Traditional Chinese medicine composition for treating hyperlipidemia and preparation method of enteric-soluble sustained-release capsule thereof

Abstract

The application belongs to the technical field of traditional Chinese medicine, and discloses a traditional Chinese medicine composition for treating hyperlipidemia and a preparation method of enteric-soluble sustained-release capsules of the traditional Chinese medicine composition. The traditional Chinese medicine composition comprises the following raw materials in parts by weight: hawthorn 12-25 parts, alisma 8-15 parts, Lithocarpus polyporus 8-15 parts, and raw licorice 5-12 parts. The enteric-soluble sustained-release capsule is obtained by filling the sustained-release penetration micro-pellets in a capsule shell. The sustained-release penetration micro-pellet is composed of a drug core and a sustained-release penetration layer wrapped outside the drug core. The drug core is made of the traditional Chinese medicine composition, and the sustained-release penetration layer is made of a mixture of hydroxypropyl methyl cellulose, glycyrrhizic acid and quercetin. The application can be used for treating hyperlipidemia of the phlegm-dampness resistance type, and the prepared enteric-soluble sustained-release capsule can utilize the penetration system composed of high-purity glycyrrhizic acid and quercetin to improve the bioavailability of triterpenoid components, and solve the problems of low drug loading, poor reproducibility or damage to the intestinal barrier in the prior art.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically relating to a traditional Chinese medicine composition for treating hyperlipidemia and a method for preparing its enteric-coated sustained-release capsules. Background Technology

[0002] Hyperlipidemia is a metabolic disorder characterized by elevated levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) and / or decreased high-density lipoprotein cholesterol (HDL-C) in blood plasma. It is a significant risk factor for atherosclerosis, coronary heart disease, and ischemic stroke. Phlegm-dampness retention type is the most common TCM syndrome of primary hyperlipidemia, clinically manifested as obesity, chest tightness, poor appetite, heaviness in the limbs, and a thick, greasy tongue coating. Currently, commonly used chemical drugs include statins, fibrates, niacin, and cholesterol absorption inhibitors, but these have adverse reactions such as hepatotoxicity and myopathy.

[0003] Lithocarpus litseifolius, also known as litsea cubeba or sweet tea, is a plant belonging to the genus Lithocarpus in the family Fagaceae. Traditionally used for clearing heat, relieving summer heat, and quenching thirst, it has been shown in modern research to be rich in dihydrochalcones and flavonoids such as phloridzin, trilobatin, and quercetin. These components exhibit hypoglycemic, lipid-lowering, and antioxidant activities. However, preclinical studies on the lipid-lowering effects of Lithocarpus litseifolius are insufficient, and its effective components and formulation bottlenecks remain unresolved.

[0004] This study, based on the principles of promoting digestion, resolving phlegm, eliminating dampness, and lowering lipids, selected four Chinese herbs—hawthorn, alisma, scutellaria barbata, and licorice root—as the principal ingredient. Hawthorn is the chief herb, promoting digestion and lowering lipids; its core active components, maslinic acid, ursolic acid, and oleanolic acid, inhibit HMG-CoA reductase and promote cholesterol degradation. Alisma is the assistant herb, promoting diuresis and eliminating dampness; its main active component, alisol B... B) Alismatol A-24-acetate has the effect of inhibiting cholesterol absorption and promoting bile acid excretion; Spiraea japonica is used as an adjuvant to clear heat and resolve phlegm. Its phlorizin, as a classic sodium-glucose cotransporter (SGLT1 / 2) inhibitor, can reduce intestinal glucose uptake and indirectly regulate cellular energy status. At the same time, studies have shown that phlorizin can upregulate liver GLUT2 expression and promote hepatocyte glucose uptake. In addition, trifolin and quercetin in Spiraea japonica can affect AMPK phosphorylation status and act on PPARα by regulating LKB1 or phosphatase activity, synergistically promoting mitochondrial fatty acid oxidation. Quercetin also has the inhibitory effect of P-glycoprotein (P-gp); Glycyrrhiza uralensis is used as an adjuvant to harmonize the various drugs and clear heat and detoxify. Its main active ingredient, glycyrrhizic acid (GA), has micelle self-assembly ability and can significantly improve the solubility of insoluble triterpenoid components.

[0005] However, the above-mentioned compositions face severe biopharmaceutical bottlenecks. The triterpenoid acids (hawthorn acid, ursolic acid) in hawthorn and the proto-triterpenoid components such as alismol B in Alisma plantago-aquatica have extremely low water solubility (<10 μg / mL), high oil-water partition coefficients (logP>5), and slow and incomplete dissolution in the gastrointestinal tract. Furthermore, most triterpenoid components are P-gp substrates, facing active efflux from the intestine, and their oral bioavailability is typically <5% (the literature reports that the oral bioavailability of some triterpenoid components, such as ursolic acid, in rats is approximately 0.7-1.2%). Existing technologies often employ cyclodextrin inclusion complexation, solid dispersions, or the addition of surfactants, but these suffer from drawbacks such as low drug loading, poor reproducibility, or disruption of the intestinal barrier. Summary of the Invention

[0006] To address the aforementioned shortcomings, this invention discloses a traditional Chinese medicine composition for treating hyperlipidemia and a method for preparing its enteric-coated sustained-release capsules. This composition can not only be used to treat hyperlipidemia of the phlegm-dampness retention type, but the prepared enteric-coated sustained-release capsules can utilize a permeation-enhancing system composed of high-purity glycyrrhizic acid and quercetin to improve the bioavailability of triterpenoid acids (crab acid, ursolic acid) and proto-triterpenoid components such as alisma plantago-aquatica B from Alisma plantago-aquatica. This solves the problems of low drug loading, poor reproducibility, or damage to the intestinal barrier associated with existing methods such as cyclodextrin inclusion complexation, solid dispersions, or the addition of surfactants.

[0007] This invention is achieved using the following technical solution: A traditional Chinese medicine composition for treating hyperlipidemia, comprising the following raw materials in parts by weight: 12-25 parts hawthorn, 8-15 parts alisma, 8-15 parts scutellaria barbata, and 5-12 parts raw licorice.

[0008] Further optimization, the traditional Chinese medicine composition for treating hyperlipidemia includes the following raw materials in parts by weight: 18-20 parts hawthorn, 10-12 parts Alisma plantago-aquatica, 10-12 parts Polygonum hydropiper, and 8-10 parts raw licorice.

[0009] The preparation method of the traditional Chinese medicine composition for treating hyperlipidemia is any one of the following three methods: Method 1 involves weighing hawthorn, alisma, spatholobus suberectus, and raw licorice root in a specific ratio, mixing them, then decocting them with water, filtering, concentrating, and drying to obtain a traditional Chinese medicine composition. Method 2 involves converting the raw materials according to their weight ratio, weighing out the corresponding Chinese herbal medicine slices of hawthorn, alisma, spatholobus suberectus, and raw licorice, mixing them, and then decocting, filtering, concentrating, and drying them to obtain the Chinese herbal medicine composition. Method three involves converting the raw materials according to their weight ratio, weighing out the corresponding Chinese medicine formula granules of hawthorn, alisma, and raw licorice, and extract of spatholobus suberectus, and then mixing them to make pills to obtain a Chinese medicine composition.

[0010] Further optimization involves preparing the *Hylocereus undatus* extract by drying and chopping the dried leaves of *Hylocereus undatus*, followed by extraction with a 50-80% ethanol solution, concentration, and drying. The yield of the dry extract is approximately 22%, and the extract contains 2.1%-4.3% quercetin, ≥18% phlorizin, and ≤5% moisture.

[0011] An enteric-coated sustained-release capsule for treating hyperlipidemia is obtained by filling a capsule shell with sustained-release and permeation-enhancing microspheres. The sustained-release and permeation-enhancing microspheres consist of a drug core and a sustained-release and permeation-enhancing layer surrounding the drug core. The drug core is made from the aforementioned traditional Chinese medicine composition, and the sustained-release and permeation-enhancing layer is made from a mixture of hydroxypropyl methylcellulose, glycyrrhizic acid, and quercetin.

[0012] Further optimization involves using a capsule shell made of hydroxypropyl methylcellulose phthalate (HPMCP) of size 0. Each enteric-coated sustained-release capsule contains 399–590 mg of sustained-release permeation-enhancing microspheres. The mass ratio of the drug core to the sustained-release permeation-enhancing layer in the sustained-release permeation-enhancing microspheres is approximately 72–75:25–28. The sustained-release permeation-enhancing layer contains 2.0–4.0 mg of glycyrrhizic acid per capsule and 1.2–2.0 mg of quercetin per capsule.

[0013] The method for preparing the enteric-coated sustained-release capsules for treating hyperlipidemia includes the following steps: (1) According to the raw material ratio conversion of the Chinese medicine composition, the corresponding Chinese medicine formula granules of hawthorn, alisma and raw licorice and extract of spatholobus suberectus are weighed and added to the mixer, and microcrystalline cellulose and lactose are added and mixed to obtain a mixture. A 40% ethanol solution is added to the mixture and mixed to form a soft material, which is then sent to an extrusion rolling mill for processing. Then, it is dried in a fluidized bed at 45°C until the moisture content is ≤5%, and then screened to obtain micro pellets of 400-700μm. (2) Hydroxypropyl methylcellulose (HPMC K4M) was added to a 75% ethanol solution and stirred at 23-27°C for 30 min to obtain a dispersion. Glycyrrhizic acid was dissolved in hot water at 60°C, then sonicated for 3 min, cooled to room temperature, and added to the dispersion to obtain a glycyrrhizic acid solution. Quercetin was dissolved in anhydrous ethanol and sonicated, then slowly added to the glycyrrhizic acid solution. The solution was then incubated in a water bath at 37°C for 30 min to obtain a composite micelle solution. A 75% ethanol solution was added to the composite micelle solution to obtain a coating solution. (3) Take the microparticles obtained in step (1) and put them into a fluidized bed for preheating. Then, use a spray atomization method to put the coating liquid obtained in step (2) into the microparticles for coating treatment. After the coating treatment is completed, fluidize and dry to obtain sustained-release and permeation-promoting microparticles. Take the capsule shell and fill the sustained-release and permeation-promoting microparticles to obtain the enteric sustained-release capsules.

[0014] Further optimization: In step (1), the mass ratio of added microcrystalline cellulose to hawthorn granules is 0.5-2.0:1; the mass ratio of added lactose to hawthorn granules is 0.5-1.0:1; the mixer is a three-dimensional motion mixer with working parameters of 25 rpm, 25 min, and 60% loading coefficient; the extrusion rounding machine has working parameters of 400 r / min, 0.8 mm screen, 1000 r / min rounding speed, and 8 min processing time.

[0015] For further optimization, in step (2), the mass ratio of added hydroxypropyl methylcellulose to glycyrrhizic acid is approximately 30 to 75:1.

[0016] Further optimization: In step (3), the working parameters of the fluidized bed are: inlet air temperature of 48-52℃, outlet air temperature of 32-36℃, material temperature of 30-34℃, atomization pressure of 0.26-0.30MPa, spraying speed of 5-8mL / min, and coating weight gain of about 35%.

[0017] Compared with existing technologies, this technical solution has the following advantages: 1. This invention reveals the differentiated roles of phlorizin and quercetin / triterpenoid components in AMPK activation within *Hylocereus undatus*, activating AMPK (upstream energy sensing) and simultaneously synergistically activating AMPK directly via LKB1 / phosphatase regulation and acting on PPARα. This dual-pathway synergistic mechanism provides a new pharmacological basis for improving lipid metabolism. The traditional Chinese medicine composition obtained by combining *Hylocereus undatus* with hawthorn, *Alisma plantago-aquatica*, and raw licorice can be used to treat hyperlipidemia of the phlegm-dampness retention type.

[0018] 2. This invention uses extracts from four herbs—hawthorn, alisma, licorice, and scutellaria barbata—as the core. A sustained-release microsphere is formed by adding high-purity glycyrrhizic acid and quercetin to hydroxypropyl methylcellulose as a base, encapsulating the core. Finally, the microspheres are filled into suitable capsule shells to obtain enteric-coated sustained-release capsules. Utilizing the synergistic permeation-enhancing effect of glycyrrhizic acid and quercetin in the sustained-release permeation-enhancing layer, the solubility of the active components (triterpenoids) in the core is significantly improved, and P-gp inhibition is also achieved, thereby greatly enhancing the bioavailability of total triterpenoids and improving the therapeutic effect on hyperlipidemia. Furthermore, the glycyrrhizic acid in the sustained-release permeation-enhancing layer can also harmonize the active components in the core, reducing or eliminating side effects.

[0019] 3. The preparation methods of the traditional Chinese medicine composition, sustained-release microspheres, and enteric-coated sustained-release capsules described in this invention are simple in process, convenient in operation, and reduce the safety risks associated with adding exogenous permeation enhancers. The permeation enhancement system of this invention is based on plant-derived active ingredients (glycyrrhizic acid, quercetin) and combined with a pharmaceutical-grade HPMCP enteric-coated capsule shell, achieving efficient delivery while ensuring the integrity of the intestinal barrier. This solves the defects of existing technologies using cyclodextrin inclusion, solid dispersions, or the addition of surfactants, such as low drug loading, poor reproducibility, or damage to the intestinal barrier. Attached Figure Description

[0020] Figure 1 This is a schematic diagram of the structure of the sustained-release permeation-enhancing microspheres described in Example 2.

[0021] Figure 2 This is a schematic diagram of the dual-effect synergistic permeation-promoting mechanism described in Experiment Example 2.

[0022] Figure 3 This refers to the enhanced permeability of the Caco-2 cell model described in Experiment Example 2 and the comparative results. Detailed Implementation

[0023] The following examples further illustrate the present invention, but are not intended to limit the invention. Specific experimental conditions and methods not specified in the following examples are generally conventional methods well-known to those skilled in the art. The hawthorn, alisma, and licorice herbal formula granules used in the following examples are all purchased products. The equivalent specifications of the herbal formula granules are as follows: each 1g of hawthorn formula granules is equivalent to approximately 2g of raw medicinal materials, each 1g of alisma formula granules is equivalent to approximately 4g of raw medicinal materials, and each 1g of licorice formula granules is equivalent to approximately 3g of raw medicinal materials. The dosage of formula granules in the following examples is calculated based on this equivalent.

[0024] Example 1: The preparation method of the extract of *Hylocereus undatus* according to the present invention is as follows: dried leaves of *Hylocereus undatus* are dried, chopped, and then extracted with a 70% ethanol solution, concentrated, and dried to obtain *Hylocereus undatus* extract. The yield of the dry extract is about 22%, and the extract contains 3.2% quercetin, 18.5% phlorizin, and 4.8% moisture.

[0025] Example 2: A traditional Chinese medicine composition for treating hyperlipidemia, comprising the following raw materials in parts by weight: 18 parts hawthorn, 10 parts alisma, 12 parts scutellaria barbata, and 10 parts licorice.

[0026] An enteric-coated sustained-release capsule for treating hyperlipidemia is obtained by filling a capsule shell with sustained-release and permeation-enhancing microspheres, wherein the sustained-release and permeation-enhancing microspheres are as follows: Figure 1 As shown, the capsule consists of a core and a sustained-release permeation-enhancing layer surrounding the core. The core is made from the traditional Chinese medicine composition described in this embodiment, and the sustained-release permeation-enhancing layer is made from a mixture of hydroxypropyl methylcellulose, glycyrrhizic acid, and quercetin. The preparation method of the enteric-coated sustained-release capsule for treating hyperlipidemia includes the following steps: (1) According to the raw material ratio conversion of the Chinese medicine composition, 96g of hawthorn Chinese medicine formula granules, 27g of Alisma Chinese medicine formula granules, 35g of raw licorice Chinese medicine formula granules and 28g of the Polysaccharide extract prepared in Example 1 were weighed and added to the mixer. 170g of microcrystalline cellulose (MCC PH101) and 85g of lactose (200 mesh) were added and mixed to obtain a mixture. A 40% ethanol solution was added to the mixture to form a soft material, which was then sent to an extrusion rounding machine for processing. After being dried in a fluidized bed at 45°C until the moisture content was ≤5%, it was then sieved to obtain microspheres of 400-700μm. The mixer was a three-dimensional motion mixer with the following working parameters: rotation speed of 25rpm, mixing time of 25min, and filling coefficient of 60%. The working parameters of the extrusion rounding machine were: extrusion speed of 400r / min, screen size of 0.8mm, rounding speed of 1000r / min, and processing time of 8min. (2) Take 145g of hydroxypropyl methylcellulose (HPMC K4M) and add it to 1450g of 75% ethanol solution, then stir at 25℃ for 30min to obtain a dispersion. Dissolve 3.0g of glycyrrhizic acid (HPLC purity ≥95%) in 40g of hot water at 60℃, then sonicate for 3min (ultrasound power is 200W, pulse mode on for 2s / off for 1s), cool to room temperature and add to the dispersion to obtain glycyrrhizic acid solution. Take 1.5g of quercetin (HPLC purity ≥95%) and dissolve it in 30g of anhydrous ethanol by sonication for 5min (ultrasound power is 200W, pulse mode on for 2s / off for 1s). Slowly add it dropwise to glycyrrhizic acid solution, and then incubate it in a water bath at 37℃ with shaking (150rpm) for 30min to obtain a composite micelle solution. Add 75% ethanol solution to the composite micelle solution to a total volume of 2500g to obtain a coating solution with a solid concentration of about 6%. (3) Take the microparticles obtained in step (1) and put them into a fluidized bed for preheating. Then, use a spray atomization method to add the coating liquid obtained in step (2) to coat the microparticles. After the coating treatment, fluidize and dry to obtain sustained-release and permeation-enhancing microparticles. Take 1000 No. 0 HPMCP enteric-coated capsule shells and fill them with sustained-release and permeation-enhancing microparticles to obtain a total of 1000 enteric-coated sustained-release capsules, with each capsule containing 399-590 mg. The working parameters of the fluidized bed are: inlet air temperature of 50℃, outlet air temperature of 34℃, material temperature of 32℃, atomization pressure of 0.28MPa, spray speed of 6mL / min, and coating weight gain of 35%.

[0027] The enteric-coated sustained-release capsules obtained in this embodiment were tested, and the test results are shown in Table 1.

[0028] Table 1. Detection results of enteric-coated sustained-release capsules obtained in this embodiment. Example 3: A traditional Chinese medicine composition for treating hyperlipidemia, comprising the following raw materials in parts by weight: 25 parts hawthorn, 15 parts alisma, 15 parts scutellaria barbata, and 12 parts raw licorice.

[0029] An enteric-coated sustained-release capsule for treating hyperlipidemia is obtained by filling a capsule shell with sustained-release and permeation-enhancing microspheres. The sustained-release and permeation-enhancing microspheres consist of a drug core and a sustained-release and permeation-enhancing layer surrounding the drug core. The drug core is made from the traditional Chinese medicine composition described in this embodiment, and the sustained-release and permeation-enhancing layer is made from a mixture of hydroxypropyl methylcellulose, glycyrrhizic acid, and quercetin. The preparation method of the enteric-coated sustained-release capsule for treating hyperlipidemia includes the following steps: (1) According to the raw material ratio conversion of the Chinese medicine composition, 133g of hawthorn Chinese medicine formula granules, 40g of Alisma Chinese medicine formula granules, 43g of raw licorice Chinese medicine formula granules and 35g of the Polysaccharide extract prepared in Example 1 were weighed and added to the mixer. 115g of microcrystalline cellulose (MCC PH101) and 73g of lactose (200 mesh) were added and mixed to obtain a mixture. A 40% ethanol solution was added to the mixture to form a soft material, which was then sent to an extrusion rounding machine for processing. After drying in a fluidized bed at 45°C until the moisture content was ≤5%, the mixture was then sieved to obtain microspheres of 400-700μm. The mixer was a three-dimensional motion mixer with the following working parameters: rotation speed of 25rpm, mixing time of 25min, and filling coefficient of 60%. The working parameters of the extrusion rounding machine were: extrusion speed of 400r / min, screen size of 0.8mm, rounding speed of 1000r / min, and processing time of 8min. (2) Take 145g of hydroxypropyl methylcellulose (HPMC K4M) and add it to 1450g of 75% ethanol solution, then stir at 25℃ for 30min to obtain a dispersion. Dissolve 4.8g of glycyrrhizic acid (HPLC purity ≥95%) in 40g of hot water at 60℃, then sonicate for 3min (ultrasound power is 200W, pulse mode on for 2s / off for 1s), cool to room temperature and add to the dispersion to obtain glycyrrhizic acid solution. Take 2.0g of quercetin (HPLC purity ≥95%) and dissolve it in 30g of anhydrous ethanol by sonication for 5min (ultrasound power is 200W, pulse mode on for 2s / off for 1s). Slowly add it dropwise to glycyrrhizic acid solution, and then incubate it in a water bath at 37℃ with shaking (150rpm) for 30min to obtain a composite micelle solution. Add 75% ethanol solution to the composite micelle solution to 2550 to obtain a coating solution with a solid concentration of about 6%. (3) Take the microparticles obtained in step (1) and put them into a fluidized bed for preheating. Then, use a spray atomization method to add the coating liquid obtained in step (2) to coat the microparticles. After the coating treatment, fluidize and dry to obtain sustained-release and permeation-enhancing microparticles. Take 1000 No. 0 HPMCP enteric-coated capsule shells and fill them with sustained-release and permeation-enhancing microparticles to obtain a total of 1000 enteric-coated sustained-release capsules, with each capsule containing 399-590 mg. The working parameters of the fluidized bed are: inlet air temperature of 50℃, outlet air temperature of 34℃, material temperature of 32℃, atomization pressure of 0.28MPa, spray speed of 7mL / min, and coating weight gain of about 35%.

[0030] The enteric-coated sustained-release capsules obtained in this embodiment were tested, and the results are shown in Table 2. When the glycyrrhizic acid concentration was close to 4.8 mg / capsule, the micelles showed a significant tendency to aggregate (particle size > 100 nm, PDI = 0.28), resulting in an enhancement ratio (ER) of 2.85 (lower than 3.22 in Example 2), proving that micelle aggregation actually reduced the permeation efficiency. Simultaneously, the TEER retention rate decreased to 88%, close to the safety margin (≥85%). Therefore, the high formulation ratio accompanied by micelle aggregation and decreased barrier stability, as well as the reverse decrease in ER value, demonstrate that the formulation of the traditional Chinese medicine composition described in this invention and the glycyrrhizic acid concentration of 2.0-4.0 mg / capsule have superior advantages in balancing efficiency and safety.

[0031] Table 2. Detection results of enteric-coated sustained-release capsules obtained in this embodiment. Example 4: The traditional Chinese medicine composition described in this example is the same as that described in Example 2. The only difference between the enteric-coated sustained-release capsule for treating hyperlipidemia and its preparation method and that described in Example 2 is that in step (2), 150g of hydroxypropyl methylcellulose (HPMC K4M) is added to 1500g of 75% ethanol solution, and then stirred at 25°C for 30min to obtain a dispersion. Dissolve 2.0g of glycyrrhizic acid (HPLC purity ≥95%) in 40g of hot water at 60℃, then sonicate for 3min (ultrasound power is 200W, pulse mode on for 2s / off for 1s), cool to room temperature and add to the dispersion to obtain glycyrrhizic acid solution. Take 1.5g of quercetin (HPLC purity ≥95%) and dissolve it in 30g of anhydrous ethanol by sonication for 5min (ultrasound power is 200W, pulse mode on for 2s / off for 1s). Slowly add it dropwise to glycyrrhizic acid solution, and then incubate it in a water bath at 37℃ with shaking (150rpm) for 30min to obtain a composite micelle solution. Add 75% ethanol solution to the composite micelle solution to a total volume of 2550g to obtain a coating solution with a solid concentration of about 6%.

[0032] The enteric-coated sustained-release capsules obtained in this example were tested, and the results are shown in Table 3. When the glycyrrhizic acid concentration dropped to 2.0 mg / capsule, the CMC reached the critical value (0.48 mg / mL). The micelle formation was still acceptable, but the stability decreased compared to Example 2. The ER=3.02 still met the ≥3.0 standard, but it was already at the critical point, proving that 2.0 mg / capsule is the effective lower limit threshold.

[0033] Table 3. Detection results of enteric-coated sustained-release capsules obtained in this embodiment. Example 5: The traditional Chinese medicine composition described in this example is the same as that described in Example 2. The only difference between the enteric-coated sustained-release capsule for treating hyperlipidemia and its preparation method and that described in Example 2 is that in step (2), 150g of hydroxypropyl methylcellulose (HPMC K4M) is added to 1500g of 75% ethanol solution, and then stirred at 25°C for 30min to obtain a dispersion. Take 4.0g of glycyrrhizic acid (HPLC purity ≥95%) and dissolve it in 40g of hot water at 60℃. Then, sonicate it for 3min (ultrasound power is 200W, pulse mode on for 2s / off for 1s). After cooling to room temperature, add it to the dispersion to obtain glycyrrhizic acid solution. Take 1.5g of quercetin (HPLC purity ≥95%) and dissolve it in 30g of anhydrous ethanol by sonication for 5min (ultrasound power is 200W, pulse mode on for 2s / off for 1s). Slowly add it dropwise to glycyrrhizic acid solution, and then incubate it in a water bath at 37℃ with shaking (150rpm) for 30min to obtain a composite micelle solution. Add 75% ethanol solution to the composite micelle solution to a total volume of 2600g to obtain a coating solution with a solid concentration of about 6%.

[0034] The enteric-coated sustained-release capsules obtained in this embodiment were tested, and the results are shown in Table 4. The concentration of glycyrrhizic acid increased by 33% (3.0 to 4.0 mg / capsule), but the ER decreased by approximately 10% (3.22 to 2.92), due to decreased permeability caused by micelle aggregation. The initial micelles were acceptable (68 nm), but after 24 hours, they aggregated to >100 nm and precipitated, resulting in poor long-term stability. The TEER decreased to 89%, close to the safety margin (≥85%). In summary, 4.0 mg / capsule is the upper limit defined in the claims, but in practical applications, exceeding 3.5 mg / capsule significantly increases the risk of micelle aggregation, thus reducing the permeation efficiency. Combined with Example 4 (2.0 mg / capsule, ER=3.02), this demonstrates that 2.0-4.0 mg / capsule is the effective range, and 3.0 mg / capsule is the optimal balance point between efficiency and stability.

[0035] Table 4. Detection results of the enteric-coated sustained-release capsules obtained in this embodiment. Example 6: The traditional Chinese medicine composition described in this example is the same as that described in Example 2. The only difference between the enteric-coated sustained-release capsule for treating hyperlipidemia and its preparation method and that described in Example 2 is that in step (2), 160g of hydroxypropyl methylcellulose (HPMC K4M) is added to 1500g of 75% ethanol solution, and then stirred at 25°C for 30min to obtain the coating solution.

[0036] The enteric-coated sustained-release capsules obtained in this embodiment were tested, and the results are shown in Table 5. After removing high-purity glycyrrhizic acid and quercetin, no micelles were formed (CMC>2.0 mg / mL), and the ER decreased to 1.58 (<3.0), which is 51% lower than that in Example 2 (P<0.01), demonstrating the necessity and synergistic effect of adding high-purity monomeric permeation enhancer to the sustained-release permeation layer.

[0037] Table 5. Detection results of the enteric-coated sustained-release capsules obtained in this embodiment. Example 7: A traditional Chinese medicine composition for treating hyperlipidemia, comprising the following raw materials in parts by weight: 12 parts hawthorn, 8 parts alisma, 8 parts scutellaria barbata, and 5 parts raw licorice.

[0038] The difference between the enteric-coated sustained-release capsule for treating hyperlipidemia and its preparation method described in this embodiment and those described in Example 2 is that in step (1), according to the raw material ratio of the traditional Chinese medicine composition, 64g of hawthorn traditional Chinese medicine formula granules, 21g of Alisma traditional Chinese medicine formula granules, 18g of raw licorice traditional Chinese medicine formula granules, and 19g of the Polypodiaceae extract prepared in Example 1 are weighed and added to the mixer, and 125g of microcrystalline cellulose (MCC PH101) and 60g of lactose (200 mesh) are added and mixed to obtain a mixture.

[0039] Experimental Example 1: Molecular Mechanism Study of Spiraea japonica Extract in Treating Hyperlipidemia (including Mechanism Differentiation) 1. Experimental objective: To verify the mechanism by which *Hylocereus undatus* extract indirectly activates AMPK via phlorizin, synergistically affects AMPK phosphorylation status by regulating LKB1 or phosphatase activity, promotes fatty acid oxidation, and promotes cholesterol reverse transport through the LXRα-ABCA1 / ABCG1 pathway.

[0040] 2. Experimental materials: Cell lines: HepG2 hepatocytes, RAW264.7 macrophages; Drugs: Spikeweed extract (quercetin content 3.2%, phlorizin content 18.5%, prepared in Example 1), phlorizin monomer (purity ≥98%), quercetin monomer (purity ≥95%). Reagents: Oleic acid (OA) inducer, AMPK inhibitor Compound C (10 μM), fluorescently labeled cholesterol (NBD-cholesterol), Western Blot antibodies (p-AMPK, AMPK, PPARα, CPT1a, ABCA1, ABCG1); Cell culture conditions: HepG2 and RAW264.7 cells were cultured in DMEM medium containing 10% FBS at 37°C and 5% CO2. Before the experiment, cells were seeded at a density of 1×10⁵ cells / mL in 6-well plates and cultured for 24 h before drug administration. Cells were starved with serum for 6 h before oleic acid induction.

[0041] 3. Experimental methods: 3.1 Differentiation of HepG2 cell lipid deposition models and mechanisms Groups: Control, Model (1 mM OA), Spiraea japonica extract (MJ, 100 μg / mL), Phlorizin monomer (PHL, equivalent dose 18.5 μg / mL, equivalent to the phlorizin content in MJ), Quercetin monomer (QUE, equivalent dose 3.2 μg / mL, equivalent to the quercetin content in MJ), Phlorizin + Quercetin (PHL + QUE, the above doses combined), Compound C pretreatment + MJ (Compound C (10 μM) pretreatment for 30 min followed by co-incubation with MJ for 24 h; note that Compound C blocks kinase activity but does not affect upstream energy metabolism); Detection methods: Oil Red O staining, TG / TC content, glucose uptake (2-NBDG), AMP / ATP ratio, and Western Blot analysis of p-AMPK, PPARα, and CPT1a protein expression.

[0042] 3.2 RAW264.7 Cholesterol Efflux Experiment Groups: Control, MJ (100 μg / mL), PHL (18.5 μg / mL), QUE (3.2 μg / mL), positive control (9-cis-retinoic acid, 1 μM); Detection: NBD-cholesterol-labeled cholesterol efflux rate, ABCA1 / ABCG1 protein expression, and apoA-I acceptor.

[0043] 4. Experimental Results 4.1 Effects on lipid deposition in HepG2 cells (see Table 6). The results showed that phlorizin alone (PHL) significantly reduced TG (by 38.9%) and significantly inhibited glucose uptake (down to 48% of normal levels), reversing the hyperuptake in the model group and increasing the AMP / ATP ratio (activating AMPK), but the effect was weaker than that of the whole extract. Quercetin alone (QUE) had no effect on glucose uptake, but reduced TG (by 28.6%) and slightly increased the AMP / ATP ratio, possibly by regulating LKB1 or phosphatase activity and affecting AMPK phosphorylation. The combined effect of phlorizin and quercetin was comparable to that of the whole extract, demonstrating a synergistic effect. Meanwhile, although Compound C almost completely blocked the lipid-lowering effect of MJ (Oil Red O and TG / TC returned to near the model group), the AMP / ATP ratio in this group remained elevated (0.34±0.06), which was not significantly different from that in the MJ group (0.38±0.06), and glucose uptake was still inhibited (51±7), indicating that Compound C... C blocked the lipid-lowering effect of MJ (TG rose from 28.5 to 87.6 μg / mg protein, P<0.01 compared with the MJ group), confirming that AMPK kinase activity is involved in the regulation of downstream lipid metabolism. Both act on different links in the AMPK pathway, producing a synergistic lipid-lowering effect.

[0044] Table 6 (Comparison with Control group, P<0.01; compared with the Model group, △ P<0.05, △△ (P<0.01) 4.2 Effects on key proteins of fatty acid oxidation (see Table 7). The results showed that phlorizin (PHL) significantly activated AMPK (p-AMPK / AMPK increased by 123%), but had weaker upregulation of PPARα and CPT1a (increased by 62% and 66%, respectively), suggesting that it could indirectly activate the AMPK pathway through energy metabolism reprogramming. Quercetin (QUE) had weaker activation of AMPK (increased by 105%), but significantly upregulated PPARα (increased by 109%) and CPT1a (increased by 134%), suggesting that it may act by regulating phosphatase activity or directly on the PPARα pathway. The whole extract (MJ) simultaneously and strongly activated AMPK (increased by 210%) and PPARα / CPT1a (increased by 205% and 229%, respectively), demonstrating the synergistic effect of phlorizin and quercetin on the dual pathways. In the Compound C blocking effect, MJ+Compound The levels of p-AMPK / AMPK (0.52±0.09), PPARα (0.57±0.08), and CPT1a (0.49±0.04) in group C were significantly lower than those in group MJ (1.18±0.21, 1.28±0.22, 1.15±0.20) (P<0.01), but slightly higher than those in the model group (0.38±0.08, 0.42±0.06, 0.35±0.06). This suggests that Compound C almost completely blocks the lipid-lowering effect of MJ, confirming that the downstream PPARα / CPT1a signaling depends on AMPK kinase activity, while the upstream energy metabolism regulation of phlorizin (increased AMP / ATP ratio) is not affected by Compound C.

[0045] Table 7 4.3 Effects on cholesterol efflux from macrophages (see Table 8). The results showed that quercetin's ability to directly upregulate ABCA1 / ABCG1 (increasing by 115% / 98%) was significantly stronger than that of phlorizin (increasing by 45% / 38%). However, phlorizin indirectly promoted cholesterol efflux through AMPK activation, and the synergistic effect of both made the MJ effect comparable to the positive control. It should be noted that ABCA1, as a transmembrane transport protein, is mainly regulated by the LXRα nuclear receptor and post-transcriptional modification, rather than by direct small molecule binding. Therefore, it was not listed in the conventional target prediction table, but its transcriptional upregulation was confirmed by protein expression detection in this experiment.

[0046] Table 8 ( P<0.05, P<0.01 vs Control) 5. Experimental Conclusion: Spikeweed extract treats hyperlipidemia through the following mechanisms: Dual pathways synergistically regulate AMPK: Phlorizin may indirectly affect the AMP / ATP ratio in hepatocytes by regulating mitochondrial energy sensing, thereby indirectly activating AMPK (upstream energy sensing, unaffected by Compound C blocking kinase activity); Quercetin affects the phosphorylation status of AMPK by regulating LKB1 or phosphatase activity and directly acts on PPARα; the two synergistically phosphorylate AMPK and upregulate PPARα-CPT1a, promoting mitochondrial fatty acid β-oxidation.

[0047] LXRα-ABCA1 / ABCG1 pathway: Quercetin significantly upregulated ABCA1 / ABCG1 expression, while phlorizin indirectly promoted it through AMPK activation, synergistically enhancing reverse cholesterol transport (RCT).

[0048] Experiment Example 2: Validation of the dual-effect synergistic permeation-enhancing mechanism using the Caco-2 cell model (including comparative experiments) 1. Experimental objective: To verify the superiority of the dual-effect synergistic permeation-enhancing scheme (high-purity glycyrrhizic acid + high-purity quercetin) in enhancing the permeation of total triterpenoid components (using hawthorn acid as a probe), and to compare it with existing technologies (β-cyclodextrin inclusion complexation and sodium decanoate chemical permeation enhancement); To elucidate the synergistic mechanism of glycyrrhizic acid micelle solubilization and quercetin P-gp inhibition; and to verify the rationality of the dosage range of glycyrrhizic acid 2.0-4.0 mg / capsule and quercetin 1.2-2.0 mg / capsule.

[0049] 2. Experimental materials: Caco-2 cells (TEER≥400 Ω·cm²); maslinic acid, high-purity glycyrrhizic acid (HPLC≥95%), high-purity quercetin (HPLC≥95%), β-cyclodextrin, sodium decanoate; verapamil (positive control).

[0050] 3. The test samples were grouped (n=6), as shown in Table 9.

[0051] Table 9 4. Key Results Table 10. Permeability and barrier function of each group (n=6, compared with the single-drug group). P<0.05, P<0.01; compared with the dual-effect synergistic group, # P<0.05, ## (P<0.01) Table 11 Synergistic Mechanism and Comparative Verification 5. Experimental Conclusions: The dual-effect synergistic penetration-promoting mechanism, such as Figure 2 As shown, the complex micelles consist of: 20. a glycyrrhizic acid hydrophilic shell encapsulating a quercetin hydrophobic core, while simultaneously solubilizing sorbic acid / ursolic acid / alizool B; 30. a P-glycoprotein (P-gp) efflux pump (inhibited by quercetin); and 30. triterpenoids (such as sorbic acid, encapsulated within the micelle's hydrophobic core). The synergistic effect of glycyrrhizic acid micelle solubilization and quercetin P-gp inhibition significantly improves the transmembrane permeation of poorly soluble triterpenoids.

[0052] like Figure 3 As shown in Figure A, comparing the enhancement ratios (ER) of each group, the dual-effect synergistic group showed a significant synergistic effect, i.e., ER=3.25, which is 83% higher than glycyrrhizic acid alone (1.78), 76% higher than quercetin alone (1.87), and 78% higher than β-cyclodextrin (1.82). In the barrier function comparison in Figure B, compared with the chemical permeation enhancer sodium decanoate, this invention maintains the integrity of the intestinal barrier (TEER 91% vs 72%) while achieving higher permeation efficiency (3.22 vs 2.44), demonstrating a significant safety advantage.

[0053] Dosage range validation: Glycyrrhizic acid 2.0-4.0 mg / capsule is the effective range. Below 2.0 mg / capsule, the ER is close to the critical value (3.02). Above 4.0 mg / capsule, micellar aggregation leads to a reverse decrease in ER (2.92). 3.0+1.5 mg / capsule is the optimal balance between efficiency and safety. Without high-purity monomer, the ER is only 1.58, a reduction of 51% (P<0.01), indicating that high-purity monomer is required.

[0054] Experimental Example 3: Therapeutic Effect and Mechanism Study on Hyperlipidemia Model Rats 1. Experimental materials: Animals: Male SD rats, weighing 180-220g; Model establishment: A hyperlipidemia model was established by feeding the animal with a high-fat diet (HFD, containing 60% fat, 2% cholesterol, and 0.5% sodium cholate) for 8 weeks. Test formulation: Enteric-coated sustained-release capsules prepared in Example 2; Conventional Capsule Control (TCM): The same proportion of four-herb mixture powder is directly filled into capsules (no sustained-release coating, no permeation enhancement system). Positive control: Atorvastatin (10 mg / kg); Normal control: Rats fed with normal diet.

[0055] 2. Experimental methods: 2.1 Preparation of test formulation suspension: The enteric-coated sustained-release capsules prepared in Example 2 were cut open, the contents were removed, and 0.5% CMC-Na was added to prepare a suspension (0.12 g crude drug / mL); Dosage design: low dose 0.6 g crude drug / kg (SR-L), high dose 1.2 g crude drug / kg (SR-H).

[0056] 2.2 Grouping and administration (see Table 12, n=10), administration was carried out for 6 weeks after modeling for 8 weeks.

[0057] Table 12 2.3 Detection Indicators: Four lipid profiles: TC, TG, LDL-C, and HDL-C; Liver function tests: ALT, AST; Antioxidants: MDA, SOD, GSH-Px; Western Blot: Expression of p-AMPK, PPARα, CPT1a, and ABCA1 proteins in the liver.

[0058] 3. Experimental Results: The effects on blood lipid levels (n=10) are shown in Table 13. The results showed that TC in the SR-H group decreased to 2.46 mmol / L (a decrease of 49.3%) and TG decreased to 1.05 mmol / L (a decrease of 53.9%), which were significantly better than those in the TCM group (a decrease of 24.1% and 24.6%), but lower than those in the atorvastatin group (a decrease of 62.3% and 83.8%, P<0.05), reflecting the therapeutic characteristics of the traditional Chinese medicine compound. Compared with the TCM group, the lipid-lowering effect of the SR-H group was about twice as high, proving that the dual-effect permeation-enhancing system significantly improved bioavailability.

[0059] Table 13 (Comparison with NC group, P<0.01; compared with the HFD model group, △ P<0.05, △△ (P<0.01) The effects on liver function and oxidative stress (n=10) are shown in Table 14.

[0060] Table 14 The expression of key proteins in liver lipid metabolism (n=6) is shown in Table 15.

[0061] Table 15 The results in Tables 14 and 15 show that the SR-H group had significantly lower levels of TC, TG, and LDL-C (reduction of 49-54%) and significantly higher levels of HDL-C (increase of 76.9%), with better efficacy than the TCM group but slightly lower than atorvastatin, demonstrating the lipid-lowering effect of the traditional Chinese medicine compound. The SR-H group had significantly lower levels of ALT and AST, which were better than the TCM group (P<0.01) and comparable to the atorvastatin group, indicating a liver-protective effect. The SR-H group significantly activated the AMPK-PPARα-CPT1a pathway and ABCA1 expression. Compared with the TCM group, the SR-H group was significantly better than the TCM group in all lipid indicators and liver protection (P<0.01), proving that the dual-effect synergistic permeation-enhancing system improved the bioavailability of total triterpenoids (ER=3.22) and significantly enhanced the overall efficacy of the formula.

[0062] 4. Experimental Conclusions: Administration of the contents of the enteric-coated sustained-release capsules prepared in Example 2 significantly reduced the levels of TC, TG, and LDL-C in hyperlipidemic rats (by approximately 50%), increased HDL-C, improved liver function, reduced oxidative stress and hepatic steatosis, and activated the AMPK / PPARα / CPT1a and ABCA1 pathways. Compared with the TCM group (ordinary capsules, without a permeation-enhancing system), the SR-H group was significantly superior to the TCM group in terms of TC reduction (49.3% vs 24.1%), TG reduction (53.9% vs 24.6%), and liver protection. This demonstrates that the dual-effect synergistic permeation-enhancing strategy significantly enhanced the efficacy of the traditional Chinese medicine composition in treating hyperlipidemia and anti-atherosclerosis by improving the bioavailability of total triterpenoids, which is consistent with the enhancement ratio result of ER=3.25 in the Caco-2 cell model.

[0063] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A traditional Chinese medicine composition for treating hyperlipidemia, characterized in that: The traditional Chinese medicine composition comprises the following raw materials in parts by weight: 12-25 parts hawthorn, 8-15 parts alisma, 8-15 parts scutellaria barbata, and 5-12 parts raw licorice.

2. The traditional Chinese medicine composition for treating hyperlipidemia according to claim 1, characterized in that: The traditional Chinese medicine composition comprises the following raw materials in parts by weight: 18-20 parts hawthorn, 10-12 parts alisma, 10-12 parts scutellaria barbata, and 8-10 parts raw licorice.

3. The method for preparing the traditional Chinese medicine composition for treating hyperlipidemia as described in claim 1 or 2, characterized in that: The preparation method is any one of the following three methods: Method 1 involves weighing hawthorn, alisma, spatholobus suberectus, and raw licorice root in a specific ratio, mixing them, then decocting them with water, filtering, concentrating, and drying to obtain a traditional Chinese medicine composition. Method 2 involves converting the raw materials according to their weight ratio, weighing out the corresponding Chinese herbal medicine slices of hawthorn, alisma, spatholobus suberectus, and raw licorice, mixing them, and then decocting, filtering, concentrating, and drying them to obtain the Chinese herbal medicine composition. Method three involves converting the raw materials according to their weight ratio, weighing out the corresponding Chinese medicine formula granules of hawthorn, alisma, and raw licorice, and extract of spatholobus suberectus, and then mixing them to make pills to obtain a Chinese medicine composition.

4. The method for preparing the traditional Chinese medicine composition for treating hyperlipidemia according to claim 3, characterized in that: The preparation method of the *Hylocereus undatus* extract is as follows: dried leaves of *Hylocereus undatus* are air-dried, chopped, and then extracted with a 50-80% ethanol solution, concentrated, and dried to obtain the *Hylocereus undatus* extract. The yield of the dry extract is approximately 22%, the quercetin content in the extract is 2.1%-4.3%, the phlorizin content is ≥18%, and the moisture content is ≤5%.

5. An enteric-coated sustained-release capsule for treating hyperlipidemia, characterized in that: The enteric-coated sustained-release capsule is obtained by filling a capsule shell with sustained-release and permeation-enhancing microspheres. The sustained-release and permeation-enhancing microspheres are composed of a drug core and a sustained-release and permeation-enhancing layer surrounding the drug core. The drug core is made from the traditional Chinese medicine composition described in any one of claims 3 to 4, and the sustained-release and permeation-enhancing layer is made from a mixture of hydroxypropyl methylcellulose, glycyrrhizic acid, and quercetin.

6. The enteric-coated sustained-release capsule for treating hyperlipidemia according to claim 5, characterized in that: The capsule shell is a No. 0 hydroxypropyl methylcellulose phthalate capsule shell. Each enteric-coated sustained-release capsule contains 399-590 mg of sustained-release permeation-enhancing microspheres. The mass ratio of the drug core to the sustained-release permeation-enhancing layer in the sustained-release permeation-enhancing microspheres is approximately 72-75:25-28. The sustained-release permeation-enhancing layer contains 2.0-4.0 mg of glycyrrhizic acid per capsule and 1.2-2.0 mg of quercetin per capsule.

7. The method for preparing enteric-coated sustained-release capsules for treating hyperlipidemia as described in claim 5 or 6, characterized in that: Includes the following steps: (1) According to the raw material ratio conversion of the Chinese medicine composition, the corresponding Chinese medicine formula granules of hawthorn, alisma and raw licorice and extract of spatholobus suberectus are weighed and added to the mixer, and microcrystalline cellulose and lactose are added and mixed to obtain a mixture. A 40% ethanol solution is added to the mixture and mixed to form a soft material, which is then sent to an extrusion rolling mill for processing. Then, it is dried in a fluidized bed at 45°C until the moisture content is ≤5%, and then screened to obtain micro pellets of 400-700μm. (2) Hydroxypropyl methylcellulose (HPMC K4M) was added to a 75% ethanol solution and stirred at 23-27°C for 30 min to obtain a dispersion. Glycyrrhizic acid was dissolved in hot water at 60°C, then sonicated for 3 min, cooled to room temperature, and added to the dispersion to obtain a glycyrrhizic acid solution. Quercetin was dissolved in anhydrous ethanol and sonicated, then slowly added to the glycyrrhizic acid solution. The solution was then incubated in a water bath at 37°C for 30 min to obtain a composite micelle solution. A 75% ethanol solution was added to the composite micelle solution to obtain a coating solution. (3) Take the microparticles obtained in step (1) and put them into a fluidized bed for preheating. Then, use a spray atomization method to put the coating liquid obtained in step (2) into the microparticles for coating treatment. After the coating treatment is completed, fluidize and dry to obtain sustained-release and permeation-promoting microparticles. Take the capsule shell and fill the sustained-release and permeation-promoting microparticles to obtain the enteric sustained-release capsules.

8. The method for preparing enteric-coated sustained-release capsules for treating hyperlipidemia according to claim 7, characterized in that: In step (1), the mass ratio of added microcrystalline cellulose to hawthorn granules is 0.5-2.0:1; the mass ratio of added lactose to hawthorn granules is 0.5-1.0:1; the mixer is a three-dimensional motion mixer with working parameters of 25 rpm, 25 min, and 60% loading coefficient; the extrusion rounding machine has working parameters of 400 r / min, 0.8 mm screen, 1000 r / min rounding speed, and 8 min processing time.

9. The method for preparing enteric-coated sustained-release capsules for treating hyperlipidemia according to claim 7, characterized in that: In step (2), the mass ratio of added hydroxypropyl methylcellulose to glycyrrhizic acid is approximately 30 to 75:

1.

10. The method for preparing the enteric-coated sustained-release capsule for treating hyperlipidemia according to claim 7, characterized in that: In step (3), the working parameters of the fluidized bed are: inlet air temperature of 48-52℃, outlet air temperature of 32-36℃, material temperature of 30-34℃, atomization pressure of 0.26-0.30MPa, spraying speed of 5-8mL / min, and coating weight gain of about 35%.

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