinalis, 6 grams of fructus alpiniae oxyphyllae, 5 grams of amomum villosum, 3 grams of cinnamon, 6 grams of galangal, 5 grams of dalbergia odorifera, 6 grams of caulis piperis kadsurae, 8 grams of rhizoma of reineckia carnea, 8 grams of houttuynia cordata, 5 grams of toddalia asiatica, 8 grams of blumea balsamifera, 7 grams of caulis spatholobi;

[0034] The above Examples 1 - 3 adopt the following preparation method:

[0035] (1) Step - by - step polar extraction: Ginseng, astragalus membranaceus, morinda officinalis and dry ice are ground into low - temperature fine powder at - 50°C in a ratio of 1:0.7, and supercritical CO 2 Circular extraction is carried out in 2 stages. The first stage: pressure 25 MPa, temperature 40°C, extraction for 2 h, the extractant is 5% ethyl acetate, and the fat - soluble components are collected; The second stage: pressure 35 MPa, temperature 65°C, extraction for 2 h, the extractant is 10% ethanol aqueous solution, and the medicinal residues are reserved;

[0036] (2) Four - dimensional directional distillation: Semen lepidii, alisma orientale, and poria cocos are placed in an ultrasonic atomization reactor, and low - pressure distillation is carried out under nitrogen protection. The pressure is - 0.08 MPa, the temperature gradient is adjusted, the bottom - layer temperature is maintained at 90°C, the middle - layer temperature is 75°C, and the top - layer temperature is 60°C. The fraction containing lactone components is collected, and the medicinal residues are reserved;

[0037] (3) Biphasic enzymatic wall-breaking: Mix the remaining medicinal materials with the medicinal residues from steps (1) and (2), add a combined enzyme accounting for 6% of the mass of the mixed medicinal residues. The combined enzyme is a cellulase, pectinase, and xylanase with a mass ratio of 3:2:1. The enzyme activity number of the cellulase is 8000 U / g, the enzyme activity number of the pectinase is 5000 U / g, and the enzyme activity number of the xylanase is 4000 U / g. Enzymatically hydrolyze for 1 h under the assistance of a 150 V / m microelectric field; after the enzymatic hydrolysis is completed, immediately subject the material to high-frequency microwave extraction at a frequency of 2500 MHz, using a pulse mode with a duty cycle of 60%, and extract in three stages. The first stage is extracted at 80 °C for 8 minutes to obtain flavonoid glycosides; the second stage is extracted at 70 °C for 10 minutes to extract organic acids; the third stage is extracted at 60 °C for 12 minutes to obtain the extract;

[0038] (4) Dynamic complex inclusion: Mix the extract obtained in step (3) with hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin in a ratio of 2:1, and process in a microfluidic homogenizer at 150 MPa to obtain an inclusion complex;

[0039] (5) Drying: Put the inclusion complex into a plasma-assisted freeze dryer. In the pre-freezing stage, quickly freeze to -50 °C at a cooling rate of 10 °C / min. In the sublimation stage, control the chamber pressure at 5 Pa, the plasma power at 300 W, and the moisture pressure reduction gradient at 0.1 Pa / min to obtain the pharmaceutical composition.

[0040] Comparative Example 1

[0041] The difference between this comparative example and Example 3 is that the pharmaceutical composition does not contain Blumea balsamifera, Ligusticum chuanxiong, and Toddalia asiatica.

[0042] Comparative Example 2

[0043] The difference between this comparative example and Example 3 is that the pharmaceutical composition does not contain Morinda officinalis and Entada phaseoloides.

[0044] Comparative Example 3

[0045] The difference between this comparative example and Example 3 is that in step (1), supercritical CO 2 Only single-stage extraction is performed at a pressure of 30 MPa, a temperature of 55 °C, and an extraction time of 2 h.

[0046] Comparative Example 4

[0047] The difference between this comparative example and Example 3 is that in step (2), microelectric field-assisted enzymatic hydrolysis is cancelled, and only normal-temperature shaking extraction is performed at a rotation speed of 150 rpm and a temperature of 20 - 25 °C for 1 - 3 h.

[0048] Comparative Example 5

[0049] The difference between this comparative example and Example 3 lies in that in step (4), ordinary magnetic stirring is used instead of microfluidic homogenization for inclusion.

[0050] I. Animal experiments

[0051] 1. Animal selection: Healthy adult male SD rats weighing 200 - 250 g were selected and provided by a regular supplier. After the rats arrived at the laboratory, they were adaptively raised in a standard animal room for 1 week. The temperature of the animal room was (22 ± 2) °C, and the relative humidity was (50 ± 10)%. A 12-hour light and 12-hour dark cycle was maintained, and the rats had free access to food and water.

[0052] 2. Construction of heart failure model:

[0053] Anesthesia process: The weight of the rats was weighed, and they were anesthetized by intraperitoneal injection of 10% chloral hydrate solution at a dose of 300 mg / kg.

[0054] Surgical operation details: The anesthetized rats were fixed supine, the chest skin was disinfected, and the chest was opened along the 3rd - 4th intercostal space on the left margin of the sternum to expose the heart. The left anterior descending coronary artery was ligated with 6-0 silk thread 1 - 2 mm below the left atrial appendage. The successful ligation was marked by the whitening of the anterior wall myocardium of the left ventricle and the elevation of the ST segment of the electrocardiogram. After ligation, the chest cavity was closed, and the muscle and skin were sutured layer by layer. Penicillin was used for anti-infection after the operation.

[0055] Model screening criteria: One week after the operation, the left ventricular ejection fraction (LVEF) of the rats was detected using a cardiac ultrasound device, and the rats with an LVEF lower than 45% were selected as successfully modeled rats with heart failure for subsequent experiments.

[0056] 3. Experimental grouping: The qualified heart failure model rats were randomly divided into the following groups, with 10 rats in each group:

[0057] Example 1 - 3 groups: The drug compositions prepared according to Examples 1 - 3 were given, configured with normal saline to a concentration of 1 mg / mL, and administered by gavage at a dose of 10 mg / kg.

[0058] Comparative example 1 - 5 groups: The drug compositions prepared in the corresponding comparative examples were given respectively, and the administration method and dose were the same as those in the Example 3 group.

[0059] Control group: Given an equal amount of normal saline by gavage.

[0060] 4. Administration method:

[0061] Gavage administration was performed once a day at a fixed time for 4 consecutive weeks.

[0062] 5. Index monitoring

[0063] (1) Detection of cardiac function indicators: After 4 weeks of drug administration, the cardiac function of rats was detected using a small animal cardiac ultrasound instrument. First, the rats were anesthetized and fixed supine. Coupling agent was applied to the ultrasound probe, which was then placed on the precordial area of the rat's chest to obtain long-axis cross-sectional images of the left ventricle. The left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD) were measured.

[0064] (2) Detection of blood indicators: After cardiac ultrasound detection, the rats were fasted for 12 hours and then anesthetized with 10% chloral hydrate solution. 5 ml of blood was drawn from the abdominal aorta. The blood was centrifuged at 3000 rpm for 15 minutes to separate the serum, and the contents of brain natriuretic peptide (BNP) and cardiac troponin I (cTnI) in the serum were detected using an ELISA kit according to the instructions to ensure accurate results.

[0065] 6. Result data

[0066]

[0067]

[0068] The above result data reflects the significant advantages of the experimental group in improving the left ventricular ejection fraction, reducing the left ventricular end-diastolic diameter and end-systolic diameter, and decreasing the contents of brain natriuretic peptide and cardiac troponin I.

[0069] Comparison between Example 3 and Comparative Example 1 shows that Blumea balsamifera, Ligusticum chuanxiong, and Toddalia asiatica can reduce ischemia-reperfusion injury and exert their effects by inhibiting the RAAS pathway.

[0070] Comparison between Example 3 and Comparative Example 2 shows that the active ingredients of Morinda officinalis and Caulis Entadae have an inhibitory effect on ventricular remodeling and can effectively improve the ability to inhibit cardiomyocyte apoptosis.

[0071] Comparison between Example 3 and Comparative Example 3 shows that cascade polarity extraction can reduce the loss of active ingredients.

[0072] Comparison between Example 3 and Comparative Example 4 shows that adding a microelectric field-assisted enzymatic hydrolysis can effectively improve the cell wall breaking rate and promote the dissolution of active ingredients.

[0073] Comparison between Example 3 and Comparative Example 5 shows that inclusion can improve the dissolution performance of the drug, enable the sustained release of the active ingredients of the drug, and achieve a better therapeutic effect.

[0074] II. Clinical trials

[0075] 1. Trial design

[0076] (1) Trial type: Randomized, double-blind, parallel control trial.

[0077] (2) Subject grouping: It is planned to recruit 300 eligible heart failure patients and randomly divide them into 3 groups, with 100 patients in each group.

[0078] Experimental group 1: The drug composition of Example 3 is administered.

[0079] Experimental group 2: The drug composition of Example 2 is administered.

[0080] Control group: A placebo is administered.

[0081] (3) Treatment period: It is 12 weeks, and the medicine is taken on time every day.

[0082] 2. Subject selection

[0083] (1) Inclusion criteria: Meeting the diagnostic criteria for heart failure, with New York Heart Association (NYHA) cardiac function classification of grade II-IV; aged between 18 and 75 years old; the patient signs an informed consent form.

[0084] (2) Exclusion criteria: Those who are allergic to the drug components; those with severe hepatic and renal insufficiency; those who have had cardiovascular events such as acute myocardial infarction and unstable angina within the recent 3 months.

[0085] 3. Treatment plan

[0086] (1) Experimental group 1 and Experimental group 2: The corresponding drug compositions are respectively administered 3 times a day, with a dose of 5 mg each time.

[0087] (2) Control group: A placebo with the same appearance and taste as the drug composition is administered, and the administration method is the same as that of the experimental group.

[0088] 4. Efficacy judgment criteria:

[0089] Clinical cure: The cardiac function returns to grade I, the symptoms and signs basically disappear, and the relevant examination indicators are basically normal.

[0090] Marked effect: The cardiac function improves by 2 grades, the symptoms and signs are significantly reduced, and the relevant examination indicators are significantly improved.

[0091] Effective: The cardiac function improves by 1 grade, the symptoms and signs are somewhat reduced, and the relevant examination indicators are somewhat improved.

[0092] Ineffective: The cardiac function shows no improvement or deteriorates, and the symptoms, signs and examination indicators show no change or deterioration.

[0093] 5. Clinical results

[0094]

[0095]

[0096] No adverse reactions were observed in the above tests.

[0097] As can be seen from the above results, the pharmaceutical composition of the present invention has a significant effect in improving heart failure function, and the experimental group 1 reached 100%.

[0098] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition for heart failure, characterized in that: The invention comprises the following raw materials in parts by weight: 10-20 parts of ginseng, 15-30 parts of astragalus, 12-25 parts of salvia miltiorrhiza, 8-15 parts of scutellaria baicalensis, 5-12 parts of cinnamon twig, 10-18 parts of poria, 6-12 parts of chuanxiong, 3-8 parts of safflower, 8-16 parts of oriental rhizome, 3-6 parts of roasted licorice, 5-10 parts of tangerine peel, 3-6 parts of patchouli, 5-10 parts of morinda officinalis, 4-8 parts of alpinia oxyphylla, 3-6 parts of amomum villosum, 2-5 parts of cinnamon bark, 4-8 parts of galangal, 3-6 parts of dalbergia odorifera, 4-8 parts of kauri vine, 5-10 parts of auspicious grass, 5-10 parts of houttuynia cordata, 3-6 parts of feilongzhang blood, 5-10 parts of linalool, and 4-9 parts of scutellaria baicalensis.

2. A pharmaceutical composition for heart failure according to claim 1, characterized in that: The invention comprises the following raw materials in parts by weight: 15 parts of ginseng, 25 parts of astragalus, 20 parts of salvia miltiorrhiza, 12 parts of scutellaria baicalensis, 10 parts of cinnamon twig, 15 parts of poria, 9 parts of chuanxiong, 5 parts of safflower, 12 parts of oriental rhizome, 5 parts of roasted licorice root, 8 parts of tangerine peel, 5 parts of patchouli, 8 parts of morinda officinalis, 6 parts of alpinia oxyphylla, 5 parts of amomum villosum, 3 parts of cinnamon bark, 6 parts of galangal, 5 parts of dalbergia odorifera, 6 parts of caesalpinia pilosula, 8 parts of herba houttuyniae, 8 parts of houttuynia cordata, 5 parts of spatholobi, 8 parts of aconite, and 7 parts of elaeagnus officinalis.

3. A method for preparing the pharmaceutical composition for heart failure according to claim 1, characterized in that: The following steps are involved: (1) Stepped polar extraction: Ginseng, Astragalus, Morinda officinalis and dry ice were ground into low-temperature powder at a ratio of 1:0.5-0.8 at -55 to -45°C, and supercritical CO2 was used for two-stage extraction to extract polar saponins, and the residue was set aside; (2) Four-dimensional directional distillation: Place the seeds of Leonurus japonicus, Rhizoma Alismatis, and Poria cocos in an ultrasonic atomization reactor and perform low-pressure distillation under nitrogen protection at a pressure of -0.09 to -0.07 MPa. Adjust the temperature gradient and collect the fraction containing lactone components. The residue is set aside for later use. (3) Biphasic enzymatic hydrolysis: the remaining medicinal materials are mixed with the medicinal residues of steps (1) and (2), and 2-10% of the combined enzyme mass of the mixed medicinal residues is added, and enzymatic hydrolysis is performed for 0.8-1.2 hours under the assistance of a 120-180 V / m micro-electric field; after the enzymatic hydrolysis is completed, the material is immediately subjected to high-frequency microwave extraction at a frequency of 2400-2500 MHz, using a pulse mode and a duty cycle of 55-65%, and the extraction is performed in three stages to obtain an extract; (4) Dynamic composite inclusion: the extract obtained in step (3) is mixed with hydroxypropyl-β-cyclodextrin and methyl-β-cyclodextrin in a ratio of 1.8-2.2:1, and treated in a microfluidizer at 130-170 MPa to obtain an inclusion compound; (5) Drying: The inclusion compound is placed in a plasma-assisted freeze dryer. In the pre-freezing stage, the inclusion compound is rapidly frozen to -55 to -45°C at a cooling rate of 8 to 12°C / min. In the sublimation stage, the chamber pressure is controlled to be 4 to 6 Pa, the plasma power is 280 to 320 W, and the water pressure reduction gradient is 0.08 to 0.12 Pa / min to obtain a pharmaceutical composition.

4. The preparation method according to claim 3, characterized in that: In the step (1), the first stage is as follows: the pressure is 20-30 MPa, the temperature is 20-60°C, the extraction is 1-3 hours, the extractant is 3-7% ethyl acetate, and the fat-soluble components are collected; the second stage is as follows: the pressure is 30-40 MPa, the temperature is 60-70°C, the extraction is 1-3 hours, and the extractant is 8-12% ethanol aqueous solution.

5. The preparation method according to claim 3, characterized in that: In step (2), the bottom layer temperature is maintained at 85-95°C, the middle layer temperature is 70-80°C, and the top layer temperature is 55-65°C.

6. The preparation method according to claim 3, characterized in that: The combined enzymes in step (3) are cellulase, pectinase and xylanase in a mass ratio of (2.5-3.5):(1.5-2.5):(0.8-1.2).

7. The preparation method according to claim 6, characterized in that: The enzymatic activity of the cellulase is 5000-10000 U / g, the enzymatic activity of the pectinase is 3000-8000 U / g, and the enzymatic activity of the xylanase is 2000-6000 U / g.

8. The preparation method according to claim 3, characterized in that: The three-stage extraction of step (3) is as follows: the first stage is extraction at 75-85°C for 7-9 minutes to obtain flavonoid glycosides; the second stage is extraction at 65-75°C for 9-11 minutes to extract organic acids; and the third stage is extraction at 55-65°C for 11-13 minutes.

9. Use of the pharmaceutical composition according to claim 1 or 2 in the preparation of a drug for treating heart failure.

10. The use according to claim 9, characterized in that: The heart failure includes acute heart failure, chronic heart failure, diastolic heart failure and systolic heart failure.

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