A traditional Chinese medicine composition for treating coronary heart disease stable angina pectoris combined with depression state and a preparation method and application thereof

Abstract

The application discloses a Chinese medicinal composition for treating coronary heart disease stable angina pectoris combined with depression and a preparation method and application thereof, and belongs to the technical field of Chinese medicines. The technical problem to be solved is to develop a Chinese medicinal composition for treating coronary heart disease stable angina pectoris combined with depression with better effect. The technical solution is characterized in that the Chinese medicinal composition comprises the following raw materials in parts by weight: 100-240 parts of Astragalus membranaceus, 30-150 parts of Earthworm, 10-50 parts of Panax notoginseng, 90-200 parts of Salvia miltiorrhiza, 10-50 parts of Hypericum perforatum, 90-200 parts of Curcuma zedoaria, 30-150 parts of Paeonia rubra, 100-240 parts of Ziziphus jujuba and 1-3 parts of borneol.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a traditional Chinese medicine composition for treating stable angina pectoris complicated with depression in coronary heart disease, its preparation method, and its application. Background Technology

[0002] Coronary heart disease (CHD) is a heart condition caused by narrowing or even blockage of the coronary arteries due to atherosclerosis, leading to myocardial ischemia and hypoxia. It is the most common cardiovascular disease in clinical practice and seriously endangers human health. Stable angina pectoris (SAP) is a major type of CHD, characterized by its persistent and recurrent nature, impacting patients' quality of life and threatening their lives.

[0003] Coronary heart disease is closely related to various psychological and emotional disorders, such as anxiety and depression. The incidence of coronary heart disease patients with depression and anxiety is higher than that of the general population, and it seriously affects the quality of life of patients. This dual-heart disease has become an urgent problem to be solved in the field of cardiovascular medicine.

[0004] Most medications on the market for treating stable angina pectoris in patients with concurrent depression involve the combined use of drugs for both conditions. However, studies have shown that many antidepressants have varying degrees of cardiovascular adverse effects. For example, the most commonly used SSRIs (Secondary Serological Inhibitors) have different cardiovascular adverse reactions. Concomitant use with aspirin and other antiplatelet / anticoagulant therapies may increase the risk of bleeding, especially in the elderly; it can also cause QTc interval prolongation. Tricyclic antidepressants can prolong the PR, QRS, and QTc intervals. Some patients have poor adherence to antidepressants due to fear of their side effects, making it difficult to achieve good clinical efficacy.

[0005] Traditional Chinese medicine has shown good clinical efficacy in treating coronary heart disease accompanied by mood disorders.

[0006] Relevant patent documents retrieved: This document, published in China (CN117100828A) on September 25, 2023, discloses a traditional Chinese medicine composition and its preparation method for treating coronary heart disease complicated with anxiety and depression. The composition comprises, by weight, the following components: 3-10 parts American ginseng powder, 3-6 parts Panax notoginseng powder, 1-2 parts amber powder, 3-10 parts turmeric powder, and 1-5 parts Hypericum perforatum powder. The composition provided by this invention can effectively treat coronary heart disease complicated with anxiety and depression.

[0007] Relevant non-patent literature retrieved: The journal title is "Master's Thesis of Heilongjiang University of Traditional Chinese Medicine", the article title is "A Study Based on Data Mining on the Medication Patterns of Professor Zhou Yabin in Treating Stable Angina Pectoris with Anxiety in Coronary Heart Disease", and the publication date is June 2022. This article uses data mining technology to organize and analyze Professor Zhou Yabin's medical records in treating stable angina pectoris with anxiety in coronary heart disease, and summarizes Professor Zhou Yabin's clinical diagnosis and treatment experience: first, select prescriptions according to the pathogenesis of the disease and symptoms, and select prescriptions with the effects of regulating qi and relieving depression, promoting blood circulation and resolving phlegm, nourishing blood and replenishing qi, and regulating yin and yang, and then supplement them with sedative drugs, providing reference and guidance for future clinical applications.

[0008] The journal title is *Doctoral Dissertation of Beijing University of Traditional Chinese Medicine*, and the article title is *The Influence of Depression on Stable Angina Pectoris in Coronary Artery Disease and Clinical Intervention Study of Qilong Tongluo Jieyu Formula*. The publication date is June 2023. This paper discloses the Qilong Tongluo Jieyu Formula (confidential), composed of nine ingredients including Astragalus membranaceus, Pheretima aspergillum, Panax notoginseng, Hypericum perforatum, and Borneol. Astragalus membranaceus is the principal ingredient, with the effects of invigorating qi, promoting blood circulation, and removing blood stasis. Pheretima aspergillum and Panax notoginseng are assistant ingredients, enhancing the principal ingredient's effects of assisting the heart to circulate blood, clearing the meridians, and relieving pain. Hypericum perforatum and other herbs are adjuvant ingredients, promoting qi circulation, relieving depression, clearing the meridians, and relieving pain. Borneol and other aromatic herbs promote qi circulation and open the orifices, serving as guiding ingredients. The entire formula works synergistically to invigorate qi, promote blood circulation, soothe the liver, relieve depression, clear the meridians, and relieve pain. It can improve angina attacks and depressive symptoms in patients with stable angina pectoris in coronary artery disease complicated by mild to moderate depression (qi deficiency and blood stasis, liver qi stagnation syndrome). Clinical application is safe and effective, possessing significant clinical significance and potential for further development.

[0009] Currently, there are few traditional Chinese medicine preparations for treating stable angina pectoris combined with depression in patients with coronary heart disease. Developing a more effective traditional Chinese medicine composition for treating stable angina pectoris combined with depression based on the Qilong Tongluo Jieyu formula is of great significance for clinical application. Summary of the Invention

[0010] The purpose of this invention is to provide: A traditional Chinese medicine composition for treating stable angina pectoris complicated with depression, its preparation method and application, can be further enhanced by adjusting the components and preparation method, resulting in better therapeutic effects on stable angina pectoris complicated with depression.

[0011] Terminology Explanation: Unless otherwise defined, all technical terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms, the definition provided in this chapter shall prevail.

[0012] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0013] Definitions of standard chemical terms can be found in the reference "Pharmacopoeia of the People's Republic of China: 2025 Edition".

[0014] Unless otherwise stated, conventional methods within the scope of the art, such as electrocardiogram examination, myocardial infarction area detection, echocardiography, behavioral examination, pathological examination, and myocardial and brain indicator detection, shall be used.

[0015] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0016] The term "Astragalus" used in this article refers to the dried root of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao, a legume. It is a commonly used qi-tonifying herb with the core functions of tonifying qi and raising yang, consolidating the exterior and stopping sweating, promoting diuresis and reducing swelling, generating fluids and nourishing blood, promoting circulation and relieving pain, promoting pus drainage and detoxification, and promoting wound healing and tissue regeneration.

[0017] The term "earthworm" used in this article refers to the dried body of Pheretima aspergillum (E. Perrier), an animal of the family Pheretidae. Its core functions are clearing heat and calming the nerves, promoting blood circulation, relieving asthma, and promoting diuresis.

[0018] The term "Sanqi" used in this article refers to the dried root and rhizome of Panax notoginseng (Burk.) FHChen, a plant of the Araliaceae family. Its core functions are to disperse blood stasis, stop bleeding, reduce swelling, and relieve pain.

[0019] The term "Danshen" as used in this article refers to the dried root and rhizome of Salvia miltiorrhiza Bge., a plant in the Lamiaceae family. Its core functions are to promote blood circulation and remove blood stasis, regulate menstruation and relieve pain, clear the mind and relieve irritability, and cool the blood and reduce swelling.

[0020] The term "Hypericumpensis" used in this article refers to the dried aerial parts of Hypericumpensis L., a plant in the Clusiaceae family. Its core effects are soothing the liver and relieving depression, clearing heat and promoting diuresis, reducing swelling and promoting lactation.

[0021] The term "turmeric" used in this article refers to the dried tuberous root of Curcuma kwangsiensis SG Lee et CF Liang from Guangxi. Its core effects are promoting blood circulation and relieving pain, regulating qi and relieving depression, clearing the heart and cooling the blood, and promoting bile secretion and reducing jaundice.

[0022] The term "red peony" used in this article refers to the dried root of Paeonia lactiflora Pall., a plant in the Ranunculaceae family. Its core functions are clearing heat and cooling blood, dispersing blood stasis and relieving pain.

[0023] The term "borneol" as used herein refers to both natural borneol (a resinous product of the plant Dryobalanopsaromatica Gaertn. f., belonging to the Dipterocarpaceae family, or crystals extracted from the leaves of the plant Blumea balsamifera (L.) DC., belonging to the Asteraceae family) and synthetic borneol (chemically synthesized from camphor, turpentine, etc.). Its core functions are to open the orifices, refresh the mind, clear heat, and relieve pain. The borneol in this invention also includes borneol inclusion complexes.

[0024] The term "sour jujube seed" used in this article refers to the dried, mature seed of Ziziphus jujuba Mill. var. spinosa (Bunge) Hu ex HF Chow, a plant of the Rhamnaceae family. Its core functions are nourishing the heart and liver, calming the mind and soothing the nerves, reducing sweating, and promoting the production of body fluids.

[0025] The term "decoction" used in this article refers to the process of heating and boiling Chinese medicinal materials with water (or other suitable solvents) in a suitable container to fully dissolve the effective components in the medicinal materials into the solvent. This is the core technological step in the preparation of Chinese herbal decoctions.

[0026] The term "solid-liquid separation" used in this article refers to the conventional operation of separating the solid components (medicinal material residues, precipitates, impurities, etc.) from the liquid components (extracts, medicinal liquids, etc.) in a traditional Chinese medicine extraction system (such as extracts, suspensions, decoctions, etc.), through methods including filtration, centrifugation, sedimentation, pressure filtration, and ultrafiltration.

[0027] The term "concentration" as used in this article refers to pharmaceutical operations that remove some of the solvent (mainly water) from the extract of traditional Chinese medicine or the liquid medicine, thereby increasing the concentration and reducing the volume of the liquid medicine, through methods including atmospheric pressure concentration, vacuum concentration, thin film concentration, and multi-effect concentration.

[0028] The term "drying" as used in this article refers to the pharmaceutical / processing operation of removing moisture (or other volatile solvents) from Chinese medicinal materials, extracts of Chinese medicinal materials, or preparations to achieve a moisture content that meets the specified standards, through methods including atmospheric pressure drying, vacuum drying, spray drying, boiling drying, microwave drying, freeze drying, etc.

[0029] In a first aspect, the present invention provides a traditional Chinese medicine composition for treating stable angina pectoris complicated with depression in coronary heart disease, comprising Astragalus membranaceus, earthworm, Panax notoginseng, Salvia miltiorrhiza, Hypericum perforatum, Curcuma longa, Paeonia lactiflora, Ziziphus jujuba var. spinosa, and borneol.

[0030] The formula of the traditional Chinese medicine composition described in this invention is as follows: Astragalus membranaceus is the principal herb, which invigorates qi and nourishes blood, and promotes circulation and relieves pain. land Dragon's Breath Wind stops spasms, unblocks meridians, and relieves pain; Panax notoginseng invigorates blood, removes blood stasis, reduces swelling, and relieves pain; Salvia miltiorrhiza invigorates blood, removes blood stasis, calms the mind, and soothes the nerves—these are the assistant herbs; Hypericum perforatum soothes the liver, relieves depression, dispels wind, unblocks meridians, and relieves pain; Curcuma longa invigorates blood, promotes qi circulation, relieves depression, and relieves pain; Paeonia lactiflora clears the liver, drains fire, removes blood stasis, and relieves pain—these are the adjuvant herbs; Borneol clears heat, drains fire, opens orifices, and relieves pain; Ziziphus jujuba var. spinosa relieves irritability and calms the mind—these are the guiding herbs.

[0031] The dosage of Astragalus membranaceus, by weight, is selected from 100-240 parts. Preferably, the dosage of Astragalus membranaceus is 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts, 135 parts, 140 parts, 145 parts, 150 parts, 155 parts, 160 parts, 165 parts, 170 parts, 175 parts, 180 parts, 185 parts, 190 parts, 195 parts, 200 parts, 205 parts, 210 parts, 215 parts, 220 parts, 225 parts, 230 parts, 235 parts, or 240 parts, or any two of the above values.

[0032] The amount of earthworm used, by weight, is selected from 30-150 parts. Preferably, the amount of earthworm used is 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts, 135 parts, 140 parts, 145 parts, 150 parts, or any range between any two of the above values.

[0033] The dosage of Panax notoginseng, by weight, is selected from 10-50 parts. Preferably, the dosage of Panax notoginseng is 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, or 50 parts, or any two of the above values.

[0034] The dosage of Danshen, by weight, is selected from 90-200 parts. Preferably, the dosage of Danshen is 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts, 135 parts, 140 parts, 145 parts, 150 parts, 155 parts, 160 parts, 165 parts, 170 parts, 175 parts, 180 parts, 185 parts, 190 parts, 195 parts, 200 parts, or any range between any two of the above values.

[0035] The amount of St. John's wort used, by weight, is selected from 10-50 parts. Preferably, the amount of St. John's wort used is 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, or 50 parts, or any two of the above values.

[0036] The amount of turmeric, by weight, is selected from 90-200 parts. Preferably, the amount of turmeric is 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts, 135 parts, 140 parts, 145 parts, 150 parts, 155 parts, 160 parts, 165 parts, 170 parts, 175 parts, 180 parts, 185 parts, 190 parts, 195 parts, 200 parts, or any range between any two of the above values.

[0037] The dosage of Paeonia lactiflora, by weight, is selected from 30-150 parts. Preferably, the dosage of Paeonia lactiflora is 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, 90 parts, 95 parts, 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts, 135 parts, 140 parts, 145 parts, or 150 parts, or any two of the above values.

[0038] The amount of jujube seed used, by weight, is selected from 100-240 parts. Preferably, the amount of jujube seed used is 100 parts, 105 parts, 110 parts, 115 parts, 120 parts, 125 parts, 130 parts, 135 parts, 140 parts, 145 parts, 150 parts, 155 parts, 160 parts, 165 parts, 170 parts, 175 parts, 180 parts, 185 parts, 190 parts, 195 parts, 200 parts, 205 parts, 210 parts, 215 parts, 220 parts, 225 parts, 230 parts, 235 parts, or 240 parts, or any two of the above values.

[0039] In some embodiments, the weight ratio of earthworm, Panax notoginseng, St. John's wort, turmeric, and red peony is 3-15:1-5:1-5:9-20:3-15; preferably 5-8:2-4:2-4:8-12:4-8; more preferably 5-7:2-4:2-4:9-11:5-7; and even more preferably 5-6:2-3:2-3:9-10:5-6.

[0040] In some embodiments, the weight ratio of earthworm, Panax notoginseng and Salvia miltiorrhiza is 3-15:1-5:9-20; preferably 5-8:2-4:8-12; and more preferably 6:3:10.

[0041] In some embodiments, the traditional Chinese medicine composition comprises, by weight, the following raw materials: 100-240 parts of Astragalus membranaceus, 30-150 parts of Pheretima aspergillum, 10-50 parts of Panax notoginseng, 90-200 parts of Salvia miltiorrhiza, 10-50 parts of St. John's wort, 90-200 parts of Curcuma longa, 30-150 parts of Paeonia lactiflora, 100-240 parts of Ziziphus jujuba var. spinosa, and 1-3 parts of Borneol.

[0042] In some embodiments, the traditional Chinese medicine composition comprises, by weight, the following raw materials: 100-150 parts of Astragalus membranaceus, 40-80 parts of Pheretima aspergillum, 20-40 parts of Panax notoginseng, 80-120 parts of Salvia miltiorrhiza, 20-40 parts of St. John's wort, 80-120 parts of Curcuma longa, 40-80 parts of Paeonia lactiflora, 100-150 parts of Ziziphus jujuba var. spinosa, and 1-2 parts of Borneol.

[0043] In some embodiments, the traditional Chinese medicine composition comprises, by weight, the following raw materials: 120 parts Astragalus membranaceus, 60 parts Earthworm, 30 parts Panax notoginseng, 100 parts Salvia miltiorrhiza, 30 parts Hypericum perforatum, 100 parts Curcuma longa, 60 parts Paeonia lactiflora, 120 parts Ziziphus jujuba var. spinosa, and 1.5 parts Borneol.

[0044] Secondly, the present invention provides a method for preparing the above-mentioned traditional Chinese medicine composition, comprising the following steps: (1) Add water to Astragalus membranaceus, earthworm, Panax notoginseng, Salvia miltiorrhiza, Hypericum perforatum, Curcuma longa, Paeonia lactiflora and Ziziphus jujuba seeds, separate the solid and liquid, combine the filtrates, concentrate and dry the filtrates, and pulverize them to obtain fine powder; (2) Simply mix the borneol with the fine powder.

[0045] The conditions for decocting in step (1) are: decocting at least once, adding 8-12 times the amount of water each time, and decocting for 0.5-2 hours each time; preferably, the conditions for decocting are: decocting 2-3 times, adding 10-12 times the amount of water each time, and decocting for 1-1.5 hours each time.

[0046] In step (1), the Panax notoginseng and Ziziphus jujuba seeds are pretreated before decoction, and the pretreatment includes at least one of crushing, breaking and pulverizing.

[0047] Thirdly, the present invention provides the application of the above-mentioned traditional Chinese medicine composition or the traditional Chinese medicine composition prepared by the above-mentioned preparation method in the preparation of a drug for treating stable angina pectoris complicated with depression in coronary heart disease.

[0048] The dosage form of the drug is tablets, capsules, granules, powders, pills, decoctions, gels, or ointments.

[0049] Fourthly, the present invention provides a medicament for treating stable angina pectoris complicated with depression in patients with coronary heart disease, which is made from the above-mentioned traditional Chinese medicine composition or the traditional Chinese medicine composition prepared by the above-mentioned preparation method and pharmaceutically acceptable excipients.

[0050] The pharmaceutically acceptable excipients include glidants and fillers.

[0051] The flow aid includes at least one of silica, talc, and titanium dioxide.

[0052] The filler includes at least one of maltodextrin, cyclodextrin, starch, and lactose.

[0053] The beneficial effects of this invention are as follows: 1. This invention targets patients with stable angina pectoris complicated by depression, which is the most common clinical syndrome of qi deficiency and blood stasis, and obstruction of collaterals and liver stagnation. The treatment principle is to invigorate qi and blood, unblock collaterals and relieve depression. The prescription is formulated strictly according to the principles of monarch, minister, assistant and guide, and the dosage is carefully considered. This can enhance the anti-anginal effect, improve depressive symptoms and improve the quality of life.

[0054] 2. Experimental verification shows that the traditional Chinese medicine composition prepared in this invention not only has a better cardioprotective effect, but also improves neurotransmitter imbalances in the hippocampus and cortex, achieving comprehensive regulation of central depression-related neural pathways and exhibiting a better antidepressant effect. Compared with the original Qilong Tongluo Jieyu formula, the traditional Chinese medicine composition prepared in this invention has a better therapeutic effect on stable angina pectoris complicated by depression in patients with coronary heart disease.

[0055] 3. All ingredients are natural and readily available. The dosage complies with the national pharmacopoeia regulations. Long-term use is highly safe and will not burden the liver and kidneys. Detailed Implementation

[0056] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0057] The present invention will be further described below with reference to specific embodiments. All instruments, devices, equipment, reagents, and products used in the embodiments of the present invention, unless otherwise specified, are obtained through conventional commercial channels. In the present invention, "multiple amounts" refers to the total weight of the extracted raw materials. For example, "adding 10 times the amount of water each time" means that the amount of water added is 10 times the total weight of 60 parts of Astragalus membranaceus, earthworm, Panax notoginseng, Salvia miltiorrhiza, Hypericum perforatum, Curcuma longa, Paeonia lactiflora, and Ziziphus jujuba var. spinosa.

[0058] Example 1 The traditional Chinese medicine composition comprises the following raw materials in parts by weight: Astragalus membranaceus 120 parts, earthworm 60 parts, Panax notoginseng 30 parts, Salvia miltiorrhiza 100 parts, St. John's wort 30 parts, Curcuma longa 100 parts, Paeonia lactiflora 60 parts, Ziziphus jujuba var. spinosa 120 parts and borneol 1.5 parts.

[0059] The preparation method of the traditional Chinese medicine composition is as follows: Panax notoginseng is crushed, and Ziziphus jujuba seeds are crushed. (1) Add water to Astragalus membranaceus, earthworm, Panax notoginseng, Salvia miltiorrhiza, Hypericum perforatum, Curcuma longa, Paeonia lactiflora and Ziziphus jujuba seeds and decoct 3 times, adding 10 times the amount of water each time, and decoct for 1.5 hours each time. Filter, combine the filtrates, concentrate the filtrate to a relative density of 1.10-1.15 (50℃), dry, pulverize, and obtain fine powder; (2) Mix the borneol and fine powder together and crush them, then pass them through an 80-mesh sieve.

[0060] Example 2 The traditional Chinese medicine composition comprises the following raw materials in parts by weight: Astragalus membranaceus 100 parts, earthworm 30 parts, Panax notoginseng 10 parts, Salvia miltiorrhiza 90 parts, St. John's wort 10 parts, Curcuma longa 90 parts, Paeonia lactiflora 30 parts, Ziziphus jujuba var. spinosa 100 parts and borneol 1 part.

[0061] The preparation method is the same as in Example 1.

[0062] Example 3 The traditional Chinese medicine composition comprises the following raw materials in parts by weight: Astragalus membranaceus 240 parts, earthworm 150 parts, Panax notoginseng 50 parts, Salvia miltiorrhiza 200 parts, St. John's wort 50 parts, Curcuma longa 200 parts, Paeonia lactiflora 150 parts, Ziziphus jujuba var. spinosa 240 parts and borneol 3 parts.

[0063] The preparation method is the same as in Example 1.

[0064] Comparative Example 1 The difference between this comparative example and Example 1 is that the weight ratio of earthworm, Panax notoginseng, St. John's wort, turmeric, and red peony is 6:3:10:3:6.

[0065] Specifically, the raw materials of the aforementioned traditional Chinese medicine composition are as follows, by weight: Astragalus membranaceus 120 parts, earthworm 60 parts, Panax notoginseng 30 parts, Salvia miltiorrhiza 100 parts, St. John's wort 100 parts, Curcuma longa 30 parts, Paeonia lactiflora 60 parts, Ziziphus jujuba var. spinosa 120 parts and borneol 1.5 parts.

[0066] The preparation method is the same as in Example 1.

[0067] Comparative Example 2 The difference between this comparative example and Example 1 is that the weight ratio of earthworm, Panax notoginseng, Hypericum perforatum, Curcuma longa and Paeonia lactiflora is 3:6:1:17:1, and the weight ratio of earthworm, Panax notoginseng and Salvia miltiorrhiza is 3:6:10.

[0068] Specifically, the raw materials of the aforementioned traditional Chinese medicine composition, by weight, are as follows: Astragalus membranaceus 120 parts, earthworm 30 parts, Panax notoginseng 60 parts, Salvia miltiorrhiza 100 parts, St. John's wort 10 parts, Curcuma longa 170 parts, Paeonia lactiflora 10 parts, Ziziphus jujuba var. spinosa 120 parts and borneol 1.5 parts.

[0069] Comparative Example 3 The difference between this comparative example and Example 1 is that the weight ratio of earthworm, Panax notoginseng and Salvia miltiorrhiza is 6:3:5.

[0070] Specifically, the raw materials of the aforementioned traditional Chinese medicine composition are as follows, by weight: Astragalus membranaceus 120 parts, earthworm 60 parts, Panax notoginseng 30 parts, Salvia miltiorrhiza 50 parts, St. John's wort 30 parts, Curcuma longa 100 parts, Paeonia lactiflora 60 parts, Ziziphus jujuba var. spinosa 120 parts and borneol 1.5 parts.

[0071] The preparation method is the same as in Example 1.

[0072] Test Example 1 Effects of Traditional Chinese Medicine Composition on a Rat Model of Stable Angina Pectoris with Depression in Coronary Artery Disease 1. Establishment of the composite model SD rats, half male and half female, weighing 180-220g, were acclimatized for one week before being divided into groups for model establishment. The model establishment consisted of two steps: first, coronary heart disease modeling was performed, and the success of the model was evaluated by electrocardiogram. Animals with successful modeling were given anti-infection treatment for 3 days after surgery, followed by depression modeling for 21 days.

[0073] Step 1: Coronary Artery Disease Model A myocardial ischemia model was established using the left anterior descending coronary artery ligation method: After intraperitoneal anesthesia with sodium pentobarbital 40 mg / kg, endotracheal intubation was performed, and positive pressure ventilation was initiated. A thoracotomy was performed at the left 3rd-4th intercostal space, and the left left anterior descending coronary artery was ligated 2 mm below the edge of the left atrial appendage and pulmonary conus. The pleural cavity was compressed to expel air, and then closed layer by layer. The model was evaluated by electrocardiogram. In sham-operated animals, the suture was threaded at the same location without ligation. Postoperative anti-infection treatment was administered for 3 days.

[0074] Step 2: Depression Model A chronic unpredictable mild stimulation model (CUMS) was used, with stimuli including: (1) 24-hour fasting; (2) 24-hour water deprivation; (3) tilting the cage (45°); (4) huddling; (5) soaking the bedding; (6) cold air; (7) noise; (8) day-night reversal; (9) empty bottle restraint; (10) food restriction; (11) placing foreign objects in the cage; and (12) tail clamping (1 cm from the tail). One to three types of chronic stimuli were selected, and the same stimulus was not used for two consecutive days to prevent the model animals from predicting the stimulus that would occur that day, and to avoid the rats developing tolerance to a single stimulus or a regular stimulus, which would prevent stress from occurring. The rats were continuously stimulated for 21 days. After the model was established, behavioral tests (open field test and 1% sucrose craving test) were used to evaluate the depressive state of the rats.

[0075] 2. Experimental grouping and drug administration methods Rats with successfully induced coronary heart disease were randomly divided into sham-operated group, model group, paroxetine group, and traditional Chinese medicine compound group (S1-S3 and D1-D3), with 8 rats in each group, half male and half female. The paroxetine group was administered paroxetine by gavage at a dose of 3.3 mg / kg. The traditional Chinese medicine compound groups (S1-S3 and D1-D3) were administered the traditional Chinese medicine compound prepared in the corresponding Examples 1-3 or Comparative Examples 1-3 by gavage at a dose of 5.6 g crude drug / kg.

[0076] Starting on day 3 of the depression modeling process, the sham-operated group and the model group were given an equal volume of purified water, while the other groups were administered the corresponding drugs by gavage at the prescribed doses, once daily for four consecutive weeks. During the drug administration and testing period, except for the sham-operated group, the rats in the other groups were randomly assigned one to three chronic stimuli daily, with the same stimulus not being used for two consecutive days. The control group consisted of eight normal rats (half male and half female), who did not undergo coronary artery ligation and were not subjected to chronic, unpredictable, mild stress. During the drug administration period, they were given an equal volume of purified water by gavage.

[0077] 3. Detection indicators (1) Echocardiographic examination. After 4 weeks of drug administration, the rats were kept under anesthesia with isoflurane, and the skin from the left clavicle to the lower edge of the ribs was prepared. Two-dimensional scanning was performed on the long axis and short axis of the left ventricle. The left ventricular ejection fraction (EF), left ventricular short axis rate (FS), and cardiac output (CO) were calculated by M-mode ultrasound on the short axis of the left ventricle. Each indicator was measured continuously for 3 cycles and the average value was taken.

[0078] (2) Behavioral testing. Open field test: The experiment was conducted in a dark, quiet room. Rats were placed in a black open box and allowed to move freely. The movement of the rats was recorded within 5 minutes using a camera above the box.

[0079] 1% Sugar Water Preference Test: Before the sugar water preference test, each group of rats was given one bottle of plain water and one bottle of 1% sugar water to drink, allowing them to adapt to the situation of drinking both plain water and sugar water simultaneously. After 12 hours of adaptation, all rats were housed individually and fasted from food and water for 12 hours. Each rat was given one bottle of plain water and one bottle of sugar water, and the weight of both bottles was measured. After 12 hours of drinking either the plain water or sugar water, the bottles were removed, and their weight was measured again. The two bottle weights were recorded as the amount of plain water or sugar water consumed by the rats, and the sugar water intake rate was calculated. Calculation formula: Sugar water intake rate = Sugar water consumption / (Plain water consumption + Sugar water consumption).

[0080] (3) Detection of myocardial and brain indicators. One hour after the last administration, the animal was anesthetized by intraperitoneal injection of 2% pentobarbital. Blood was collected from the abdominal aorta, centrifuged (4℃, 3500 r / min) for 15 min, and the serum was collected and stored at -80℃ for testing. The heart was harvested, and the tissue was homogenized using a high-speed tissue homogenizer according to the instructions of the extraction and detection kit. The levels of CK (creatine kinase), CK-MB (creatine kinase isoenzyme), and LDH (lactate dehydrogenase) in the cardiac tissue homogenate were detected. The animal was decapitated, and the brain was quickly dissected on ice. The hippocampus and cerebral cortex were stored at -80℃. The 5-HT and DA indicators were detected using a triple quadrupole mass spectrometer.

[0081] 4. Results Analysis 4.1 Echocardiographic results The results are shown in Table 1.

[0082] Table 1 Comparison of ultrasound examination results in rats of different groups (mean ± standard deviation, n=8)

[0083] Compared with the model group, P<0.05; compared with the control group, P<0.05.

[0084] Compared with the control group, the ejection fraction (EF), fractional shortening (FS), and cardiac output (CO) of the model group rats were significantly reduced (P<0.05), indicating that the left ventricular systolic function of the rats was significantly impaired, the heart pumping function was significantly reduced, myocardial ischemia led to decreased cardiac function, and the stable angina pectoris model of coronary heart disease was successfully established.

[0085] Compared with the model group, the ejection fraction (EF), fractional shortening (FS), and cardiac output (CO) of rats in the traditional Chinese medicine composition group S1-S3 were significantly increased (P<0.05), indicating that the traditional Chinese medicine composition provided in this embodiment of the invention can improve the left ventricular systolic function and cardiac pumping capacity of rats, and has a protective effect on ischemic heart damage, and its effect is better than that of paroxetine.

[0086] Compared with the model group, there were no significant changes in ejection fraction (EF), fractional shortening (FS), and cardiac output (CO) in rats in the Chinese herbal composition groups D1 to D3 (P > 0.05), indicating that the Chinese herbal composition provided in the comparative example of this invention does not have the ability to improve left ventricular systolic function and cardiac pumping capacity in rats.

[0087] 4.2 Behavioral Indicator Testing 4.2.1 Results of the open field experiment The results are shown in Table 2.

[0088] Table 2 Comparison of open field test results among different groups of rats (mean ± standard deviation, n=8)

[0089] Compared with the model group, P<0.05; compared with the control group, P<0.05.

[0090] Compared with the control group, the total distance traveled in the open field, the total time spent in the open field, and the distance traveled in the center of the open field were significantly reduced in the model group rats (P<0.05), indicating that the spontaneous activity ability of the model group rats was significantly reduced, the exploratory behavior was reduced, and obvious depressive-like behavior was observed, suggesting that the coronary heart disease combined with depression composite model was successfully constructed.

[0091] Compared with the model group, the total open field distance, total open field activity time, and central open field distance of rats in the Chinese herbal medicine composition groups S1-S3 and paroxetine group were significantly increased (P<0.05); the total open field distance and central open field distance of rats in the Chinese herbal medicine composition group D3 were significantly increased (P<0.05); and the total open field distance of rats in the Chinese herbal medicine composition groups D1-D2 were significantly increased (P<0.05). This indicates that the above-mentioned drugs can effectively improve the depressive-like behavior of rats with coronary heart disease and depression and have antidepressant effects. Among them, the Chinese herbal medicine compositions prepared in Examples 1-3 have better effects.

[0092] 4.2.2 Results of the sugar water experiment The results are shown in Table 3.

[0093] Table 3 Comparison of sucrose intake rate among rats in each group (mean ± standard deviation, n=8)

[0094] Compared with the model group, P<0.05; compared with the control group, P<0.05.

[0095] Compared with the control group, the sugar intake rate of rats in the model group was significantly reduced (P<0.05). After drug intervention, the sugar intake rate of rats in all groups was significantly increased (P<0.05). This indicates that the above-mentioned drugs can improve the depressive behavior of rats in the model group.

[0096] 4.3 Results of myocardial related index tests The results are shown in Table 4.

[0097] Table 4. Levels of CK, CK-MB, and LDH in myocardial tissue of rats in each group (mean ± standard deviation, n=8)

[0098] Compared with the model group, P<0.05; compared with the control group, P<0.05.

[0099] Compared with the control group, the levels of CK, CK-MB, and LDH in the model group rats were significantly increased (P<0.05), indicating that the modeling caused damage to rat cardiomyocytes, disruption of cell membrane integrity, and significant myocardial ischemia.

[0100] Compared with the model group, the levels of CK, CK-MB, and LDH in the myocardium of rats in the traditional Chinese medicine composition groups S1 to S3 were significantly reduced (P<0.05); the levels of CK and LDH in the myocardium of rats in the paroxetine group were significantly reduced (P<0.05); the levels of CK-MB and LDH in the myocardium of rats in the traditional Chinese medicine composition group D3 were significantly reduced (P<0.05); and the levels of LDH in the myocardium of rats in the traditional Chinese medicine composition groups D1 to D2 were significantly reduced (P<0.05). This indicates that after drug intervention, the above-mentioned drugs can alleviate ischemic myocardial injury and exert a cardioprotective effect. Among them, the traditional Chinese medicine compositions provided in Examples 1-3 of this invention have a better cardioprotective effect.

[0101] 4.4 Results of brain tissue-related index tests The results are shown in Table 5.

[0102] Table 5 Comparison of 5-HT and DA levels in rat brain tissue among different groups (mean ± standard deviation, n=8)

[0103] Compared with the model group, P<0.05; compared with the control group, P<0.05.

[0104] Compared with the control group, the levels of 5-HT and DA in the hippocampus and cortex of rats in the model group were significantly reduced (P<0.05), indicating that the modeling caused disordered metabolism of neurotransmitters in the central nervous system of rats and resulted in neurobiological changes related to depression.

[0105] Compared with the model group, the levels of 5-HT and DA in the hippocampus of rats in all groups were significantly increased (P<0.05); the levels of 5-HT and DA in the cortex of rats in the herbal composition groups S1-S3 and the paroxetine group were significantly increased (P<0.05); the levels of 5-HT and DA in the cortex of rats in the herbal composition groups D1-D3 showed no significant change (P>0.05). This indicates that the herbal compositions prepared in Comparative Examples 1-3 can only regulate hippocampal neurotransmitter metabolism disorders and have no significant effect on cortical 5-HT and DA. In contrast, the herbal compositions provided in Examples 1-3 of this invention can improve neurotransmitter disorders in the hippocampus and cortex, achieving comprehensive regulation of central depression-related neural pathways and exhibiting superior antidepressant effects.

[0106] In summary, the traditional Chinese medicine composition prepared in the embodiments of the present invention has a better therapeutic effect on a rat model of coronary heart disease complicated with depression, and is significantly superior to the original Qilong Tongluo Jieyu formula.

[0107] Test Example 2 Toxicity studies Forty Kunming mice (half male and half female) were used and acclimatized for 7 days. After fasting for 12 hours, they were given free access to water. Each mouse was administered the herbal composition (Example 1) by gavage at a volume of 40 mL / kg body weight, twice a day, with an interval of 4-5 hours between gavages. The animals' condition was closely observed and recorded within 1 hour after each gavage, and the observation was repeated once a day for 14 days.

[0108] Observation indicators include clinical symptoms (such as animal appearance, behavior, diet, response to stimuli, secretions, excretions, etc.), mortality (time of death, pre-mortem reactions, etc.), weight changes (weighed once before administration and once at the end of the observation period, and can be weighed multiple times during the observation period; weighed when the animal dies or is near death), etc.

[0109] Preliminary experimental results show that the maximum dose administered to mice under these experimental conditions was 179 times the clinical human dose, and no obvious toxic reactions were observed during the experiment, indicating that the traditional Chinese medicine composition of the present invention has good safety within the experimental dose range.

[0110] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A traditional Chinese medicine composition for treating stable angina pectoris complicated with depressive state in patients with coronary heart disease, characterized in that, The ingredients, by weight, include the following: Astragalus membranaceus 100-240 parts, earthworm 30-150 parts, Panax notoginseng 10-50 parts, Salvia miltiorrhiza 90-200 parts, St. John's wort 10-50 parts, Curcuma longa 90-200 parts, Paeonia lactiflora 30-150 parts, Ziziphus jujuba var. spinosa 100-240 parts, and borneol 1-3 parts.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The weight ratio of earthworm, Panax notoginseng, St. John's wort, turmeric, and red peony is 5-8:2-4:2-4:8-12:4-8.

3. The traditional Chinese medicine composition according to claim 1, characterized in that, The weight ratio of earthworm, Panax notoginseng, St. John's wort, turmeric, and red peony root is 5-7:2-4:2-4:9-11:5-7.

4. The traditional Chinese medicine composition according to claim 1, characterized in that, The weight ratio of earthworm, Panax notoginseng and Salvia miltiorrhiza is 5-8:2-4:8-12.

5. The traditional Chinese medicine composition according to claim 1, characterized in that, The ingredients, by weight, include the following: 100-150 parts Astragalus membranaceus, 40-80 parts Earthworm, 20-40 parts Panax notoginseng, 80-120 parts Salvia miltiorrhiza, 20-40 parts St. John's wort, 80-120 parts Curcuma longa, 40-80 parts Paeonia lactiflora, 100-150 parts Ziziphus jujuba var. spinosa, and 1-2 parts Borneol.

6. The traditional Chinese medicine composition according to claim 1, characterized in that, The ingredients, by weight, include the following: 120 parts Astragalus membranaceus, 60 parts Earthworm, 30 parts Panax notoginseng, 100 parts Salvia miltiorrhiza, 30 parts St. John's wort, 100 parts Curcuma longa, 60 parts Paeonia lactiflora, 120 parts Ziziphus jujuba var. spinosa, and 1.5 parts Borneol.

7. A method for preparing the traditional Chinese medicine composition according to any one of claims 1-6, characterized in that, Includes the following steps: (1) Add water to Astragalus membranaceus, earthworm, Panax notoginseng, Salvia miltiorrhiza, Hypericum perforatum, Curcuma longa, Paeonia lactiflora and Ziziphus jujuba seeds, separate the solid and liquid, combine the filtrates, concentrate and dry the filtrates, and pulverize them to obtain fine powder; (2) Simply mix borneol or borneol inclusion complex with fine powder.

8. The preparation method according to claim 7, characterized in that, The conditions for decocting in step (1) are: decocting at least once, adding 8-12 times the amount of water each time, and decocting for 0.5-2 hours each time.

9. The use of the traditional Chinese medicine composition according to any one of claims 1-6 or the traditional Chinese medicine composition prepared by the preparation method according to any one of claims 7-8 in the preparation of a medicament for treating stable angina pectoris complicated with depression in coronary heart disease.

10. A drug for treating stable angina pectoris complicated by depression in patients with coronary heart disease, characterized in that, It is made from the traditional Chinese medicine composition according to any one of claims 1-6 or the preparation method according to any one of claims 7-8, and pharmaceutically acceptable excipients.

Images