Traditional Chinese medicine composition patch for adjuvant treatment of chronic heart failure and preparation method thereof

Abstract

The invention belongs to the field of traditional Chinese medicines, and particularly discloses a traditional Chinese medicine composition patch for adjuvant treatment of chronic heart failure and a preparation method thereof. The traditional Chinese medicine composition patch is prepared from radix aconiti lateralis preparata, radix phytolaccae, semen lepidii and rhizoma chuanxiong. The traditional Chinese medicine composition patch is prepared from the medicine and an adhesive in proportion, the bioavailability of the medicine is high, the components are clear, and the treatment effect is good. And by controlling the specific types and proportions of the effective components of the medicines, the mutual synergistic effect of the components is improved, and the effect of treating the chronic heart failure with reduced ejection fraction is improved. The components of the medicine are reasonably matched, and the clinical symptoms and life quality of chronic heart failure patients with reduced ejection fraction can be remarkably improved by acting on the Shenque acupoint.

Description

Technical Field

[0001] The present invention belongs to the field of traditional Chinese medicine, and particularly relates to a traditional Chinese medicine composition plaster for assisting in the treatment of chronic heart failure and a preparation method thereof. Background Art

[0002] As the terminal stage of cardiovascular diseases, the prevalence of heart failure has increased by 44% in the past 15 years. At present, the prevalence of heart failure in Chinese residents aged ≥35 years is 1.3%, and the number of heart failure patients is as high as 13.7 million, resulting in high mortality and rehospitalization rates. According to the left ventricular ejection fraction (LVEF), heart failure can be divided into heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF), and heart failure with mildly reduced ejection fraction (HFmrEF). The "2020 China Heart Failure Medical Quality Control Report" analyzed the data from the national cardiovascular disease center's heart failure specialized medical consortium database, showing that HFrEF, HFmrEF, and HFpEF accounted for 40%, 22%, and 38% respectively. Heart failure with reduced ejection fraction is still the most common type in the composition of heart failure in China. The conventional treatment for chronic heart failure is to initiate the "new quadruple" drug combination therapy at an early stage, combined with device intervention and personalized management, and appropriately add oral traditional Chinese medicine preparations. Although it helps to further improve the clinical symptoms of chronic heart failure patients, enhance exercise tolerance, and improve the quality of life, chronic heart failure patients often have multiple underlying diseases and often need to take combined medications, which increases the incidence of adverse drug reactions. At the same time, water and sodium retention in heart failure patients leads to gastrointestinal congestion, affecting the absorption effect of oral medications; there are many combined medications and complex drug interactions. For example, the combination of MRA and diuretics is likely to cause electrolyte disorders or renal function deterioration, and β-blockers may exacerbate bradycardia or hypotension, and some patients cannot tolerate it due to complications.

[0003] External treatment methods of traditional Chinese medicine have a history of thousands of years and are an effective treatment method with the characteristics of "simple, convenient, effective, and inexpensive". External treatment methods of traditional Chinese medicine can not only avoid the potential increased incidence of adverse reactions caused by taking multiple oral medications, but also reduce the impact on the absorption effect of oral medications due to gastrointestinal congestion. However, there is currently a lack of traditional Chinese medicine external preparations for the treatment of chronic heart failure in China. Chinese medicine acupoint application is one of the typical external treatment methods of traditional Chinese medicine, with advantages such as significant clinical efficacy, wide application range, high acceptance, and small side effects. It is pointed out in "Qianjin Yaofang" that "changing decoctions to external treatments actually opens up infinite ways for future generations". Acupoint application is based on theories such as the zang-fu organs and meridians of traditional Chinese medicine. Under the guidance of syndrome differentiation and treatment of traditional Chinese medicine, effective prescriptions are directly applied to body surface acupoints, and the active ingredients are absorbed through the skin and reach the meridians, zang-fu organs through the acupoints to regulate the balance of yin and yang in the human body.

[0004] Patent CN106729591A proposes to prepare acupuncture patch with 4-6g ginseng, 8-12g stir-fried mustard, 4-6g raw mustard, 8-12g Corydalis, 8-12g Ginseng, 2.5-3.5%, 4-6g cinnamon, 2.5-3.5% Panax notoginseng and ginger juice. It has many medicinal flavors and a large dosage. The acupuncture points used include bilateral Neiguan, Zusanli, Xinshu, Feishu and Tanzhong points. The use time is the coldest days of winter and the hottest days of summer, which limits its users to professional doctors or people with certain knowledge of traditional Chinese medicine. It is not suitable as a long-term auxiliary treatment for chronic heart failure and is difficult to promote widely. The efficacy evaluation is relatively single and does not highlight the advantages of traditional Chinese medicine treatment. Summary of the invention

[0005] The present invention inherits the idea of "those with phlegm and fluid should be treated with warm medicine", and innovatively adopts "processed aconite, smilax china, chuanxiong, and scutellaria baicalensis" to make acupoint plasters, which play the effects of warming yang, removing blood stasis and promoting diuresis, and are applied to the Shenque acupoint to stimulate the qi of the meridians, coordinate the functions of various internal organs, dredge the meridians, and promote the circulation of qi and blood. The prescription and medication are precise, the dosage is concise, the acupoints are simple and easy to understand, and are not restricted by operators, places, and time. The plaster of the present invention can be used as an adjuvant treatment for conventional clinical western medicine medications, further improve the cardiac function of patients with heart failure, and improve the quality of life of patients.

[0006] The invention provides acupuncture point application of traditional Chinese medicine, the medicine composition of which is prepared aconite root, phytolacca, scutellaria baicalensis seed and ligusticum chuanxiong.

[0007] The present invention provides a prescription explanation of the Chinese medicine acupoint application: Academician Chen Keji believes that "those with phlegm and fluid should be treated with warm medicine" is the general principle for the prevention and treatment of heart failure by later doctors. Aconite is the first choice of medicine for warming yang and replenishing qi. "Its nature is good at moving. It reaches the skin and fur to eliminate the surface cold, and reaches the lower abdomen to warm the chronic cold." It can not only enhance the myocardial contractility, but also reduce the myocardial oxygen consumption, improve the myocardial ischemia and hypoxia state, and achieve the purpose of "benefiting the source of fire to eliminate the Yin", which is the main medicine. "The Yellow Emperor's Classic of Internal Medicine" says: "Those who stay should be attacked." Attacking and expelling water and fluid is an effective method to eliminate fluid retention. Rhizoma Phytophthora, "tastes spicy and flat. It is mainly used to treat water swelling, hernia, lumps and numbness, ironing and removing carbuncle swelling, and killing ghosts and spirits." Its effective ingredients, rhizoma sapogenins and potassium salts, have diuretic effects and are widely used in the clinical diagnosis and treatment of edema, which is the ministerial medicine. "If the blood is not smooth, it will become water." Jin and blood have the same origin. Activating blood circulation can promote water circulation. Chuanxiong is pungent, warm, fragrant and dry. It moves but does not stay. It can both disperse and enter the blood. It can reach the top of the head and the sea of blood. It is a blood Qi medicine, which has the functions of pungent dispersion, unblocking, activating blood circulation, promoting qi circulation and relieving pain. Tinglizi "tastes pungent and cold. It is mainly used for accumulation of lumps, cold and hot diet, breaking up hardness and expelling evil, and promoting water circulation." It is mainly used to treat water congestion in the lungs, chest fullness, wheezing and coughing. Its active ingredient quercetin has multiple effects such as diuresis, positive inotropic effect, inhibition of ventricular remodeling and protection of myocardial cells. Chuanxiong and Tinglizi promote blood circulation and promote water circulation, and help Fuzi and Shanglu promote the dissipation of blood stasis and water pathological products. Together, they are adjuvant drugs. All the drugs are used together to warm the yang, activate blood circulation and promote water circulation.

[0008] Support of traditional Chinese medicine theory: Heart failure belongs to the categories of "edema", "dyspnea", "chest pain", "palpitation", "phlegm retention" in traditional Chinese medicine. It is mostly caused by the long-term progression of heart diseases or the invasion of the heart by chronic diseases, resulting in the deficiency of qi, blood, yin and yang of the heart. Over time, it affects the kidney yang. Kidney yang is the root of yang qi in the body. When kidney yang is deficient, it is unable to warm and transform phlegm-dampness, leading to the retention of water-dampness in the body, overflowing to the skin and causing limb edema; the heart yang loses the warming of kidney yang and is unable to promote blood circulation, resulting in chest tightness and dyspnea; when the kidney fails to receive qi, it causes shortness of breath and inability to lie flat. Therefore, this disease belongs to the syndrome of deficiency in origin and excess in superficiality, and the pathogenesis can be summarized as "deficiency", "stasis" and "water". Warming yang, promoting blood circulation and promoting diuresis are the basic treatment principles for heart failure.

[0009] Among them, prepared aconite root: pokeberry root: semen lepidii: chuanxiong in proportion and with adhesives into a traditional Chinese medicine acupoint patch. The drug has high bioavailability, clear components and good treatment effects. By controlling the specific types and ratios of the effective components of the drug, the synergistic effect between components is improved, and the effect of treating chronic heart failure with reduced ejection fraction (EF<50%) is enhanced. The components are rationally matched. By acting on the specific Shenque acupoint (navel), it significantly improves the clinical symptoms and quality of life of chronic heart failure patients with reduced ejection fraction (EF<50%). Specifically, it includes the following aspects: 1. Based on high-level clinical verification of evidence-based medicine, clarify the improvement of cardiac function and biomarkers Technical advantages: Through the design of double-blind, randomized, placebo-controlled study (RCT), for the first time, it is confirmed by the internationally recognized strict evidence-based method that the core efficacy of this patch for heart failure with reduced ejection fraction (EF<50%) is superior to the current situation of lack of high-quality evidence in conventional traditional Chinese medicine external treatment methods. (1) Standardized research design: Adopt the RCT method (randomized, double-blind, placebo-controlled) to eliminate subjective bias and ensure the objectivity of efficacy data. (2) Multi-index joint verification: Synchronously monitor objective indexes such as LVEF (left ventricular ejection fraction), NT-ProBNP (heart failure biomarker), etc., and combine 24-hour urine volume (reflecting diuretic effect) and NYHA classification (cardiac function status) to form a multi-dimensional efficacy evaluation system. (3) Pharmacological mechanism support: The yang-warming components (such as aconitine glycoside) in the patch directly enhance myocardial contractility, the blood-activating components (tetramethylpyrazine) improve myocardial microcirculation, and the diuretic components (pokeberry root saponin) regulate body fluid metabolism, synergistically improving cardiac function at the molecular level.

[0010] 2. Comprehensive evaluation of efficacy in multiple dimensions, breaking through the limitations of traditional single index Comprehensive quantification of symptom improvement through a composite evaluation system (Lee's heart failure score, NYHA classification, biomarkers, urine output) is superior to the single assessment mode of conventional treatment that only relies on LVEF or symptom scores. (1) Dynamic symptom monitoring technology: Lee's heart failure score integrates 6 subjective symptoms and objective signs such as dyspnea and edema, accurately reflecting changes before and after treatment. (2) Biomarker quantification technology: Use NT-ProBNP detection technology (fluorescence immunochromatography) to quantitatively evaluate the degree of myocardial stress. (3) Standardized acquisition of echocardiogram: Adopt a unified ultrasound section and measurement protocol (such as calculating LVEF by the SimPson method) to reduce operator-dependent errors.

[0011] 3. Significantly improve the quality of life of patients and fill the blind spots of western medicine treatment It is confirmed by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) that the patch can significantly improve the daily activity ability and mental state of patients, while conventional western medicine treatments (such as diuretics and beta blockers) have limited improvement in the quality of life. Regional studies suggest that the quality of life of about 50% of patients is significantly impaired. (1) Transdermal drug delivery technology at acupoints: The patch acts on the Shenque acupoint, which has a special vascular biological acupoint structure. It regulates the running of meridian qi and blood through percutaneous absorption of drugs and local stimulation of acupoints. (2) Synergistic effect of multiple components: The diuretic components quickly reduce edema (improve physical discomfort), and the yang-warming components enhance energy metabolism (relieve fatigue), forming a synchronous improvement effect of "symptom-psychology".

[0012] 4. Non-invasive drug delivery and safety advantages, solving the problem of cumulative toxicity of western medicine Avoid the liver and kidney toxicity of oral drugs (such as the risk of digoxin poisoning) and electrolyte disorders (such as hypokalemia caused by loop diuretics) through transdermal absorption, especially suitable for elderly patients with combined liver and kidney insufficiency. (1) Transdermal controlled release technology: Select the Shenque acupoint with thin skin and rich local blood vessels at acupoints to enhance the percutaneous absorption efficiency of drugs, reduce the systemic exposure dose, and lower the toxicity risk. (2) Optimization technology of traditional Chinese medicine formula: Simplify and select representative traditional Chinese medicines for warming yang, promoting blood circulation, and promoting diuresis, and synergistically play the therapeutic effect. (3) Design of local metabolic pathway: Drugs directly enter the systemic circulation through the capillaries of acupoints, avoiding the first-pass effect and reducing the metabolic burden.

[0013] 5. Synergistic effect with western medicine to break through the efficacy bottleneck of traditional treatment Clinical data show that when the patch is used in combination with "new quadruple" drugs (such as ARNI, SGLT2i), the total effective rate can be further improved. The yang-warming components of the patch enhance myocardial contractility, the diuretic components assist in sodium excretion (complementary to ARNI and diuretics), and the blood-activating components improve coronary blood flow (alleviating the microcirculation disorder caused by beta blockers). For example, the present invention can be used in combination with the following western medicine treatments: renin-angiotensin-aldosterone system inhibitors (angiotensin receptor neprilysin inhibitor such as sacubitril / valsartan starting at 50 mg bid - 200 mg bid; angiotensin-converting enzyme inhibitor drugs such as captopril 6.25 mg tid - 50 mg tid; angiotensin II receptor antagonist drugs such as candesartan starting at 4 mg / d - 32 mg / d), beta blockers (such as metoprolol succinate sustained-release tablets starting at 23.75 mg / d - 190 mg / d), aldosterone receptor antagonists (such as spironolactone 20 mg / d - 40 mg / d), and sodium-glucose cotransporter 2 inhibitors (such as dapagliflozin at a fixed dose of 10 mg qd. Soluble guanylate cyclase stimulator such as vericiguat: 2.5 - 10 mg qd (three times a day: tid; twice a day: bid; once a day: qd).

[0014] Based on the research of the present inventors, the present invention is thus proposed. The specific invention includes the following technical solutions.

[0015] First, a traditional Chinese medicine composition patch for adjuvant treatment of chronic heart failure is provided, which is made of processed aconite root, pokeweed, lepidium seed, and chuanxiong rhizome.

[0016] Specifically, the proportion of each drug is processed aconite root:pokeweed:lepidium seed:chuanxiong rhizome = 1.8 - 2.2:1:1.8 - 2.2:2.8 - 3.2.

[0017] Preferably, the proportion of each drug is processed aconite root:pokeweed:lepidium seed:chuanxiong rhizome = 1.9 - 2.1:1:1.9 - 2.1:2.9 - 3.1.

[0018] More preferably, the proportion of each drug is processed aconite root:pokeweed:lepidium seed:chuanxiong rhizome = 2:1:2:3.

[0019] The present invention also provides a preparation method of the traditional Chinese medicine composition patch. Weigh each drug according to the proportion, dry it at 70 - 80 °C, crush it into fine drug powder, mix it evenly, add a binder, and make an ointment after fully mixing.

[0020] Specifically, the fine drug powder passes through an 80-mesh sieve; the binder is refined honey and corn oil.

[0021] Preferably, the fine powder of the drug, the refined honey and the corn oil are mixed in a mass ratio of 12-20:1-5:1, preferably 14-18:2-4:1, and more preferably 16:3:1; wherein, the honey is heated to 110-120 °C and refined until it becomes stringy like beads, and then cooled to 50-70 °C for use.

[0022] Furthermore, a paste is obtained by homogenization with a colloid mill. Specifically, the rotation speed is 2000-4000 rpm and the time is 10-30 min, preferably 2500-3500 rpm and the time is 15-25 min, and more preferably the rotation speed is 3000 rpm and the time is 20 min.

[0023] It further includes the steps of dispensing and packaging. Specifically, the patch of the traditional Chinese medicine composition patch is made of non-woven fabric. An anti-seepage film is pasted in the center of the patch. The ointment is pressed into a medicine core, dispensed onto the anti-seepage film, covered with a release paper, and the prepared acupoint patch is stored in a sealed manner away from light.

[0024] More specifically, the patch is cut into a rounded rectangle with a length and width of about 5 cm × 5 cm. One side of the cut patch is covered with an easy-to-tear strip with a width of about 0.5 cm. An anti-seepage film of 2.5 cm × 2.5 cm is pasted in the center of the patch. The ointment is pressed into a medicine core with a diameter of 2.5 cm, that is, 1 g per patch. It is dispensed onto the anti-seepage film in the acupoint patch and covered with a release paper. The prepared acupoint patch is stored in a sealed manner away from light.

[0025] Therefore, the present invention also provides the acupoint patch (also known as the heart failure patch) prepared by the above method. When in use, calculated according to the mass of 1 g per patch, each patch contains 0.1-0.3 g of prepared aconite root, accounting for 10-30%, 0.05-0.15 g of phytolacca acinosa, accounting for 5-15%, 0.1-0.3 g of semen lepidii, accounting for 10-30%, and 0.2-0.4 g of chuanxiong rhizome, accounting for 20-40%; preferably, calculated according to the mass of 1 g per patch, each patch contains 0.2 g of prepared aconite root, accounting for 20%, 0.1 g of phytolacca acinosa, accounting for 10%, 0.2 g of semen lepidii, accounting for 20%, 0.3 g of chuanxiong rhizome, accounting for 30%, and the rest is adhesive.

[0026] The present invention also provides a drug combination or medicine box for treating chronic heart failure, which includes the above-mentioned traditional Chinese medicine composition patch or acupoint patch for adjuvant treatment of chronic heart failure of the present invention, and a drug for treating chronic heart failure. The drug for treating chronic heart failure is selected from renin-angiotensin-aldosterone system inhibitors (angiotensin receptor neprilysin inhibitors such as sacubitril / valsartan, angiotensin-converting enzyme inhibitor drugs such as captopril, angiotensin II receptor antagonist drugs such as candesartan, etc.), β-blockers (such as sustained-release tablets of metoprolol succinate), aldosterone receptor antagonists (such as spironolactone) and sodium-glucose cotransporter 2 inhibitors (such as dapagliflozin), soluble guanylate cyclase agonists (vericiguat). Brief Description of the Drawings

[0027] Figure 1 . Flow chart of the randomized controlled trial. Among them, the safety indicators include blood and urine routine, liver and kidney, and ions; the efficacy evaluation indicators include Lee's heart failure score, NYHA heart function classification, NT-proBNP, LVEF, 24-hour urine volume, traditional Chinese medicine syndrome scale, and Minnesota heart failure quality of life questionnaire; the main efficacy evaluation indicator is Lee's heart failure score.

[0028] Figure 2 . Flow chart for the preparation of the traditional Chinese medicine composition patch.

[0029] Figure 3 . Model diagram of the traditional Chinese medicine composition patch. Detailed Description of the Invention

[0030] The present invention will be described below through specific embodiments in order to better understand the present invention, but it does not constitute a limitation to the present invention.

[0031] Example 1. Overall processing and preparation process: 1. Raw materials and preparation process Composition and ratio of the medicine (mass ratio): processed aconite root: pokeweed: semen lepidii: chuanxiong rhizome = 2:1:2:3.

[0032] Total feeding amount: 0.2 g of aconite root, 0.1 g of pokeweed, 0.2 g of semen lepidii, and 0.3 g of chuanxiong rhizome.

[0033] 2. Process steps: Processing: All are processed and produced in the pharmaceutical factory of Xiyuan Hospital, China Academy of Chinese Medical Sciences.

[0034] Processing and drying: Processed aconite root: The aconite root is soaked in clear water for 48 hours (changing water 6 times), then steamed for 4 hours until there is no numbness in the tongue, sliced, and dried at 70°C until the moisture content ≤ 8%; Pokeweed: Stir-fried with vinegar (soaked in rice vinegar for 2 hours, stir-fried over low heat until dry), dried at 80°C until the moisture content ≤ 10%; Semen lepidii and chuanxiong rhizome: Hot air dried at 80°C for 6 hours, moisture content ≤ 9%.

[0035] Crushing and sieving: The four herbs are dried and crushed and then sieved through an 80-mesh sieve (particle size ≤ 180 μm), and mixed evenly.

[0036] Preparation of refined honey: Heat the honey to 116°C (medium heat) until it becomes stringy like beads, and cool it to 60°C; Mixing: Mix the medicinal powder with refined honey and corn oil in a ratio of 16:3:1 (medicinal powder: refined honey: corn oil), homogenize with a colloid mill (rotation speed 3000 rpm, time 20 min) to make a paste with appropriate viscosity (for the flow chart of the preparation of the traditional Chinese medicine composition patch, see Figure 2 )

[0037] Sub-packaging and Packaging: The acupoint patch is made of non-woven fabric and cut into a rounded rectangle with a length and width of about 5 cm × 5 cm. One side of the cut patch is covered with an easy-to-tear strip about 0.5 cm wide, and a 2.5 cm × 2.5 cm anti-seepage membrane is pasted in the center of the patch. The medicinal paste is pressed into a medicine core with a diameter of 2.5 cm (1 g / patch), sub-packed onto the anti-seepage membrane in the acupoint patch, covered with release paper, and the prepared acupoint patch is stored sealed and away from light (for the model diagram of the acupoint patch, see Figure 3 )

[0038] Comparative Example 1 (the effective drug composition is 5% of that in Example 1, and it is the placebo control group in the subsequent clinical randomized controlled trial) Drug Composition and Ratio (mass ratio): Prepared Aconite Root (after processing): Phytolacca acinosa Roxb.: Lepidium apetalum Willd.: Ligusticum chuanxiong Hort. = 2:1:2:3

[0039] Total feeding amount: Aconite Root 0.01 g, Phytolacca acinosa Roxb. 0.005 g, Lepidium apetalum Willd. 0.01 g, Ginseng 0.015 g

[0040] The preparation method is as in Example 1

[0041] Comparative Example 2 Drug Composition and Ratio (mass ratio): Prepared Aconite Root (after processing): Phytolacca acinosa Roxb.: Lepidium apetalum Willd.: Ginseng = 2:1:2:3

[0042] Total feeding amount: Aconite Root 0.2 g, Phytolacca acinosa Roxb. 0.1 g, Lepidium apetalum Willd. 0.2 g, Ginseng 0.3 g

[0043] The preparation method is as in Example 1

[0044] Comparative Example 3 Drug Composition and Ratio (mass ratio): Prepared Aconite Root (after processing): Poria cocos (Schw.) Wolf: Lepidium apetalum Willd.: Ligusticum chuanxiong Hort. = 2:1:2:3

[0045] Total feeding amount: Aconite Root 0.2 g, Poria cocos (Schw.) Wolf 0.1 g, Lepidium apetalum Willd. 0.2 g, Ligusticum chuanxiong Hort. 0.3 g

[0046] The preparation method is as in Example 1

[0047] Example 2. Performance Test Data: 1. Overall Design Adopt a multi-center, randomized, double-blind, placebo-controlled clinical research design method

[0048] 2. Research Subjects The research subjects were 108 patients with heart failure with reduced ejection fraction (EF < 50%) who were outpatients and inpatients in the cardiology departments of three medical institutions, including Xiyuan Hospital of China Academy of Chinese Medical Sciences, Changping District Traditional Chinese Medicine Hospital, and Affiliated Hospital of Shanxi University of Traditional Chinese Medicine. Currently, the mid-term blinding procedure is being carried out, and 68 cases with the blinding completed are analyzed. There are no significant differences in the baseline data between the two groups ( P> 0.05 ). Subsequently, the remaining stages of the clinical trial were strictly continued in accordance with the original research protocol, including the whole process of data collection, endpoint evaluation, and statistical analysis.

[0049] Table 1. Comparison of baseline data between the two groups

[0050] 3. Diagnostic criteria The western medicine diagnostic criteria refer to "Chinese Guidelines for the Diagnosis and Treatment of Heart Failure 2018". The traditional Chinese medicine diagnostic criteria refer to the syndrome of yang qi deficiency and blood stasis combined with phlegm retention in "Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure in Traditional Chinese Medicine", "Expert Consensus on the Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Chronic Heart Failure", and "Technical Guidelines for the Clinical Research of Traditional Chinese New Drugs for Chronic Heart Failure".

[0051] 4. Inclusion and exclusion criteria 4.1 Inclusion criteria (1) Aged between 18 and 80 years old; (2) Meeting the diagnostic criteria for the stable stage of chronic heart failure; (3) New York Heart Association (NYHA) heart function classification of II - III; (4) Patients with reduced ejection fraction (LVEF < 50%); (5) Patients with traditional Chinese medicine syndrome differentiation of yang qi deficiency and blood stasis combined with phlegm retention; (6) Lee heart failure score ≥ 6 points; (7) The subjects gave full informed consent, voluntarily participated in this study, and signed the informed consent form by themselves.

[0052] 4.2 Exclusion criteria (1) Patients with heart failure caused by the failure of important organs such as the kidneys and liver; (2) Patients with severe heart failure are not suitable for inclusion in the trial cases; (3) Patients with various malignant tumors or suspected malignant tumors; (4) History of thromboembolic disease within 6 months; (5) Suffering from obvious liver and kidney diseases or ALT and AST higher than 1.5 times the ULN, creatinine and urea nitrogen higher than 1.5 times the ULN; (6) Patients with major diseases such as severe mental illness and hematopoietic system diseases; (7)Female subjects who are pregnant, lactating, or have a positive pregnancy test, or who have a fertility plan within a certain period of time; (8)Subjects with skin redness, ulcers, or skin diseases; (9)Subjects who have participated in or are currently participating in other clinical studies within the past three months; (10)Subjects who are suspected or definitely allergic to the study drug; (11)All factors that can increase mortality: such as cardiogenic shock, severe ventricular arrhythmia, complete atrioventricular block, obstructive cardiomyopathy, un-repaired valvular disease, constrictive pericarditis, cardiac tamponade, pulmonary embolism, those with obvious infections, and patients with uncontrolled hypertension, acute myocarditis, combined with acute coronary syndrome, chronic heart failure patients who need device treatment recently, etc., are not eligible for inclusion.

[0053] 4.3 Exclusion Criteria (1)After the start of the study, it is found that the subject does not meet the case inclusion criteria or meets the exclusion criteria; (2)No data is recorded after randomization; (3)Cases in which prohibited drugs are used so that the effectiveness and safety cannot be determined.

[0054] 4.4 Withdrawal Criteria: All subjects who fill out the informed consent form and are screened and qualified to enter the study, regardless of when and for what reason they withdraw, and those who do not complete the observation period specified in the protocol are regarded as withdrawn cases.

[0055] 4.5 Exit Criteria: During the treatment period, if an adverse event occurs in a subject and the researcher determines that drug treatment is required, the researcher should instruct the subject to complete all the examinations and tests during the visit and then withdraw from the trial. This case is counted as a completed case and included in the statistical analysis.

[0056] 4.6 Suspension / Termination Criteria In the subjects who have been included in the study, situations that are not suitable for continuing the study occur during the study period, such as adverse reactions such as skin allergies, etc., resulting in the case being unable to complete the study according to the study protocol is the suspension of the study case. After the case is suspended, its case record form should be retained, and the last test result should be used as the final result for the analysis of its efficacy and adverse reactions. If serious safety problems occur during the study or there are major mistakes in the study protocol, etc., the clinical study should be terminated comprehensively.

[0057] 5. Study Grouping and Drug Administration Plan All subjects continued to receive the standardized anti-heart failure treatment regimen formulated by the attending physician, including conventional Western medicine treatments such as diuretics, beta blockers, ACEI / ARB / ARNI, and aldosterone receptor antagonists, and were randomly divided into an experimental group and a control group. All traditional Chinese medicines, proprietary Chinese medicines, and external Chinese medicine therapies were discontinued. After a 3- to 7-day lead-in period, the treatment period began, during which no additional traditional Chinese medicine treatment was given. The subjects were randomly divided into an experimental group and a control group (the flow chart of the randomized controlled trial can be seen in Figure 1 ).

[0058] (1) Experimental group: Traditional Chinese medicine composition plaster group - On the basis of conventional Western medicine treatment, a traditional Chinese medicine composition plaster was used in combination. The traditional Chinese medicine composition plaster was processed and produced by the pharmaceutical factory of Xiyuan Hospital, China Academy of Chinese Medical Sciences. The drug composition: processed aconite root, pokeweed, chuanxiong rhizome, and lepidium seed; Drug specification: The patch is 5 cm × 5 cm, the weight of the drug core is 1 g, and the diameter is 2.5 cm; Application site: Shenque acupoint; Applied once a day for 4 hours each time.

[0059] (2) Control group: Placebo group of traditional Chinese medicine composition plaster - On the basis of conventional Western medicine treatment, a placebo of the traditional Chinese medicine composition plaster was used in combination. The placebo of the traditional Chinese medicine composition plaster was processed and produced by the pharmaceutical factory of Xiyuan Hospital, China Academy of Chinese Medical Sciences, and its appearance and smell were consistent with those of the traditional Chinese medicine composition plaster. Drug specification: The patch is 5 cm × 5 cm, the weight of the drug core is 1 g, and the diameter is 2.5 cm; Application site: Shenque acupoint; Applied once a day for 4 hours each time.

[0060] (3) Course of treatment: Acupoint application was continuously given for 14 days.

[0061] 6. Concomitant medications and combined treatments Drugs that must be taken for other combined diseases can be continued to be taken. It is prohibited to use traditional Chinese patent medicines with clear heart failure indications or with clear effects of warming yang, promoting blood circulation, and promoting diuresis, such as Xinmailong injection, Shengmai injection, Shenmai injection, Qishen Yiqi dripping pills, Qiliqiangxin capsules, Shexiang Baoxin pills, Naoxintong capsules, Tongxinluo capsules, Shenfu Qiangxin pills, Xinbao pills, and Xuefu Zhuyu capsules.

[0062] 7. Observation items (1) Main efficacy index: Lee's heart failure score; (2) Secondary efficacy indexes: NYHA heart function classification, NT-proBNP, LVEF, 24-hour urine volume, evaluation of the curative effect of traditional Chinese medicine syndromes, and Minnesota heart failure quality of life questionnaire; (3) Safety indexes: Changes in vital signs and laboratory indexes (such as liver and kidney functions); Occurrence of adverse events and adverse reactions.

[0063] 8. Statistical methods Using SPSS 21.0, measurement data conforming to a normal distribution were expressed as mean ± standard deviation (x ± s), and the t-test was used. Quantitative data not conforming to a normal distribution were expressed as median (interquartile range) [M(P25, P75)], and the Mann-Whitney U test was used. Count data were expressed as the number of cases and percentage (%), and the χ2 test, corrected chi-square test, Fisher's exact test, etc. were used; rank data were analyzed using the Ridit analysis and CMH method. A two-sided test was used, with P <0.05 indicating statistical significance.

[0064] 9. Evaluation indicators: 9.1 Lee's heart failure score The results are shown in Table 2. The Lee's score in the experimental group was significantly lower than that in the control group, and the difference was statistically significant (P < 0.05), indicating that the traditional Chinese medicine composition patch could significantly improve the Lee's score of the patients, that is, improve the subjective and objective indicators of the patients, including heart failure signs such as limb edema, hepatomegaly, and pulmonary congestion indicators on the posterior-anterior chest X-ray.

[0065] Table 2. Comparison of Lee's heart failure scores between the two groups

[0066] Note: The difference in Lee's heart failure score: experimental group (before) - experimental group (after), control group (before) - control group (after).

[0067] 9.2 NT-ProBNP The results are shown in Table 3. There was no significant difference in the difference of NT-ProBNP between the experimental group and the control group (P > 0.05), indicating that the traditional Chinese medicine composition patch had no significant effect on the NT-ProBNP of the patients.

[0068] Table 3. Comparison of NT-ProBNP between the two groups

[0069] Note: The difference in NT-ProBNP: experimental group (before) - experimental group (after), control group (before) - control group (after).

[0070] 9.3 EF value The results are shown in Table 4. There was no significant difference in the EF value between the experimental group and the control group ( P (P > 0.05), indicating that the traditional Chinese medicine composition patch had no significant effect on the ejection fraction of the patients in the short term (within 14 days).

[0071] Table 4. Comparison of EF values between the two groups

[0072] Note: EF difference: experimental group (after) - experimental group (before), control group (after) - control group (before).

[0073] 9.4 24-hour urine volume The results are shown in Table 5. There was no significant difference in the difference of 24-hour urine volume between the experimental group and the control group ( P (>0.05), indicating that the traditional Chinese medicine composition patch had no significant effect on the urine volume of patients.

[0074] Table 5. Comparison of 24-hour urine volume between the two groups

[0075] Note: Md is the difference in 24-hour urine volume before and after using the traditional Chinese medicine composition patch: experimental group (after) - experimental group (before), control group (after) - control group (before).

[0076] 9.5 Traditional Chinese medicine syndrome score The results are shown in Table 6. The effective rate of the experimental group was 63.89%, higher than that of the control group (31.25%), and the difference was statistically significant ( P (<0.05), indicating that the traditional Chinese medicine composition patch could significantly improve the traditional Chinese medicine syndrome of patients.

[0077] Table 6. Comparison of traditional Chinese medicine syndrome scores between the two groups

[0078] Note: Marked effect: improvement of clinical symptoms and signs score n≥70%; effective: improvement of clinical symptoms and signs score n≥30% and <70%; ineffective: improvement of clinical symptoms and signs score n<30%.

[0079] 9.6 NYHA cardiac function The results are shown in Table 7. The effective rate of the experimental group was 69.44%, higher than that of the control group (43.48%), and the difference was statistically significant ( P (<0.05), indicating that the traditional Chinese medicine composition patch could significantly improve the cardiac function of patients.

[0080] Table 7. Comparison of NYHA cardiac function between the two groups

[0081] Note: No obvious change in cardiac function: ineffective, improvement of cardiac function by 1 grade: effective, improvement of cardiac function by 2 grades: marked effect.

[0082] 9.7 Minnesota Living with Heart Failure Questionnaire The results are shown in Table 8. The effective rate of the experimental group was 66.67%, higher than that of the control group (43.48%), but the difference was not statistically significant ( P (>0.05).

[0083] Table 8. Comparison of Minnesota Heart Failure Quality of Life between Two Groups

[0084] Note: Recent clinical control: Improvement in the scores of clinical symptoms and signs, n≥60%; Marked effect: Improvement in the scores of clinical symptoms and signs, n≥20% and <40%; Effective: Improvement in the scores of clinical symptoms and signs, n>20%; Ineffective: Improvement in the scores of clinical symptoms and signs, n<20%.

[0085] 9.8 Adverse Reactions After application treatment, local skin flushing and fever are normal phenomena. The skin will naturally repair after 2 - 3 days without special treatment. During the medication period, no adverse reactions were found, indicating the safety, stability and reliability of the medication.

[0086] 10. Conclusion From the above experimental data, it can be seen that the traditional Chinese medicine composition patch (experimental group) prepared by the present invention can significantly improve the cardiac function and clinical symptoms of patients with chronic heart failure: there are significant differences in the Lee's heart failure score, traditional Chinese medicine syndrome efficacy, and Minnesota heart failure quality of life efficacy of the experimental group compared with Comparative Example 1 (placebo control group) ( P <0.05).

[0087] Conclusion: The acupoint patch prepared by the present invention has proven in high-quality clinical trials that its formula optimization and preparation and usage methods can break through the efficacy bottleneck of traditional technologies, and it can be used as an effective auxiliary means for traditional Chinese medicine in the treatment of heart failure.

[0088] Example 3. Observational Clinical Comparative Data (Comparative Example 2)

[0089] Observe 20 patients with chronic heart failure with reduced ejection fraction (EF<50%) hospitalized in the First Department of Cardiovascular Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences from May 2024 to August 2024. Compare the effects of the traditional Chinese medicine composition patch on the cardiac function classification of patients. The number of patients in each group is [Example 1: Prepared Aconite Lateralis Preparata: Phytolacca acinosa Roxb: Lepidium apetalum Willd: Ligusticum chuanxiong Hort = 2:1:2:3]: [Comparative Example 2: Prepared Aconite Lateralis Preparata: Phytolacca acinosa Roxb: Lepidium apetalum Willd: Ginseng = 2:1:2:3] = 10:10. On the basis of conventional Western medicine treatment, acupoint application patches composed of the corresponding drugs were used on the Shenque acupoint for 4 hours a day for 14 consecutive days. Using SPSS21.0 software, the statistical method used Fisher's exact probability method, and a two-sided test was used. With P <0.05 being statistically significant, compare the effective rates of the two groups. No obvious change in cardiac function: Ineffective, improvement in cardiac function by 1 level: Effective, improvement in cardiac function by 2 levels: Marked effect. The effective rate of Example 1 is 90%, and the effective rate of Comparative Example 2 is 30%. The traditional Chinese medicine composition patch of Example 1 has significant advantages (P = 0.020).

[0090] Table 9. Comparison of NYHA cardiac function of two groups of traditional Chinese medicine composition patches

[0091] Example 4. Observational clinical comparison data (control example 3) Twenty patients with heart failure with reduced ejection fraction (EF < 50%) who were hospitalized in the First Department of Cardiology, Xiyuan Hospital, China Academy of Chinese Medical Sciences from August 2024 to October 2024 were observed to compare the effect of the traditional Chinese medicine composition patch on the cardiac function classification of the patients. The number of patients in each group was [Example 1: Prepared aconite root (after processing): Phytolacca acinosa Roxb.: Lepidium apetalum Willd.: Ligusticum chuanxiong Hort. = 2:1:2:3]: [Control example 3: Prepared aconite root (after processing): Poria cocos (Schw.) Wolf: Lepidium apetalum Willd.: Ligusticum chuanxiong Hort. = 2:1:2:3] = 10:10. On the basis of conventional western medicine treatment, the navel acupoint was applied with the corresponding drug composition for 4 hours a day for 14 consecutive days. Using SPSS 21.0 software, the statistical method was Fisher's exact probability method, and a two-sided test was used. Statistical significance was set at P < 0.05 to compare the effective rates of the two groups. No obvious change in cardiac function: ineffective; cardiac function improved by 1 level: effective; cardiac function improved by 2 levels: markedly effective. The effective rate of Example 1 was 80%, and the effective rate of Control example 3 was 20%. The traditional Chinese medicine composition patch in Example 1 had a significant advantage (P = 0.023).

[0092] Table 10. Comparison of NYHA cardiac function of two groups of traditional Chinese medicine composition patches .

Claims

1. A traditional Chinese medicine composition plaster for adjuvant treatment of chronic heart failure, characterized in that, It is made from prepared aconite root, pokeberry root, semen lepidii and chuanxiong rhizome.

2. The traditional Chinese medicine composition patch according to claim 1, wherein The proportion of each drug is prepared aconite root:pokeberry root:semen lepidii:chuanxiong rhizome = 1.8 - 2.2:1:1.8 - 2.2:2.8 - 3.

2.

3. The traditional Chinese medicine composition plaster according to claim 2, wherein, The proportion of each drug is prepared aconite root:pokeberry root:semen lepidii:chuanxiong rhizome = 1.9 - 2.1:1:1.9 - 2.1:2.9 - 3.

1.

4. The traditional Chinese medicine composition plaster according to claim 2, wherein, The proportion of each drug is prepared aconite root:pokeberry root:semen lepidii:chuanxiong rhizome = 2:1:2:

3.

5. The preparation method of the traditional Chinese medicine composition plaster according to any one of claims 1 to 4, characterized in that, Weigh each drug according to the proportion, dry it at 70 - 80 °C, then crush it into fine drug powder, mix it evenly, add binder, and after fully mixing, make an ointment to obtain it. Preferably, the fine drug powder passes through an 80 - mesh sieve; the binder is refined honey and corn oil.

6. The preparation method according to claim 5, characterized in that, The fine drug powder, refined honey and corn oil are mixed in a mass ratio of 12 - 20:1 - 5:1, preferably 14 - 18:2 - 4:1, and more preferably 16:3:1; among them, the honey is heated to 110 - 120 °C and refined until it forms a drawn bead, and then cooled to 50 - 70 °C for use.

7. The preparation method according to claim 5, wherein Then use a colloid mill for homogenization to obtain a paste. Specifically, the rotation speed is 2000 - 4000 rpm, and the time is 10 - 30 min. Preferably, the rotation speed is 2500 - 3500 rpm, and the time is 15 - 25 min. More preferably, the rotation speed is 3000 rpm, and the time is 20 min.

8. The preparation method according to claim 6, wherein It further includes the steps of dispensing and packaging. Specifically, the patch of the traditional Chinese medicine composition patch is made of non - woven fabric. An anti - leakage membrane is pasted in the center of the patch. The ointment is pressed into a medicine core, dispensed onto the anti - leakage membrane, covered with release paper, made into an acupoint patch, and stored sealed and away from light. More specifically, the patch is cut into a rounded - corner rectangle with a length and width of about 5 cm × 5 cm. One side of the cut patch is covered with an easy - tear strip with a width of about 0.5 cm. An anti - leakage membrane of 2.5 cm × 2.5 cm is pasted in the center of the patch. The ointment is pressed into a medicine core with a diameter of 2.5 cm, that is, 1 g per patch, dispensed onto the anti - leakage membrane in the acupoint patch, covered with release paper, and the made acupoint patch is stored sealed and away from light.

9. An acupoint patch for adjuvant treatment of chronic heart failure, characterized in that, It is obtained by the preparation method according to claim 8.

10. A pharmaceutical combination or medicine box for treating chronic heart failure, characterized in that, It includes the traditional Chinese medicine composition patch according to any one of claims 1 to 4 or the acupoint patch according to claim 9, and a drug for treating chronic heart failure. The drug for treating chronic heart failure is selected from renin - angiotensin - aldosterone system inhibitors (angiotensin receptor neprilysin inhibitors such as sacubitril / valsartan, angiotensin - converting enzyme inhibitor drugs such as captopril, angiotensin II receptor antagonist drugs such as candesartan, etc.), β - receptor blockers (such as metoprolol succinate sustained - release tablets), aldosterone receptor antagonists (such as spironolactone) and sodium - glucose cotransporter 2 inhibitors (such as dapagliflozin), soluble guanylate cyclase agonists (vericiguat).

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