A traditional Chinese medicine composition patch for adjuvant treatment of chronic heart failure and its preparation method

Abstract

This invention belongs to the field of traditional Chinese medicine, specifically disclosing a traditional Chinese medicine composition patch for the adjunctive treatment of chronic heart failure and its preparation method. The traditional Chinese medicine composition patch is made from processed aconite root, pokeweed, lepidium seed, and chuanxiong rhizome. The drugs of this invention are prepared into a traditional Chinese medicine composition patch by mixing the ingredients with an adhesive in a specific ratio. The patch exhibits high bioavailability, clearly defined components, and good therapeutic effects. Furthermore, by controlling the specific types and proportions of the active ingredients, the synergistic effect between the components is improved, enhancing the therapeutic effect on chronic heart failure with reduced ejection fraction. The rational combination of the drug components, when applied to the Shenque acupoint, can significantly improve the clinical symptoms and quality of life of patients with chronic heart failure and reduced ejection fraction.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine, specifically relating to a traditional Chinese medicine composition patch for adjuvant treatment of chronic heart failure and its preparation method. Background Technology

[0002] Heart failure, as the end-stage of cardiovascular disease, has seen its prevalence increase by 44% in the past 15 years. Currently, the prevalence of heart failure among residents aged ≥35 years in my country is 1.3%, with as many as 13.7 million heart failure patients. The resulting mortality and readmission rates remain high. Based on left ventricular ejection fraction (LVEF), heart failure can be classified 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 using the National Cardiovascular Disease Center's Heart Failure Specialty Medical Consortium database, shows that HFrEF, HFmrEF, and HFPEF account for 40%, 22%, and 38% respectively, with heart failure with reduced ejection fraction remaining the most common type of heart failure in my country. The conventional treatment for chronic heart failure involves early initiation of a "new quadruple therapy" combination, combined with device intervention and personalized management, and the rational addition of oral Chinese medicine preparations. While this helps to further improve the clinical symptoms, enhance exercise tolerance, and improve the quality of life of patients with chronic heart failure, patients with chronic heart failure often have multiple underlying diseases and often need to use combination drugs, which increases the incidence of adverse drug reactions. At the same time, water and sodium retention in heart failure patients can lead to gastrointestinal congestion, affecting the absorption of oral drugs. With multiple medications used concurrently, drug interactions are complex. For example, the combined use of MRA and diuretics can easily cause electrolyte disturbances or renal function deterioration, and β-blockers may aggravate bradycardia or hypotension. Some patients cannot tolerate these medications due to comorbidities.

[0003] Traditional Chinese medicine (TCM) external therapies, with a history spanning thousands of years, are an effective treatment method characterized by simplicity, convenience, efficacy, and affordability. TCM external therapies not only avoid the increased potential adverse reactions associated with oral medications but also reduce the impact of gastrointestinal congestion on the absorption of oral drugs. However, currently, there is a lack of TCM external preparations for treating chronic heart failure in China. Acupoint application of TCM is a typical TCM external therapy method, boasting significant clinical efficacy, wide applicability, high acceptance, and minimal side effects. The *Qianjin Yaofang* states that "transforming decoctions into external therapies truly opens up countless avenues for future generations." Acupoint application is based on TCM theories of the internal organs and meridians. Under the guidance of TCM syndrome differentiation and treatment, effective medicinal formulas are directly applied to acupoints on the body surface. The active ingredients are absorbed transdermally, reaching deep into the meridians and internal organs through the acupoints to regulate the body's Yin-Yang balance.

[0004] Patent CN106729591A proposes an acupoint patch made from 4-6g of ginseng, 8-12g of stir-fried mustard seeds, 4-6g of raw mustard seeds, 8-12g of Corydalis rhizome, 8-12g of Euphorbia kansui, 2.5-3.5% of Asarum, 4-6g of cinnamon, 2.5-3.5% of Panax notoginseng, and ginger juice. This patch contains many ingredients and is used in large quantities. Furthermore, the acupoints used include bilateral Neiguan (PC6), Zusanli (ST36), Xinshu (BL15), Feishu (BL13), and Tanzhong (CV17). The application is limited to the coldest days of winter and the hottest days of summer, thus restricting its use to professional physicians or individuals with some knowledge of Traditional Chinese Medicine. It is not suitable as a long-term adjunctive treatment for chronic heart failure, making widespread adoption difficult. Moreover, its efficacy evaluation is relatively limited, failing to highlight the advantages of Traditional Chinese Medicine treatment. Summary of the Invention

[0005] This invention inherits the principle that "for those suffering from phlegm and fluid retention, warming medicines should be used to harmonize them," and innovatively uses prepared aconite root, pokeweed, chuanxiong rhizome, and lepidium seed to create an acupoint patch. This patch works synergistically to warm the yang, dispel blood stasis, and promote diuresis. Applied to the Shenque acupoint, it stimulates the qi of the meridians, coordinates the functions of various organs, unblocks the meridians, and promotes the circulation of qi and blood. The formula is precise, the dosage is concise, and the acupoints are easy to understand, not limited by the operator, location, or time. This patch can be used as an adjunct to routine Western medicine treatments, further improving cardiac function and enhancing the quality of life for patients with heart failure.

[0006] This invention provides a traditional Chinese medicine acupoint patch, the composition of which is prepared aconite root, pokeweed, lepidium seed and chuanxiong rhizome.

[0007] This invention provides an explanation of the formula for applying traditional Chinese medicine to acupoints: Academician Chen Keji believed that "for those suffering from phlegm and fluid retention, warm medicines should be used to harmonize them," which is the general principle for later generations of physicians in preventing and treating heart failure. Aconite is the first choice for warming yang and tonifying qi. "Its nature is to move quickly; externally, it reaches the skin and hair to dispel external cold, and internally, it reaches the lower abdomen to warm the stubborn cold." It can not only enhance myocardial contractility but also reduce myocardial oxygen consumption, improve myocardial ischemia and hypoxia, and achieve the purpose of "benefiting the source of fire to dispel yin stagnation," thus serving as the principal drug. The *Neijing* states, "What is retained should be attacked," and attacking and expelling water and fluid retention is an effective method for eliminating fluid retention. Phytolacca acinosa, "pungent and neutral in nature, mainly treats edema, hernia, and numbness; it can be used to treat carbuncles and boils, and kill demonic substances." Its active ingredients, phytolacca saponin and potassium salts, both have diuretic effects and are widely used in the clinical diagnosis and treatment of edema, thus serving as the assistant drug. "When blood is not flowing smoothly, it becomes water retention." Blood and body fluids share the same origin; invigorating blood circulation promotes water retention. Chuanxiong (Ligusticum striatum) is pungent, warm, fragrant, and drying in nature; it moves without lingering, dispersing and entering the blood. It can ascend to the top of the head and descend to the lower abdomen, acting as a qi-regulating herb within the blood, embodying the functions of dispersing, clearing, invigorating blood, regulating qi, and relieving pain. Tinglizi (Lepidium apetalum) is pungent and cold in nature, primarily treating masses and accumulations, relieving the effects of hot and cold foods, breaking up hard masses, expelling pathogens, and promoting urination. It is mainly used to treat water retention in the lungs, chest fullness, and coughing. Its active ingredient, quercetin, has multiple effects including diuresis, positive inotropic properties, inhibition of ventricular remodeling, and protection of myocardial cells. Chuanxiong and Tinglizi invigorate blood and promote water retention, assisting Fuzi (Aconitum carmichaelii) and Shanglu (Phytolacca acinosa) in promoting the dissipation of blood stasis and pathological products of water retention, serving as adjuvant herbs. The combined effects of these herbs are to warm the yang, invigorate blood, and promote water retention.

[0008] Traditional Chinese Medicine (TCM) theory supports this view: Heart failure falls under the TCM categories of "edema," "asthma," "chest pain," "palpitation," and "phlegm retention." It often results from prolonged heart disease or a condition affecting the heart itself, leading to deficiency of Qi, blood, Yin, and Yang in the heart. Over time, this affects the kidney Yang, the foundation of Yang Qi in the body. Kidney Yang deficiency weakens the body's ability to warm and transform fluids and dampness, causing internal retention and overflowing into the skin, resulting in edema. Without the warmth of kidney Yang, the heart Yang lacks the power to propel blood circulation, leading to chest tightness and shortness of breath. Kidney deficiency also impairs the intake of Qi, causing shortness of breath and inability to lie flat. Therefore, this disease is a case of deficiency in the root and excess in the branch, and its pathogenesis can be summarized as "deficiency," "stasis," and "water retention." Warming Yang, activating blood circulation, and promoting diuresis are the basic treatment principles for heart failure.

[0009] The herbal patch, prepared with processed aconite, pokeweed, lepidium seed, and chuanxiong rhizome in a specific ratio and binder, boasts high bioavailability, clearly defined components, and good therapeutic effects. Furthermore, by controlling the specific types and proportions of the active ingredients, the synergistic effect between the components is enhanced, improving the treatment efficacy for chronic heart failure with reduced ejection fraction (EF < 50%). The well-balanced combination of components, acting on the specific Shenque acupoint (navel), significantly improves the clinical symptoms and quality of life of patients with chronic heart failure and reduced ejection fraction (EF < 50%). Specifically, this includes the following aspects:

[0010] 1. Based on high-level clinical validation using evidence-based medicine, clearly identify the effects of improved cardiac function and biomarkers.

[0011] Technical advantages: Through a double-blind, randomized, placebo-controlled study (RCT) design, this study is the first to demonstrate the core efficacy of this patch in reducing ejection fraction in heart failure (EF<50%) using internationally recognized rigorous evidence-based methods, which is superior to the current situation where conventional TCM external treatments lack high-quality evidence. (1) Standardized study design: The RCT method (randomized, double-blind, placebo-controlled) is used to eliminate subjective bias and ensure the objectivity of efficacy data. (2) Multi-indicator joint verification: Objective indicators such as LVEF (left ventricular ejection fraction) and NT-ProBNP (heart failure marker) are monitored simultaneously, and combined with 24-hour urine output (reflecting diuretic effect) and NYHA classification (cardiac function status) to form a multi-dimensional efficacy evaluation system. (3) Pharmacological mechanism support: The warming yang components (such as aconitine) in the patch directly enhance myocardial contractility, the blood-activating components (tetramethylpyrazine) improve myocardial microcirculation, and the diuretic components (phytolacca saponins) regulate body fluid metabolism, thus synergistically improving cardiac function at the molecular level.

[0012] 2. Multi-dimensional comprehensive assessment of efficacy, overcoming the limitations of traditional single indicators.

[0013] The comprehensive evaluation system (Lee's heart failure score, NYHA classification, biomarkers, and urine output) comprehensively quantifies symptom improvement, which is superior to the single assessment mode that relies solely on LVEF or symptom scores in conventional treatment. (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: NT-ProBNP detection technology (fluorescence immunochromatography) is used to quantitatively assess the degree of myocardial stress. (3) Standardized echocardiography acquisition: A unified ultrasound section and measurement protocol (such as SimPson method for calculating LVEF) is adopted to reduce operator-dependent errors.

[0014] 3. Significantly improves patients' quality of life and fills the gaps in Western medicine treatment.

[0015] The Minnesota Heart Failure Quality of Life Scale (MLHFQ) confirmed that the patch can significantly improve patients' daily activity ability and psychological state, while conventional Western medicine treatment (such as diuretics and beta-blockers) has limited effect on improving quality of life. Regional studies suggest that about 50% of patients have significantly impaired quality of life. (1) Local transdermal drug delivery technology at acupoints: The patch acts on the Shenque acupoint, which has a special vascular biological structure. The drug is absorbed through the skin and the local stimulation of the acupoint regulates the flow of Qi and blood in the meridians. (2) Synergistic effect of multiple components: The diuretic component quickly reduces edema (improves physical discomfort), and the warming Yang component enhances energy metabolism (relieves fatigue), forming a "symptom-psychological" synchronous improvement effect.

[0016] 4. Non-invasive drug delivery and safety advantages, solving the problem of accumulated toxicity of Western medicines.

[0017] Transdermal absorption avoids the hepatotoxicity and nephrotoxicity (such as the risk of digoxin poisoning) and electrolyte disturbances (such as hypokalemia caused by loop diuretics) of oral drugs, and is especially suitable for elderly patients with liver and kidney dysfunction. (1) Transdermal controlled release technology: Select Shenque acupoint with thin skin and rich local blood vessels to enhance the transdermal absorption efficiency of drugs, reduce the systemic exposure dose, and reduce the risk of toxicity. (2) Traditional Chinese medicine formulation optimization technology: Select representative Chinese medicines that warm yang, activate blood and promote diuresis, and synergistically exert therapeutic effects. (3) Local metabolic pathway design: Drugs enter the systemic circulation directly through the capillaries of acupoints, avoiding the first-pass effect and reducing the metabolic burden.

[0018] 5. Synergistic effect of combined Western medicine, breaking through the bottleneck of traditional treatment efficacy.

[0019] Clinical data show that when the patch is used in combination with "new quadruple therapy" drugs (such as ARNI and SGLT2i), the overall effective rate can be further improved. The warming components of the patch enhance myocardial contractility, the diuretic components assist in sodium excretion (complementing ARNI and diuretics), and the blood-activating components improve coronary blood flow (relieving microcirculatory disturbances caused by beta-blockers). For example, this invention can be used in combination with the following Western medicine treatments: renin-angiotensin-aldosterone system inhibitors (angiotensin receptor neprilysin inhibitors such as sacubitril / valsartan, starting at 50 mg bid-200 mg bid; angiotensin-converting enzyme inhibitors such as captopril 6.25 mg tid-50 mg tid; angiotensin II receptor antagonists such as candesartan, starting at 4 mg / d-32 mg / d), β-blockers (such as metoprolol succinate extended-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, fixed dose 10 mg qd; and guanylate cyclase agonists such as viriceguanidine: 2.5-10 mg qd (3 times daily: tid; 2 times daily: bid; 1 time daily: qd)).

[0020] This invention is proposed based on the inventor's research. The specific invention includes the following technical solutions.

[0021] Firstly, a traditional Chinese medicine composition patch for adjuvant treatment of chronic heart failure is provided, which is made from prepared aconite root, pokeweed, lepidium seed, and chuanxiong rhizome.

[0022] Specifically, the ratio 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.

[0023] Preferably, the ratio 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.

[0024] More preferably, the ratio of each drug is: processed aconite root: pokeweed: lepidium seed: chuanxiong root = 2:1:2:3.

[0025] The present invention also provides a method for preparing the traditional Chinese medicine composition plaster, wherein each drug is weighed in proportion, dried at 70-80°C, pulverized into fine powder, mixed, and then a binder is added and mixed thoroughly to form a medicated ointment.

[0026] Specifically, the drug powder passes through an 80-mesh sieve; the binder is refined honey and corn oil.

[0027] Preferably, the fine powder of the medicine, refined honey and corn oil are mixed in a mass ratio of 12-20:1-5:1, more preferably 14-18:2-4:1, and even more preferably 16:3:1; wherein the honey is heated to 110-120°C and refined until it can be drawn into beads, and then cooled to 50-70°C before use.

[0028] Further, the paste is then homogenized using a colloid mill, specifically at a speed of 2000-4000 rpm for 10-30 min, preferably at 2500-3500 rpm for 15-25 min, and more preferably at a speed of 3000 rpm for 20 min.

[0029] Further steps include dispensing and packaging. Specifically, the patch of the traditional Chinese medicine composition plaster is made of non-woven fabric, with a waterproof membrane pasted in the center of the patch. The ointment is pressed into a core, dispensed onto the waterproof membrane, and covered with release paper. The resulting acupoint patch is sealed and stored away from light.

[0030] More specifically, the patch is cut into a rounded rectangle approximately 5cm x 5cm in length and width. One side of the cut patch is covered with an easy-tear strip approximately 0.5cm wide. A 2.5cm x 2.5cm impermeable membrane is pasted in the center of the patch. The ointment is pressed into a 2.5cm diameter core (1g / patch), which is then dispensed onto the impermeable membrane in the acupoint patch. The patch is then covered with release paper. The finished acupoint patch is sealed and stored away from light.

[0031] Therefore, this invention also provides acupoint patches (also known as heart failure patches) prepared by the above method. When used, based on a 1g / patch weight conversion, each patch contains 0.1-0.3g of prepared aconite root (10-30%), 0.05-0.15g of pokeweed (5-15%), 0.1-0.3g of lepidium seed (10-30%), and 0.2-0.4g of chuanxiong rhizome (20-40%). Preferably, based on a 1g / patch weight conversion, each patch contains 0.2g of prepared aconite root (20%), 0.1g of pokeweed (10%), 0.2g of lepidium seed (20%), and 0.3g of chuanxiong rhizome (30%), with the remainder being adhesive.

[0032] The present invention also provides a drug combination or kit for treating chronic heart failure, comprising the above-mentioned traditional Chinese medicine composition patch or acupoint patch for adjuvant treatment of chronic heart failure, and a drug for treating chronic heart failure, wherein 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 inhibitors such as captopril, angiotensin II receptor antagonists such as candesartan, etc.), β-blockers (such as metoprolol succinate sustained-release tablets, aldosterone receptor antagonists (such as spironolactone) and sodium-glucose cotransporter 2 inhibitors (such as dapagliflozin), and soluble guanylate cyclase agonists (velixithidine). Attached Figure Description

[0033] Figure 1 Flowchart of the randomized controlled trial. Safety indicators include routine blood and urine tests, liver and kidney function tests, and electrolyte levels; efficacy evaluation indicators include Lee's heart failure score, NYHA functional classification, NT-proBNP, LVEF, 24-hour urine output, Traditional Chinese Medicine syndrome scale, and Minnesota Heart Failure Quality of Life Survey; the primary efficacy evaluation indicator is the Lee's heart failure score.

[0034] Figure 2 Flowchart for the preparation of traditional Chinese medicine plasters.

[0035] Figure 3 A model diagram of a traditional Chinese medicine plaster. Detailed Implementation

[0036] The present invention will be described below through specific embodiments in order to better understand the present invention, but this does not constitute a limitation of the present invention.

[0037] Example 1: Overall processing and preparation process:

[0038] 1. Raw materials and preparation process

[0039] Drug composition and ratio (mass ratio): Prepared aconite root (after processing): Phytolacca acinosa: Lepidium apetalum: Ligusticum chuanxiong = 2:1:2:3.

[0040] Total feed amount: Aconitum carmichaelii 0.2g, Phytolacca acinosa 0.1g, Lepidium apetalum 0.2g, Ligusticum chuanxiong 0.3g.

[0041] 2. Process steps:

[0042] Processing: All products are processed and produced at the Xiyuan Hospital Pharmaceutical Factory of the China Academy of Chinese Medical Sciences.

[0043] Processing and drying: Prepared aconite: After soaking in water for 48 hours (changing the water 6 times), steam for 4 hours until there is no numbness on the tongue, slice, and dry at 70℃ until the moisture content is ≤8%; Pokeweed: vinegar-processed (soaked in rice vinegar for 2 hours, stir-fried over low heat until dry), and dried at 80℃ until the moisture content is ≤10%; Lepidium seed and Ligusticum: dried in hot air at 80℃ for 6 hours until the moisture content is ≤9%.

[0044] Crushing and sieving: The four medicinal materials are dried, crushed, and then passed through an 80-mesh sieve (particle size ≤180μm) and mixed evenly.

[0045] Honey preparation: Heat the honey to 116℃ (medium heat) and refine it until it can be pulled into beads, then cool it to 60℃;

[0046] Mixing: Mix the medicinal powder with refined honey and corn oil in a ratio of 16:3:1 (medicinal powder: refined honey: corn oil), and homogenize using a colloid mill (3000 rpm, 20 min) to form a paste of suitable viscosity (see the flowchart for the preparation of traditional Chinese medicine plaster). Figure 2 ).

[0047] Packaging and Dispensing: The acupoint patches are made of non-woven fabric and cut into rounded rectangles approximately 5cm x 5cm in length and width. One side of the cut patch is covered with a 0.5cm wide easy-tear strip. A 2.5cm x 2.5cm impermeable membrane is attached to the center of the patch. The ointment is pressed into a 2.5cm diameter core (1g / patch), dispensed onto the impermeable membrane inside the acupoint patch, and covered with release paper. The finished acupoint patches should be sealed and stored away from light (acupoint patch model image can be seen). Figure 3 ).

[0048] Comparative Example 1 (the effective drug composition is 5% of that in Example 1, and the placebo control group in the subsequent randomized controlled clinical trial)

[0049] Drug composition and ratio (mass ratio): Prepared aconite root (after processing): Phytolacca acinosa: Lepidium apetalum: Ligusticum chuanxiong = 2:1:2:3.

[0050] Total feed amount: Aconitum carmichaelii 0.01g, Phytolacca acinosa 0.005g, Lepidium apetalum 0.01g, Panax ginseng 0.015g.

[0051] The preparation method is as described in Example 1.

[0052] Comparative Example 2

[0053] Drug composition and ratio (mass ratio): Prepared aconite root (after processing): Phytolacca acinosa: Lepidium apetalum: Ginseng = 2:1:2:3.

[0054] Total ingredients: Aconitum carmichaelii 0.2g, Phytolacca acinosa 0.1g, Lepidium apetalum 0.2g, Ginseng 0.3g.

[0055] The preparation method is as described in Example 1.

[0056] Comparative Example 3

[0057] Drug composition and ratio (mass ratio): Prepared aconite root (after processing): Poria cocos: Lepidium apetalum: Ligusticum chuanxiong = 2:1:2:3.

[0058] Total feed amount: Aconitum carmichaelii 0.2g, Poria cocos 0.1g, Lepidium apetalum 0.2g, Ligusticum chuanxiong 0.3g.

[0059] The preparation method is as described in Example 1.

[0060] Example 2, Performance Test Data:

[0061] 1. Overall Design

[0062] A multicenter, randomized, double-blind, placebo-controlled clinical study design was adopted.

[0063] 2. Research Subjects

[0064] The study included 108 patients with chronic heart failure and reduced ejection fraction (EF < 50%) admitted to the cardiology outpatient and inpatient departments of three medical institutions: Xiyuan Hospital of China Academy of Chinese Medical Sciences, Changping District Hospital of Chinese Medicine, and Affiliated Hospital of Shanxi University of Chinese Medicine. An interim unblinding procedure is currently underway, with 68 cases completed and analyzed. There were no significant differences in baseline data between the two groups. P> 0.05 Subsequently, the remaining phases of the clinical trial were completed strictly following the original research protocol, including the entire process of data collection, endpoint assessment, and statistical analysis.

[0065] Table 1. Comparison of baseline data between the two groups

[0066]

[0067] 3. Diagnostic criteria

[0068] The Western medicine diagnostic criteria refer to the "Guidelines for the Diagnosis and Treatment of Heart Failure in China 2018" and the Chinese medicine diagnostic criteria refer to the "Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Traditional Chinese Medicine", "Expert Consensus on the Diagnosis and Treatment of Chronic Heart Failure with Integrated Traditional Chinese and Western Medicine", and "Technical Guidelines for Clinical Research of New Traditional Chinese Medicine Drugs for Chronic Heart Failure", which are based on the syndrome of Yang deficiency and blood stasis combined with phlegm retention.

[0069] 4. Discharge Standards

[0070] 4.1 Inclusion criteria

[0071] (1) Age between 18 and 80 years old;

[0072] (2) Meets the diagnostic criteria for stable chronic heart failure;

[0073] (3) The New York Heart Association (NYHA) classifies heart function as Class II to III;

[0074] (4) Patients with reduced ejection fraction (LVEF < 50%);

[0075] (5) Those diagnosed by traditional Chinese medicine as having deficiency of Yang Qi and blood stasis with phlegm retention;

[0076] (6) Lee's heart failure score ≥ 6 points;

[0077] (7) The participants were fully informed and voluntarily participated in this study, and signed the informed consent form.

[0078] 4.2 Exclusion Criteria

[0079] (1) Heart failure caused by failure of vital organs such as the kidneys and liver;

[0080] (2) Individuals with severe heart failure should not be included in the trial cases;

[0081] (3) Those with various malignant tumors or suspected malignant tumors;

[0082] (4) History of thromboembolic disease within the past 6 months;

[0083] (5) Having obvious liver and kidney diseases or ALT and AST levels higher than 1.5 times the ULN, or creatinine and blood urea nitrogen levels higher than 1.5 times the ULN;

[0084] (6) Patients with serious mental illness, hematopoietic system diseases, or other major diseases;

[0085] (7) Female subjects who are pregnant, breastfeeding, or have a positive pregnancy test, or who have plans to have children within a certain period of time;

[0086] (8) Patients with redness, swelling, ulceration, or skin diseases;

[0087] (9) Those who have participated in or are currently participating in other clinical studies within the past three months;

[0088] (10) Individuals with suspected or confirmed allergies to the investigational drug;

[0089] (11) Any factors that may increase mortality, such as cardiogenic shock, severe ventricular arrhythmia, complete atrioventricular block, obstructive cardiomyopathy, unrepaired valvular heart disease, constrictive pericarditis, cardiac tamponade, pulmonary embolism, patients with obvious infection, as well as uncontrolled hypertension, acute myocarditis, patients with acute coronary syndrome, and patients with chronic heart failure who need device therapy in the near future, should not be included.

[0090] 4.3 Rejection Criteria

[0091] (1) After the study began, it was found that the subjects did not meet the inclusion criteria or met the exclusion criteria;

[0092] (2) No data was recorded after randomization;

[0093] (3) Cases in which prohibited drugs were used, making it impossible to determine their effectiveness and safety.

[0094] 4.4 Dropout Criteria: All subjects who have completed the informed consent form and passed the screening to enter the study, regardless of when or why they withdraw, and who have not completed the observation period specified in the protocol, shall be considered dropout cases.

[0095] 4.5 Withdrawal Criteria: If a subject experiences an adverse event during treatment and the investigator determines that drug treatment is necessary, the investigator should instruct the subject to complete all examinations and tests during the visit before withdrawing from the trial. This case will be counted as a completed case and included in the statistical analysis.

[0096] 4.6 Termination Criteria

[0097] If a participant who has been enrolled experiences adverse reactions during the study that make it unsuitable to continue, such as skin allergies, preventing the completion of the study according to the protocol, the study is terminated. After termination, the participant's medical record should be retained, and the final test result should be used for efficacy and adverse reaction data analysis. If serious safety issues or significant errors in the study protocol occur, the entire clinical study should be terminated.

[0098] 5. Study grouping and dosing regimen

[0099] All subjects continued to receive the standard anti-heart failure treatment regimen prescribed by their attending physicians, including conventional Western medicine treatments such as diuretics, beta-blockers, ACEI / ARB / ARNI, and aldosterone receptor antagonists. They were randomly assigned to the experimental group and the control group. All traditional Chinese medicine, proprietary Chinese medicines, and external Chinese medicine therapies were discontinued. After a 3-7 day induction period, the treatment period began. During the treatment period, no additional traditional Chinese medicine treatment was administered. Subjects were randomly assigned to the experimental group and the control group (the flowchart of the randomized controlled trial is available). Figure 1 ).

[0100] (1) Experimental group: Traditional Chinese medicine composition patch group - Traditional Chinese medicine composition patch was used in combination with conventional Western medicine treatment. The traditional Chinese medicine composition patch was processed and produced by the pharmaceutical factory of Xiyuan Hospital of China Academy of Chinese Medical Sciences. The drug composition was: processed aconite, pokeweed, chuanxiong, and lepidium seed. The drug specifications were: patch 5cm×5cm, core weight 1g, diameter 2.5cm. The application location was Shenque acupoint. The patch was applied once a day for 4 hours each time.

[0101] (2) Control group: Traditional Chinese medicine composition patch placebo group - Traditional Chinese medicine composition patch placebo was used in combination with conventional Western medicine treatment. The traditional Chinese medicine composition patch placebo was processed and produced by the pharmaceutical factory of Xiyuan Hospital of China Academy of Chinese Medical Sciences. Its appearance and smell were consistent with the traditional Chinese medicine composition patch. The drug specifications were: patch 5cm×5cm, core weight 1g, diameter 2.5cm; application location: Shenque acupoint; applied once a day for 4 hours each time.

[0102] (3) Treatment course: Apply acupoint patches continuously for 14 days.

[0103] 6. Combined medication and combined treatment

[0104] Medications necessary for other co-existing conditions may continue to be taken. However, the following traditional Chinese medicines with clear indications for heart failure or with clear effects of warming yang, activating blood circulation, and promoting diuresis are prohibited: Xinmailong Injection, Shengmai Injection, Shenmai Injection, Qishen Yiqi Dripping Pills, Qili Qiangxin Capsules, Shexiang Baoxin Pills, Naoxintong Capsules, Tongxinluo Capsules, Shenfu Qiangxin Pills, Xinbao Pills, Xuefu Zhuyu Capsules, etc.

[0105] 7. Observation Items

[0106] (1) Main efficacy indicator: Lee's heart failure score;

[0107] (2) Secondary efficacy indicators: NYHA functional classification, NT-proBNP, LVEF, 24-hour urine output, TCM syndrome efficacy evaluation, Minnesota Heart Failure Quality of Life Questionnaire;

[0108] (3) Safety indicators: changes in vital signs and laboratory indicators (liver and kidney function, etc.); occurrence of adverse events and adverse reactions.

[0109] 8. Statistical Methods

[0110] SPSS 21.0 was used. Normally distributed quantitative data were expressed as mean ± standard deviation (x ± s) and analyzed using t-tests. Non-normally distributed quantitative data were expressed as median (interquartile range) [M (P25, P75)] and analyzed using the Mann-Whitney U test. Categorical data were expressed as number of cases and percentages (%) and analyzed using χ² test, corrected chi-square test, Fisher's exact test, etc. Ordinal data were analyzed using Ridit analysis and the CMH method. Two-tailed tests were used. P <0.05 is statistically significant.

[0111] 9. Evaluation Indicators:

[0112] 9.1 Lee's Heart Failure Scoring

[0113] The results are shown in Table 2. The Lee score in the experimental group was significantly lower than that in the control group, and the difference was statistically significant (P<0.05). This indicates that the traditional Chinese medicine patch can significantly improve the Lee score of patients, that is, improve the subjective and objective indicators of patients, including signs of heart failure, such as limb edema, hepatomegaly, and pulmonary congestion on chest X-ray.

[0114] Table 2. Comparison of Lee's heart failure scores between the two groups

[0115]

[0116] Note: Lee's heart failure score difference: experimental group (before) - experimental group (after), control group (before) - control group (after).

[0117] 9.2 NT-ProBNP

[0118] The results are shown in Table 3. There was no statistically significant difference in NT-ProBNP between the experimental group and the control group (P>0.05), indicating that the herbal patch had no significant effect on the patients' NT-ProBNP.

[0119] Table 3. Comparison of NT-ProBNP between the two groups

[0120]

[0121] Note: NT-ProBNP difference: experimental group (before) - experimental group (after), control group (before) - control group (after).

[0122] 9.3 EF value

[0123] The results are shown in Table 4. There was no statistically significant difference in EF values ​​between the experimental group and the control group. P >0.05), indicating that the herbal composition patch has no significant effect on the patient's ejection fraction in the short term (within 14 days).

[0124] Table 4. Comparison of EF values ​​between the two groups

[0125]

[0126] Note: EF difference: experimental group (after) - experimental group (before), control group (after) - control group (before).

[0127] 9.4 24-hour urine output

[0128] The results are shown in Table 5. There was no statistically significant difference in 24-hour urine output between the experimental group and the control group. P >0.05), indicating that the herbal composition patch had no significant effect on the patient's urine output.

[0129] Table 5. Comparison of 24-hour urine output between the two groups

[0130]

[0131] Note: Md is the difference in 24-hour urine output before and after using the herbal patch: experimental group (after) - experimental group (before), control group (after) - control group (before).

[0132] 9.5 Traditional Chinese Medicine Syndrome Scoring

[0133] The results are shown in Table 6. The effective rate of the experimental group was 63.89%, which was higher than that of the control group (31.25%), and the difference was statistically significant. P The value <0.05 indicates that the traditional Chinese medicine composition plaster can significantly improve the patient's TCM syndrome.

[0134] Table 6. Comparison of TCM syndrome scores between the two groups

[0135]

[0136] Note: Significant effect: improvement of clinical symptoms and signs scores n≥70%; Effective: improvement of clinical symptoms and signs scores n≥30% and <70%; Ineffective: improvement of clinical symptoms and signs scores n<30%.

[0137] 9.6 NYHA Cardiac Function

[0138] The results are shown in Table 7. The effective rate of the experimental group was 69.44%, which was higher than that of the control group (43.48%), and the difference was statistically significant. P The value <0.05 indicates that the traditional Chinese medicine composition patch can significantly improve the patient's cardiac function.

[0139] Table 7. Comparison of NYHA cardiac function between the two groups

[0140]

[0141] Note: No significant change in cardiac function: ineffective; improvement of cardiac function by 1 grade: effective; improvement of cardiac function by 2 grades: significantly effective.

[0142] 9.7 Minnesota Heart Failure Quality of Life Questionnaire

[0143] The results are shown in Table 8. The effective rate in the experimental group was 66.67%, which was higher than that in the control group (43.48%), but the difference was not statistically significant. P >0.05).

[0144] Table 8. Comparison of Quality of Life Between the Two Groups in Minnesota with Heart Failure

[0145]

[0146] Note: Recent clinical control: improvement of clinical symptoms and signs scores n≥60%; significant effect: improvement of clinical symptoms and signs scores n≥20% and <40%; effective: improvement of clinical symptoms and signs scores n>20%; ineffective: improvement of clinical symptoms and signs scores n<20%.

[0147] 9.8 Adverse Reactions

[0148] After application, local skin redness and warmth are normal phenomena and will heal naturally within 2-3 days without special treatment. No adverse reactions were observed during the course of treatment, indicating that the medication is safe and its efficacy is stable and reliable.

[0149] 10. Conclusion

[0150] The above experimental data show that the traditional Chinese medicine composition patch prepared in this invention (experimental group) can significantly improve cardiac function and clinical symptoms in patients with chronic heart failure: the experimental group showed significant differences in Lee's heart failure score, TCM syndrome efficacy, and Minnesota heart failure quality of life efficacy compared to Comparative Example 1 (placebo control group). P <0.05).

[0151] Conclusion: The acupoint patch prepared in this invention has been demonstrated in high-quality clinical trials that its optimized formulation and preparation method can overcome the efficacy bottleneck of traditional technologies and serve as an effective adjunct to the treatment of heart failure with traditional Chinese medicine.

[0152] Example 3: Observational Clinical Comparison Data (Comparative Example 2)

[0153] This study observed 20 patients with chronic heart failure and reduced ejection fraction (EF < 50%) hospitalized in the Department of Cardiovascular Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences from May to August 2024. The effects of traditional Chinese medicine (TCM) patch compositions on cardiac function classification were compared. The group ratio was 10:10: [Example 1: Processed Aconitum carmichaelii (after processing): Phytolacca acinosa: Lepidium apetalum: Ligusticum chuanxiong = 2:1:2:3] : [Comparative Example 2: Processed Aconitum carmichaelii (after processing): Phytolacca acinosa: Lepidium apetalum: Ginseng = 2:1:2:3]. In addition to routine Western medicine treatment, patients received patch application of the corresponding herbal composition to the Shenque acupoint for 4 hours daily for 14 consecutive days. SPSS 21.0 software was used, and Fisher's exact test was employed for statistical analysis using a two-tailed test. P <0.05 is statistically significant. Comparing the efficacy rates of the two groups, no significant change in cardiac function: ineffective; improvement of cardiac function by 1 grade: effective; improvement of cardiac function by 2 grades: significantly effective. Example 1 had an efficacy rate of 90%, and Comparative Example 2 had an efficacy rate of 30%. The herbal composition patch of Example 1 has significant advantages (…). P =0.020).

[0154] Table 9. Comparison of cardiac function between the two groups of traditional Chinese medicine combination patches with NYHA.

[0155]

[0156] Example 4: Observational Clinical Comparison Data (Comparative Example 3)

[0157] This study observed 20 patients with chronic heart failure and reduced ejection fraction (EF < 50%) hospitalized in the Department of Cardiovascular Medicine, Xiyuan Hospital, China Academy of Chinese Medical Sciences, from August to October 2024. The effects of a traditional Chinese medicine (TCM) patch composition on the patients' cardiac function classification were compared. The group ratio was 10:10: [Example 1: Processed Aconitum carmichaelii (after processing): Phytolacca acinosa: Lepidium apetalum: Ligusticum chuanxiong = 2:1:2:3] : [Comparative Example 3: Processed Aconitum carmichaelii (after processing): Poria cocos: Lepidium apetalum: Ligusticum chuanxiong = 2:1:2:3]. In addition to routine Western medicine treatment, the patients received patch application of the corresponding herbal composition to the Shenque acupoint for 4 hours daily for 14 consecutive days. SPSS 21.0 software was used, and Fisher's exact test was employed for statistical analysis. A two-tailed test was used, with P < 0.05 considered statistically significant. The effective rates of the two groups were compared. No significant change in cardiac function: ineffective; improvement of cardiac function by 1 grade: effective; improvement of cardiac function by 2 grades: significantly effective. Example 1 showed an efficacy rate of 80%, while Comparative Example 3 showed an efficacy rate of 20%. The herbal composition patch in Example 1 demonstrated a significant advantage (P=0.023).

[0158] Table 10. Comparison of cardiac function between the two groups of traditional Chinese medicine combination patches with NYHA.

[0159] .

Claims

1. A traditional Chinese medicine composition patch for adjuvant treatment of chronic heart failure, characterized in that, It is made from processed aconite, pokeweed, lepidium seed, and chuanxiong; and the ratio of each drug is processed aconite: pokeweed: lepidium seed: chuanxiong = 1.8-2.2:1:1.8-2.2:2.8-3.

2.

2. The traditional Chinese medicine composition plaster as described in claim 1, characterized in that, The ratio of each drug is as follows: processed aconite root: pokeweed: lepidium seed: chuanxiong rhizome = 1.9-2.1:1:1.9-2.1:2.9-3.

1.

3. The traditional Chinese medicine composition plaster as described in claim 2, characterized in that, The ratio of each drug is: processed aconite root: pokeweed: lepidium seed: chuanxiong rhizome = 2:1:2:

3.

4. The method for preparing the traditional Chinese medicine composition plaster according to any one of claims 1 to 3, characterized in that, Weigh out each drug according to the proportion, dry them at 70-80℃, pulverize them into fine powder, mix them evenly, add a binder, mix thoroughly, and then make an ointment.

5. The preparation method according to claim 4, characterized in that, The powder is pulverized into a fine powder and then passed through an 80-mesh sieve; the binder is refined honey and corn oil.

6. The preparation method according to claim 4, characterized in that, The fine powdered medicine, refined honey, and corn oil are mixed in a mass ratio of 12-20:1-5:

1.

7. The preparation method according to claim 6, characterized in that, The mass ratio of fine drug powder, refined honey, and corn oil is 14-18:2-4:

1.

8. The preparation method according to claim 7, characterized in that, The fine powdered medicine, refined honey, and corn oil are mixed in a mass ratio of 16:3:

1.

9. The preparation method according to claim 4, characterized in that, Heat the honey to 110-120℃ until it can be drawn into threads and beads, then cool it to 50-70℃ before use.

10. The preparation method according to claim 4, characterized in that, The ointment was further homogenized using a colloid mill to obtain a paste, with the colloid mill speed being 2000-4000 rpm and the time being 10-30 min.

11. The preparation method according to claim 10, characterized in that, The homogenization speed of the colloid mill is 2500-3500 rpm, and the time is 15-25 min.

12. The preparation method according to claim 11, characterized in that, The homogenization process in the colloid mill was carried out at a speed of 3000 rpm for 20 minutes.

13. The preparation method according to claim 10, characterized in that, Further steps include repackaging and packaging.

14. The preparation method according to claim 13, characterized in that, The patch of the traditional Chinese medicine composition plaster is made of non-woven fabric, with a waterproof membrane pasted in the center of the patch. The ointment is pressed into a core, packaged onto the waterproof membrane, covered with release paper, and made into an acupoint patch. It is then sealed and stored away from light.

15. The preparation method according to claim 14, characterized in that, The patch is cut into a rounded rectangle approximately 5cm x 5cm in length and width. One side of the cut patch is covered with an easy-tear strip approximately 0.5cm wide. A 2.5cm x 2.5cm waterproof membrane is pasted in the center of the patch. The ointment is pressed into a 2.5cm diameter core (1g / patch) and dispensed onto the waterproof membrane of the acupoint patch. The patch is then covered with release paper and sealed and stored away from light.

16. An acupoint patch for adjuvant treatment of chronic heart failure, characterized in that, It is obtained by the preparation method as described in any one of claims 13 to 15.

17. A combination drug for treating chronic heart failure, characterized in that, The application includes the traditional Chinese medicine composition patch as described in any one of claims 1 to 3 or the acupoint patch as described in claim 16, as well as a drug for treating chronic heart failure, wherein the drug for treating chronic heart failure is selected from renin-angiotensin-aldosterone system inhibitors, β-blockers, aldosterone receptor antagonists, sodium-glucose cotransporter 2 inhibitors or soluble guanylate cyclase agonists.

18. The combination medicine for treating chronic heart failure as described in claim 17, characterized in that, The renin-angiotensin-aldosterone system inhibitor is an angiotensin receptor neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin II receptor antagonist; the β-receptor blocker is metoprolol succinate extended-release tablets; the aldosterone receptor antagonist is spironolactone; the sodium-glucose cotransporter 2 inhibitor is dapagliflozin; and the soluble guanylate cyclase agonist is veliximenine.

19. The combination drug for treating chronic heart failure as described in claim 18, characterized in that, The angiotensin receptor neprilysin inhibitor is selected from sacubitril / valsartan; the angiotensin-converting enzyme inhibitor is captopril; and the angiotensin II receptor antagonist is candesartan.

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