A traditional Chinese medicine compound preparation and its application in the preparation of drugs for treating cardiovascular and cerebrovascular diseases

Abstract

This invention provides a traditional Chinese medicine compound preparation and its application in the preparation of drugs for treating cardiovascular and cerebrovascular diseases, belonging to the field of traditional Chinese medicine technology. The traditional Chinese medicine compound preparation comprises the following raw materials in parts by weight: 10-20 parts bee pollen, 8-15 parts curcumin, 5-10 parts γ-aminobutyric acid, 5-12 parts Litsea cubeba leaf, 10-20 parts hawthorn, 5-10 parts Lindera strychnifolia leaf, 10-20 parts kudzu root, 5-12 parts ginseng, 8-15 parts Polygonatum sibiricum, 6-12 parts Sophora japonica flower bud, 3-8 parts tangerine peel, and 1-5 parts L-cysteine. This invention significantly improves the water solubility, stability, and bioavailability of curcumin by constructing a chlorophyll zinc / LDH nanosheet composite carrier to load curcumin. A compound preparation of traditional Chinese medicine was prepared by combining a complex loaded with curcumin with various food and medicine homologous ingredients. This traditional Chinese medicine compound preparation can significantly reduce whole blood viscosity, plasma viscosity and platelet aggregation rate in rats with acute blood stasis model, has anti-thrombotic effect, and significantly promotes the recovery of neurological function in rats with focal cerebral ischemia and reduces the volume of cerebral infarction.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a traditional Chinese medicine compound preparation and its application in the preparation of drugs for treating cardiovascular and cerebrovascular diseases. Background Technology

[0002] Cardiovascular and cerebrovascular diseases (such as cerebral infarction, coronary heart disease, angina pectoris, and hypertension) are the leading causes of death and disability worldwide. Their core pathological basis lies in circulatory disorders, specifically manifested as vascular endothelial damage, lipid metabolism disorders, abnormal blood rheology (hyperviscosity, hypercoagulability, and hyperaggregation), and the formation of atherosclerotic plaques. These pathological changes can lead to blockage of cerebral and cardiac blood vessels, ultimately causing serious clinical events such as ischemic stroke and myocardial infarction.

[0003] Currently, commonly used clinical drugs mainly include antiplatelet aggregation drugs (such as aspirin and clopidogrel), statins, and anticoagulants. Although these drugs have clear efficacy in acute interventions, long-term use has significant limitations: First, they are prone to adverse reactions such as gastrointestinal bleeding, liver and kidney damage, and myalgia; second, some patients experience "aspirin resistance" or "statin escape," leading to decreased treatment efficacy; third, traditional drugs have relatively single targets, making it difficult to simultaneously regulate multiple pathological processes such as vascular, blood, metabolism, and nerve repair. Traditional Chinese medicine has accumulated rich experience in treating cardiovascular and cerebrovascular diseases through "activating blood circulation and removing blood stasis," possessing the unique advantage of multi-target and multi-pathway synergistic effects. However, traditional Chinese medicine compound prescriptions face the following technical bottlenecks: First, the low solubility of active ingredients severely restricts the efficacy; second, traditional decoction or crude extraction processes cannot guarantee the stability and controllability of active ingredients; third, existing prescriptions are mostly limited to herbal plants and do not fully integrate functional factors with clear pharmacological activity from modern nutritional science.

[0004] Curcumin is a natural polyphenolic active ingredient extracted from ginger plants. It possesses various pharmacological effects, including anti-inflammatory, antioxidant, immunomodulatory, and adjuvant anti-tumor properties, and has broad application prospects in the food, health product, and pharmaceutical fields. However, curcumin faces significant application bottlenecks: its molecular structure is highly hydrophobic, resulting in extremely low water solubility under neutral and acidic conditions. After oral administration, it is difficult to be absorbed by the gastrointestinal mucosa, with a bioavailability of less than 5%. Furthermore, curcumin is easily degraded by gastric acid and pepsin in the gastrointestinal environment, and its rapid metabolism and excretion in vivo severely limit its practical application value. In addition, traditional microencapsulation preparation processes (such as simple spray drying and emulsification) suffer from uneven particle size, low encapsulation rate, and poor retention of active ingredients, further limiting the product's application efficacy and industrialization prospects.

[0005] Therefore, developing a rehabilitation product that can leverage the synergistic effects of multiple targets of traditional Chinese medicine, combine highly active ingredients from modern pharmacology, enhance the bioavailability of active ingredients through formulation technology, and possess good safety is of significant clinical value and social importance. Summary of the Invention

[0006] Technical Problem to be Solved: Addressing the issues of poor water solubility, easy destruction of active ingredients, and low bioavailability of curcumin in existing technologies, this invention provides a traditional Chinese medicine compound preparation and its application in the preparation of drugs for treating cardiovascular and cerebrovascular diseases. By innovating the composite wall material system and preparation process, the water solubility, stability, and bioavailability of curcumin are improved. Simultaneously, by combining it with food-grade medicinal materials, the overall efficacy of the compound preparation is effectively enhanced, making it suitable for improving or treating cardiovascular and cerebrovascular diseases. Its preparation process is simple, cost-controllable, and easily scalable for industrial production, demonstrating promising application prospects.

[0007] Technical solution: A traditional Chinese medicine compound preparation, composed of the following raw materials in parts by weight: 10-20 parts bee pollen, 8-15 parts curcumin, 5-10 parts γ-aminobutyric acid, 5-12 parts Litsea cubeba, 10-20 parts hawthorn, 5-10 parts Lindera strychnifolia, 10-20 parts kudzu root, 5-12 parts ginseng, 8-15 parts Polygonatum sibiricum, 6-12 parts Sophora japonica, 3-8 parts tangerine peel, and 1-5 parts L-cysteine.

[0008] Preferably, the above-mentioned traditional Chinese medicine compound preparation is composed of the following raw materials in parts by weight: 15 parts bee pollen, 12 parts curcumin, 8 parts γ-aminobutyric acid, 8 parts Litsea cubeba, 15 parts hawthorn, 8 parts Lindera strychnifolia, 15 parts kudzu root, 8 parts ginseng, 12 parts Polygonatum sibiricum, 9 parts Sophora japonica buds, 5 parts tangerine peel, and 3 parts L-cysteine.

[0009] The preparation method of the above-mentioned traditional Chinese medicine compound preparation includes the following steps:

[0010] S1. Hawthorn, Lindera leaf, kudzu root, ginseng, Polygonatum rhizome, Sophora japonica flower bud, tangerine peel, and Litsea cubeba leaf are mixed, pulverized and sieved, and the volatile oil of the Chinese medicine is obtained by supercritical CO2 extraction technology; ethanol is added to the residue for extraction, the extract is concentrated and dried to obtain the Chinese medicine extract; the residue is refluxed with 70% ethanol at a material-to-liquid ratio of 1:10~30, extracted at 60~75℃ for 1~3 h, and the extraction is repeated once. The extracts are combined, concentrated under reduced pressure at 60℃ to a relative density of 1.20~1.25, and spray dried to obtain the Chinese medicine extract;

[0011] S2. Formamide solution was added to magnesium aluminum hydrotalcite, stirred and ultrasonically treated, and the precipitate was washed and dried after centrifugation to obtain LDH nanosheets;

[0012] S3. LDH nanosheets were prepared by adding water to prepare LDH nanosheet dispersion, and chlorophyll zinc sodium salt was prepared by adding PBS buffer to prepare chlorophyll zinc sodium salt solution. The LDH nanosheet dispersion and chlorophyll zinc sodium salt solution were mixed evenly, stirred, centrifuged and dried to obtain chlorophyll zinc / LDH nanosheet complex.

[0013] S4. Curcumin was dissolved in a small amount of anhydrous ethanol to prepare a curcumin solution. The zinc chlorophyll / LDH nanosheet complex was dispersed in deionized water. The curcumin solution was added, and after stirring, the ethanol was removed by rotary evaporation. The solid was dried to obtain the zinc chlorophyll / LDH-curcumin complex.

[0014] S5. Mix the volatile oil of traditional Chinese medicine, the extract of traditional Chinese medicine, the zinc chlorophyll / LDH-curcumin complex, bee pollen, γ-aminobutyric acid, and L-cysteine ​​evenly, and add pharmaceutically acceptable excipients to prepare a traditional Chinese medicine compound preparation.

[0015] Preferably, in step S1, the extraction pressure is 20-30 MPa, the extraction temperature is 40-50℃, the extraction time is 60-150 min, the mass-to-volume ratio of the residue to ethanol is 1:10-20, the ethanol extraction temperature is 60-80℃, and the ethanol extraction time is 1-3 h.

[0016] Preferably, in step S2, the mass-to-volume ratio of magnesium aluminum hydrotalcite to formamide solution is 1:200~330, the concentration of formamide solution is 15~30%, the stirring temperature is 24~26℃, and the stirring time is 3~8 h.

[0017] Preferably, in step S3, the mass-to-volume ratio of sodium zinc chlorophyll salt to PBS buffer is 1:150~400, the mass ratio of LDH nanosheets to sodium zinc chlorophyll salt is 1:0.5~2, the stirring temperature is 24~26℃, and the stirring time is 1~5 h.

[0018] Preferably, in step S4, the mass ratio of curcumin to zinc chlorophyll / LDH nanosheet composite is 1:0.5~3, the stirring time is 6~12 h, and the rotary evaporation temperature is 38~45℃.

[0019] The application of the above-mentioned traditional Chinese medicine compound preparations in the preparation of drugs for treating cardiovascular and cerebrovascular diseases.

[0020] The aforementioned cardiovascular and cerebrovascular diseases include coronary heart disease, angina pectoris, myocardial infarction, thrombosis, stroke, and cerebral infarction.

[0021] The aforementioned drugs also include pharmaceutically acceptable excipients.

[0022] The dosage forms of the above-mentioned drugs include tablets, granules, capsules, pills, and oral liquids.

[0023] Beneficial effects:

[0024] 1. The traditional Chinese medicine compound preparation prepared by this invention significantly improves the water solubility of curcumin. This invention utilizes a zinc chlorophyll / LDH nanosheet complex formed by electrostatic interaction between sodium zinc chlorophyll and exfoliated LDH nanosheets. This complex serves as a carrier for loading curcumin. In aqueous phase, the complex exhibits stable dispersion without aggregation due to electrostatic repulsion caused by the positive surface charge. Simultaneously, its high specific surface area and abundant surface hydroxyl groups endow the system with strong hydrophilicity, providing active sites for subsequent drug loading. The porphyrin ring of sodium zinc chlorophyll provides a hydrophobic region, undergoing hydrophobic inclusion and π-π stacking interactions with curcumin. The Zn at the center of the porphyrin ring... 2+ By forming coordination bonds with the β-diketone structure of curcumin, curcumin is anchored to the complex. The hydrophilicity of the complex effectively isolates the hydrophobic core, preventing the self-aggregation and crystallization of curcumin molecules, thus significantly improving its water solubility. This invention enables curcumin to synergistically disperse with other pharmacological components in compound preparations, avoiding the weakening of the overall dissolution effect of the compound preparation due to curcumin self-aggregation, thereby ensuring the balanced release and absorption of all components in the compound preparation.

[0025] 2. This invention achieves slow release of the active ingredient and avoids burst release. The zinc chlorophyll / LDH-curcumin complex effectively reduces the degradation of curcumin by gastrointestinal enzymes. After the formulation enters the stomach, the LDH structure undergoes initial dissolution in the acidic environment, but the electrostatic and coordination interactions between zinc chlorophyll and LDH delay the release of curcumin, avoiding burst release. Upon entering the intestine, anions such as phosphate groups in the environment enter the LDH interlayer through ion exchange, leading to structural instability. The coordination effect of zinc chlorophyll provides additional stabilizing effect, thereby delaying the release of curcumin. This slow-release behavior allows the loaded substance to maintain an effective concentration in the intestine for a longer period, rather than being rapidly metabolized and cleared after a single release in the duodenum. The slow release of curcumin complements the rapid release of other unencapsulated components in the compound (such as volatile oils, extracts, and γ-aminobutyric acid), prolonging the overall action time of the compound formulation in the intestine and enhancing the synergistic therapeutic effect of the multi-component formulation on cardiovascular and cerebrovascular diseases.

[0026] 3. This invention increases the bioavailability of curcumin to 4.8 times that of the raw curcumin drug. Curcumin tends to aggregate in gastrointestinal fluids, making it difficult to achieve sufficient contact with the intestinal epithelium. Loading curcumin onto the complex increases the concentration of absorbable drug. The layered structure of LDH nanosheets provides a large specific surface area, enabling higher drug loading. Furthermore, the complex undergoes electrostatic adsorption with intestinal mucus protein MUC2, prolonging the drug's residence time in the intestine, preventing rapid clearance, and increasing the drug absorption window. The improved bioavailability directly enhances the in vivo exposure level of the core active ingredient in the compound formulation, allowing the compound formulation to fully exert its efficacy in the treatment of cardiovascular and cerebrovascular diseases such as coronary heart disease, angina pectoris, and cerebral infarction due to cerebral blood stasis.

[0027] 4. The compound preparation prepared in this invention breaks through the limitations of traditional Chinese medicine compound preparations, which are limited to herbal plants. It organically integrates insect-based drugs (bee pollen) with neurotransmitter-like active substances (γ-aminobutyric acid) and natural monomeric compounds (curcumin). Simultaneously, it utilizes the detoxification function of L-cysteine ​​to promote glutathione synthesis, reducing the potential risk of liver damage from long-term use. This achieves an organic combination of the "principal, assistant, adjuvant, and guide" theory of traditional Chinese medicine and the precise supplementation of "modern nutritional medicine." It constructs a complete therapeutic closed loop of "promoting qi circulation, activating blood circulation, removing blood stasis, and unblocking collaterals," covering the entire process of cardiovascular and cerebrovascular diseases from etiology (metabolic disorders, qi deficiency) to pathology (plaque formation, thrombosis) and sequelae (nerve damage, functional impairment), realizing the logical unity of traditional Chinese medicine theory and Western medical molecular mechanisms. Furthermore, the raw materials of this compound preparation are all derived from the list of medicinal and edible substances or ingredients permitted by food safety standards. Compared with chemical drugs, it has less gastrointestinal irritation and a lighter burden on liver and kidney function, making it suitable for long-term rehabilitation use by patients with chronic cardiovascular and cerebrovascular diseases. Attached Figure Description

[0028] Figure 1 This represents the cumulative release rate of curcumin in gastric juice;

[0029] Figure 2 This represents the cumulative release rate of curcumin in intestinal fluid. Detailed Implementation

[0030] The present invention will be further described below with reference to embodiments. These embodiments are illustrative of the present invention, but the present invention is not limited to these embodiments:

[0031] Example 1

[0032] This embodiment describes a method for preparing a traditional Chinese medicine compound preparation, including the following steps:

[0033] S1. 15 parts hawthorn, 8 parts Lindera leaf, 15 parts kudzu root, 8 parts ginseng, 12 parts Polygonatum rhizome, 9 parts Sophora flower bud, 5 parts dried tangerine peel, and 8 parts Litsea cubeba leaves were mixed, pulverized through an 80-mesh sieve, and extracted using supercritical CO2 extraction technology at an extraction pressure of 25 MPa and an extraction temperature of 45℃ for 90 min. The volatile oil of the Chinese herbal medicine was separated, dried with anhydrous sodium sulfate, and stored at 4℃. The residue was extracted with 70% ethanol under reflux at a material-to-liquid ratio of 1:15 at 70℃ for 1.5 h. The extraction was repeated once. The extracts were combined and concentrated under reduced pressure at 60℃ to a relative density of 1.20~1.25. The extract was then spray-dried to obtain the Chinese herbal medicine extract.

[0034] S2. Magnesium aluminum hydrotalcite (LDH) and 20% formamide solution were mixed at a ratio of 1:250, stirred at 25℃ for 6 h, ultrasonically treated for 20 min at an ultrasonic power of 200 W and an ultrasonic frequency of 40 kHz, centrifuged at 8000 rpm for 5 min, and the precipitate was washed three times with ethanol solution and deionized water and dried to obtain LDH nanosheets.

[0035] S3. LDH nanosheets and deionized water were mixed at a ratio of 1:130 to prepare an LDH nanosheet dispersion. Sodium zinc chlorophyll and PBS buffer (pH 7.0) were mixed at a ratio of 1:200 to prepare a sodium zinc chlorophyll solution. The LDH nanosheet dispersion was added to the solution, and the mass ratio of LDH nanosheets to sodium zinc chlorophyll was 1:1.2. The mixture was stirred at 25°C for 3 h, centrifuged at 8000 rpm for 10 min, and dried to obtain a zinc chlorophyll / LDH nanosheet complex.

[0036] S4. Take 12 parts of curcumin and dissolve it in a small amount of anhydrous ethanol to prepare curcumin solution. Disperse the zinc chlorophyll / LDH nanosheet complex in deionized water and add curcumin solution. The mass ratio of curcumin to zinc chlorophyll / LDH nanosheet complex is 1:1.5. Stir for 10 h at pH 6.5. Remove ethanol by rotary evaporation at 40℃. Dry the resulting solid at 40℃ to obtain zinc chlorophyll / LDH-curcumin complex.

[0037] S5. After mixing the above-mentioned volatile oil of traditional Chinese medicine, extract of traditional Chinese medicine, zinc chlorophyll / LDH-curcumin complex, 15 parts of bee pollen, 8 parts of γ-aminobutyric acid and 3 parts of L-cysteine ​​evenly, a traditional Chinese medicine compound preparation is obtained.

[0038] Example 2

[0039] The difference between this embodiment and Embodiment 1 is that the raw materials of the traditional Chinese medicine compound preparation in this embodiment include the following parts by weight: 12 parts bee pollen, 10 parts curcumin, 6 parts γ-aminobutyric acid, 6 parts Litsea cubeba, 12 parts hawthorn, 6 parts Lindera strychnifolia, 12 parts kudzu root, 6 parts ginseng, 10 parts Polygonatum sibiricum, 8 parts Sophora japonica buds, 4 parts tangerine peel, and 2 parts L-cysteine. The remaining steps are the same as in Embodiment 1.

[0040] Example 3

[0041] The difference between this embodiment and Embodiment 1 is that the raw materials of the traditional Chinese medicine compound preparation in this embodiment include the following parts by weight: 18 parts bee pollen, 14 parts curcumin, 9 parts γ-aminobutyric acid, 10 parts Litsea cubeba, 18 parts hawthorn, 9 parts Lindera strychnifolia, 18 parts kudzu root, 10 parts ginseng, 14 parts Polygonatum sibiricum, 11 parts Sophora japonica, 7 parts tangerine peel, and 4 parts L-cysteine. The remaining steps are the same as in Embodiment 1.

[0042] Example 4

[0043] The difference between this embodiment and Embodiment 1 is that the mass-to-volume ratio of magnesium aluminum hydrotalcite to formamide solution in this embodiment is 1:300, while the remaining steps are the same as in Embodiment 1.

[0044] Example 5

[0045] The difference between this embodiment and Embodiment 1 is that the concentration of the formamide solution in this embodiment is 20%, while the remaining steps are the same as in Embodiment 1.

[0046] Example 6

[0047] The difference between this embodiment and Embodiment 1 is that the mass ratio of LDH nanosheets to sodium zinc chlorophyll salt is 1:2 in this embodiment, and the remaining steps are the same as in Embodiment 1.

[0048] Example 7

[0049] The difference between this embodiment and Embodiment 1 is that the mass ratio of curcumin and zinc chlorophyll / LDH nanosheet composite in this embodiment is 1:2.5, and the remaining steps are the same as in Embodiment 1.

[0050] To further illustrate the technical effects of the present invention, a comparative example is also provided, as follows:

[0051] Comparative Example 1

[0052] The difference between this comparative example and Example 1 is that LDH in this comparative example is not treated with formamide solution, while the other steps are the same as in Example 1.

[0053] Comparative Example 2

[0054] The difference between this comparative example and Example 1 is that sodium zinc chlorophyll is not added in this comparative example, while the other steps are the same as in Example 1.

[0055] Comparative Example 3

[0056] The difference between this comparative example and Example 1 is that in this comparative example, LDH is not treated with formamide solution and no sodium zinc chlorophyll salt is added; the remaining steps are the same as in Example 1.

[0057] Comparative Example 4

[0058] The difference between this comparative example and Example 1 is that the chlorophyll zinc / LDH-curcumin complex is replaced with curcumin in this comparative example, while the other steps are the same as in Example 1.

[0059] Comparative Example 5

[0060] The difference between this comparative example and Example 1 is that in this comparative example, zinc zinc salt is replaced with zinc sulfate, while the other steps are the same as in Example 1.

[0061] Table 1 Encapsulation efficiency, drug loading, and water solubility of curcumin

[0062]

[0063] As shown in Table 1, the encapsulation efficiency of curcumin in Examples 1-7 was 92.66-97.28%, and the drug loading was 32.62-36.24%. Compared with Comparative Examples 1-5, both the encapsulation efficiency and drug loading were at a higher level, indicating that the preparation method of the present invention has good process stability and batch-to-batch repeatability, and can stably achieve high-efficiency loading of curcumin. Comparative Example 1 (LDH nanosheets replaced with LDH) was without LDH stripping, and its encapsulation efficiency and drug loading were lower than those of Examples 1-7, indicating that LDH stripping is the key to improving loading efficiency. Unstripped LDH has a smaller specific surface area and insufficient active sites, making it difficult to achieve high-efficiency loading of curcumin. Comparative Example 2 (without adding sodium zinc chlorophyll) had lower encapsulation efficiency and drug loading than Examples 1-7, indicating that the hydrophobic region provided by the porphyrin ring of sodium zinc chlorophyll and Zn 2+ The provided coordination sites are the core driving force for curcumin anchoring to the complex. Comparative Example 3 (LDH nanosheets replaced with LDH, no sodium zinc chlorophyll salt added) had the lowest encapsulation efficiency and drug loading among all groups, showing the largest decrease compared to Example 1, and lower than Comparative Examples 1-2. This indicates a synergistic effect between LDH exfoliation and sodium zinc chlorophyll salt; the absence of either significantly reduces loading performance, and the absence of both results in the lowest performance. Comparative Example 5 (sodium zinc chlorophyll salt replaced with zinc sulfate) had lower encapsulation efficiency and drug loading than Examples 1-7, but higher than Comparative Example 2 (no sodium zinc chlorophyll salt added), indicating that zinc sulfate provides Zn... 2+ Although it can produce some coordination, it lacks a porphyrin ring structure and cannot form hydrophobic inclusion and π-π stacking interactions, so its loading efficiency is far inferior to the overall effect of chlorophyll zinc sodium salt.

[0064] Examples 1-7 of this invention utilize complexes formed from LDH nanosheets and sodium zinc chlorophyll to load curcumin. The LDH nanosheets provide a high specific surface area and positive surface charge. The hydrophobic regions of the porphyrin rings in the sodium zinc chlorophyll interact with curcumin through π-π stacking and coordination (Zn) 2+ (Compared with β-diketone), the zinc chlorophyll / LDH-curcumin complex is stably dispersed due to electrostatic repulsion, effectively preventing curcumin self-aggregation and crystallization, and significantly improving the water solubility of curcumin. Compared with Comparative Example 4 (curcumin monomer), the water solubility is increased by 120-139 times. The water solubility of each example group is at a high level, and the overall performance is stable. Comparative Example 1 (LDH nanosheets replaced with LDH) has a low specific surface area without LDH exfoliation, the layers are tightly stacked, the surface hydroxyl groups are not sufficiently exposed, and the hydrophilicity and dispersibility are extremely poor. Even with the addition of sodium zinc chlorophyll, it can be dispersed through hydrophobic inclusion, π-π stacking and Zn 2+ Coordination captures curcumin, but because the carrier itself fails to form a stable dispersion system, the entire complex is prone to aggregation and precipitation in the aqueous phase. Curcumin settles along with the carrier and cannot exist stably in water in a dissolved state. Comparative Example 2 (without added sodium zinc chlorophyll) LDH nanosheets have good hydrophilicity and high specific surface area, but lack specific binding forces (hydrophobic inclusion, π-π stacking, coordination bonds) with curcumin. Curcumin can only adhere to the LDH surface through weak physical adsorption or electrostatic interaction, and is easily displaced or desorbed in the aqueous phase. The free curcumin molecules then undergo self-aggregation and crystallization, resulting in a significant decrease in water solubility.

[0065] Comparative Example 3 (LDH nanosheets replaced with LDH, no addition of zinc zinc salt): Curcumin could not be effectively loaded onto the coarse, aggregated LDH particles, nor did it have the binding force to stabilize it in a hydrophilic environment. Therefore, curcumin existed in the system almost entirely in the form of pure drug crystals. Hydrophobic intermolecular interactions drove its rapid aggregation, crystallization, and precipitation, resulting in extremely low water solubility. Comparative Example 5 (Zinc zinc salt replaced with zinc sulfate): Zn 2+ It may coordinate with the β-diketone of curcumin, but lacks the porphyrin ring and the hydrophobic region it provides, thus missing the two key interactions of hydrophobic inclusion and π-π stacking. Zinc sulfate cannot form a stable and functionalized complex interface with LDH nanosheets. Therefore, the binding force between curcumin and the support is significantly weakened, making it prone to desorption and self-aggregation.

[0066] like Figures 1-2As shown, after 15 hours in gastric juice, the cumulative release rate of curcumin in Examples 1-7 was 35.62-47.33%, lower than the 55.8-95.7% in Comparative Examples 1-5; after 15 hours in intestinal juice, the cumulative release rate of curcumin in Examples 1-7 was 57.7%-68.4%, while that in Comparative Examples 1-5 was as high as 79.6%-93.8%. This indicates that Examples 1-7 of the present invention can effectively achieve low release of curcumin in gastric juice and controlled slow release in intestinal juice, avoiding burst release. The reason is that although the LDH structure undergoes initial dissolution in the acidic environment of gastric juice, the electrostatic and coordination interactions between zinc chlorophyll and LDH can delay the release of curcumin; after entering the intestine, phosphate and bicarbonate anions enter the LDH interlayer through ion exchange, causing structural instability, but the coordination effect of zinc chlorophyll provides an additional stabilizing effect, thereby further delaying the release. In contrast, due to the lack of a stripping structure or zinc chlorophyll, LDH is deconstructed too quickly in the intestine or curcumin is directly exposed, leading to burst release.

[0067] Example 8

[0068] This embodiment describes the effect of a traditional Chinese medicine compound preparation on an acute blood stasis model in rats, including the following steps:

[0069] Sixty male SD rats, weighing 180-220 g, were randomly divided into 6 groups of 10 rats each: normal control group, model group, positive control group (aspirin 10 mg / kg), low-dose group (200 mg / kg) of Example 1, medium-dose group (400 mg / kg) of Example 1, and high-dose group (600 mg / kg) of Example 1. An acute blood stasis model was established by subcutaneous injection of adrenaline (0.8 mg / kg) with ice water stimulation. After 7 days of continuous administration, blood rheological parameters and platelet aggregation rate were measured.

[0070] Table 2. Effects of traditional Chinese medicine compound preparations on an acute blood stasis model in rats.

[0071]

[0072] Note: Compared with the normal control group, **P<0.01; compared with the model group, #P<0.05, ##P<0.01.

[0073] As shown in Table 2, the traditional Chinese medicine compound preparation of the present invention can significantly reduce whole blood viscosity, plasma viscosity and platelet aggregation rate in rats with acute blood stasis. The effect of the high-dose group is comparable to that of the positive control group. In addition, no obvious bleeding points were observed in the gastric mucosa of the rats in Example 1 group (while the positive control group had mild gastric mucosal damage), suggesting that the present invention has better gastrointestinal safety.

[0074] Example 9

[0075] This embodiment describes the effect of a traditional Chinese medicine compound preparation on arteriovenous bypass thrombosis in rats, including the following steps:

[0076] S1. Seventy male SD rats, weighing 180-220 g, were randomly divided into seven groups of 10 rats each: normal control group, model group, positive control group (tirofiban 10 mg / kg), low-dose group of Example 1 (200 mg / kg), medium-dose group of Example 1 (400 mg / kg), high-dose group of Example 1 (600 mg / kg), and comparative groups (comparative examples 1-5).

[0077] S2. Take a 12 cm long PE-160 tube, insert a 10 cm long cotton thread (pre-weighed dry and wet weights), and form a cannula with two 4 cm long PE-60 tubes. Inject physiological saline to moisten the cannula. Seven days after administration to rats, anesthetize the rats, make a midline incision in the neck, separate the right common carotid artery and the left external jugular vein, insert the cannula after making incisions, inject heparinized physiological saline, release the arterial clamps, allow blood circulation for 20 minutes, remove the cotton thread and weigh its wet weight, dry it at 60℃ for 20 minutes, and weigh its dry weight. Subtract the pre-measured wet and dry weights of the cotton thread to obtain the wet and dry weights of the thrombus, and calculate the thrombus formation inhibition rate.

[0078] Table 3. Effects of traditional Chinese medicine compound preparations on arteriovenous bypass thrombosis in rats.

[0079]

[0080] Note: Compared with the normal control group, **P<0.01; compared with the model group, ##P<0.01.

[0081] As shown in Table 3, the different dosage groups of the traditional Chinese medicine compound preparation of the present invention all have antithrombotic effects, and the high-dose group has a better antithrombotic effect than the aspirin positive control group.

[0082] Example 10

[0083] This embodiment describes the effect of a traditional Chinese medicine compound preparation on the recovery of neurological function in rats with focal cerebral ischemia, including the following steps:

[0084] Seventy male SD rats, weighing 180-220 g, were randomly divided into seven groups of ten rats each: normal control group, model group, positive control group (nimodipine 10 mg / kg), low-dose group of Example 1 (200 mg / kg), medium-dose group of Example 1 (400 mg / kg), high-dose group of Example 1 (600 mg / kg), and comparative groups (comparative examples 1-5). A rat model of focal cerebral ischemia was established using the middle cerebral artery occlusion (MCAO) method. Drug administration began 24 h after modeling and continued for 14 days. The Longa score was used to evaluate neurological deficits, and TTC staining was used to determine the infarct volume.

[0085] Table 4. Effects of traditional Chinese medicine compound preparations on the recovery of neurological function in rats with focal cerebral ischemia.

[0086]

[0087] Note: Compared with the model group, *P<0.01, **P<0.01.

[0088] As shown in Table 4, the traditional Chinese medicine compound preparation of the present invention can significantly promote the recovery of neurological function and reduce the volume of cerebral infarction in rats with focal cerebral ischemia, and its effect is better than that of the positive control drug nimodipine.

[0089] Example 11

[0090] This embodiment is a validation of improving the bioavailability of curcumin in a traditional Chinese medicine compound preparation, including the following steps:

[0091] Twelve male SD rats, weighing 180-220 g, were randomly divided into two groups of six each. The rats were administered conventional curcumin raw material and the traditional Chinese medicine compound preparation of this invention (100 mg / kg of curcumin) by gavage. Blood samples were collected before administration and at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 h after administration. The concentration of curcumin in plasma was determined by HPLC.

[0092] Table 5. Pharmacokinetic parameters and bioavailability of curcumin

[0093]

[0094] Note: Compared with the curcumin group, *P<0.01, **P<0.01.

[0095] As shown in Table 5, the traditional Chinese medicine compound preparation of the present invention increases the relative bioavailability of curcumin to 4.8 times that of ordinary curcumin, effectively solving the technical problem of poor curcumin absorption. The significant increase in bioavailability directly improves the in vivo exposure level of the core active ingredient, providing a guarantee for the efficacy of cardiovascular and cerebrovascular diseases.

[0096] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any person skilled in the art can make many possible variations and modifications to the technical solutions of the present invention, or modify them into equivalent embodiments, without departing from the spirit and technical essence of the present invention. Therefore, any simple modifications, equivalent substitutions, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention, without departing from the content of the technical solutions of the present invention, shall still fall within the scope of protection of the present invention.

Claims

1. A traditional Chinese medicine compound preparation, characterized in that: The traditional Chinese medicine compound preparation is composed of the following raw materials in parts by weight: 10-20 parts bee pollen, 8-15 parts curcumin, 5-10 parts γ-aminobutyric acid, 5-12 parts Litsea cubeba, 10-20 parts hawthorn, 5-10 parts Lindera strychnifolia, 10-20 parts kudzu root, 5-12 parts ginseng, 8-15 parts Polygonatum sibiricum, 6-12 parts Sophora japonica, 3-8 parts tangerine peel, and 1-5 parts L-cysteine.

2. The method for preparing a traditional Chinese medicine compound preparation according to claim 1, characterized in that, Includes the following steps: S1. Hawthorn, Lindera leaf, kudzu root, ginseng, Polygonatum rhizome, Sophora japonica flower bud, tangerine peel, and Litsea cubeba leaf are mixed, pulverized and sieved, and the volatile oil of the Chinese medicine is obtained by supercritical CO2 extraction technology; ethanol is added to the residue for extraction, the extract is concentrated and dried to obtain the Chinese medicine extract; the residue is refluxed with 70% ethanol at a material-to-liquid ratio of 1:10~30, extracted at 60~75℃ for 1~3 h, and the extraction is repeated once. The extracts are combined, concentrated under reduced pressure at 60℃ to a relative density of 1.20~1.25, and spray dried to obtain the Chinese medicine extract; S2. Formamide solution was added to magnesium aluminum hydrotalcite, stirred and ultrasonically treated, and the precipitate was washed and dried after centrifugation to obtain LDH nanosheets; S3. LDH nanosheets were prepared by adding water to prepare LDH nanosheet dispersion, and chlorophyll zinc sodium salt was prepared by adding PBS buffer to prepare chlorophyll zinc sodium salt solution. The LDH nanosheet dispersion and chlorophyll zinc sodium salt solution were mixed evenly, stirred, centrifuged and dried to obtain chlorophyll zinc / LDH nanosheet complex. S4. Curcumin was dissolved in a small amount of anhydrous ethanol to prepare a curcumin solution. The zinc chlorophyll / LDH nanosheet complex was dispersed in deionized water. The curcumin solution was added, and after stirring, the ethanol was removed by rotary evaporation. The solid was dried to obtain the zinc chlorophyll / LDH-curcumin complex. S5. Mix the volatile oil of traditional Chinese medicine, the extract of traditional Chinese medicine, the zinc chlorophyll / LDH-curcumin complex, bee pollen, γ-aminobutyric acid, and L-cysteine ​​evenly to prepare a compound preparation of traditional Chinese medicine.

3. The method for preparing a traditional Chinese medicine compound preparation according to claim 2, characterized in that: In step S1, the extraction pressure is 20-30 MPa, the extraction temperature is 40-50℃, the extraction time is 60-150 min, the mass-volume ratio of the residue to ethanol is 1:10-20, the ethanol extraction temperature is 60-80℃, and the ethanol extraction time is 1-3 h.

4. The method for preparing a traditional Chinese medicine compound preparation according to claim 2, characterized in that: In step S2, the mass-to-volume ratio of magnesium aluminum hydrotalcite to formamide solution is 1:200~330, the concentration of formamide solution is 15~30%, the stirring temperature is 24~26℃, and the stirring time is 3~8 h.

5. The method for preparing a traditional Chinese medicine compound preparation according to claim 2, characterized in that: In step S3, the mass-to-volume ratio of chlorophyll zinc sodium salt to PBS buffer is 1:150~400, the mass ratio of LDH nanosheets to chlorophyll zinc sodium salt is 1:0.5~2, the stirring temperature is 24~26℃, and the stirring time is 1~5 h.

6. The method for preparing a traditional Chinese medicine compound preparation according to claim 2, characterized in that: In step S4, the mass ratio of curcumin to zinc chlorophyll / LDH nanosheets is 1:0.5~3, the stirring time is 6~12 h, and the rotary evaporation temperature is 38~45℃.

7. The application of the traditional Chinese medicine compound preparation according to claim 1 in the preparation of drugs for treating cardiovascular and cerebrovascular diseases.

8. The application according to claim 7, characterized in that: The cardiovascular and cerebrovascular diseases mentioned include coronary heart disease, angina pectoris, myocardial infarction, thrombosis, stroke, and cerebral infarction.

9. The application according to claim 7, characterized in that: The drug also includes pharmaceutically acceptable excipients.

10. The application according to claim 7 or 9, characterized in that: The dosage forms of the drug include tablets, granules, capsules, pills, and oral liquids.

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