Traditional Chinese medicine preparation for treating heart failure and diuretic resistance and preparation method thereof

Abstract

The invention relates to the technical field of traditional Chinese medicine preparations, and particularly discloses a traditional Chinese medicine preparation for treating heart failure and diuretic resistance and a preparation method of the traditional Chinese medicine preparation. The active extract is prepared from the following raw material medicines: astragalus membranaceus, ginseng, cinnamon, salvia miltiorrhiza, red paeony root, radix rehmanniae recen, cassia twig, ligusticum wallichii and pseudo-ginseng. On the basis of a traditional qi-tonifying and blood-activating treatment method, a treatment method for enhancing the effect of dredging collaterals and the effect of nourishing yin is combined, the cinnamon serves as a core monarch drug to warm and tonify yang of the heart and the kidney, and compatibility is scientific; the cortex cinnamomi is used for completely replacing radix aconiti lateralis preparata, so that potential cardiotoxicity and neurotoxicity risks caused by aconitum alkaloids are fundamentally eliminated; the traditional Chinese medicine preparation disclosed by the invention provides a solid guarantee for long-term and safe medication of patients with heart failure, is more suitable for treating intractable and complicated heart failure, and has a good clinical application value.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparations, specifically to a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance and its preparation method. Background Technology

[0002] Heart failure (HF) is the end-stage of many heart diseases, and its morbidity and mortality rates are rising year by year, making it a major global public health problem. Diuretics are one of the core drugs for treating heart failure, especially for relieving volume overload. However, in clinical practice, approximately 20%-30% of heart failure patients develop diuretic resistance during treatment, meaning a weakened diuretic and sodium excretion effect of conventional or even high-dose diuretics. This leads to difficulty in correcting water and sodium retention, worsening of symptoms such as dyspnea and edema, frequent readmissions, and a very poor prognosis.

[0003] Current interventions for diuretic resistance are limited, mainly including the combined use of diuretics with different mechanisms of action, short-term use of vasoactive drugs or renal replacement therapy, etc. However, these methods are often accompanied by risks such as electrolyte disturbances, renal function deterioration and hemodynamic instability, and have failed to fundamentally improve cardiac function and neuroendocrine activation.

[0004] Traditional Chinese medicine (TCM) theory holds that the fundamental pathogenesis of heart failure lies in "deficiency of the root and excess of the branch." The root deficiency refers to a deficiency of Qi and Yang in the heart, spleen, kidneys, and other organs, leading to weakened functions in promoting blood circulation and regulating fluid metabolism. The branch excess refers to the internal retention of pathological products such as fluid retention, phlegm, and blood stasis. Current TCM prescriptions largely follow the principle of "tonifying Qi and warming Yang, promoting blood circulation and diuresis." For example, they use Astragalus membranaceus, ginseng, and Aconitum carmichaelii to tonify Qi and warm Yang, combined with Poria cocos and Alisma plantago-aquatica to promote diuresis, and Salvia miltiorrhiza and Paeonia lactiflora to promote blood circulation. These methods have achieved certain clinical efficacy.

[0005] However, after in-depth research, the inventors discovered that the existing technical solutions still have the following shortcomings: 1. Insufficient application of the "collateral disease" theory: The prolonged course of heart failure, with its long-term deficiency of Qi and Yang, inevitably leads to blood stasis, deep-seated blood stasis, and obstruction of the heart vessels. This "collateral stasis" formed by "prolonged illness entering the collaterals" is an important pathological basis for refractory heart failure and diuretic resistance. However, existing prescriptions still lack consideration for powerfully clearing the collaterals, expelling pathogens, and directly reaching the site of the disease.

[0006] 2. Easily depletes Yin fluids, leading to Yin-Yang imbalance: In order to achieve rapid effects, current prescriptions often heavily use strong, pungent, and hot herbs such as processed aconite and cinnamon twig to warm Yang and promote diuresis. However, such drugs easily deplete Yin fluids. Heart failure patients already have a pathological state of Qi and Yin deficiency. Long-term or excessive use of warming and drying drugs may aggravate the Yin-Yang imbalance, manifesting as symptoms such as dry mouth, irritability, and a red tongue with little saliva, making the condition more complicated.

[0007] 3. Potential safety risks exist: The main component of processed aconite root, widely used in existing technologies, is aconitine alkaloids. Although processing can significantly reduce its toxicity, the toxic-efficacy dose remains close, resulting in a narrow therapeutic window. Improper clinical application or individual patient differences may still induce severe cardiotoxicity (such as arrhythmias) and neurotoxicity, greatly limiting its use in patients with chronic heart failure requiring long-term medication, especially elderly patients with impaired liver or kidney function, where the safety risks are even higher.

[0008] 4. Low Bioavailability Due to Traditional Preparation Processes: Most existing traditional Chinese medicine preparations employ the traditional decoction method. While this method is acceptable for extracting water-soluble components, it has low extraction efficiency for volatile oils in herbs such as cinnamon twig and chuanxiong rhizome, as well as saponins and fat-soluble components (such as tanshinone, notoginsenosides, and ginsenosides) in herbs like danshen, sanqi, and ginseng. Furthermore, most saponins are large-molecule proto-saponins, which are poorly absorbed in the intestines after oral administration and are easily destroyed by the first-pass effect in the liver. This results in extremely low concentrations of effective components actually entering the bloodstream, making it difficult to reach the effective therapeutic threshold and thus affecting the final clinical efficacy.

[0009] Based on the above statements, this invention proposes a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance and its preparation method. Summary of the Invention

[0010] To address the technical problems of existing traditional Chinese medicine (TCM) preparations for treating heart failure with diuretic resistance, such as insufficient application of collaterals theory, easy depletion of Yin fluid leading to Yin-Yang imbalance, potential safety risks, and low bioavailability of core active ingredients due to traditional preparation processes, this invention proposes a TCM preparation for treating heart failure with diuretic resistance and its preparation method. This invention features a rigorous formulation, combining collaterals-clearing and Yin-nourishing methods with existing TCM formulas. It replaces processed aconite root (Cinnamomum cassia) commonly used in traditional formulas with cinnamon, and integrates a two-step microbial fermentation process with a self-nanoemulsification delivery system, effectively improving in vivo absorption and delivery of the drug. Compared with traditional processes, this increases the bioavailability of the core active ingredients, thereby contributing to improved clinical efficacy and safety.

[0011] In a first aspect, the present invention provides a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, employing the following technical solution: A traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising an active extract and pharmaceutically acceptable excipients; The active extract is prepared from the following raw materials in parts by weight: Astragalus membranaceus 20-40 parts, Ginseng 5-15 parts, Cinnamomum cassia 5-15 parts, Salvia miltiorrhiza 10-20 parts, Paeonia lactiflora 10-20 parts, Rehmannia glutinosa 10-20 parts, Cinnamomum cassia twig 3-9 parts, Ligusticum chuanxiong 5-15 parts, Panax notoginseng 3-9 parts.

[0012] Preferably, the active extract is prepared from the following raw materials in parts by weight: 30 parts Astragalus membranaceus, 10 parts Ginseng, 10 parts Cinnamomum cassia, 15 parts Salvia miltiorrhiza, 15 parts Paeonia lactiflora, 15 parts Rehmannia glutinosa, 6 parts Cinnamomum cassia, 10 parts Ligusticum chuanxiong, and 6 parts Panax notoginseng.

[0013] The formula of this invention is based on the rigorous combination of principal, assistant, adjuvant, and guide herbs according to traditional Chinese medicine theory: Astragalus, ginseng, and cinnamon are the principal herbs. Astragalus and ginseng greatly replenish vital energy, strengthen the heart and replenish qi, and support the body's resistance. Cinnamon is pungent, sweet, and very hot, replenishing fire and assisting yang, and warming and unblocking the blood vessels. This invention replaces processed aconite, which is commonly used in traditional prescriptions, with cinnamon, achieving the same effect of warming and tonifying the heart and kidney yang, while completely avoiding the toxicity risk of aconite alkaloids from the source.

[0014] The formula uses Danshen (Salvia miltiorrhiza), Chishao (Paeonia lactiflora), Chuanxiong (Ligusticum chuanxiong), and Sanqi (Panax notoginseng) as assistant herbs. Danshen and Chishao invigorate blood circulation, remove blood stasis, cool the blood, and clear the heart; Chuanxiong is a "qi-regulating herb in the blood," invigorating blood and promoting qi circulation; Sanqi is a hemostatic herb that also invigorates blood circulation and unblocks the collaterals. The four herbs work together to powerfully invigorate blood circulation, remove blood stasis, and unblock the micro-collaterals of the heart, targeting the "collateral stasis" of "prolonged illness entering the collaterals," thereby improving intractable edema and restoring sensitivity to diuretics.

[0015] Cinnamon twig and Rehmannia root are used as adjuvant herbs. Cinnamon twig is pungent, sweet, and warm, warming and unblocking the meridians, assisting yang and transforming qi. It can not only assist the principal herb in warming and unblocking the heart yang, but also guide the other herbs to reach the extremities. Rehmannia root is sweet and cold, nourishing yin and cooling the blood, nourishing yin and generating fluids. In this formula, Rehmannia root is added to the herbs that tonify qi, warm yang, and invigorate blood, aiming to restrain the warming and drying properties of cinnamon twig and cinnamon bark, and prevent the depletion of yin fluids. This reflects the compatibility concept of "tonifying qi and nourishing yin" and "seeking yang within yin," making the whole formula warm without being drying and tonifying without being stagnant.

[0016] The entire formula uses Astragalus and Ginseng to invigorate Qi, allowing the other herbs to ascend and act as guiding herbs. When used together, the herbs work synergistically to invigorate Qi and warm Yang, promote blood circulation and unblock the meridians, nourish Yin and promote diuresis, forming a comprehensive treatment plan of "strengthening the body's resistance, eliminating pathogens, unblocking the meridians, and harmonizing the body," and the overall formula has a higher safety profile.

[0017] Preferably, the ginseng is red ginseng or sun-dried ginseng.

[0018] Preferably, the mass ratio of the active extract to the pharmaceutically acceptable excipient is 1:2-5.

[0019] Preferably, the pharmaceutically acceptable excipients include an oil phase, a surfactant, and a co-surfactant in a mass ratio of 2-4:3-6:1-3.

[0020] Preferably, the oil phase is at least one of ethyl oleate, medium-chain triglycerides, and castor oil.

[0021] Preferably, the surfactant is at least one of Tween-80, polyoxyethylene castor oil, and poloxamer 188.

[0022] Preferably, the co-surfactant is at least one of propylene glycol, ethanol, and polyethylene glycol 400.

[0023] Preferably, the dosage form of the traditional Chinese medicine preparation is oral liquid, capsule, granule or pill, which is convenient for patients to take and improves compliance.

[0024] Preferably, the dosage form of the traditional Chinese medicine preparation is a soft capsule, which is convenient for encapsulation from the nanoemulsion pre-concentrated liquid.

[0025] Secondly, the present invention provides a method for preparing a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, using the following technical solution: A method for preparing a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising the following steps: S1. Take the prescribed amounts of Astragalus membranaceus, ginseng and Panax notoginseng, combine and crush them, sterilize and adjust the moisture to obtain material A, inoculate Aspergillus oryzae for solid-state fermentation, and obtain the initial fermentation product. S2. The initial fermentation product is mixed with cinnamon, salvia miltiorrhiza, red peony root, rehmannia root, cinnamon twig and chuanxiong to obtain a mixture. After sterilization with water, the mixture is used to obtain material B. Bifidobacterium longum is inoculated for anaerobic fermentation to obtain the final fermentation product. S3. After reflux extraction with ethanol solution, the fermentation end product is filtered, concentrated under reduced pressure, and dried to obtain the active extract. S4. Mix and dissolve the active extract with pharmaceutically acceptable excipients, then encapsulate to obtain a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance.

[0026] Preferably, the material in S1 is pulverized through an 80-100 mesh sieve.

[0027] Preferably, the viable count of Aspergillus oryzae in material A of S1 is 1.8 × 10⁻⁶. 7 -3.5×10 7 CFU / g.

[0028] Preferably, the solid-state fermentation temperature in S1 is 28-32℃, the relative humidity is 80-90%, and the time is 60-72h.

[0029] Preferably, the viable count of Bifidobacterium longum in material B of S2 is 4.3 × 10⁻⁶. 7 -5.0×10 7 CFU / g.

[0030] Preferably, the anaerobic fermentation temperature in S2 is 35-39℃, the stirring speed is 300-500rpm, and the time is 40-50h.

[0031] Preferably, the reflux extraction in S3 specifically refers to: adding the fermentation end product to an ethanol solution with a mass of 6-10 times and a volume concentration of 70-80%, and refluxing at 60-70℃ for 2-3 times, each time for 1-1.5 hours, and combining the extracts.

[0032] Preferably, the vacuum concentration in S3 refers to: concentrating the extract under vacuum at a vacuum degree of -0.07 to -0.09 MPa and a temperature of 55-65°C to a relative density of 1.15-1.25 (measured at 60°C).

[0033] Preferably, the drying in S3 refers to vacuum drying at 50-70°C for 20-24 hours.

[0034] In summary, the present invention has the following beneficial effects: 1. This invention, based on traditional methods of invigorating qi and promoting blood circulation, integrates the effects of enhancing the flow of qi and blood (Panax notoginseng and Ligusticum chuanxiong) with the effects of nourishing yin (Rehmannia glutinosa), and uses cinnamon to warm and tonify the yang of the heart and kidneys. The entire formula is rationally combined. This invention uses cinnamon instead of processed aconite, which is commonly used in traditional formulas, fundamentally avoiding the potential cardiotoxicity and neurotoxicity risks of aconitine alkaloids. This provides a guarantee for long-term, safe medication for patients with heart failure, and is especially suitable for the treatment of refractory and complex heart failure.

[0035] 2. The two-step fermentation process employed in this invention, combining solid-state fermentation with *Aspergillus oryzae* and liquid fermentation with *Bifidobacterium longum*, effectively transforms large-molecule proto-saponins (such as ginsenoside Rb1 and notoginsenoside R1) in the medicinal matrix, which are difficult for the human body to absorb, into highly active, highly lipid-soluble rare saponins (such as ginsenoside CK). The rare saponins obtained through biotransformation have smaller molecular weights and stronger lipid solubility, enabling them to penetrate intestinal cell membranes via passive diffusion. This significantly improves their oral bioavailability, enhances efficacy, and improves quality stability, thus fundamentally solving the absorption problem of saponin components in traditional Chinese medicine.

[0036] 3. This invention combines a biotransformed active extract with a self-nanoemulsifying drug delivery system. After oral administration, this formulation spontaneously forms uniform nano-sized droplets under the influence of gastrointestinal motility and digestive juices. These nano-droplets effectively promote drug absorption through the intestinal lymphatic system, thereby significantly mitigating the first-pass effect of the liver and ensuring that more absorbed active ingredients enter the systemic circulation unchanged, further improving the absolute bioavailability of the drug.

[0037] 4. The traditional Chinese medicine preparation of this invention can significantly increase left ventricular ejection fraction (LVEF) and reduce serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Through multiple mechanisms, including strengthening the heart, improving renal blood perfusion, and regulating neuroendocrine function, it effectively restores the body's sensitivity to diuretics. Compared with traditional preparations, the preparation of this invention has a faster onset of action, better efficacy, and a significantly improved overall clinical effective rate. Furthermore, the combination of Rehmannia glutinosa and cinnamon effectively balances the drying properties of the warming herbs, fundamentally eliminating the potential cardiotoxicity and neurotoxicity risks associated with aconite alkaloids, and reducing the risk of side effects from long-term use. Detailed Implementation

[0038] The present invention will be further described in detail below with reference to the embodiments.

[0039] For experiments not specifically described in the examples, the procedures or conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0040] Examples 1-3 provide a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance and its preparation method.

[0041] Example 1 A traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising an active extract and pharmaceutically acceptable excipients in a mass ratio of 1:5. The active extract is made from the following raw materials in parts by weight: Astragalus membranaceus 20 parts, red ginseng 5 parts, cinnamon 5 parts, salvia miltiorrhiza 10 parts, red peony root 10 parts, rehmannia glutinosa 10 parts, cinnamon twig 3 parts, chuanxiong rhizome 5 parts, and notoginseng 3 parts. Pharmaceutically acceptable excipients include castor oil, Tween-80, and propylene glycol in a mass ratio of 2:6:1.

[0042] A method for preparing a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising the following steps: S1. Take the prescribed amounts of Astragalus membranaceus, red ginseng, and Panax notoginseng, combine and pulverize them, pass through a 100-mesh sieve, sterilize at 121℃ for 30 minutes using moist heat, adjust the moisture content to 55% with sterile water, and cool to 35℃ to obtain material A. Place material A in a solid-state fermentation tank and inoculate it with Aspergillus oryzae (product number TS333862, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of Aspergillus oryzae in material A is 1.8 × 10⁻⁶. 7 CFU / g was subjected to solid-state fermentation at 28℃ and 90% relative humidity for 72 hours to obtain the initial fermentation product. S2. The initial fermentation product is mixed with the prescribed amounts of cinnamon, salvia miltiorrhiza, red peony root, rehmannia root, cinnamon twig, and chuanxiong rhizome to obtain a mixture. Five times the weight of the mixture is added to sterile water, and the mixture is sterilized by moist heat at 121℃ for 30 minutes. After cooling to 38℃, material B is obtained. Material B is transferred to a liquid fermentation tank and inoculated with *Bifidobacterium longum* (product number TS349600, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of *Bifidobacterium longum* in material B is 4.3 × 10⁻⁶. 7 The fermentation end product was obtained by stirring and culturing at 300 rpm for 50 h at a temperature of 35℃ and anaerobic conditions with CFU / g. S3. Add 10 times the mass of the fermentation end product to an ethanol solution with a volume concentration of 70%, and reflux extract three times at 60℃ for 1.5h each time. Combine the extracts, filter, and concentrate the filtrate under reduced pressure at a vacuum degree of -0.09MPa and a temperature of 55℃ to obtain an extract with a relative density of 1.15 (measured at 60℃). Dry the extract under vacuum at 50℃ for 24h to obtain the active extract. S4. Mix the active extract with pharmaceutically acceptable excipients and magnetically stir in a 40°C water bath until completely dissolved to form a homogeneous self-nanoemulsion pre-concentrated solution. Encapsulate the self-nanoemulsion pre-concentrated solution into soft capsules at a dosage of 0.5g per capsule to obtain a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance.

[0043] Example 2 A traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising an active extract and pharmaceutically acceptable excipients in a mass ratio of 1:3.5; The active extract is made from the following raw materials in parts by weight: Astragalus membranaceus 30 parts, red ginseng 10 parts, cinnamon 10 parts, salvia miltiorrhiza 15 parts, red peony root 15 parts, rehmannia glutinosa 15 parts, cinnamon twig 6 parts, chuanxiong rhizome 10 parts, and notoginseng 6 parts. Pharmaceutically acceptable excipients include castor oil, Tween-80, and propylene glycol in a mass ratio of 3:4.5:1.5.

[0044] A method for preparing a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising the following steps: S1. Take the prescribed amounts of Astragalus membranaceus, red ginseng, and Panax notoginseng, combine and pulverize them, pass through an 80-mesh sieve, sterilize by moist heat at 121℃ for 30 minutes, adjust the moisture content to 50% with sterile water, cool to 30℃, and obtain material A. Place material A in a solid-state fermentation tank and inoculate it with Aspergillus oryzae (product number TS333862, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of Aspergillus oryzae in material A is 2.5 × 10⁻⁶. 7 CFU / g was subjected to solid-state fermentation at 30℃ and 85% relative humidity for 66 hours to obtain the initial fermentation product. S2. The initial fermentation product is mixed with the prescribed amounts of cinnamon, salvia miltiorrhiza, red peony root, rehmannia root, cassia twig, and chuanxiong rhizome to obtain a mixture. Four times the weight of the mixture is added to sterile water, and the mixture is sterilized by moist heat at 121℃ for 30 minutes. After cooling to 35℃, material B is obtained. Material B is transferred to a liquid fermentation tank and inoculated with *Bifidobacterium longum* (product number TS349600, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of *Bifidobacterium longum* in material B is 4.6 × 10⁻⁶. 7 The fermentation end product was obtained by stirring and culturing at 400 rpm for 45 h at a temperature of 37℃ and anaerobic conditions with CFU / g. S3. Add 8 times the mass of the fermentation end product to an ethanol solution with a volume concentration of 75%, and reflux extract twice at 65℃ for 1.5h each time. Combine the extracts, filter, and concentrate the filtrate under reduced pressure at a vacuum degree of -0.08MPa and a temperature of 60℃ to a paste with a relative density of 1.20 (measured at 60℃). Dry the paste under vacuum at 60℃ for 22h to obtain the active extract. S4. Mix the active extract with pharmaceutically acceptable excipients and stir magnetically in a 45°C water bath until completely dissolved to form a homogeneous self-nanoemulsion pre-concentrated solution. Encapsulate the self-nanoemulsion pre-concentrated solution into soft capsules at a dosage of 0.5g per capsule to obtain a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance.

[0045] Example 3 A traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising an active extract and pharmaceutically acceptable excipients in a mass ratio of 1:2. The active extract is made from the following raw materials in parts by weight: Astragalus membranaceus 40 parts, red ginseng 15 parts, cinnamon 15 parts, salvia miltiorrhiza 20 parts, red peony root 20 parts, rehmannia glutinosa 20 parts, cinnamon twig 9 parts, chuanxiong rhizome 15 parts, and notoginseng 9 parts. Pharmaceutically acceptable excipients include castor oil, Tween-80, and propylene glycol in a mass ratio of 4:3:3.

[0046] A method for preparing a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising the following steps: S1. Take the prescribed amounts of Astragalus membranaceus, red ginseng, and Panax notoginseng, combine and pulverize them, pass through an 80-mesh sieve, sterilize by moist heat at 121℃ for 30 minutes, adjust the moisture content to 60% with sterile water, cool to 40℃ to obtain material A. Place material A in a solid-state fermentation tank and inoculate it with Aspergillus oryzae (product number TS333862, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of Aspergillus oryzae in material A is 3.5 × 10⁻⁶. 7 CFU / g was subjected to solid-state fermentation at 32℃ and 80% relative humidity for 60 hours to obtain the initial fermentation product; S2. The initial fermentation product is mixed with the prescribed amounts of cinnamon, salvia miltiorrhiza, red peony root, rehmannia root, cassia twig, and chuanxiong rhizome to obtain a mixture. Three times the weight of the mixture is added to sterile water, and the mixture is sterilized by moist heat at 121℃ for 30 minutes. After cooling to 40℃, material B is obtained. Material B is transferred to a liquid fermentation tank and inoculated with *Bifidobacterium longum* (product number TS349600, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of *Bifidobacterium longum* in material B is 5.0 × 10⁻⁶. 7 The fermentation end product was obtained by stirring and culturing at 500 rpm for 40 h at a temperature of 39℃ and anaerobic conditions. S3. Add 6 times the mass of the fermentation end product to an 80% ethanol solution, and reflux extract twice at 70℃ for 1 hour each time. Combine the extracts, filter, and concentrate the filtrate under reduced pressure at -0.07MPa and 65℃ to a paste with a relative density of 1.25 (measured at 60℃). Dry the paste under vacuum at 70℃ for 20 hours to obtain the active extract. S4. Mix the active extract with pharmaceutically acceptable excipients and magnetically stir in a 50°C water bath until completely dissolved to form a homogeneous self-nanoemulsion pre-concentrated solution. Encapsulate the self-nanoemulsion pre-concentrated solution into soft capsules at a dosage of 0.5g per capsule to obtain a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance.

[0047] To verify the comprehensive efficacy of the traditional Chinese medicine preparation provided by this invention for treating heart failure complicated with diuretic resistance, comparative examples 1-5 were set up, wherein: Comparative Example 1 Comparative Example 1 is the same as Example 2, except that the weight of Panax notoginseng is replaced with Ligusticum chuanxiong. Details are as follows: A traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising an active extract and pharmaceutically acceptable excipients in a mass ratio of 1:3.5; The active extract is made from the following raw materials in parts by weight: Astragalus membranaceus 30 parts, red ginseng 10 parts, cinnamon 10 parts, salvia miltiorrhiza 15 parts, red peony root 15 parts, rehmannia glutinosa 15 parts, cinnamon twig 6 parts, and chuanxiong rhizome 16 parts. Pharmaceutically acceptable excipients include castor oil, Tween-80, and propylene glycol in a mass ratio of 3:4.5:1.5.

[0048] A method for preparing a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising the following steps: S1. Take the prescribed amounts of Astragalus membranaceus and red ginseng, combine and pulverize them, pass through an 80-mesh sieve, sterilize at 121℃ for 30 minutes using moist heat, adjust the moisture content to 50% with sterile water, and cool to 30℃ to obtain material A. Place material A in a solid-state fermentation tank and inoculate it with Aspergillus oryzae (product number TS333862, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of Aspergillus oryzae in material A is 2.5 × 10⁻⁶. 7 CFU / g was subjected to solid-state fermentation at 30℃ and 85% relative humidity for 66 hours to obtain the initial fermentation product. S2. The initial fermentation product is mixed with the prescribed amounts of cinnamon, salvia miltiorrhiza, red peony root, rehmannia root, cassia twig, and chuanxiong rhizome to obtain a mixture. Four times the weight of the mixture is added to sterile water, and the mixture is sterilized by moist heat at 121℃ for 30 minutes. After cooling to 35℃, material B is obtained. Material B is transferred to a liquid fermentation tank and inoculated with *Bifidobacterium longum* (product number TS349600, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of *Bifidobacterium longum* in material B is 4.6 × 10⁻⁶. 7 The fermentation end product was obtained by stirring and culturing at 400 rpm for 45 h at a temperature of 37℃ and anaerobic conditions with CFU / g. S3. Add 8 times the mass of the fermentation end product to an ethanol solution with a volume concentration of 75%, and reflux extract twice at 65℃ for 1.5h each time. Combine the extracts, filter, and concentrate the filtrate under reduced pressure at a vacuum degree of -0.08MPa and a temperature of 60℃ to a paste with a relative density of 1.20 (measured at 60℃). Dry the paste under vacuum at 60℃ for 22h to obtain the active extract. S4. Mix the active extract with pharmaceutically acceptable excipients and stir magnetically in a 45°C water bath until completely dissolved to form a homogeneous self-nanoemulsion pre-concentrated solution. Encapsulate the self-nanoemulsion pre-concentrated solution into soft capsules at a dosage of 0.5g per capsule to obtain a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance.

[0049] Comparative Example 2 Comparative Example 2 is the same as Example 2, except that the amount of Rehmannia glutinosa is replaced with Cinnamomum cassia. Details are as follows: A traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising an active extract and pharmaceutically acceptable excipients in a mass ratio of 1:3.5; The active extract is made from the following raw materials in parts by weight: Astragalus membranaceus 30 parts, red ginseng 10 parts, cinnamon 10 parts, salvia miltiorrhiza 15 parts, red peony root 15 parts, cinnamon twig 21 parts, chuanxiong rhizome 10 parts, and notoginseng 6 parts. Pharmaceutically acceptable excipients include castor oil, Tween-80, and propylene glycol in a mass ratio of 3:4.5:1.5.

[0050] A method for preparing a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising the following steps: S1. Take the prescribed amounts of Astragalus membranaceus, red ginseng, and Panax notoginseng, combine and pulverize them, pass through an 80-mesh sieve, sterilize by moist heat at 121℃ for 30 minutes, adjust the moisture content to 50% with sterile water, cool to 30℃, and obtain material A. Place material A in a solid-state fermentation tank and inoculate it with Aspergillus oryzae (product number TS333862, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of Aspergillus oryzae in material A is 2.5 × 10⁻⁶. 7 CFU / g was subjected to solid-state fermentation at 30℃ and 85% relative humidity for 66 hours to obtain the initial fermentation product. S2. The initial fermentation product is mixed with the prescribed amounts of cinnamon, salvia miltiorrhiza, red peony root, cassia twig, and chuanxiong rhizome to obtain a mixture. Four times the weight of the mixture is added to sterile water, and the mixture is sterilized by moist heat at 121℃ for 30 minutes. After cooling to 35℃, material B is obtained. Material B is transferred to a liquid fermentation tank and inoculated with *Bifidobacterium longum* (product number TS349600, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of *Bifidobacterium longum* in material B is 4.6 × 10⁻⁶. 7 The fermentation end product was obtained by stirring and culturing at 400 rpm for 45 h at a temperature of 37℃ and anaerobic conditions with CFU / g. S3. Add 8 times the mass of the fermentation end product to an ethanol solution with a volume concentration of 75%, and reflux extract twice at 65℃ for 1.5h each time. Combine the extracts, filter, and concentrate the filtrate under reduced pressure at a vacuum degree of -0.08MPa and a temperature of 60℃ to a paste with a relative density of 1.20 (measured at 60℃). Dry the paste under vacuum at 60℃ for 22h to obtain the active extract. S4. Mix the active extract with pharmaceutically acceptable excipients and stir magnetically in a 45°C water bath until completely dissolved to form a homogeneous self-nanoemulsion pre-concentrated solution. Encapsulate the self-nanoemulsion pre-concentrated solution into soft capsules at a dosage of 0.5g per capsule to obtain a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance.

[0051] Comparative Example 3 Comparative Example 3 is the same as Example 2, except that the two-step fermentation process is replaced with a single-step mixed fermentation process. Details are as follows: A traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising an active extract and pharmaceutically acceptable excipients in a mass ratio of 1:3.5; The active extract is made from the following raw materials in parts by weight: Astragalus membranaceus 30 parts, red ginseng 10 parts, cinnamon 10 parts, salvia miltiorrhiza 15 parts, red peony root 15 parts, rehmannia glutinosa 15 parts, cinnamon twig 6 parts, chuanxiong rhizome 10 parts, and notoginseng 6 parts. Pharmaceutically acceptable excipients include castor oil, Tween-80, and propylene glycol in a mass ratio of 3:4.5:1.5.

[0052] A method for preparing a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising the following steps: S1. Take the prescribed amounts of Astragalus membranaceus, red ginseng, cinnamon, Salvia miltiorrhiza, Paeonia lactiflora, Rehmannia glutinosa, Cinnamomum cassia, Ligusticum chuanxiong, and Panax notoginseng, combine and pulverize them, pass them through an 80-mesh sieve to obtain mixed medicinal powder, add 4 times the mass of the mixed medicinal powder to sterile water, sterilize at 121℃ for 30 minutes with moist heat, cool to 35℃, and obtain material C. S2. Transfer material C into a liquid fermentation tank, and simultaneously inoculate with *Aspergillus oryzae* (product number TS333862, purchased from Ningbo Taiste Biotechnology Co., Ltd.) and *Bifidobacterium longum* (product number TS349600, purchased from Ningbo Taiste Biotechnology Co., Ltd.), so that the viable count of *Aspergillus oryzae* in material C is 2.5 × 10⁻⁶. 7 The CFU / g and viable count of Bifidobacterium longum were 4.6 × 10⁻⁶. 7 The fermentation final product was obtained by stirring and culturing at 400 rpm for 111 h under anaerobic conditions at 37℃ with CFU / g (based on the total weight of dry medicinal materials). S3. Add 8 times the mass of the fermentation end product to an ethanol solution with a volume concentration of 75%, and reflux extract twice at 65℃ for 1.5h each time. Combine the extracts, filter, and concentrate the filtrate under reduced pressure at a vacuum degree of -0.08MPa and a temperature of 60℃ to a paste with a relative density of 1.20 (measured at 60℃). Dry the paste under vacuum at 60℃ for 22h to obtain the active extract. S4. Mix the active extract with pharmaceutically acceptable excipients and stir magnetically in a 45°C water bath until completely dissolved to form a homogeneous self-nanoemulsion pre-concentrated solution. Encapsulate the self-nanoemulsion pre-concentrated solution into soft capsules at a dosage of 0.5g per capsule to obtain a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance.

[0053] Comparative Example 4 Comparative Example 4 was the same as Example 2, except that the pharmaceutically acceptable excipients were replaced with microcrystalline cellulose and corn starch by mass, and the tablets were compressed into ordinary tablets. Details are as follows: A traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising an active extract and pharmaceutically acceptable excipients in a mass ratio of 1:3.5; The active extract is made from the following raw materials in parts by weight: Astragalus membranaceus 30 parts, red ginseng 10 parts, cinnamon 10 parts, salvia miltiorrhiza 15 parts, red peony root 15 parts, rehmannia glutinosa 15 parts, cinnamon twig 6 parts, chuanxiong rhizome 10 parts, and notoginseng 6 parts. Pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, and magnesium stearate in a mass ratio of 1.5:0.5:0.02.

[0054] A method for preparing a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising the following steps: S1. Take the prescribed amounts of Astragalus membranaceus, red ginseng, and Panax notoginseng, combine and pulverize them, pass through an 80-mesh sieve, sterilize by moist heat at 121℃ for 30 minutes, adjust the moisture content to 50% with sterile water, cool to 30℃, and obtain material A. Place material A in a solid-state fermentation tank and inoculate it with Aspergillus oryzae (product number TS333862, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of Aspergillus oryzae in material A is 2.5 × 10⁻⁶. 7 CFU / g was subjected to solid-state fermentation at 30℃ and 85% relative humidity for 66 hours to obtain the initial fermentation product. S2. The initial fermentation product is mixed with the prescribed amounts of cinnamon, salvia miltiorrhiza, red peony root, rehmannia root, cassia twig, and chuanxiong rhizome to obtain a mixture. Four times the weight of the mixture is added to sterile water, and the mixture is sterilized by moist heat at 121℃ for 30 minutes. After cooling to 35℃, material B is obtained. Material B is transferred to a liquid fermentation tank and inoculated with *Bifidobacterium longum* (product number TS349600, purchased from Ningbo Taisto Biotechnology Co., Ltd.) until the viable count of *Bifidobacterium longum* in material B is 4.6 × 10⁻⁶. 7 The fermentation end product was obtained by stirring and culturing at 400 rpm for 45 h at a temperature of 37℃ and anaerobic conditions with CFU / g. S3. Add 8 times the mass of the fermentation end product to an ethanol solution with a volume concentration of 75%, and reflux extract twice at 65℃ for 1.5h each time. Combine the extracts, filter, and concentrate the filtrate under reduced pressure at a vacuum degree of -0.08MPa and a temperature of 60℃ to a paste with a relative density of 1.20 (measured at 60℃). Dry the paste under vacuum at 60℃ for 22h to obtain the active extract. S4. Place the active extract, the prescribed amount of microcrystalline cellulose, and lactose in a three-dimensional mixer and mix at 250 rpm for 20 minutes until homogeneous. Then add the prescribed amount of magnesium stearate and mix for 5 minutes. Use a rotary tablet press to compress the mixed powder into tablets. Control the tablet weight so that the mass of active extract contained in each tablet is equivalent to the mass of active extract contained in each soft capsule in Example 2, thus obtaining a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance.

[0055] Comparative Example 5 Comparative Example 5 is the same as Example 2, except that it does not use fermentation treatment, but only a traditional extraction process. Details are as follows: A traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising an active extract and pharmaceutically acceptable excipients in a mass ratio of 1:3.5; Among them, the active extract is prepared from the following raw medicinal materials in parts by weight: 30 parts of Astragalus membranaceus, 10 parts of red ginseng, 10 parts of cinnamon, 15 parts of Salvia miltiorrhiza, 15 parts of Paeonia lactiflora, 15 parts of Rehmannia glutinosa, 6 parts of Ramulus Cinnamomi, 10 parts of Ligusticum wallichii, and 6 parts of Panax notoginseng; Pharmaceutically acceptable excipients include castor oil, Tween - 80 and propylene glycol with a mass ratio of 3:4.5:1.5.

[0056] A preparation method of a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, comprising the following steps: S1. Take the formula amount of Astragalus membranaceus, red ginseng, cinnamon, Salvia miltiorrhiza, Paeonia lactiflora, Rehmannia glutinosa, Ramulus Cinnamomi, Ligusticum wallichii, and Panax notoginseng, combine and pulverize, and pass through an 80 - mesh sieve to obtain a mixed medicinal powder; S2. Add 8 times the mass of the mixed medicinal powder of an ethanol solution with a volume concentration of 75%, reflux and extract twice at 65°C for 1.5 h each time. Combine the extracts, filter, and concentrate the filtrate under reduced pressure at a vacuum degree of - 0.08 MPa and a temperature of 60°C to an extract with a relative density of 1.20 (measured at 60°C). Vacuum - dry the extract at 60°C for 22 h to obtain the active extract; S3. Mix the active extract with pharmaceutically acceptable excipients, stir magnetically in a 45°C water bath until completely dissolved to form a homogeneous self - nano - emulsifying pre - concentrate, and encapsulate the self - nano - emulsifying pre - concentrate into soft capsules according to a loading amount of 0.5 g per capsule, thus obtaining the traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance.

[0057] Test the comprehensive efficacy of the traditional Chinese medicine preparations for treating heart failure complicated with diuretic resistance prepared in Examples 1 - 3 and Comparative Examples 1 - 5 of the present invention respectively.

[0058] I. Animal experiment 1. Model establishment and grouping: Take 180 healthy male SD rats with a body weight of 200 - 220 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., and the experimental animal production license number: SCXK (Beijing) 2016 - 0006. Establish a heart failure model by ligating the left anterior descending branch of the coronary artery. Four weeks after the operation, confirm that LVEF < 40% by echocardiography to indicate successful model establishment. The rats after successful model establishment were intraperitoneally injected with furosemide (20 mg / kg) daily for 8 consecutive weeks to establish a diuretic resistance model (with the standard that the 24 - h urine volume is significantly lower than that of normal rats, that is, 24 - h urine volume < 10 ml). The successfully modeled animals were divided into a control group, Example 1 - 3 groups, and Comparative Example 1 - 5 groups according to the random number table method, with 20 animals in each group.

[0059] 2. Administration method: After the rat model was successfully established, each group of rats was given the drug. The control group was given an equal volume of physiological saline, while the groups of Examples 1-3 and Comparative Examples 1-5 were given the corresponding prepared traditional Chinese medicine preparations (the dosage was calculated based on the human equivalent dose, and the raw drug amount was 10g / kg), which were administered by gavage twice a day for 6 consecutive weeks.

[0060] 3. Observation indicators: (1) Cardiac function indicators: The left ventricular ejection fraction (LVEF) was measured by color Doppler ultrasound of the small animal heart before and after treatment.

[0061] (2) Serological indicators: Blood was collected from the orbital venous plexus before and after treatment, plasma was separated, and serum N-terminal pro-B-type brain natriuretic peptide (NT-proBNP) levels were detected by ELISA.

[0062] 4. Statistical methods: SPSS 22.0 software was used for data analysis. Quantitative data were expressed as mean ± standard deviation (x ± s). One-way ANOVA was used for comparisons among multiple groups, and LSD-t test was used for pairwise comparisons between groups. P < 0.05 was considered statistically significant.

[0063] The test results are shown in Table 1: Table 1: Comparison of the efficacy of traditional Chinese medicine preparations in Examples 1-3 and Comparative Examples 1-5 after 6 weeks of treatment Note: Compared with the control group, P<0.05, P<0.01; compared with Example 2 group, # P<0.05, ## P<0.01.

[0064] As shown in Table 1, compared with the control group, the traditional Chinese medicine preparations prepared in Examples 1-3 and Comparative Examples 1-5 for treating heart failure complicated with diuretic resistance all showed excellent comprehensive efficacy. After treatment, LVEF was significantly increased, NT-proBNP level was significantly decreased, and the total clinical effective rate was significantly increased (P<0.01).

[0065] As can be seen from Example 2 and Comparative Examples 1 and 2, the efficacy of Comparative Example 1 (lacking Panax notoginseng) and Comparative Example 2 (lacking Rehmannia glutinosa) was significantly lower than that of Example 2 (P<0.01), which proves that the strong meridian-clearing effect of Panax notoginseng and the yin-nourishing and dryness-relieving effect of Rehmannia glutinosa can further enhance the comprehensive efficacy of traditional Chinese medicine preparations.

[0066] As can be seen from Example 2 and Comparative Example 3: The therapeutic effect of Comparative Example 3 (single-step mixed fermentation) was inferior to that of Example 2 (P<0.01), indicating that the two-step collaborative fermentation process of "first solid-state fermentation for cell wall breaking and then liquid-state fermentation for transformation" adopted in the present invention is significantly superior to single-step mixed fermentation in the biotransformation efficiency of active ingredients, thereby producing a stronger clinical effect.

[0067] As can be seen from Example 2 and Comparative Examples 4 and 5: The therapeutic effects of Comparative Example 5 (unfermented) and Comparative Example 4 (conventional tablets) were significantly lower than that of Example 2 (P<0.01), indicating that the combination of the two-step fermentation process and the self-nanoemulsifying drug delivery system of the present invention can further improve the absolute bioavailability of the drug and thus enhance the comprehensive therapeutic effect.

[0068] II. Animal pharmacokinetic verification test 1. Test subjects: 80 healthy male SD rats weighing 200-220 g were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., with the experimental animal production license number: SCXK (Beijing) 2016-0006. They were randomly divided into 8 groups, with 10 rats in each group, which were respectively denoted as Example 1-3 groups and Comparative Example 1-5 groups.

[0069] 2. Administration method: After fasting the rats in each group for 12 h, the rats in Example 1-3 groups and Comparative Example 1-5 groups were respectively intragastrically administered the traditional Chinese medicine preparations of Example 1-3 and Comparative Example 1-5 (the dose was converted according to the human equivalent dose and was 10 g / kg in terms of the crude drug amount).

[0070] 3. Sample collection and treatment: At 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 h after administration, 0.3 mL of blood was collected from the orbital venous plexus into heparinized centrifuge tubes, centrifuged at 4000 rpm for 10 min to separate plasma, and stored at -80°C for later use.

[0071] 4. Detection indexes and methods: The concentration of the representative rare saponin ginsenoside CK in plasma was determined by UPLC-MS / MS method. Chromatographic conditions: Waters ACQUITY UPLC BEH C18 chromatographic column (2.1 mm×100 mm, 1.7 μm); the mobile phase was gradient elution of acetonitrile-0.1% formic acid aqueous solution; the flow rate was 0.3 mL / min; the column temperature was 40°C. Mass spectrometry conditions: Electrospray ionization source (ESI), positive ion mode; detection was carried out by multiple reaction monitoring (MRM) mode, and the monitored ion pair was m / z 623.5→459.3.

[0072] Data processing: The pharmacokinetic parameters Cmax (peak plasma concentration) and AUC(0-t) (area under the drug-time curve at 0-t) were calculated using DAS 2.1.1 software. The relative bioavailability of each group was calculated (F% = [AUC(experimental group) / AUC(comparative group 5)] × 100%), with the AUC(0-t) of Comparative Example 5 as the baseline (100%).

[0073] The test results are shown in Table 2: Table 2: Comparison of pharmacokinetic parameters of ginsenoside CK in traditional Chinese medicine preparations of Examples 1-3 and Comparative Examples 1-5 Note: Compared with the 5 control groups, P<0.05, P<0.01; compared with Example 2 group, # P<0.05, ## P<0.01.

[0074] As shown in Table 2, the technical solutions of Examples 1-3 of the present invention can significantly improve the oral bioavailability of the active ingredient ginsenoside CK. Compared with Comparative Example 5 (100%), the relative bioavailability of Example 2 reached 450.0%, and its total in vivo exposure (AUC(0-24)) increased by about 4.5 times (P<0.01).

[0075] As can be seen from Example 2 and Comparative Examples 1 and 2, the pharmacokinetic parameters of Comparative Examples 1 and 2 are not significantly different from those of Example 2, which proves that Panax notoginseng and Rehmannia glutinosa mainly enhance the efficacy through pharmacodynamic synergy, rather than by directly affecting the conversion or absorption of CK.

[0076] As can be seen from Example 2 and Comparative Example 3, the relative bioavailability of Comparative Example 3 (single-step mixed fermentation) is only 260.5%, which is significantly lower than that of Example 2 (450.0%) (P<0.01), indicating that the two-step synergistic fermentation process of the present invention is significantly better than single-step mixed fermentation in terms of bioconversion efficiency.

[0077] As can be seen from Example 2 and Comparative Example 4, under the premise of using the same fermentation extract, the self-nanoemulsification system can significantly increase the in vivo exposure of the drug (P<0.01), indicating that the self-nanoemulsification drug delivery system of the present invention can significantly promote the in vivo absorption of the active ingredients after fermentation.

[0078] This specific embodiment is merely an explanation of the present invention and is not intended to limit the invention. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they are within the scope of the claims of the present invention.

Claims

1. A traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance, characterized in that, Including active extracts and pharmaceutically acceptable excipients; The active extract is prepared from the following raw materials in parts by weight: Astragalus membranaceus 20-40 parts, Ginseng 5-15 parts, Cinnamomum cassia 5-15 parts, Salvia miltiorrhiza 10-20 parts, Paeonia lactiflora 10-20 parts, Rehmannia glutinosa 10-20 parts, Cinnamomum cassia twig 3-9 parts, Ligusticum chuanxiong 5-15 parts, Panax notoginseng 3-9 parts.

2. The traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance according to claim 1, characterized in that, The mass ratio of the active extract to pharmaceutically acceptable excipients is 1:2-5.

3. The traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance according to claim 2, characterized in that, The pharmaceutically acceptable excipients include an oil phase, a surfactant, and a co-surfactant in a mass ratio of 2-4:3-6:1-3.

4. The traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance according to claim 3, characterized in that, The oil phase is at least one of ethyl oleate, medium-chain triglycerides, and castor oil.

5. The traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance according to claim 3, characterized in that, The surfactant is at least one of Tween-80, polyoxyethylene castor oil, and poloxamer 188.

6. The traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance according to claim 3, characterized in that, The co-surfactant is at least one of propylene glycol, ethanol, and polyethylene glycol 400.

7. A method for preparing a traditional Chinese medicine preparation according to any one of claims 1-6 for treating heart failure complicated with diuretic resistance, characterized in that, Includes the following steps: S1. Take the prescribed amounts of Astragalus membranaceus, ginseng and Panax notoginseng, combine and crush them, sterilize and adjust the moisture to obtain material A, inoculate Aspergillus oryzae for solid-state fermentation, and obtain the initial fermentation product. S2. The initial fermentation product is mixed with cinnamon, salvia miltiorrhiza, red peony root, rehmannia root, cinnamon twig and chuanxiong to obtain a mixture. After sterilization with water, the mixture is used to obtain material B. Bifidobacterium longum is inoculated for anaerobic fermentation to obtain the final fermentation product. S3. After reflux extraction with ethanol solution, the fermentation end product is filtered, concentrated under reduced pressure, and dried to obtain the active extract. S4. Mix and dissolve the active extract with pharmaceutically acceptable excipients, then encapsulate to obtain a traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance.

8. The method for preparing the traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance according to claim 7, characterized in that, The viable count of Aspergillus oryzae in material A of S1 is 1.8 × 10⁻⁶. 7 -3.5×10 7 CFU / g.

9. The method for preparing the traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance according to claim 7, characterized in that, The viable count of Bifidobacterium longum in material B of S2 is 4.3 × 10⁻⁶. 7 -5.0×10 7 CFU / g.

10. The method for preparing the traditional Chinese medicine preparation for treating heart failure complicated with diuretic resistance according to claim 7, characterized in that, The reflux extraction in S3 specifically refers to adding the fermentation end product to an ethanol solution with a mass of 6-10 times and a volume concentration of 70-80%, and refluxing at 60-70℃ for 2-3 times, each time for 1-1.5 hours, and then combining the extracts.

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