Pharmaceutical composition for resisting chronic heart failure as well as preparation method and application of pharmaceutical composition

Abstract

The invention provides a pharmaceutical composition for resisting chronic heart failure as well as a preparation method and application thereof, and belongs to the technical field of medicines. The traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: radix aconiti lateralis preparata, semen lepidii, poria cocos, rhizoma atractylodis macrocephalae, radix paeoniae alba, fresh ginger, rhizoma alismatis, peach kernels, flos carthami, radix salviae miltiorrhizae, radix angelicae sinensis, rhizoma chuanxiong, radix achyranthis bidentatae, radix bupleuri, fructus aurantii, radix platycodonis, radix astragali, fructus jujubae and radix glycyrrhizae preparata. The prepared pharmaceutical composition for resisting chronic heart failure is simple in preparation method and good in treatment effect, has very good effects of regulating vascular tension, myocardial contractility and heart remodeling, inhibits ferroptosis of myocardial cells so as to protect myocardial cells from being damaged and prevent heart failure, and is small in side effect, high in patient compliance and free of toxic and side effects. Wide application prospects are realized.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a pharmaceutical composition for resisting chronic heart failure, a preparation method and application thereof. Background Art

[0002] Chronic heart failure (CHF) is a complex clinical symptom group and the terminal stage of various heart diseases. It has a high incidence and mortality rate. According to statistics, the prevalence rate in the general population is about 1.0%-2.0%, and it can reach 6%-10% for those over 65 years old. The results of a random sampling survey of 15,518 urban and rural residents aged 35-74 in my country showed that the prevalence rate of heart failure was 0.9%. According to calculations, there are about 4 million heart failure patients, including 0.7% for males and 1.0% for females, with females being higher than males. With the aging of the population, its prevalence rate is on the rise. For patients over 65 years old, CHF is the main reason for hospitalization. For this reason, the treatment of CHF will be the top priority of every cardiovascular doctor.

[0003] Patients with chronic heart failure (CHF) often have sodium and water retention. Diuretics play a key role in the treatment of CHF, and most patients can effectively improve CHF symptoms through diuretic treatment. However, as the disease progresses, some patients cannot effectively control cardiogenic edema even with adequate diuretic treatment, and diuretic resistance occurs. Currently, there is a lack of effective treatment methods.

[0004] The main types of drug treatment for CHF in Western medicine are as follows: 1) Angiotensin converting enzyme inhibitors (ACEI), which are suitable for all heart failure patients with reduced left ventricular ejection fraction (less than 40%), to improve the patient's quality of life, symptoms and cardiac function, and reduce hospitalization time. There are problems such as differences between different types of angiotensin inhibitors, gaps between target doses and commonly used doses, economic affordability, adverse reactions, and high incidence in the treatment of CHF with ACEI. 2) Diuretics, diuretics reduce fluid retention in heart failure patients through diuresis, improve cardiac function, symptoms and exercise tolerance, and a single diuretic is not enough. The combined use of ACEI, beta-blockers, and digitalis drugs can reduce the risk of clinical decompensation. Diuretics may cause adverse reactions such as hyponatremia, acid-base imbalance, hyperuricemia, and hypomagnesemia. Thiazides may cause adverse reactions such as hypokalemia, hypomagnesemia, hyponatremia, hyperaciduria, impaired glucose tolerance, and acid-base imbalance. Therefore, patients need to frequently test serum creatinine and electrolyte levels. As the disease progresses, some patients cannot effectively control cardiogenic edema under the condition of adequate diuretic treatment, and diuretic resistance occurs. There is currently a lack of effective treatment methods. 3) β-blockers. The pathophysiological basis of β-blockers in the treatment of CHF is to reduce myocardial oxygen consumption and improve cardiac function: However, different β-blockers may have different clinical effects on patients with heart failure. Receptor blockers are not suitable for acute heart failure and can only be used in a stable state. 4) Angiotensin II receptor blockers. For patients with symptomatic heart failure who cannot tolerate ACEI, angiotensin II receptor blockers can be used instead of ACEI to reduce mortality and complications. Angiotensin II receptor blockers and ACEI seem to have similar effects on reducing the mortality and morbidity of chronic heart failure. Angiotensin receptor blockers can also cause hypotension, hyperkalemia and worsening renal function. When using them, attention should be paid to blood pressure, blood electrolytes and renal function. 5) Aldosterone inhibitors. Aldosterone has adverse effects on cardiac structure and function independent of angiotensin II, promotes myocardial fibrosis, and is prone to ventricular arrhythmias and crushing death. Currently, the FDA has approved eplerenone only for the treatment of patients with heart failure after acute myocardial infarction. The patient's blood potassium and serum creatinine levels should be tested during the use of aldosterone inhibitors. In summary, it is still necessary to develop new CHF treatment drugs.

[0005] There is no corresponding disease name for heart failure in ancient Chinese medicine books, but the descriptions of some symptoms in ancient Chinese medicine books are very similar to the descriptions of heart failure in modern medicine. For example, "cannot rest due to fluid retention" (Treatise on Febrile Diseases); "coughing and shortness of breath, unable to lie down, or edema all over the body" (Compendium of Materia Medica); "when the water starts to form, the eye sockets are slightly swollen, as if just getting up from lying down, the neck pulse is beating, and coughing occurs from time to time. ... The feet and shins are swollen, the abdomen is enlarged, and the water has formed." (Inner Canon of Medicine). This is similar to the dyspnea, sitting breathing, edema, and jugular vein dilation that occur in heart failure. These descriptions are more scattered in the "asthma syndrome" and "edema" of traditional Chinese medicine. The "asthma, inability to lie flat, edema, and neck pulse" described by traditional Chinese medicine are very similar to the descriptions of heart failure in modern medicine.

[0006] At present, there is no traditional Chinese medicine that has a good therapeutic effect on chronic heart failure. Summary of the invention

[0007] The purpose of the present invention is to provide a pharmaceutical composition for treating chronic heart failure, a preparation method thereof and an application thereof. The preparation method is simple, the therapeutic effect is good, the composition has a good effect of regulating vascular tension, myocardial contractility and cardiac remodeling, inhibits myocardial cell ferroptosis, thereby protecting myocardial cells from damage and preventing the occurrence of heart failure, and has few side effects, high patient compliance and broad application prospects.

[0008] The technical solution of the present invention is achieved in this way:

[0009] The invention provides a traditional Chinese medicine composition for resisting chronic heart failure. The traditional Chinese medicine composition is prepared from the following raw materials by weight: 5-15 parts of processed aconite root, 5-15 parts of scutellaria baicalensis seeds, 10-20 parts of tuckahoe, 10-20 parts of atractylodes macrocephala, 10-20 parts of white peony root, 5-15 parts of ginger, 10-20 parts of oriental arisaema, 5-15 parts of peach kernel, 5-15 parts of safflower, 15-25 parts of salvia miltiorrhiza, 10-20 parts of angelica sinensis, 5-15 parts of chuanxiong, 10-20 parts of achyranthes bidentata, 5-15 parts of bupleurum, 10-20 parts of fructus aurantii, 5-15 parts of platycodon grandiflorum, 25-35 parts of astragalus, 2-4 pieces of jujube and 3-7 parts of roasted liquorice.

[0010] The present invention further protects a method for preparing the above-mentioned Chinese medicine composition for treating chronic heart failure, comprising the following steps:

[0011] S1. Wash, dry, and crush the prepared aconite root, add it to water, and heat it to boiling for extraction;

[0012] S2. Add dried scutellaria baicalensis, Poria, Atractylodes macrocephala, white peony root, ginger, oriental rhizome, peach kernel, safflower, salvia miltiorrhiza, angelica, ligusticum chuanxiong, Achyranthes bidentata, bupleurum, fructus aurantii, platycodon grandiflorum, astragalus, jujube and licorice, and continue heating and boiling extraction;

[0013] S3. Filter and dry the filtrate to obtain a Chinese medicine composition for treating chronic heart failure.

[0014] As a further improvement of the present invention, the time for the heating and boiling extraction in step S1 is 2-4 hours, and the time for the heating and boiling extraction in step S2 is 0.5-1 hour.

[0015] The present invention further protects the use of the above-mentioned Chinese medicine composition for resisting chronic heart failure in preparing medicine for preventing and treating chronic heart failure.

[0016] The present invention further protects a method for preparing a drug for treating chronic heart failure, comprising the following steps:

[0017] (1) dissolving berberine in hot water to obtain solution 1, dissolving icariin in ethanol to obtain solution 2; dissolving resveratrol in acetone to obtain solution 3, mixing solution 1, solution 2, and solution 3 uniformly, cooling to room temperature, evaporating the solvent in an open manner, filtering, washing, and drying to obtain a co-crystal of the effective ingredient of the traditional Chinese medicine;

[0018] (2) dissolving alginic acid and gelatin in water, adding the co-crystal of effective Chinese medicine ingredients, the above-mentioned Chinese medicine composition for treating chronic heart failure and lecithin, stirring and mixing uniformly to obtain an aqueous phase; dropping the aqueous phase into soybean oil, emulsifying, dropping a mixed solution containing calcium chloride and EDC, solidifying at room temperature, centrifuging, washing, and drying to obtain embedded particles;

[0019] (3) Add the embedded particles into water, add EDC (1-ethyl-(3-dimethylaminopropyl) carbodiimide) and NHS (N-hydroxysuccinimide), stir to activate, add small molecule agonists 2-APQC and Vericipirab, stir to react, centrifuge, wash, and dry to obtain a drug for treating chronic heart failure.

[0020] As a further improvement of the present invention, in step (1), the mass ratio of berberine, icariin and resveratrol is 3-5:1-2:2-4, the temperature of the hot water is 60-70° C., and the time for the solvent to evaporate in the open air is 3-5 days.

[0021] As a further improvement of the present invention, the mass ratio of alginate, gelatin, Chinese medicine effective ingredient eutectic, Chinese medicine composition for treating chronic heart failure, lecithin, calcium chloride and EDC in step (2) is 10-12:7-10:4-5:7-10:1-2:0.5-1:0.8-1.2, and the room temperature curing time is 20-30 min.

[0022] As a further improvement of the present invention, the mass ratio of the embedded particles, EDC, NHS, small molecule agonist 2-APQC and Vericipiracil in step (3) is 10:3-4:2-4:0.5-1:0.2-0.4, the stirring activation time is 20-35 min, and the stirring reaction time is 10-12 h.

[0023] The present invention further protects a drug for resisting chronic heart failure prepared by the above preparation method.

[0024] The present invention further protects the use of the above-mentioned drug for resisting chronic heart failure in the preparation of drugs for resisting chronic heart failure, improving heart function, improving cardiovascular function, and treating coronary heart disease.

[0025] The present invention has the following beneficial effects:

[0026] Traditional Chinese medicine believes that the pathogenesis of heart failure is that the heart disease lasts for a long time, the spleen and kidney yang qi are weak, water and dampness overflow, qi deficiency and blood stasis, and the heart meridian is blocked. Because the spleen controls water, and the kidney controls water, spleen yang deficiency makes it difficult to transport dampness, and kidney yang deficiency makes water unable to transform into qi, resulting in water and dampness stagnation; yang qi is weak, blood transportation is weak, and water and dampness stagnate, qi and blood are not smooth, resulting in blood stasis, blood stasis and water stagnation, blocking the heart meridian, and the heart meridian is exhausted and heart failure occurs.

[0027] In this prescription, the processed aconite and ginger are pungent and hot in nature, which can warm the kidney and assist yang, transform qi and promote water circulation, and warm and transport water and dampness; Poria, Atractylodes, Alisma, and Lepidium can strengthen the spleen, promote water circulation and eliminate dampness; Peach Kernel, Carthamus, Ligusticum chuanxiong, Salvia miltiorrhiza, Angelica, and White Peony can promote blood circulation and remove blood stasis to open up the heart meridian, and at the same time, White Peony can restrain the dry and hot nature of the processed aconite; Bupleurum, Citrus aurantium, and Platycodon can regulate qi and remove stagnation, so that qi can flow and blood can flow; Achyranthes bidentata can promote blood circulation and remove blood stasis, and guide blood downward; blood is the mother of qi, and qi is the commander of blood. Astragalus and jujube can replenish qi to help blood circulation; roasted licorice is the guiding drug to neutralize all the drugs.

[0028] Icariin is one of the main components of the traditional Chinese medicine Epimedium, and has a potential effect on the treatment of circulatory system diseases such as myocardial ischemia and arrhythmia. Berberine can inhibit myocardial cell ferroptosis by reducing lipid peroxides in myocardial cells, thereby protecting myocardial cells from damage and preventing the occurrence of heart failure. Resveratrol is a non-flavonoid polyphenol organic compound with antioxidant, anti-inflammatory, cardiovascular protection and other effects, which can improve myocardial hypertrophy and fibrosis, and improve cardiac function. However, the solubility of the three in water is not good, so that their bioavailability is not high, the therapeutic effect decreases, and the single component therapeutic effect is not good. The present invention prepares the three into eutectic, greatly improves its water solubility, improves its bioavailability and therapeutic effect, and the synergistic effect greatly improves the improvement of myocardial hypertrophy and fibrosis, and the effect of improving cardiac function, with a synergistic effect.

[0029] Camptothecin derivative analogue 2-APQC is a targeted small molecule agonist that can not only regulate the classic SIRT3-mediated pathway for improving heart failure, but also affect mitochondrial proline metabolism and reactive oxygen metabolism by regulating the SIRT3-PYCR1 pathway, thereby maintaining the mitochondria in a stable state. More importantly, the molecule is also a targeted drug. Therefore, the present invention designs and prepares a nano-microsphere, grafted with the targeted small molecule agonist, so that the microsphere can be targeted for drug administration and fixed-point release, exerting a better therapeutic effect.

[0030] Vericipirat is a soluble guanylate cyclase (sGC) stimulator, which means it can directly stimulate sGC, thereby increasing the level of intracellular cyclic guanosine monophosphate (cGMP). As a second messenger, cGMP can regulate vascular tone, myocardial contractility, and cardiac remodeling. In addition, Vericipirat is a direct water-soluble guanylate cyclase agonist that can restore the function of the key signaling pathway of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) by activating sGC.

[0031] Vericipirat is also grafted onto the surface of the nanoparticles of the present invention, and during the drug transport process, Vericipirat is continuously and slowly released, thereby extending the drug efficacy period and better playing the role of regulating vascular tension, myocardial contractility and cardiac remodeling.

[0032] The preparation method of the pharmaceutical composition for treating chronic heart failure prepared by the present invention is simple, the therapeutic effect is good, it has a good effect of regulating vascular tension, myocardial contractility and cardiac remodeling, inhibits myocardial cell ferroptosis, thereby protecting myocardial cells from damage and preventing the occurrence of heart failure, and it has few side effects, high patient compliance, and has broad application prospects. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. 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.

[0034] Small molecule agonist 2-APQC (Sirtuin-3, SIRT3, is an important histone deacetylase in mitochondria, closely related to mitochondrial dynamics, ROS generation and redox dynamic balance), the structural formula is as follows:

[0035]

[0036] Example 1

[0037] Raw material composition (by weight): 5 parts of processed aconite, 5 parts of scutellaria, 10 parts of poria, 10 parts of atractylodes, 10 parts of white peony root, 5 parts of ginger, 10 parts of oriental rhizome, 5 parts of peach kernel, 5 parts of safflower, 15 parts of salvia miltiorrhiza, 10 parts of angelica, 5 parts of chuanxiong, 10 parts of Achyranthes bidentata, 5 parts of bupleurum, 10 parts of fructus aurantii, 5 parts of platycodon, 25 parts of astragalus, 2 jujubes, and 3 parts of roasted licorice.

[0038] This embodiment provides a method for preparing a Chinese medicine composition, comprising the following steps:

[0039] S1. Wash, dry, and crush the prepared aconite root, add it into water, and heat it to boiling for 2 hours;

[0040] S2. Add dried scutellaria baicalensis, Poria cocos, Atractylodes macrocephala, white peony root, ginger, oriental rhizome, peach kernel, safflower, salvia miltiorrhiza, angelica sinensis, ligusticum chuanxiong, Achyranthes bidentata, bupleurum, fructus aurantii, platycodon grandiflorum, astragalus, jujube and licorice, and continue heating and boiling extraction for 0.5h;

[0041] S3. Filter and dry the filtrate to obtain a Chinese medicine composition for treating chronic heart failure.

[0042] Example 2

[0043] Raw material composition (by weight): 15 parts of processed aconite, 15 parts of scutellaria baicalensis, 20 parts of poria, 20 parts of atractylodes, 20 parts of white peony root, 15 parts of ginger, 20 parts of oriental atractylodes, 15 parts of peach kernel, 15 parts of safflower, 25 parts of salvia miltiorrhiza, 20 parts of angelica, 15 parts of chuanxiong, 20 parts of Achyranthes bidentata, 15 parts of bupleurum, 20 parts of fructus aurantii, 15 parts of platycodon, 35 parts of astragalus, 4 jujubes, and 7 parts of roasted licorice.

[0044] This embodiment provides a method for preparing a Chinese medicine composition, comprising the following steps:

[0045] S1. Wash, dry, and crush the prepared aconite root, add it to water, and heat it to boiling for 4 hours;

[0046] S2. Add dried scutellaria baicalensis, Poria cocos, Atractylodes macrocephala, White peony root, ginger, Alisma orientalis, peach kernel, safflower, Salvia miltiorrhiza, Angelica sinensis, Ligusticum chuanxiong, Achyranthes bidentata, Bupleurum chinense, Citrus aurantium, Platycodon grandiflorum, Astragalus membranaceus, jujube and licorice, and continue heating and boiling extraction for 1 hour;

[0047] S3. Filter and dry the filtrate to obtain a Chinese medicine composition for treating chronic heart failure.

[0048] Example 3

[0049] Raw material composition (by weight): 10 parts of processed aconite, 10 parts of scutellaria baicalensis, 15 parts of poria, 15 parts of atractylodes, 15 parts of white peony root, 10 parts of ginger, 15 parts of oriental rhizome, 10 parts of peach kernel, 10 parts of safflower, 20 parts of salvia miltiorrhiza, 15 parts of angelica, 10 parts of chuanxiong, 15 parts of Achyranthes bidentata, 10 parts of bupleurum, 15 parts of fructus aurantii, 10 parts of platycodon, 35 parts of astragalus, 3 jujubes, and 6 parts of roasted licorice.

[0050] This embodiment provides a method for preparing a Chinese medicine composition, comprising the following steps:

[0051] S1. Wash, dry, and crush the prepared aconite root, add it into water, and heat it to boiling for 3 hours;

[0052] S2. Add dried scutellaria baicalensis, Poria cocos, Atractylodes macrocephala, White peony root, ginger, Alisma orientalis, peach kernel, safflower, Salvia miltiorrhiza, Angelica sinensis, Ligusticum chuanxiong, Achyranthes bidentata, Bupleurum chinense, Citrus aurantium, Platycodon grandiflorum, Astragalus membranaceus, jujube and licorice, and continue heating and boiling extraction for 1 hour;

[0053] S3. Filter and dry the filtrate to obtain a Chinese medicine composition for treating chronic heart failure.

[0054] Example 4

[0055] This embodiment provides a method for preparing a drug for treating chronic heart failure, comprising the following steps:

[0056] (1) 3 g of berberine was dissolved in 200 mL of hot water to obtain solution 1, 1 g of icariin was dissolved in 100 mL of ethanol to obtain solution 2; 2 g of resveratrol was dissolved in 100 mL of acetone to obtain solution 3, solution 1, solution 2, and solution 3 were stirred and mixed for 15 min, cooled to room temperature, the solvent was evaporated in an open state for 3 d, filtered, washed, and dried to obtain a co-crystal of the effective ingredient of traditional Chinese medicine;

[0057] (2) Dissolve 10 g of alginic acid and 7 g of gelatin in 300 mL of water, add 4 g of Chinese medicine active ingredient eutectic, 7 g of the Chinese medicine composition for treating chronic heart failure prepared in Example 1, and 1 g of lecithin, and stir and mix uniformly to obtain an aqueous phase; drop the aqueous phase into 500 mL of soybean oil, emulsify at 8000 r / min for 15 min, drop 50 mL of a mixed aqueous solution containing 0.5 g of calcium chloride and 0.8 g of EDC, solidify at room temperature for 20 min, centrifuge, wash, and dry to obtain embedded particles;

[0058] (3) 10 g of the embedded particles were added to 200 mL of water, 3 g of EDC and 2 g of NHS were added, and the mixture was stirred and activated for 20 min. 0.5 g of the small molecule agonist 2-APQC and 0.2 g of vericipiracil were added, and the mixture was stirred and reacted for 10 h. The mixture was centrifuged, washed, and dried to obtain a drug for treating chronic heart failure.

[0059] Example 5

[0060] This embodiment provides a method for preparing a drug for treating chronic heart failure, comprising the following steps:

[0061] (1) Dissolve 5 g of berberine in 200 mL of hot water to obtain solution 1, dissolve 2 g of icariin in 100 mL of ethanol to obtain solution 2; dissolve 4 g of resveratrol in 100 mL of acetone to obtain solution 3, stir and mix solution 1, solution 2, and solution 3 for 15 min, cool to room temperature, evaporate the solvent in an open state for 5 d, filter, wash, and dry to obtain a co-crystal of the effective ingredient of traditional Chinese medicine;

[0062] (2) Dissolve 12 g of alginic acid and 10 g of gelatin in 300 mL of water, add 5 g of Chinese medicine active ingredient eutectic, 10 g of the Chinese medicine composition for treating chronic heart failure prepared in Example 2, and 2 g of lecithin, and stir and mix uniformly to obtain an aqueous phase; drop the aqueous phase into 500 mL of soybean oil, emulsify at 8000 r / min for 15 min, drop 50 mL of a mixed aqueous solution containing 1 g of calcium chloride and 1.2 g of EDC, solidify at room temperature for 30 min, centrifuge, wash, and dry to obtain embedded particles;

[0063] (3) 10 g of the embedded particles were added to 200 mL of water, 4 g of EDC and 4 g of NHS were added, and the mixture was stirred and activated for 35 min. 1 g of the small molecule agonist 2-APQC and 0.4 g of Vericipiracil were added, and the mixture was stirred and reacted for 12 h. The mixture was centrifuged, washed, and dried to obtain a drug for treating chronic heart failure.

[0064] Example 6

[0065] This embodiment provides a method for preparing a drug for treating chronic heart failure, comprising the following steps:

[0066] (1) Dissolve 4 g of berberine in 200 mL of hot water to obtain solution 1, dissolve 1.5 g of icariin in 100 mL of ethanol to obtain solution 2; dissolve 3 g of resveratrol in 100 mL of acetone to obtain solution 3, stir and mix solution 1, solution 2, and solution 3 for 15 min, cool to room temperature, evaporate the solvent in an open state for 4 d, filter, wash, and dry to obtain a co-crystal of the effective ingredient of traditional Chinese medicine;

[0067] (2) Dissolve 11 g of alginic acid and 8 g of gelatin in 300 mL of water, add 4.5 g of Chinese medicine active ingredient eutectic, 8 g of the Chinese medicine composition for treating chronic heart failure prepared in Example 3, and 1.5 g of lecithin, and stir to mix uniformly to obtain an aqueous phase; drop the aqueous phase into 500 mL of soybean oil, emulsify at 8000 r / min for 15 min, drop 50 mL of a mixed aqueous solution containing 0.7 g of calcium chloride and 1 g of EDC, solidify at room temperature for 25 min, centrifuge, wash, and dry to obtain embedded particles;

[0068] (3) 10 g of the embedded particles were added to 200 mL of water, 3.5 g of EDC and 3 g of NHS were added, and the mixture was stirred and activated for 28 min. 0.7 g of the small molecule agonist 2-APQC and 0.4 g of vericipiracil were added, and the mixture was stirred and reacted for 11 h. The mixture was centrifuged, washed, and dried to obtain a drug for treating chronic heart failure.

[0069] Comparative Example 1

[0070] Compared with Example 6, the difference is that berberine is not added in step (1).

[0071] The details are as follows:

[0072] (1) Dissolve 1.5 g of icariin in 100 mL of ethanol to obtain solution 2; dissolve 3 g of resveratrol in 100 mL of acetone to obtain solution 3. Stir solution 2 and solution 3 for 15 minutes, cool to room temperature, evaporate the solvent in an open container for 4 days, filter, wash, and dry to obtain a co-crystal of the effective ingredient of traditional Chinese medicine.

[0073] Comparative Example 2

[0074] Compared with Example 6, the difference is that icariin is not added in step (1).

[0075] The details are as follows:

[0076] (1) Dissolve 4 g of berberine in 200 mL of hot water to obtain solution 1, and dissolve 3 g of resveratrol in 100 mL of acetone to obtain solution 3. Stir and mix solution 1 and solution 3 for 15 min, cool to room temperature, evaporate the solvent in an open state for 4 days, filter, wash, and dry to obtain a co-crystal of the effective ingredient of traditional Chinese medicine.

[0077] Comparative Example 3

[0078] Compared with Example 6, the difference is that resveratrol is not added in step (1).

[0079] The details are as follows:

[0080] (1) 4 g of berberine was dissolved in 200 mL of hot water to obtain solution 1, and 1.5 g of icariin was dissolved in 100 mL of ethanol to obtain solution 2; solution 1 and solution 2 were stirred and mixed for 15 minutes, cooled to room temperature, the solvent was evaporated in an open state for 4 days, filtered, washed, and dried to obtain a co-crystal of the effective ingredient of the traditional Chinese medicine.

[0081] Comparative Example 4

[0082] Compared with Example 6, the difference is that no Chinese medicine active ingredient co-crystal is added in step (2).

[0083] The details are as follows:

[0084] (2) 11 g of alginic acid and 8 g of gelatin were dissolved in 300 mL of water, 12.5 g of the Chinese medicine composition for treating chronic heart failure prepared in Example 3 and 1.5 g of lecithin were added, and the mixture was stirred and mixed to obtain an aqueous phase; the aqueous phase was added dropwise to 500 mL of soybean oil, emulsified at 8000 r / min for 15 min, 50 mL of a mixed aqueous solution containing 0.7 g of calcium chloride and 1 g of EDC was added dropwise, and the mixture was cured at room temperature for 25 min, centrifuged, washed, and dried to obtain embedded particles.

[0085] Comparative Example 5

[0086] Compared with Example 6, the difference is that no Chinese medicine composition for treating chronic heart failure is added in step (2).

[0087] The details are as follows:

[0088] (2) 11 g of alginic acid and 8 g of gelatin were dissolved in 300 mL of water, 12.5 g of the effective component of traditional Chinese medicine eutectic and 1.5 g of lecithin were added, and the mixture was stirred to obtain an aqueous phase; the aqueous phase was added dropwise to 500 mL of soybean oil, and emulsified at 8000 r / min for 15 min, and 50 mL of a mixed aqueous solution containing 0.7 g of calcium chloride and 1 g of EDC was added dropwise, and the mixture was cured at room temperature for 25 min, centrifuged, washed, and dried to obtain embedded particles.

[0089] Comparative Example 6

[0090] Compared with Example 6, the difference is that the small molecule agonist 2-APQC is not added in step (3).

[0091] The details are as follows:

[0092] (3) 10 g of the embedded particles were added to 200 mL of water, 3.5 g of EDC and 3 g of NHS were added, and the mixture was stirred and activated for 28 min. 1.1 g of Vericipiracil was added, and the mixture was stirred and reacted for 11 h. The mixture was centrifuged, washed, and dried to obtain a drug for treating chronic heart failure.

[0093] Comparative Example 7

[0094] Compared with Example 6, the difference is that Vericipirat is not added in step (3).

[0095] The details are as follows:

[0096] (3) 10 g of the embedded particles were added to 200 mL of water, 3.5 g of EDC and 3 g of NHS were added, and the mixture was stirred and activated for 28 min. 1.1 g of the small molecule agonist 2-APQC was added, and the mixture was stirred and reacted for 11 h. The mixture was centrifuged, washed, and dried to obtain a drug for treating chronic heart failure.

[0097] Comparative Example 8

[0098] Compared with Example 6, the difference is that step (3) is not performed.

[0099] The details are as follows:

[0100] (1) Dissolve 4 g of berberine in 200 mL of hot water to obtain solution 1, dissolve 1.5 g of icariin in 100 mL of ethanol to obtain solution 2; dissolve 3 g of resveratrol in 100 mL of acetone to obtain solution 3, stir and mix solution 1, solution 2, and solution 3 for 15 min, cool to room temperature, evaporate the solvent in an open state for 4 d, filter, wash, and dry to obtain a co-crystal of the effective ingredient of traditional Chinese medicine;

[0101] (2) 11 g of alginic acid and 8 g of gelatin were dissolved in 300 mL of water, 4.5 g of the Chinese medicine effective ingredient eutectic, 8 g of the Chinese medicine composition for treating chronic heart failure prepared in Example 3 and 1.5 g of lecithin were added, and the mixture was stirred and mixed uniformly to obtain an aqueous phase; the aqueous phase was added dropwise to 500 mL of soybean oil, emulsified at 8000 r / min for 15 min, 50 mL of a mixed aqueous solution containing 0.7 g of calcium chloride and 1 g of EDC was added dropwise, solidified at room temperature for 25 min, centrifuged, washed, and dried to obtain embedded particles, which are drugs for treating chronic heart failure.

[0102] Comparative Example 9

[0103] Compared with Example 6, the difference is that the components are simply mixed to obtain the product.

[0104] The details are as follows:

[0105] (1) Dissolve 4 g of berberine in 200 mL of hot water to obtain solution 1, dissolve 1.5 g of icariin in 100 mL of ethanol to obtain solution 2; dissolve 3 g of resveratrol in 100 mL of acetone to obtain solution 3, stir and mix solution 1, solution 2, and solution 3 for 15 min, cool to room temperature, evaporate the solvent in an open state for 4 d, filter, wash, and dry to obtain a co-crystal of the effective ingredient of traditional Chinese medicine;

[0106] (2) 4.5 g of the Chinese medicine active ingredient co-crystal and 8 g of the Chinese medicine composition for treating chronic heart failure prepared in Example 3 were stirred and mixed for 10 min to prepare a mixture;

[0107] (3) 10 g of the mixture, 0.7 g of the small molecule agonist 2-APQC and 0.4 g of vericipiracil were stirred and mixed for 10 min to prepare a drug for treating chronic heart failure.

[0108] Test Example 1

[0109] Selected from SPF grade male C57BL / 6J mice, 8-10 weeks old, body weight 22-25g, randomly divided into sham operation group, model group, perindopril group, Example 1-3 group, Example 4-6 group, Comparative Example 1-9 group, 6 mice in each group, except the sham operation group, each group of mice underwent thoracic aortic constriction to replicate the pressure load CHF model, mice were anesthetized by intraperitoneal injection of sodium pentobarbital (50mg / kg), and thoracotomy was performed while connected to a ventilator, and a 27G needle and 8-0 suture were used to ligate the aorta between the right innominate artery and the left common carotid artery, so that the cross-sectional area of ​​the abdominal aorta was narrowed to about 25%-30% of the original, causing abdominal aortic constriction, and closing the chest cavity. The sham operation group only had thoracotomy and threading without ligation. The Example 1-3 group, the Example 4-6 group, and the Comparative Example 1-9 group were intragastrically administered with 10 mg / kg of the corresponding prepared drugs, the Perindopril group was administered with 0.607 mg / kg, and the sham operation group and the model group were intragastrically administered with an equal amount of 0.9% sodium chloride solution. The administration was continued for 4 weeks.

[0110] Small animal ultrasound detection of changes in cardiac function of mice in each group: Small animal ultrasound was used to detect the cardiac function level of mice. After the mice were anesthetized with isoflurane, the hair from the neck to the chest was removed with depilatory cream, and then the coupling agent was applied and the corresponding probe was used for ultrasound observation. The left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular internal diameter at end-diastole (LVIDd), and left ventricular internal diameter at end-systole (LVIDs) of the mice were calculated. The results are shown in Table 1.

[0111] Table 1

[0112]

[0113]

[0114] Note: * compared with the sham operation group, P < 0.05; # compared with the model group, P < 0.05.

[0115] It can be seen from the above table that the Chinese medicinal compositions for treating chronic heart failure prepared in Examples 1-3 of the present invention and the drugs for treating chronic heart failure prepared in Examples 4-6 can significantly increase LVEF and LVFS values ​​and reduce LVIDd and LVIDs values.

[0116] Western Blot method was used to detect the changes in cardiac protein levels in each group of mice: protein lysis buffer was added to extract total protein, and the protein concentration was determined by BCA method. Loading buffer was denatured and then electrophoresis was performed. 25 μg of protein was loaded in each lane. After SDS-PAGE electrophoresis, the membrane was electrotransferred to PVDF membrane, blocked with 5% skim milk powder, and 1:1000 rabbit anti-mouse MLK3, JNK, p53, COX2 were added. The membrane was blocked overnight at 4°C, washed 3 times with TBST for 10 min / time, and HRP-labeled goat anti-rabbit secondary antibody was added. After 1 hour, TBST was washed 3 times with 10 min / time. Luminescent solution A and B were mixed according to the instructions of the kit. After reacting with the membrane, the relative expression of MLK3 / GAPDH, JNK / GAPDH, p53 / GAPDH, and COX2 / GAPDH was calculated using the Bio-Rad chemiluminescence imaging system.

[0117] The results are shown in Table 2.

[0118] Table 2

[0119]

[0120]

[0121] Note: * compared with the sham operation group, P < 0.05; # compared with the model group, P < 0.05.

[0122] As can be seen from the above table, the Chinese medicinal compositions for treating chronic heart failure prepared in Examples 1-3 of the present invention and the drugs for treating chronic heart failure prepared in Examples 4-6 can significantly reduce the levels of MLK3, JNK, p53 and COX2 proteins.

[0123] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A Chinese medicine composition for treating chronic heart failure, characterized in that: The invention is prepared from the following raw materials by weight: 5-15 parts of processed aconite root, 5-15 parts of scutellaria baicalensis seeds, 10-20 parts of tuckahoe, 10-20 parts of atractylodes macrocephala, 10-20 parts of white peony root, 5-15 parts of ginger, 10-20 parts of oriental arisaema, 5-15 parts of peach kernel, 5-15 parts of safflower, 15-25 parts of salvia miltiorrhiza, 10-20 parts of angelica sinensis, 5-15 parts of ligusticum chuanxiong, 10-20 parts of achyranthes bidentata, 5-15 parts of bupleurum, 10-20 parts of fructus aurantii, 5-15 parts of platycodon grandiflorum, 25-35 parts of astragalus, 2-4 jujubes and 3-7 parts of roasted liquorice.

2. A method for preparing the Chinese medicine composition according to claim 1, characterized in that: The following steps are involved: S1. Wash, dry, and crush the prepared aconite root, add it to water, and heat it to boiling for extraction; S2. Add dried scutellaria baicalensis, Poria, Atractylodes macrocephala, white peony root, ginger, oriental rhizome, peach kernel, safflower, salvia miltiorrhiza, angelica, ligusticum chuanxiong, Achyranthes bidentata, bupleurum, fructus aurantii, platycodon grandiflorum, astragalus, jujube and licorice, and continue heating and boiling extraction; S3. Filter and dry the filtrate to obtain a Chinese medicine composition for treating chronic heart failure.

3. The preparation method according to claim 2, characterized in that: The time of the heating and boiling extraction in step S1 is 2-4 hours, and the time of the heating and boiling extraction in step S2 is 0.5-1 hour.

4. Use of the Chinese medicinal composition for preventing and treating chronic heart failure as claimed in claim 1 in the preparation of medicines for preventing and treating chronic heart failure.

5. A method for preparing a drug for treating chronic heart failure, characterized in that: The following steps are involved: (1) dissolving berberine in hot water to obtain solution 1, dissolving icariin in ethanol to obtain solution 2; dissolving resveratrol in acetone to obtain solution 3, mixing solution 1, solution 2, and solution 3 uniformly, cooling to room temperature, evaporating the solvent in an open manner, filtering, washing, and drying to obtain a co-crystal of the effective ingredient of the traditional Chinese medicine; (2) dissolving alginic acid and gelatin in water, adding the co-crystal of effective Chinese medicine ingredients, the Chinese medicine composition for treating chronic heart failure according to claim 1 and lecithin, stirring and mixing uniformly to obtain an aqueous phase; dropping the aqueous phase into soybean oil, emulsifying, dropping a mixed solution containing calcium chloride and EDC, solidifying at room temperature, centrifuging, washing, and drying to obtain embedded particles; (3) Add the embedded particles into water, add EDC and NHS, stir to activate, add small molecule agonists 2-APQC and Vericipirat, stir to react, centrifuge, wash, and dry to obtain a drug for treating chronic heart failure.

6. The preparation method according to claim 5, characterized in that: In step (1), the mass ratio of berberine, icariin and resveratrol is 3-5:1-2:2-4, the temperature of the hot water is 60-70° C., and the time for the solvent to evaporate in the open air is 3-5 days.

7. The preparation method according to claim 5, characterized in that: The mass ratio of alginate, gelatin, Chinese medicine active ingredient eutectic, Chinese medicine composition for treating chronic heart failure, lecithin, calcium chloride and EDC in step (2) is 10-12:7-10:4-5:7-10:1-2:0.5-1:0.8-1.2, and the room temperature curing time is 20-30min.

8. The preparation method according to claim 5, characterized in that: In step (3), the mass ratio of the embedded particles, EDC, NHS, small molecule agonist 2-APQC and Vericipiracil is 10:3-4:2-4:0.5-1:0.2-0.4, the stirring activation time is 20-35 min, and the stirring reaction time is 10-12 h.

9. A drug for treating chronic heart failure obtained by the preparation method according to any one of claims 5 to 8.

10. Use of the drug for treating chronic heart failure according to claim 9 in the preparation of drugs for treating chronic heart failure, improving heart function, improving cardiovascular function, and treating coronary heart disease.

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