A Fukang capsule for treating deficiency of both qi and blood and a preparation method thereof

Abstract

This invention relates to the field of traditional Chinese medicine preparation technology, specifically disclosing a Fukang capsule for treating qi and blood deficiency and its preparation method. The Fukang capsule comprises the following raw materials: ginseng, angelica, chicken blood vine, prepared rehmannia root, poria cocos, prepared licorice root, a modified leonurus alkaloid derivative, donkey-hide gelatin, and excipients. This invention, through structural modification of leonurus, significantly improves the dissolution rate and permeability of poorly soluble active ingredients, enabling rapid release and efficient absorption in the gastrointestinal tract. This greatly enhances the systemic bioavailability of qi-tonifying and blood-nourishing components, rapidly alleviating core symptoms such as fatigue and pale complexion caused by qi and blood deficiency.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine preparation technology, specifically to a Fukang capsule for treating deficiency of both qi and blood and its preparation method. Background Technology

[0002] Qi and blood deficiency is a common gynecological syndrome, clinically manifested as irregular menstruation, reduced menstrual flow, pale menstrual blood, postmenstrual abdominal pain, sallow complexion, fatigue, and weakness. Traditional Chinese medicine treatment focuses on tonifying qi and blood, promoting blood circulation, and regulating menstruation. Classic formulas such as Bazhen Tang and Danggui Buxue Tang, as well as commercially available prepared Chinese medicines with added herbs like Leonurus japonicus and Cyperus rotundus (such as Bazhen Yimu Capsules and Wuji Baifeng Wan), are widely used in clinical practice.

[0003] However, existing gynecological qi and blood tonifying preparations still have many shortcomings: traditional prescriptions often use decoction of herbs, whole powder preparation, or conventional water extraction and alcohol precipitation processes, resulting in limited dissolution of active ingredients (such as motherwort alkaloids, ginsenosides, ferulic acid, etc.) and a first-pass effect, leading to poor absorption in the body. Long-term medication is required to see results, resulting in poor patient compliance. Existing preparations are mostly based on classic ancient prescriptions with simple additions and subtractions, and the raw materials and ratios are highly homogenized. They fail to address the core pathogenesis of "qi and blood deficiency with blood stasis" and fail to conduct in-depth design and raw material innovation for synergistic effects of blood activation and blood nourishment, resulting in a bottleneck in efficacy. Existing capsules focus on formation and disintegration, and their excipient systems only play a filling and lubricating role, failing to synergize with active ingredients to solve the dissolution and absorption problems of poorly soluble components (such as donkey-hide gelatin and some fat-soluble components), thus failing to meet the needs of modern patients for highly effective and fast-acting preparations.

[0004] In summary, existing gynecological qi and blood tonifying preparations have significant shortcomings in terms of raw material activity utilization, synergistic innovation of formulation, and enhanced efficacy of preparation technology, making it difficult to meet the modern clinical demand for highly effective gynecological tonifying drugs that are fast-acting, well-absorbed, and highly targeted. Based on the above, this invention proposes a Fukang capsule for treating qi and blood deficiency and its preparation method. Summary of the Invention

[0005] In order to address the significant shortcomings of existing gynecological qi and blood tonifying preparations in terms of raw material activity utilization, synergistic innovation of formulation, and enhancement of formulation technology, this invention proposes a Fukang capsule for treating qi and blood deficiency and its preparation method.

[0006] In a first aspect, the present invention provides a Fukang capsule for treating deficiency of both qi and blood, employing the following technical solution: A type of Fukang capsule for treating deficiency of both qi and blood includes the following raw materials in parts by weight: ginseng 8-15 parts, angelica 10-20 parts, chicken blood vine 15-25 parts, prepared rehmannia root 18-25 parts, poria cocos 10-15 parts, prepared licorice root 6-10 parts, modified leonurine derivative 10-30 parts, donkey-hide gelatin 15-20 parts, and excipients 30-50 parts.

[0007] Preferably, the modified leonurine derivative is prepared by sequentially etherifying leonurine, performing a mercapto-olefin click reaction, metal coordination, and folic acid-targeted modification.

[0008] Preferably, the modified leonurine derivative is prepared by the following steps: S1. Dissolve leonurine in anhydrous N,N-dimethylformamide, add an acid-binding agent and stir evenly, then add allyl bromide dropwise at room temperature, heat to 50-60℃ and stir for 12-16 h. After the reaction is completed, extract, wash, dry, concentrate under reduced pressure and purify to obtain O-allylleonurine. S2. O-Allyllecithin and 2-aminoethanethiol were dissolved in a polar mixed solvent and stirred until dissolved. Under nitrogen protection, a photoinitiator was added and the reaction was carried out at room temperature and under 365nm ultraviolet light for 2-4 hours. After the reaction was completed, the mixture was purified by column chromatography to obtain the amino-terminated lecithin conjugate. S3. The amino-terminated leonurine conjugate was dissolved in anhydrous ethanol and stirred evenly. Then, under constant temperature and stirring conditions of 50-55℃, aluminum acetylacetone solution was added dropwise over 30-40 min. The reaction was continued to be stirred for 4-8 h. After the reaction was completed, the amino-terminated leonurine-aluminum complex was obtained by centrifugation and washing with ethanol. S4. Disperse the terminal amino-terminated leonurine-aluminum complex in phosphate buffer, and sonicate to obtain a complex dispersion; dissolve folic acid in 2-(N-morpholine)ethanesulfonic acid buffer, and under stirring and light-protected conditions, add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt in sequence, and activate at room temperature for 15-30 min to obtain an activated folic acid solution; S5. Add activated folic acid solution dropwise to the complex dispersion, and adjust the pH of the system to 7.5-8.0 with alkaline solution. Stir the reaction for 2-3 hours. After the reaction is completed, separate, purify and freeze dry to obtain the modified Leonurus alkaloid derivative.

[0009] In this invention, step S1 utilizes the Williamson ether synthesis principle. The phenolic hydroxyl group on the benzene ring of leonurine undergoes deprotonation under alkaline conditions such as potassium carbonate to form a phenoxy anion, which then undergoes a nucleophilic substitution reaction on the allyl carbon of allyl bromide. Compared to transesterification routes that disrupt the parent nucleus ester bond, this etherification reaction can proceed efficiently under mild conditions and completely preserves the intact skeleton structure and pharmacological activity of leonurine (benzoic acid derivative combined with guanidine). Simultaneously, it introduces a reactive terminal double bond into the molecular side chain, providing a reaction site for subsequent modifications. Step S2 introduces a primary amine functional group through mercapto-alkene click chemistry. The thiol group of the 2-aminoethanethiol molecule undergoes free radical addition to the terminal double bond of O-allyl leonurine under the action of a photoinitiator, forming a stable thioether bond, while simultaneously covalently attaching a highly reactive primary amine group to the molecule's end. The folic acid modification in steps S4 and S5 is based on... Based on the principle of primary amine-carboxylic acid coupling reaction (amidation), firstly, the γ-carboxyl group of the folic acid molecule is activated using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt to form a highly reactive NHS ester intermediate. Subsequently, this activated NHS ester intermediate reacts with a "terminal amino-leonurine-aluminum complex". The primary amine group introduced by 2-aminoethanethiol on the complex acts as a highly efficient nucleophile, nucleophilically substituting the activated carbonyl group of the folic acid-NHS ester with an acyl group to form a stable amide bond. Through this reaction, the folic acid targeting molecule is firmly attached to the surface of the complex, ultimately yielding a modified leonurine derivative.

[0010] Preferably, the stirring rate in step S1 is 250-300 rpm.

[0011] Preferably, in step S1, the mass ratio of leonurine, anhydrous N,N-dimethylformamide, acid-binding agent and allyl bromide is 1:10-15:0.8-1.2:0.5-1.

[0012] Preferably, the acid-binding agent in step S1 is potassium carbonate.

[0013] Preferably, the vacuum concentration in step S1 refers to the process carried out in a water bath at 40-45°C and a vacuum of -0.08MPa to -0.10MPa.

[0014] Preferably, the stirring rate in step S2 is 200-400 rpm.

[0015] Preferably, in step S2, the mass ratio of O-allyl leonurine, 2-aminoethanethiol, polar mixed solvent and photoinitiator is 1:0.5-1.2:10-15:0.02-0.05.

[0016] Preferably, the photoinitiator in step S2 is selected from at least one of 2,2-dimethoxy-2-phenylacetophenone, 1-hydroxycyclohexylbenzophenone, 2-hydroxy-2-methylacetone, and 2-phenylbenzyldimethylamine.

[0017] Preferably, the photoinitiator in step S2 is 2,2-dimethoxy-2-phenylacetophenone.

[0018] Preferably, the polar mixed solvent in step S2 can be selected from a mixed system of tetrahydrofuran and water, acetonitrile and water, N,N-dimethylformamide and water, or dioxane and water.

[0019] Preferably, the polar mixed solvent in step S2 is a mixture of tetrahydrofuran and water.

[0020] Preferably, in step S2, the volume ratio of tetrahydrofuran to water is 3-5:1.

[0021] Preferably, the stationary phase used for column chromatography purification in step S2 is silica gel, alumina, or bonded silica gel.

[0022] Preferably, the eluent used for column chromatography purification in step S2 is a mixture of petroleum ether and ethyl acetate.

[0023] Preferably, the eluent for column chromatography purification in step S2 is petroleum ether and ethyl acetate in a volume ratio of 1-5:1.

[0024] Preferably, the stirring rate in step S3 is 200-300 rpm; the stirring reaction rate is 400-600 rpm.

[0025] Preferably, the amount of anhydrous ethanol used in step S3 is 8-10 times the amount of the amino-terminated leonurine coupling agent.

[0026] Preferably, in step S3, the mass ratio of the terminal amino-functionalized leonurine conjugate to the aluminum acetylacetone solution is 1:0.5-1.2.

[0027] Preferably, the mass fraction of the aluminum acetylacetonate solution in step S3 is 8-12%.

[0028] Preferably, the alcohol solvent for the aluminum acetylacetonate solution in step S3 is selected from one or more of methanol, ethanol, and isopropanol.

[0029] Preferably, the alcohol solvent for the aluminum acetylacetonate solution in step S3 is ethanol.

[0030] Preferably, in step S4, the mass-to-volume ratio of the terminal amino-leonurine-aluminum complex to the phosphate buffer is 1:5-20 (g / ml).

[0031] Preferably, the ultrasonic processing parameters in step S4 are: power 300-500W, frequency 20-40KHz, and processing time 10-30min.

[0032] Preferably, in step S4, the mass ratio of folic acid, 2-(N-morpholine)ethanesulfonic acid buffer, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt is 1:30-40:1.2-1.5:0.6-0.9.

[0033] Preferably, the stirring rate in step S4 is 300-550 rpm.

[0034] Preferably, in step S5, the mass ratio of the complex dispersion to the activated folic acid solution is 1:0.2-0.4.

[0035] Preferably, the alkaline solution in step S5 is an alkali metal hydroxide or an alkali metal carbonate solution.

[0036] Preferably, the alkaline solution in step S5 is a 0.1-0.3M sodium hydroxide solution.

[0037] Preferably, the stirring rate in step S5 is 200-400 rpm.

[0038] Preferably, the separation and purification in step S5 includes ultrafiltration, dialysis, or gel chromatography.

[0039] Preferably, in step S5, the separation and purification are carried out by ultrafiltration centrifugation.

[0040] Preferably, the ultrafiltration centrifugation refers to centrifuging at 5000-10000 rpm for 5-15 min at 2-8℃ using an ultrafiltration centrifuge tube with a molecular weight cutoff of 30-100kDa, discarding the filtrate, adding phosphate buffer solution at pH 7.4, and repeating the centrifugation operation 2-4 times.

[0041] Preferably, freeze drying in step S5 refers to pre-freezing at -60°C to -80°C for 4-8 hours, followed by drying at a cold trap temperature of -60°C to -80°C and a vacuum degree of 10-30 Pa for 24-48 hours.

[0042] Preferably, the excipient is a mixture of trehalose and microcrystalline cellulose.

[0043] Preferably, the excipients are trehalose and microcrystalline cellulose in a mass ratio of 1:1-2.

[0044] Secondly, the present invention provides a method for preparing Fukang capsules, which are mainly used to treat deficiency of both qi and blood, using the following technical solution: A method for preparing a Fukang capsule for treating deficiency of both qi and blood includes the following steps: Step 1: Ginseng, Angelica sinensis, Spatholobus suberectus, Rehmannia glutinosa, Poria cocos, and Glycyrrhiza uralensis are pulverized separately and passed through a 40-60 mesh sieve. They are then mixed evenly to obtain a mixed coarse powder. Deionized water at 60-65℃ and 8-10 times its own weight is added to the mixed coarse powder. The mixture is kept at a constant temperature for 40-45 minutes under stirring. Then, it is heated to extract the extract. The extract is filtered through a 180-200 mesh sieve while hot. The residue is extracted again. The two filtrates are combined and then evaporated and concentrated under vacuum at 55-60℃ to obtain a tonic medicinal material composition. Step 2: After mixing the tonic herbal composition with donkey-hide gelatin evenly, add the modified leonurine derivative and ethanol solution, mix evenly again, and dry under vacuum at 60-70℃ until the moisture content is ≤5% to obtain the herbal gelatin mixture. Step 3: Crush the drug-gel mixture together with the excipients, pass it through a 100-120 mesh sieve, add a wetting agent to make a soft mass, then granulate it through a 14-16 mesh sieve, and dry it with hot air circulation at 55-60℃ to obtain dry granules with a moisture content of ≤5%. Step 4: After the dried granules are sieved through an 18-20 mesh sieve, they are filled into capsule shells, with each capsule containing 0.2-0.4g. The capsules are then packaged in aluminum-plastic blister packs to obtain Fukang Capsules, which are mainly used to treat deficiency of both qi and blood.

[0045] Preferably, the stirring rate in step 1 is 30-50 rpm.

[0046] Preferably, the heating extraction in step 1 refers to first heating to 80-85℃ and holding for 30-40 minutes, and then heating to 95-100℃ for 50-60 minutes.

[0047] Preferably, the relative density of the tonic medicinal material composition in step 1 is 1.20-1.30.

[0048] Preferably, the amount of ethanol solution used in step 2 is 15-30 times the mass of the tonic medicinal material composition.

[0049] Preferably, the volume fraction of the ethanol solution in step 2 is 60-70%.

[0050] Preferably, the amount of wetting agent used in step 3 is 20-40% of the total mass of the drug-adhesive mixture and excipients.

[0051] Preferably, the wetting agent in step 3 is an ethanol solution with a volume fraction of 85-90%.

[0052] In summary, the present invention has the following beneficial effects: 1. The modified leonurine derivative in this invention not only improves its own bioavailability, but also allows the macromolecular complex to undergo partial proton dissociation in the acidic environment of the gastrointestinal tract, which not only promotes its own transmembrane absorption, but also releases coordination network fragments that can promote the encapsulation and solubilization of poorly soluble components such as ginsenoside Rg1 in the formula, and help reduce the intestinal excretion of these active ingredients. This synergistic mechanism improves the overall absorption efficiency of the main active ingredients, enabling them to more quickly and comprehensively alleviate the core symptoms of qi and blood deficiency, such as fatigue and pale complexion.

[0053] 2. This invention uses modified leonurine derivatives as the core for promoting blood circulation, combined with refined qi-tonifying and blood-nourishing herbs such as ginseng, angelica, rehmannia, and donkey-hide gelatin. It can not only tonify qi and nourish blood to enhance physical fitness, but also promote blood circulation. The two work together to enhance the overall improvement effect on symptoms related to qi and blood deficiency, and the therapeutic effect is stable.

[0054] 3. This invention uses a synergistic excipient system of trehalose and microcrystalline cellulose. Trehalose, as a bioprotective agent, can effectively maintain the integrity of the modified leonurine derivative structure during granulation, drying and subsequent storage, preventing its inactivation and aggregation. Microcrystalline cellulose provides excellent disintegration properties, ensuring that the capsules can disintegrate and release rapidly after entering the body. Detailed Implementation

[0055] The present invention will be further described in detail below with reference to the embodiments.

[0056] 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.

[0057] The key raw materials used in this invention are sourced from the following sources: Leonurus alkaloid: Product No. L888349-1g, purity 98%, purchased from Shanghai Maclean Biochemical Technology Co., Ltd.; Allyl bromide: CAS No. 106-95-6, purchased from Kandis Chemical (Hubei) Co., Ltd.; N,N-Dimethylformamide: CAS No. 68-12-2, purchased from Suzhou Kelun Chemical Co., Ltd.; Potassium carbonate: CAS No. 584-08-7, purchased from Shandong Junteng Chemical Co., Ltd.; Ethyl acetate: CAS No. 141-78-6, purchased from Shandong Juxing Chemical Co., Ltd.; 2-Aminoethanethiol: CAS No. 60-23-1, purchased from Hubei Langbowan Biopharmaceutical Co., Ltd.; Tetrahydrofuran: CAS No. 109-99-9, purchased from Shandong Qiyun Chemical Technology Co., Ltd.; 2,2-Dimethoxy-2-phenylacetophenone: CAS No. 24650-42-8, purchased from Hubei Xingyan New Material Technology Co., Ltd.; Aluminum acetylacetone: CAS No. 13963-57-0, purchased from Shandong Liande Biotechnology Co., Ltd.; Folic acid: CAS No. 59-30-3, purchased from Jiangxi Ruiwei Biotechnology Co., Ltd.; N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride: CAS No. 25952-53-8, purchased from Beijing Bailingwei Technology Co., Ltd.; Sodium N-hydroxythiosuccinimide: CAS No. 106627-54-7, purchased from Hefei Bomei Biotechnology Co., Ltd. Trehalose: CAS No. 99-20-7, purchased from Guangzhou Huayu Biotechnology Co., Ltd.; Microcrystalline cellulose: Product number 1023300500, purchased from Merck.

[0058] Preparation Examples 1-3 and Comparative Preparation Examples 1-3 provide a method for preparing a modified leonurine derivative.

[0059] Preparation Example 1 The modified leonurine derivatives were prepared by the following method: S1. The mass ratio of leonurine, anhydrous N,N-dimethylformamide, potassium carbonate, and allyl bromide was controlled at 1:10:0.8:0.5. Leonurine was dissolved in anhydrous N,N-dimethylformamide, and potassium carbonate was added and stirred at 250 rpm for 20 min. Allyl bromide was then added dropwise at a uniform rate at room temperature, with the addition completed within 30 min. The temperature was raised to 50℃ and stirred for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate (extracted 3 times and the organic phases were combined), washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure in a 40℃ water bath at -0.08 MPa, and purified by silica gel column chromatography to obtain O-allyl leonurine. S2. The mass ratio of O-allyl leonurine, 2-aminoethanethiol, polar mixed solvent, and 2,2-dimethoxy-2-phenylacetophenone was controlled at 1:0.5:10:0.02. O-allyl leonurine and 2-aminoethanethiol were dissolved in a polar mixed solvent (a mixture of tetrahydrofuran and water with a volume ratio of 3:1). After stirring and dissolving, 2,2-dimethoxy-2-phenylacetophenone was added under nitrogen protection. The reaction was carried out at room temperature and under 365 nm ultraviolet light irradiation, with stirring at 200 rpm for 4 h. After the reaction was completed, the fraction containing the target product was collected by silica gel column chromatography using petroleum ether and ethyl acetate with a volume ratio of 1:1 as eluents. The fraction was concentrated under reduced pressure in a 40 °C water bath at -0.08 MPa to obtain the amino-terminated leonurine conjugate. S3. The mass ratio of the leonurine conjugate and the aluminum acetylacetone alcohol solution was controlled at 1:0.5. The amino-terminated leonurine conjugate was dissolved in 8 times its own mass of anhydrous ethanol. After stirring at 200 rpm for 30 min, the 8% (w / w) aluminum acetylacetone alcohol solution was added dropwise over 30 min under constant temperature and stirring conditions at 50℃. The reaction was then stirred at 400 rpm for 8 h. After the reaction was completed, the mixture was centrifuged at 4℃ and 12000 rpm for 10 min and washed with ethanol to obtain the amino-terminated leonurine-aluminum complex. S4. The terminal amino-aluminum complex was dispersed in phosphate buffer at a mass-to-volume ratio of 1:5 (g / ml) in pH 6.5. After sonication at 300W and 20kHz for 30 min, the complex dispersion was obtained. The mass ratio of folic acid, 2-(N-morpholine)ethanesulfonic acid buffer, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt was controlled at 1:30:1.2:0.6. Folic acid was dissolved in 2-(N-morpholine)ethanesulfonic acid buffer. Under stirring at 300 rpm and in the dark, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt were added sequentially. The mixture was activated at room temperature for 30 min to obtain an activated folic acid solution. S5. Control the mass ratio of the complex dispersion and the activated folic acid solution to 1:0.2. Add the activated folic acid solution dropwise to the complex dispersion and adjust the pH of the system to 7.5 with 0.2M sodium hydroxide solution. Stir the reaction at 200 rpm for 3 h. After the reaction is complete, transfer the solution to an ultrafiltration centrifuge tube with a molecular weight cutoff of 30 kDa. Centrifuge at 5000 rpm for 5 min at 2 °C. Discard the filtrate and add phosphate buffer solution with pH 7.4. Repeat the centrifugation operation twice. Pre-freeze at -60 °C for 8 h and then dry at a cold trap temperature of -60 °C and a vacuum degree of 10 Pa for 48 h to obtain the modified leonurine derivative.

[0060] Preparation Example 2 The modified leonurine derivatives were prepared by the following method: S1. The mass ratio of leonurine, anhydrous N,N-dimethylformamide, potassium carbonate, and allyl bromide was controlled at 1:12:1:0.8. Leonurine was dissolved in anhydrous N,N-dimethylformamide, and potassium carbonate was added and stirred at 250 rpm for 20 min. Allyl bromide was then added dropwise at a uniform rate at room temperature, with the addition completed within 30 min. The temperature was raised to 55℃ and stirred for 14 h. After the reaction was completed, the mixture was extracted with ethyl acetate (extracted 3 times and the organic phases were combined), washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure in a 42℃ water bath at -0.09 MPa, and purified by silica gel column chromatography to obtain O-allylleonurine. S2. The mass ratio of O-allyl leonurine, 2-aminoethanethiol, polar mixed solvent, and 2,2-dimethoxy-2-phenylacetophenone was controlled at 1:0.8:12:0.03. O-allyl leonurine and 2-aminoethanethiol were dissolved in a polar mixed solvent (a mixture of tetrahydrofuran and water with a volume ratio of 4:1). After stirring and dissolving, 2,2-dimethoxy-2-phenylacetophenone was added under nitrogen protection. The reaction was carried out at room temperature and under 365 nm ultraviolet light irradiation, with stirring at 300 rpm for 3 h. After the reaction was completed, the fraction containing the target product was collected by silica gel column chromatography using petroleum ether and ethyl acetate with a volume ratio of 3:1 as eluents. The fraction was concentrated under reduced pressure in a 42 °C water bath at -0.09 MPa to obtain the amino-terminated leonurine conjugate. S3. The mass ratio of the leonurine conjugate and the aluminum acetylacetone alcohol solution was controlled at 1:0.7. The amino-terminated leonurine conjugate was dissolved in anhydrous ethanol at 9 times its own mass. After stirring at 250 rpm for 30 min, the 10% aluminum acetylacetone alcohol solution was added dropwise over 35 min under constant temperature and stirring conditions at 52℃. The reaction was then stirred at 500 rpm for 6 h. After the reaction was completed, the mixture was centrifuged at 6℃ and 10000 rpm for 12 min and washed with ethanol to obtain the amino-terminated leonurine-aluminum complex. S4. The terminal amino-aluminum complex was dispersed in phosphate buffer at a mass-to-volume ratio of 1:10 (g / ml) at pH 6.5. After sonication at 400W and 30kHz for 20 min, the complex dispersion was obtained. The mass ratio of folic acid, 2-(N-morpholine)ethanesulfonic acid buffer, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt was controlled at 1:35:1.3:0.8. Folic acid was dissolved in 2-(N-morpholine)ethanesulfonic acid buffer. Under stirring at 400 rpm and in the dark, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt were added sequentially. The mixture was activated at room temperature for 23 min to obtain an activated folic acid solution. S5. Controlling the mass ratio of the complex dispersion and the activated folic acid solution to 1:0.3, the activated folic acid solution was added dropwise to the complex dispersion, and the pH of the system was adjusted to 7.7 with 0.2M sodium hydroxide solution. The mixture was stirred at 300 rpm for 2.5 h. After the reaction was completed, the mixture was transferred to an ultrafiltration centrifuge tube with a molecular weight cutoff of 50 kDa and centrifuged at 7000 rpm for 10 min at 6 °C. The filtrate was discarded, and phosphate buffer solution with pH 7.4 was added. The centrifugation operation was repeated 3 times. The mixture was then pre-frozen at -70 °C for 6 h and then dried at a cold trap temperature of -70 °C and a vacuum degree of 20 Pa for 30 h to obtain the modified leonurine derivative.

[0061] Preparation Example 3 The modified leonurine derivatives were prepared by the following method: S1. The mass ratio of leonurine, anhydrous N,N-dimethylformamide, potassium carbonate, and allyl bromide was controlled at 1:15:1.2:1. Leonurine was dissolved in anhydrous N,N-dimethylformamide, potassium carbonate was added, and the mixture was stirred at 250 rpm for 20 min. Allyl bromide was then added dropwise at a uniform rate at room temperature, with the addition completed within 30 min. The temperature was raised to 60℃ and the mixture was stirred for 12 h. After the reaction was completed, the mixture was extracted with ethyl acetate (extracted 3 times and the organic phases were combined), washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure in a 45℃ water bath at -0.10 MPa, and purified by silica gel column chromatography to obtain O-allyl leonurine. S2. The mass ratio of O-allyl leonurine, 2-aminoethanethiol, polar mixed solvent, and 2,2-dimethoxy-2-phenylacetophenone was controlled at 1:1.2:15:0.05. O-allyl leonurine and 2-aminoethanethiol were dissolved in a polar mixed solvent (a mixture of tetrahydrofuran and water with a volume ratio of 5:1). After stirring and dissolving, 2,2-dimethoxy-2-phenylacetophenone was added under nitrogen protection. The reaction was carried out at room temperature and under 365 nm ultraviolet light irradiation, with stirring at 400 rpm for 2 h. After the reaction was completed, the fraction containing the target product was collected by silica gel column chromatography using petroleum ether and ethyl acetate with a volume ratio of 5:1 as eluents. The fraction was concentrated under reduced pressure in a 45 °C water bath at -0.10 MPa to obtain the amino-terminated leonurine conjugate. S3. The mass ratio of the leonurine conjugate and the aluminum acetylacetone alcohol solution was controlled at 1:1.2. The amino-terminated leonurine conjugate was dissolved in 10 times its own weight of anhydrous ethanol. After stirring at 300 rpm for 30 min, the 12% aluminum acetylacetone alcohol solution was added dropwise over 40 min under constant temperature and stirring conditions at 55℃. The reaction was then stirred at 600 rpm for 4 h. After the reaction was completed, the mixture was centrifuged at 8℃ and 8000 rpm for 15 min and washed with ethanol to obtain the amino-terminated leonurine-aluminum complex. S4. The terminal amino-aluminum complex was dispersed in phosphate buffer at a mass-to-volume ratio of 1:20 (g / ml) in pH 6.5. After sonication at 500W and 40kHz for 10 min, the complex dispersion was obtained. The mass ratio of folic acid, 2-(N-morpholine)ethanesulfonic acid buffer, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt was controlled at 1:40:1.5:0.9. Folic acid was dissolved in 2-(N-morpholine)ethanesulfonic acid buffer. Under stirring at 550 rpm and in the dark, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt were added sequentially. The mixture was activated at room temperature for 15 min to obtain an activated folic acid solution. S5. Control the mass ratio of the complex dispersion and the activated folic acid solution to 1:0.4. Add the activated folic acid solution dropwise to the complex dispersion and adjust the pH of the system to 8.0 with 0.2M sodium hydroxide solution. Stir the reaction at 400 rpm for 2 h. After the reaction is complete, transfer the solution to an ultrafiltration centrifuge tube with a molecular weight cutoff of 100 kDa. Centrifuge at 10,000 rpm for 5 min at 8 °C. Discard the filtrate and add phosphate buffer solution with pH 7.4. Repeat the centrifugation operation 4 times. Then pre-freeze at -80 °C for 4 h and dry at a cold trap temperature of -80 °C and a vacuum degree of 30 Pa for 24 h to obtain the modified leonurine derivative.

[0062] Comparative Preparation Example 1 The folic acid-leonurine complex was prepared by the following method: S1. The mass ratio of leonurine, anhydrous N,N-dimethylformamide, and potassium carbonate was controlled at 1:10:0.8. Leonurine was dissolved in anhydrous N,N-dimethylformamide, and potassium carbonate was added. The mixture was stirred at 250 rpm for 20 min, then heated to 50 °C and stirred for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate (extracted 3 times and the organic phases were combined), washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure in a 40 °C water bath at -0.08 MPa, and purified by silica gel column chromatography to obtain the unetherified leonurine recovery product. S2. The mass ratio of the unetherified leonurine recovery product, 2-aminoethanethiol, polar mixed solvent, and 2,2-dimethoxy-2-phenylacetophenone was controlled to be 1:0.5:10:0.02. The unetherified leonurine recovery product and 2-aminoethanethiol were dissolved in a polar mixed solvent (a mixture of tetrahydrofuran and water with a volume ratio of 3:1). After stirring and dissolving, 2,2-dimethoxy-2-phenylacetophenone was added under nitrogen protection. The reaction was carried out at room temperature and under 365 nm ultraviolet light irradiation, with stirring at a rate of 200 rpm for 4 h. After the reaction was completed, the fraction containing the target product was collected by silica gel column chromatography using petroleum ether and ethyl acetate with a volume ratio of 1:1 as eluents. The fraction was concentrated under reduced pressure in a 40 °C water bath at a vacuum degree of -0.08 MPa to obtain the leonurine-ethylamine derivative. S3. The mass ratio of leonurine-ethylamine derivative and acetylacetone aluminum alcohol solution was controlled at 1:0.5. Leonurine-ethylamine derivative was dissolved in 8 times its own mass of anhydrous ethanol. After stirring at 200 rpm for 30 min, 8% acetylacetone aluminum alcohol solution was added dropwise over 30 min under constant temperature and stirring conditions at 50℃. The reaction was continued to be stirred at 400 rpm for 8 h. After the reaction was completed, the mixture was centrifuged at 4℃ and 12000 rpm for 10 min and washed with ethanol to obtain leonurine-aluminum complex. S4. The leonurine-aluminum complex was dispersed in phosphate buffer at a mass-to-volume ratio of 1:5 (g / ml) at pH 6.5. After sonication at 300W and 20kHz for 30 min, a leonurine dispersion was obtained. The mass ratio of folic acid, 2-(N-morpholine)ethanesulfonic acid buffer, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt was controlled at 1:30:1.2:0.6. Folic acid was dissolved in 2-(N-morpholine)ethanesulfonic acid buffer. Under stirring at 300 rpm and in the dark, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt were added sequentially. The mixture was activated at room temperature for 30 min to obtain an activated folic acid solution. S5. Controlling the mass ratio of leonurine dispersion and activated folic acid solution to 1:0.2, add activated folic acid solution dropwise to the complex dispersion, and adjust the pH of the system to 7.5 with 0.2M sodium hydroxide solution. Stir the reaction at 200 rpm for 3 h. After the reaction is complete, transfer to an ultrafiltration centrifuge tube with a molecular weight cutoff of 30 kDa, centrifuge at 5000 rpm for 5 min at 2 °C, discard the filtrate, add phosphate buffer solution at pH 7.4, repeat the centrifugation operation twice, pre-freeze at -60 °C for 8 h, and then dry at a cold trap temperature of -60 °C and a vacuum degree of 10 Pa for 48 h to obtain the folic acid-leonurine complex.

[0063] Comparative Preparation Example 2 The folic acid-leonurine-aluminum complex was prepared by the following method: S1. The mass ratio of leonurine, anhydrous N,N-dimethylformamide, potassium carbonate, and allyl bromide was controlled at 1:10:0.8:0.5. Leonurine was dissolved in anhydrous N,N-dimethylformamide, potassium carbonate was added, and the mixture was stirred at 250 rpm for 20 min. Allyl bromide was then added dropwise at a uniform rate at room temperature, with the addition completed within 30 min. The temperature was raised to 50 °C and the mixture was stirred for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate (extracted 3 times and the organic phases were combined), washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure in a 40 °C water bath at -0.08 MPa, and purified by silica gel column chromatography to obtain O-allyl leonurine. S2. Controlling the mass ratio of O-allyl leonurine, polar mixed solvent, and 2,2-dimethoxy-2-phenylacetophenone to 1:10:0.02, O-allyl leonurine was dissolved in the polar mixed solvent (a mixture of tetrahydrofuran and water in a volume ratio of 3:1). After stirring and dissolving, 2,2-dimethoxy-2-phenylacetophenone was added under nitrogen protection. The reaction was carried out at room temperature and under 365 nm ultraviolet light irradiation, with stirring at 200 rpm for 4 h. After the reaction was completed, petroleum ether and ethyl acetate in a volume ratio of 1:1 were used as eluents. The fraction containing the target product was collected by silica gel column chromatography and concentrated under reduced pressure in a 40 °C water bath at -0.08 MPa to obtain unburned O-allyl leonurine. S3. Controlling the mass ratio of O-allyl leonurine and aluminum acetylacetone alcohol solution to 1:0.5, the unclicked O-allyl leonurine was dissolved in 8 times its own mass of anhydrous ethanol. After stirring at 200 rpm for 30 min, under constant temperature and stirring conditions at 50℃, an 8% (w / w) aluminum acetylacetone alcohol solution was added dropwise over 30 min. The reaction was continued to be stirred at 400 rpm for 8 h. After the reaction was completed, the mixture was centrifuged at 4℃ and 12000 rpm for 10 min and washed with ethanol to obtain the unclicked leonurine-aluminum complex. S4. The unselected leonurine-aluminum complex was dispersed in phosphate buffer at a mass-to-volume ratio of 1:5 (g / ml) in pH 6.5. After sonication at 300W and 20kHz for 30 min, a leonurine-aluminum complex dispersion was obtained. The mass ratio of folic acid, 2-(N-morpholine)ethanesulfonic acid buffer, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt was controlled at 1:30:1.2:0.6. Folic acid was dissolved in 2-(N-morpholine)ethanesulfonic acid buffer. Under stirring at 300 rpm and in the dark, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt were added sequentially. The mixture was activated at room temperature for 30 min to obtain an activated folic acid solution. S5. Control the mass ratio of the leonurine-aluminum complex dispersion and the activated folic acid solution to 1:0.2. Add the activated folic acid solution dropwise to the complex dispersion and adjust the pH of the system to 7.5 with 0.2M sodium hydroxide solution. Stir the reaction at 200 rpm for 3 h. After the reaction is completed, transfer the mixture to an ultrafiltration centrifuge tube with a molecular weight cutoff of 30 kDa. Centrifuge at 5000 rpm for 5 min at 2 °C. Discard the filtrate, add phosphate buffer solution with pH 7.4, repeat the centrifugation operation twice, and then pre-freeze at -60 °C for 8 h. Subsequently, dry the mixture at a cold trap temperature of -60 °C and a vacuum degree of 10 Pa for 48 h to obtain the folic acid-leonurine-aluminum complex.

[0064] Comparative preparation example 3 The folic acid-leonurine-zinc complex was prepared by the following method: S1. The mass ratio of leonurine, anhydrous N,N-dimethylformamide, potassium carbonate, and allyl bromide was controlled at 1:10:0.8:0.5. Leonurine was dissolved in anhydrous N,N-dimethylformamide, potassium carbonate was added, and the mixture was stirred at 250 rpm for 20 min. Allyl bromide was then added dropwise at a uniform rate at room temperature, with the addition completed within 30 min. The temperature was raised to 50 °C and the mixture was stirred for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate (extracted 3 times and the organic phases were combined), washed with saturated brine, dried with anhydrous sodium sulfate, concentrated under reduced pressure in a 40 °C water bath at -0.08 MPa, and purified by silica gel column chromatography to obtain O-allyl leonurine. S2. The mass ratio of O-allyl leonurine, 2-aminoethanethiol, polar mixed solvent, and 2,2-dimethoxy-2-phenylacetophenone was controlled at 1:0.5:10:0.02. O-allyl leonurine and 2-aminoethanethiol were dissolved in a polar mixed solvent (a mixture of tetrahydrofuran and water with a volume ratio of 3:1). After stirring and dissolving, 2,2-dimethoxy-2-phenylacetophenone was added under nitrogen protection. The reaction was carried out at room temperature and under 365 nm ultraviolet light irradiation, with stirring at 200 rpm for 4 h. After the reaction was completed, the fraction containing the target product was collected by silica gel column chromatography using petroleum ether and ethyl acetate with a volume ratio of 1:1 as eluents. The fraction was concentrated under reduced pressure in a 40 °C water bath at -0.08 MPa to obtain the amino-terminated leonurine conjugate. S3. The mass ratio of leonurine conjugate to zinc acetylacetone alcohol solution was controlled at 1:0.5. The amino-terminated leonurine conjugate was dissolved in 8 times its own mass of anhydrous ethanol. After stirring at 200 rpm for 30 min, 8% zinc acetylacetone alcohol solution was added dropwise at a constant temperature of 50℃ and stirring over 30 min. The reaction was continued at 400 rpm for 8 h. After the reaction was completed, the mixture was centrifuged at 4℃ and 12000 rpm for 10 min and washed with ethanol to obtain the leonurine-zinc complex. S4. The leonurine-zinc complex was dispersed in phosphate buffer at a mass-to-volume ratio of 1:5 (g / ml) at pH 6.5. After sonication at 300W and 20kHz for 30 min, a leonurine-zinc complex dispersion was obtained. The mass ratio of folic acid, 2-(N-morpholine)ethanesulfonic acid buffer, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt was controlled at 1:30:1.2:0.6. Folic acid was dissolved in 2-(N-morpholine)ethanesulfonic acid buffer. Under stirring at 300 rpm and in the dark, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt were added sequentially. The mixture was activated at room temperature for 30 min to obtain an activated folic acid solution. S5. Control the mass ratio of the leonurine-zinc complex dispersion and the activated folic acid solution to 1:0.2. Add the activated folic acid solution dropwise to the complex dispersion and adjust the pH of the system to 7.5 with 0.2M sodium hydroxide solution. Stir the reaction at 200 rpm for 3 h. After the reaction is complete, transfer the mixture to an ultrafiltration centrifuge tube with a molecular weight cutoff of 30 kDa. Centrifuge at 5000 rpm for 5 min at 2 °C. Discard the filtrate, add phosphate buffer solution at pH 7.4, repeat the centrifugation operation twice, and then pre-freeze at -60 °C for 8 h. Subsequently, dry the mixture at a cold trap temperature of -60 °C and a vacuum degree of 10 Pa for 48 h to obtain the folic acid-leonurine-zinc complex.

[0065] Examples 1-3 provide a Fukang capsule for treating deficiency of both qi and blood, and its preparation method.

[0066] Example 1 A type of Fukang capsule for treating deficiency of both qi and blood includes the following ingredients in parts by weight: 8 parts ginseng, 10 parts angelica, 15 parts chicken blood vine, 18 parts prepared rehmannia root, 10 parts poria cocos, 6 parts prepared licorice root, 10 parts modified leonurine derivative, 15 parts donkey-hide gelatin, and 30 parts excipients.

[0067] The modified leonurine derivative was prepared in Preparation Example 1; the excipients were trehalose and microcrystalline cellulose in a mass ratio of 1:1.

[0068] A type of Fukang capsule, primarily used to treat deficiency of both qi and blood, is prepared using the following method: Step 1: Ginseng, Angelica sinensis, Spatholobus suberectus, Rehmannia glutinosa, Poria cocos, and Glycyrrhiza uralensis are pulverized separately and passed through a 40-mesh sieve. They are then mixed evenly to obtain a mixed coarse powder. Deionized water at 60°C and 8 times its own weight are added to the mixed coarse powder. The mixture is kept at a constant temperature and immersion temperature of 30 rpm for 45 minutes. Then, the temperature is raised to 80°C and maintained for 40 minutes. Finally, the temperature is raised to 95°C and extracted for 60 minutes to obtain an extract. The extract is filtered through a 180-mesh sieve while hot. The residue is extracted again. The two filtrates are combined and then evaporated and concentrated under vacuum at 55°C to obtain a tonic medicinal material composition with a relative density of 1.20. Step 2: After mixing the tonic herbal composition with donkey-hide gelatin evenly, add the modified leonurine derivative and a 60% ethanol solution (the amount is 15 times the mass of the tonic herbal composition), mix evenly again, and dry under vacuum at 60°C until the moisture content is ≤5% to obtain the herbal gelatin mixture. Step 3: Crush the drug-gel mixture and excipients together, pass them through a 100-mesh sieve, add an 85% ethanol solution (20% of the total mass of the drug-gel mixture and excipients) to make a soft mass, then granulate it through a 14-mesh sieve, and dry it with hot air circulation at 55℃ to obtain dry granules with a moisture content of ≤5%. Step 4: After the dried granules are sieved through an 18-mesh sieve, they are filled into capsule shells, with each capsule containing 0.2g. The capsules are then packaged in aluminum-plastic blister packs to obtain Fukang Capsules, which are mainly used to treat deficiency of both qi and blood.

[0069] Example 2 A type of Fukang capsule for treating deficiency of both qi and blood includes the following ingredients in parts by weight: 10 parts ginseng, 15 parts angelica, 19 parts chicken blood vine, 20 parts prepared rehmannia root, 13 parts poria cocos, 8 parts prepared licorice root, 20 parts modified leonurine derivative, 17 parts donkey-hide gelatin, and 40 parts excipients.

[0070] The modified leonurine derivative was prepared in Preparation Example 2; the excipients were trehalose and microcrystalline cellulose in a mass ratio of 1:1.5.

[0071] A type of Fukang capsule, primarily used to treat deficiency of both qi and blood, is prepared using the following method: Step 1: Ginseng, Angelica sinensis, Spatholobus suberectus, Rehmannia glutinosa, Poria cocos, and Glycyrrhiza uralensis are pulverized separately and passed through a 50-mesh sieve. They are then mixed evenly to obtain a coarse powder. Deionized water at 62°C and 9 times its own weight are added to the coarse powder. The mixture is stirred at 40 rpm for 42 minutes and kept at a constant temperature. Then, the temperature is raised to 82°C and held for 35 minutes. Finally, the temperature is raised to 97°C and extracted for 55 minutes to obtain an extract. The extract is filtered through a 190-mesh sieve while hot. The residue is extracted again. The two filtrates are combined and then evaporated and concentrated under vacuum at 57°C to obtain a tonic herbal composition with a relative density of 1.25. Step 2: After mixing the tonic herbal composition with donkey-hide gelatin evenly, add the modified leonurine derivative and a 65% ethanol solution (the amount is 23 times the mass of the tonic herbal composition), mix evenly again, and dry under vacuum at 65°C until the moisture content is ≤5% to obtain the herbal gelatin mixture. Step 3: Crush the drug-gel mixture and excipients together, pass them through a 110-mesh sieve, add an 88% volume fraction ethanol solution (30% of the total mass of the drug-gel mixture and excipients) to make a soft mass, then pass it through a 15-mesh sieve to granulate, and dry it with hot air circulation at 57℃ to obtain dry granules with a moisture content of ≤5%. Step 4: After the dried granules are sieved through a 19-mesh sieve, they are filled into capsule shells, with each capsule containing 0.3g. The capsules are then packaged in aluminum-plastic blister packs to obtain Fukang Capsules, which are mainly used to treat deficiency of both qi and blood.

[0072] Example 3 A type of Fukang capsule for treating deficiency of both qi and blood includes the following ingredients in parts by weight: 15 parts ginseng, 20 parts angelica, 25 parts chicken blood vine, 25 parts prepared rehmannia root, 15 parts poria cocos, 10 parts prepared licorice root, 30 parts modified leonurine derivative, 20 parts donkey-hide gelatin, and 50 parts excipients.

[0073] The modified leonurine derivative was prepared in Preparation Example 3; the excipients were trehalose and microcrystalline cellulose in a mass ratio of 1:2.

[0074] A type of Fukang capsule, primarily used to treat deficiency of both qi and blood, is prepared using the following method: Step 1: Ginseng, Angelica sinensis, Spatholobus suberectus, Rehmannia glutinosa, Poria cocos, and Glycyrrhiza uralensis are pulverized separately and passed through a 60-mesh sieve. They are then mixed evenly to obtain a coarse powder. Deionized water at 65°C and 10 times its own weight are added to the coarse powder. The mixture is stirred at 50 rpm for 40 minutes at a constant temperature. The temperature is then raised to 85°C and maintained for 30 minutes. Finally, the temperature is raised to 100°C and extracted for 50 minutes to obtain an extract. The extract is filtered through a 200-mesh sieve while hot. The residue is extracted again. The two filtrates are combined and then evaporated and concentrated under vacuum at 60°C to obtain a tonic herbal composition with a relative density of 1.30. Step 2: After mixing the tonic herbal composition with donkey-hide gelatin evenly, add the modified leonurine derivative and a 70% ethanol solution (the amount is 30 times the mass of the tonic herbal composition), mix evenly again, and dry under vacuum at 70°C until the moisture content is ≤5% to obtain the herbal gelatin mixture. Step 3: Crush the drug-gel mixture and excipients together, pass them through a 120-mesh sieve, add a 90% volume fraction ethanol solution (40% of the total mass of the drug-gel mixture and excipients) to make a soft mass, then granulate it through a 16-mesh sieve, and dry it with hot air circulation at 60℃ to obtain dry granules with a moisture content of ≤5%. Step 4: After the dried granules are sieved through a 20-mesh sieve, they are filled into capsule shells, with each capsule containing 0.4g. The capsules are then packaged in aluminum-plastic blister packs to obtain Fukang Capsules, which are mainly used to treat deficiency of both qi and blood.

[0075] To verify the comprehensive performance of the Fukang Capsule for treating deficiency of both qi and blood provided by this invention, comparative examples 1-5 were set up, wherein: Comparative Example 1 Comparative Example 1 is the same as Example 1, except that the modified leonurine derivative obtained in Preparation Example 1 is replaced with the folic acid-leonurine complex obtained in Comparative Preparation Example 1. Specifically: A type of Fukang capsule for treating deficiency of both qi and blood includes the following ingredients in parts by weight: 8 parts ginseng, 10 parts angelica, 15 parts chicken blood vine, 18 parts prepared rehmannia root, 10 parts poria cocos, 6 parts prepared licorice root, 10 parts folic acid-leonurine complex, 15 parts donkey-hide gelatin, and 30 parts excipients.

[0076] The folic acid-leonurine complex was prepared by comparative preparation example 1; the excipients were trehalose and microcrystalline cellulose in a mass ratio of 1:1.

[0077] A type of Fukang capsule, primarily used to treat deficiency of both qi and blood, is prepared using the following method: Step 1: Ginseng, Angelica sinensis, Spatholobus suberectus, Rehmannia glutinosa, Poria cocos, and Glycyrrhiza uralensis are pulverized separately and passed through a 40-mesh sieve. They are then mixed evenly to obtain a mixed coarse powder. Deionized water at 60°C and 8 times its own weight are added to the mixed coarse powder. The mixture is kept at a constant temperature and immersion temperature of 30 rpm for 45 minutes. Then, the temperature is raised to 80°C and maintained for 40 minutes. Finally, the temperature is raised to 95°C and extracted for 60 minutes to obtain an extract. The extract is filtered through a 180-mesh sieve while hot. The residue is extracted again. The two filtrates are combined and then evaporated and concentrated under vacuum at 55°C to obtain a tonic medicinal material composition with a relative density of 1.20. Step 2: After mixing the tonic herbal composition with donkey-hide gelatin evenly, add folic acid-leonurine complex and 60% ethanol solution (the amount is 15 times the mass of the tonic herbal composition), mix evenly again, and dry under vacuum at 60℃ until the moisture content is ≤5% to obtain the herbal gelatin mixture. Step 3: Crush the drug-gel mixture and excipients together, pass them through a 100-mesh sieve, add an 85% ethanol solution (20% of the total mass of the drug-gel mixture and excipients) to make a soft mass, then granulate it through a 14-mesh sieve, and dry it with hot air circulation at 55℃ to obtain dry granules with a moisture content of ≤5%. Step 4: After the dried granules are sieved through an 18-mesh sieve, they are filled into capsule shells, with each capsule containing 0.2g. The capsules are then packaged in aluminum-plastic blister packs to obtain Fukang Capsules, which are mainly used to treat deficiency of both qi and blood.

[0078] Comparative Example 2 Comparative Example 2 is the same as Example 1, except that the modified leonurine derivative obtained in Preparation Example 1 is replaced with the folic acid-leonurine-aluminum complex obtained in Comparative Preparation Example 2. Specifically: A type of Fukang capsule for treating deficiency of both qi and blood includes the following ingredients in parts by weight: 8 parts ginseng, 10 parts angelica, 15 parts chicken blood vine, 18 parts prepared rehmannia root, 10 parts poria cocos, 6 parts prepared licorice root, 10 parts folic acid-leonurine-aluminum complex, 15 parts donkey-hide gelatin, and 30 parts excipients.

[0079] The folic acid-leonurine-aluminum complex was prepared by comparative preparation example 2; the excipients were trehalose and microcrystalline cellulose in a mass ratio of 1:1.

[0080] A type of Fukang capsule, primarily used to treat deficiency of both qi and blood, is prepared using the following method: Step 1: Ginseng, Angelica sinensis, Spatholobus suberectus, Rehmannia glutinosa, Poria cocos, and Glycyrrhiza uralensis are pulverized separately and passed through a 40-mesh sieve. They are then mixed evenly to obtain a mixed coarse powder. Deionized water at 60°C and 8 times its own weight are added to the mixed coarse powder. The mixture is kept at a constant temperature and immersion temperature of 30 rpm for 45 minutes. Then, the temperature is raised to 80°C and maintained for 40 minutes. Finally, the temperature is raised to 95°C and extracted for 60 minutes to obtain an extract. The extract is filtered through a 180-mesh sieve while hot. The residue is extracted again. The two filtrates are combined and then evaporated and concentrated under vacuum at 55°C to obtain a tonic medicinal material composition with a relative density of 1.20. Step 2: After mixing the tonic herbal composition with donkey-hide gelatin evenly, add folic acid-leonurine-aluminum complex and 60% ethanol solution (the amount is 15 times the mass of the tonic herbal composition), mix evenly again, and dry under vacuum at 60℃ until the moisture content is ≤5% to obtain the herbal gelatin mixture. Step 3: Crush the drug-gel mixture and excipients together, pass them through a 100-mesh sieve, add an 85% ethanol solution (20% of the total mass of the drug-gel mixture and excipients) to make a soft mass, then granulate it through a 14-mesh sieve, and dry it with hot air circulation at 55℃ to obtain dry granules with a moisture content of ≤5%. Step 4: After the dried granules are sieved through an 18-mesh sieve, they are filled into capsule shells, with each capsule containing 0.2g. The capsules are then packaged in aluminum-plastic blister packs to obtain Fukang Capsules, which are mainly used to treat deficiency of both qi and blood.

[0081] Comparative Example 3 Comparative Example 3 is the same as Example 1, except that the modified leonurine derivative obtained in Preparation Example 1 is replaced with the folic acid-leonurine-zinc complex obtained in Comparative Preparation Example 3. Details are as follows: A type of Fukang capsule for treating deficiency of both qi and blood includes the following ingredients in parts by weight: 8 parts ginseng, 10 parts angelica, 15 parts chicken blood vine, 18 parts prepared rehmannia root, 10 parts poria cocos, 6 parts prepared licorice root, 10 parts folic acid-leonurine-zinc complex, 15 parts donkey-hide gelatin, and 30 parts excipients.

[0082] The folic acid-leonurine-zinc complex was prepared by comparative preparation example 3; the excipients were trehalose and microcrystalline cellulose in a mass ratio of 1:1.

[0083] A type of Fukang capsule, primarily used to treat deficiency of both qi and blood, is prepared using the following method: Step 1: Ginseng, Angelica sinensis, Spatholobus suberectus, Rehmannia glutinosa, Poria cocos, and Glycyrrhiza uralensis are pulverized separately and passed through a 40-mesh sieve. They are then mixed evenly to obtain a mixed coarse powder. Deionized water at 60°C and 8 times its own weight are added to the mixed coarse powder. The mixture is kept at a constant temperature and immersion temperature of 30 rpm for 45 minutes. Then, the temperature is raised to 80°C and maintained for 40 minutes. Finally, the temperature is raised to 95°C and extracted for 60 minutes to obtain an extract. The extract is filtered through a 180-mesh sieve while hot. The residue is extracted again. The two filtrates are combined and then evaporated and concentrated under vacuum at 55°C to obtain a tonic medicinal material composition with a relative density of 1.20. Step 2: After mixing the tonic herbal composition with donkey-hide gelatin evenly, add folic acid-leonurine-zinc complex and 60% ethanol solution (the amount is 15 times the mass of the tonic herbal composition), mix evenly again, and dry under vacuum at 60℃ until the moisture content is ≤5% to obtain the herbal gelatin mixture. Step 3: Crush the drug-gel mixture and excipients together, pass them through a 100-mesh sieve, add an 85% ethanol solution (20% of the total mass of the drug-gel mixture and excipients) to make a soft mass, then granulate it through a 14-mesh sieve, and dry it with hot air circulation at 55℃ to obtain dry granules with a moisture content of ≤5%. Step 4: After the dried granules are sieved through an 18-mesh sieve, they are filled into capsule shells, with each capsule containing 0.2g. The capsules are then packaged in aluminum-plastic blister packs to obtain Fukang Capsules, which are mainly used to treat deficiency of both qi and blood.

[0084] Comparative Example 4 Comparative Example 4 is the same as Example 1, except that the only excipient is trehalose. Details are as follows: A type of Fukang capsule for treating deficiency of both qi and blood includes the following ingredients in parts by weight: 8 parts ginseng, 10 parts angelica, 15 parts chicken blood vine, 18 parts prepared rehmannia root, 10 parts poria cocos, 6 parts prepared licorice root, 10 parts modified leonurine derivative, 15 parts donkey-hide gelatin, and 30 parts excipients.

[0085] The modified leonurine derivative was prepared in Preparation Example 1; the excipient was trehalose.

[0086] A type of Fukang capsule, primarily used to treat deficiency of both qi and blood, is prepared using the following method: Step 1: Ginseng, Angelica sinensis, Spatholobus suberectus, Rehmannia glutinosa, Poria cocos, and Glycyrrhiza uralensis are pulverized separately and passed through a 40-mesh sieve. They are then mixed evenly to obtain a mixed coarse powder. Deionized water at 60°C and 8 times its own weight are added to the mixed coarse powder. The mixture is kept at a constant temperature and immersion temperature of 30 rpm for 45 minutes. Then, the temperature is raised to 80°C and maintained for 40 minutes. Finally, the temperature is raised to 95°C and extracted for 60 minutes to obtain an extract. The extract is filtered through a 180-mesh sieve while hot. The residue is extracted again. The two filtrates are combined and then evaporated and concentrated under vacuum at 55°C to obtain a tonic medicinal material composition with a relative density of 1.20. Step 2: After mixing the tonic herbal composition with donkey-hide gelatin evenly, add the modified leonurine derivative and a 60% ethanol solution (the amount is 15 times the mass of the tonic herbal composition), mix evenly again, and dry under vacuum at 60°C until the moisture content is ≤5% to obtain the herbal gelatin mixture. Step 3: Crush the drug-gel mixture and excipients together, pass them through a 100-mesh sieve, add an 85% ethanol solution (20% of the total mass of the drug-gel mixture and excipients) to make a soft mass, then granulate it through a 14-mesh sieve, and dry it with hot air circulation at 55℃ to obtain dry granules with a moisture content of ≤5%. Step 4: After the dried granules are sieved through an 18-mesh sieve, they are filled into capsule shells, with each capsule containing 0.2g. The capsules are then packaged in aluminum-plastic blister packs to obtain Fukang Capsules, which are mainly used to treat deficiency of both qi and blood.

[0087] Comparative Example 5 Comparative Example 5 is the same as Example 1, except that the excipient is only microcrystalline cellulose. Details are as follows: A type of Fukang capsule for treating deficiency of both qi and blood includes the following ingredients in parts by weight: 8 parts ginseng, 10 parts angelica, 15 parts chicken blood vine, 18 parts prepared rehmannia root, 10 parts poria cocos, 6 parts prepared licorice root, 10 parts modified leonurine derivative, 15 parts donkey-hide gelatin, and 30 parts excipients.

[0088] The modified leonurine derivative was prepared in Preparation Example 1; the excipient was microcrystalline cellulose.

[0089] A type of Fukang capsule, primarily used to treat deficiency of both qi and blood, is prepared using the following method: Step 1: Ginseng, Angelica sinensis, Spatholobus suberectus, Rehmannia glutinosa, Poria cocos, and Glycyrrhiza uralensis are pulverized separately and passed through a 40-mesh sieve. They are then mixed evenly to obtain a mixed coarse powder. Deionized water at 60°C and 8 times its own weight are added to the mixed coarse powder. The mixture is kept at a constant temperature and immersion temperature of 30 rpm for 45 minutes. Then, the temperature is raised to 80°C and maintained for 40 minutes. Finally, the temperature is raised to 95°C and extracted for 60 minutes to obtain an extract. The extract is filtered through a 180-mesh sieve while hot. The residue is extracted again. The two filtrates are combined and then evaporated and concentrated under vacuum at 55°C to obtain a tonic medicinal material composition with a relative density of 1.20. Step 2: After mixing the tonic herbal composition with donkey-hide gelatin evenly, add the modified leonurine derivative and a 60% ethanol solution (the amount is 15 times the mass of the tonic herbal composition), mix evenly again, and dry under vacuum at 60°C until the moisture content is ≤5% to obtain the herbal gelatin mixture. Step 3: Crush the drug-gel mixture and excipients together, pass them through a 100-mesh sieve, add an 85% ethanol solution (20% of the total mass of the drug-gel mixture and excipients) to make a soft mass, then granulate it through a 14-mesh sieve, and dry it with hot air circulation at 55℃ to obtain dry granules with a moisture content of ≤5%. Step 4: After the dried granules are sieved through an 18-mesh sieve, they are filled into capsule shells, with each capsule containing 0.2g. The capsules are then packaged in aluminum-plastic blister packs to obtain Fukang Capsules, which are mainly used to treat deficiency of both qi and blood.

[0090] The comprehensive performance of the Fukang capsules for treating deficiency of both qi and blood prepared in Examples 1-3 and Comparative Examples 1-5 of this invention was tested respectively.

[0091] 1. Qi-tonifying and blood-nourishing activity test Twenty-four healthy female SPF-grade KM mice weighing 18-22g were acclimatized for 3 days and then randomly divided into a normal control group, a model control group, and an experimental group according to their weight. On the morning of the first day of the experiment, the model control group and the experimental group were injected subcutaneously with acetylphenylhydrazine solution (20mg / kg) and intraperitoneally with cyclophosphamide solution (40mg / kg) in the afternoon. The subcutaneous injection of acetylphenylhydrazine solution (20mg / kg) was repeated on the mornings of the fourth and seventh days to establish an anemia model. The normal control group was injected with an equal volume of physiological saline during the same period. Starting from the second day after modeling (day 2), the experimental group was given a daily gavage of a suspension of the contents of Fukang capsules (prepared to a concentration of 180 mg / mL, administered at 0.1 mL / 10 g). The normal control group and the model control group were given an equal volume of distilled water daily by gavage. The administration was continued for 14 days. On days 3, 7, and 14 after administration, all mice underwent behavioral tests (including a swimming test with a tail bearing 5% of body weight, recording the time to exhaustion, and a grip test, recording the maximum grip force). Simultaneously, a small amount of blood was collected via the tail vein, and the hemoglobin (HGB) content was measured using a portable hematology analyzer. After the last administration, the mice were fasted for 12 hours, and blood was collected by enucleation. The red blood cell count (RBC) and hemoglobin (HGB) content were measured using a fully automated hematology analyzer, and the serum erythropoietin (EPO) level was measured using an ELISA kit.

[0092] 2. In vitro antiplatelet aggregation test Venous blood was collected from healthy volunteers and anticoagulated with 109 mmol / L sodium citrate (blood:anticoagulant = 9:1). Platelet-rich plasma was obtained by gradient centrifugation. A positive control group (with only plasma and adenosine diphosphate solution added) and a sample group were set up. In the turbidity tube of the platelet aggregator, 250 μL of plasma and 50 μL of sample solutions of different concentrations (the contents of the Fukang capsule were prepared with physiological saline to 0.1, 0.5, 1.0, 5.0, and 10.0 mg / mL, with 3 replicates for each concentration) were added. After pre-incubation at 37℃ for 3 min, 20 μL of adenosine diphosphate solution (final concentration 5 μmol / L) was added to induce aggregation. The aggregator was then placed in the aggregator, and the transmittance change curve was continuously monitored and recorded over 5 min. The maximum transmittance change of the positive control group was taken as the 100% aggregation rate benchmark. The platelet aggregation inhibition rate (%) of each well was calculated as: [(maximum aggregation rate of positive control well - maximum aggregation rate of drug-added well) / maximum aggregation rate of positive control well] × 100%. The average and standard deviation of the inhibition rates of the 3 replicates at the same concentration were calculated to obtain the average aggregation inhibition rate at each concentration. Finally, the half-maximum inhibitory concentration (IC50) was calculated by nonlinear regression fitting with the logarithm of the sample concentration as the x-axis and the corresponding average aggregation inhibition rate as the y-axis. 50 ).

[0093] 3. Pharmacokinetic testing Twelve SPF-grade SD rats weighing 200g were randomly divided into an experimental group and a control group after fasting for 12 hours, with six rats in each group. The experimental group was administered a suspension of the contents of Fukang capsules (prepared to a concentration of 180mg / mL, administered at 10mL / kg) by gavage, while the control group was administered the same dose of control capsules containing an unmodified Leonurus japonicus alkaloid derivative. Blood samples of 0.3mL were collected from the orbital venous plexus before administration (0h) and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24h after administration. The samples were placed in heparin sodium anticoagulant tubes and centrifuged at 3500rpm for 10min at 4℃ to separate the plasma. 100μL of plasma was then added to 50μL of... Hydrolyzing the extract in 0.5M hydrochloric acid solution at 37℃ for 30 min disrupts the structure of the extracted complex, releasing bound leonurine. Then, 300 μL of acetonitrile containing an internal standard is added to precipitate the protein. The mixture is vortexed for 3 min, centrifuged at 12000 rpm for 10 min at 4℃. The supernatant is collected, and the concentrations of total leonurine and ginsenoside Rg1 in plasma are simultaneously determined using high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). A plasma concentration-time curve is plotted, and the peak concentration (C0.05) is calculated using a non-compartmental model. max Peak time (T) max ) and the area under the curve (AUC) of the drug administration time from 0 to 24 hours 0-24 ).

[0094] 4. Aluminum content determination Weigh 0.3g of the contents of each sample capsule and place them in a microwave digestion vessel. Add 5mL of pure nitric acid and 2mL of hydrogen peroxide and perform microwave digestion according to the standard procedure. After complete digestion, transfer the solution to a 50mL volumetric flask, dilute to volume with ultrapure water, and use an inductively coupled plasma mass spectrometer (ICP-MS) to plot a standard curve with aluminum standard solution. Determine the aluminum concentration in each sample solution and calculate the total aluminum content of each capsule based on the sample amount and capsule volume.

[0095] 5. In vitro release test of aluminum ions The contents of the sample capsules were placed in a dissolution apparatus. 900 mL of artificial gastric juice (SGF) at pH 1.2 or artificial intestinal juice (SIF) at pH 6.8 was used as the dissolution medium. The dissolution test was conducted at 37℃ and 75 rpm. 10 mL samples were taken at 120 min and 240 min, respectively. After filtration through a 0.22 μm filter membrane, the aluminum ion concentration in the filtrate was determined by ICP-MS, and the cumulative release rate was calculated.

[0096] The test results are shown in Table 1-6: Table 1: Dynamic changes in HGB and behavioral indicators of Fukang capsules (for treating qi and blood deficiency) during administration in Examples 1-3 and Comparative Examples 1-5 (mean ± standard deviation, n=6). Note: Compared with the normal control group, a P < 0.05 aa P < 0.01; compared with the model control group, b P < 0.05 bb P < 0.01; compared with Example 1, c P < 0.05 cc P < 0.01.

[0097] Table 2: Endpoint hematological data (mean ± standard deviation, n=6) of Fukang capsules for treating qi and blood deficiency in Examples 1-3 and Comparative Examples 1-5 after 14 days of administration. Note: Compared with the normal control group, a P < 0.05 aa P < 0.01; compared with the model control group, b P < 0.05 bb P < 0.01; compared with Example 1, c P < 0.05 cc P < 0.01.

[0098] Table 3: In vitro antiplatelet aggregation test data of Fukang capsules (for treating deficiency of both qi and blood) in Examples 1-3 and Comparative Examples 1-5 (mean ± standard deviation) Note: Compared with Example 1, c P < 0.05 cc P < 0.01.

[0099] Table 4: Pharmacokinetic test data of Fukang capsules for treating deficiency of both qi and blood in Examples 1-3 and Comparative Examples 1-5 (mean ± standard deviation, n=6) Note: Compared with Example 1, c P < 0.05 cc P < 0.01.

[0100] Table 5: Aluminum content determination data of Fukang capsules for treating qi and blood deficiency in Examples 1-3 and Comparative Examples 1-5 Table 6: In vitro aluminum ion release test data of Fukang capsules (for treating qi and blood deficiency) in Examples 1-3 and Comparative Examples 1-5 As shown in Tables 1-4, the results indicate that the Fukang capsules prepared in Examples 1-3 of this invention, which are mainly used to treat qi and blood deficiency, are significantly superior to the respective comparative examples in terms of qi-tonifying and blood-nourishing activity, in vitro antiplatelet aggregation activity, and in vivo pharmacokinetics. The examples can effectively restore hemoglobin and red blood cell count in mice with blood deficiency, and improve exercise endurance and physical strength.

[0101] As shown in Tables 5-6, the formulations of Examples 1-3 of this invention contain a controllable amount of aluminum, the content of which increases with the increase of the amount of modified leonurine derivative. In contrast, no aluminum was detected in Comparative Example 1, which does not contain aluminum acetylacetone, proving that the aluminum element originates from a specific preparation step of this invention. As shown in Table 6, the aluminum complex exhibits excellent stability in a simulated gastrointestinal environment, with an extremely low cumulative release rate of aluminum ions within 240 minutes, indicating that most of the aluminum exists in a stable complex form and is not easily released into free aluminum ions for absorption by the body. In addition, combined with the provisional tolerable weekly intake (PTWI) of aluminum set by the Joint FAO / WHO Expert Committee on Food Additives (JECFA) at 2 mg / kg body weight, this proves that while the formulation of this invention brings significant efficacy enhancement, the content of aluminum element introduced and the release risk are within the recognized safety range.

[0102] As can be seen from Example 1 and Comparative Examples 1, 2, and 3, the complete "etherification, mercapto-ene click chemistry, aluminum ion coordination, and folic acid modification" of leonurine in this invention is the key to improving efficacy. Among them, Comparative Example 1 (without etherification) and Comparative Example 2 (without click chemistry) failed to form the key covalent conjugate and thus failed to exert the absorption-promoting and targeting effects of the macromolecular carrier. The measured total blood drug concentration and corresponding blood-activating activity were significantly lower than those in Example 1. However, since the leonurine core was still present, the basic efficacy was still retained.

[0103] As can be seen from Example 1 and Comparative Examples 4 and 5, the pharmacodynamic and pharmacokinetic indicators of Comparative Example 4 (using only trehalose) and Comparative Example 5 (using only microcrystalline cellulose) are significantly inferior to those of Example 1. This indicates that a single excipient cannot simultaneously protect the active structure of the modified leonurine derivative and the rapid disintegration of the formulation. The combined application of trehalose and microcrystalline cellulose achieves high stability and high dissolution rate of the active ingredient, ultimately resulting in statistically significantly higher bioavailability and stronger pharmacological activity.

[0104] 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 Fukang capsule for treating deficiency of both qi and blood, characterized in that, The ingredients include the following parts by weight: ginseng 8-15 parts, angelica 10-20 parts, chicken blood vine 15-25 parts, prepared rehmannia root 18-25 parts, poria cocos 10-15 parts, prepared licorice root 6-10 parts, modified leonurine derivative 10-30 parts, donkey-hide gelatin 15-20 parts, and excipients 30-50 parts.

2. The Fukang capsule for treating deficiency of both qi and blood according to claim 1, characterized in that, The modified leonurine derivative was prepared by sequentially etherifying leonurine, performing mercapto-olefin click reaction, metal coordination, and folic acid targeted modification.

3. The Fukang capsule for treating deficiency of both qi and blood according to claim 2, characterized in that, The modified leonurine derivative is prepared by the following steps: S1. Dissolve leonurine in anhydrous N,N-dimethylformamide, add an acid-binding agent and stir evenly, then add allyl bromide dropwise at room temperature, heat to 50-60℃ and stir for 12-16 h. After the reaction is completed, extract, wash, dry, concentrate under reduced pressure and purify to obtain O-allylleonurine. S2. O-Allyllecithin and 2-aminoethanethiol were dissolved in a polar mixed solvent and stirred until dissolved. Under nitrogen protection, a photoinitiator was added and the reaction was carried out at room temperature and under 365nm ultraviolet light for 2-4 hours. After the reaction was completed, the mixture was purified by column chromatography to obtain the amino-terminated lecithin conjugate. S3. The amino-terminated leonurine conjugate was dissolved in anhydrous ethanol and stirred evenly. Then, under constant temperature and stirring conditions of 50-55℃, aluminum acetylacetone solution was added dropwise over 30-40 min. The reaction was continued to be stirred for 4-8 h. After the reaction was completed, the amino-terminated leonurine-aluminum complex was obtained by centrifugation and washing with ethanol. S4. Disperse the terminal amino-terminated leonurine-aluminum complex in phosphate buffer, and sonicate to obtain a complex dispersion; dissolve folic acid in 2-(N-morpholine)ethanesulfonic acid buffer, and under stirring and light-protected conditions, add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxythiosuccinimide sodium salt in sequence, and activate at room temperature for 15-30 min to obtain an activated folic acid solution; S5. Add activated folic acid solution dropwise to the complex dispersion, and adjust the pH of the system to 7.5-8.0 with alkaline solution. Stir the reaction for 2-3 hours. After the reaction is completed, separate, purify and freeze dry to obtain the modified Leonurus alkaloid derivative.

4. The Fukang capsule for treating deficiency of both qi and blood according to claim 3, characterized in that, In step S1, the mass ratio of leonurine, anhydrous N,N-dimethylformamide, acid-binding agent, and allyl bromide is 1:10-15:0.8-1.2:0.5-1.

5. The Fukang capsule for treating deficiency of both qi and blood according to claim 3, characterized in that, In step S2, the mass ratio of O-allyl leonurine, 2-aminoethanethiol, polar mixed solvent, and photoinitiator is 1:0.5-1.2:10-15:0.02-0.

05.

6. The Fukang capsule for treating deficiency of both qi and blood according to claim 3, characterized in that, In step S3, the mass ratio of the terminal amino-functionalized leonurine conjugate to the alcoholic solution of aluminum acetylacetonate is 1:0.5-1.

2.

7. The Fukang capsule for treating deficiency of both qi and blood according to claim 3, characterized in that, The ultrasonic processing parameters in step S4 are: power 300-500W, frequency 20-40KHz, and processing time 10-30min.

8. The Fukang capsule for treating deficiency of both qi and blood according to claim 1, characterized in that, The excipient is a mixture of trehalose and microcrystalline cellulose.

9. The Fukang capsule for treating deficiency of both qi and blood according to claim 8, characterized in that, The excipients are trehalose and microcrystalline cellulose in a mass ratio of 1:1-2.

10. A method for preparing the Fukang capsule for treating deficiency of both qi and blood as described in any one of claims 1-9, characterized in that, Includes the following steps: Step 1: Ginseng, Angelica sinensis, Spatholobus suberectus, Rehmannia glutinosa, Poria cocos, and Glycyrrhiza uralensis are pulverized separately and passed through a 40-60 mesh sieve. They are then mixed evenly to obtain a mixed coarse powder. Deionized water at 60-65℃ and 8-10 times its own weight is added to the mixed coarse powder. The mixture is kept at a constant temperature for 40-45 minutes under stirring. Then, it is heated to extract the extract. The extract is filtered through a 180-200 mesh sieve while hot. The residue is extracted again. The two filtrates are combined and then evaporated and concentrated under vacuum at 55-60℃ to obtain a tonic medicinal material composition. Step 2: After mixing the tonic herbal composition with donkey-hide gelatin evenly, add the modified leonurine derivative and ethanol solution, mix evenly again, and dry under vacuum at 60-70℃ until the moisture content is ≤5% to obtain the herbal gelatin mixture. Step 3: Crush the drug-gel mixture together with the excipients, pass it through a 100-120 mesh sieve, add a wetting agent to make a soft mass, then granulate it through a 14-16 mesh sieve, and dry it with hot air circulation at 55-60℃ to obtain dry granules with a moisture content of ≤5%. Step 4: After the dried granules are sieved through an 18-20 mesh sieve, they are filled into capsule shells, with each capsule containing 0.2-0.4g. The capsules are then packaged in aluminum-plastic blister packs to obtain Fukang Capsules, which are mainly used to treat deficiency of both qi and blood.

Images