Yin-nourishing and lung-clearing pill and preparation method thereof

Abstract

The invention relates to the field of traditional Chinese medicine preparations, and discloses a preparation method of yin-nourishing and lung-clearing pills, which comprises the following steps: S1, extracting effective components in rehmannia, radix ophiopogonis, radix scrophulariae, radix paeoniae alba, bulbus fritillariae cirrhosae, moutan bark and liquorice to obtain corresponding extracts; s2, mixing the radix rehmanniae extract, the bulbus fritillariae cirrhosae extract and the radix scrophulariae extract with L-glutamine in proportion, and assembling to form supramolecular powder; s3, mixing the bulbus fritillariae cirrhosae extract and the moutan bark extract with silicon dioxide in proportion, and forming eutectic through solvent evaporation crystallization. By adopting a supramolecular assembly technology, the radix rehmanniae, bulbus fritillariae cirrhosae and radix scrophulariae extracts are synergistically assembled with L-glutamine, and supramolecular powder with high stability and high solubility is formed through intermolecular hydrogen bonds and pi-pi accumulation action, so that the problems of low component release rate and low bioavailability in the prior art are solved.

Description

Technical Field

[0001] The invention relates to the technical field of traditional Chinese medicine preparations, in particular to a Yangyin Qingfei pill and a preparation method thereof. Background Art

[0002] Yangyin Qingfei Pills have broad application prospects in the clinical treatment of various respiratory diseases caused by lung heat and dryness in traditional Chinese medicine, such as the relief of symptoms such as cough and sore throat.

[0003] In the field of traditional Chinese medicine, there are many drug formulas for the treatment of lung diseases, among which Yin-nourishing and lung-clearing prescriptions are more common, but they generally have problems such as unstable efficacy and low absorption rate. In recent years, with the development of Chinese herbal medicine extraction technology and Chinese medicine preparation technology, the research on new Chinese medicine preparations has made significant progress, but it still faces technical difficulties in improving the stability of efficacy and bioavailability.

[0004] In the traditional preparation process of Yangyin Qingfei Pills, insufficient crushing of medicinal materials, low extraction efficiency of effective ingredients and poor stability of finished products have become key factors restricting its efficacy. Currently, Yangyin Qingfei Pills on the market are mainly prepared by decoction, concentration and drying. Although they can retain certain efficacy, they have the limitation of large loss of active ingredients and cannot meet the needs of modern people for high-quality health products. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a Yangyin Qingfei Pill and a preparation method thereof, which solves the problems of low extraction efficiency of effective ingredients, poor stability of finished products and large loss of active ingredients in the prior art.

[0006] To achieve the above objectives, the present invention is implemented through the following technical scheme: a Yangyin Qingfei Pill, comprising the following components in parts by weight: Rehmannia root extract: 180-220 parts; Ophiopogon japonicus extract: 100-140 parts; Scrophulariaceae extract: 150-170 parts; White peony root extract: 70-90 parts; Fritillaria cirrhosa extract: 70-90 parts; Paeonia suffruticosa root extract: 70-90 parts; Licorice extract: 35-45 parts; Excipients include: Cyclodextrin: 15-25 parts; Phosphatidylcholine: 10-20 parts; Silicon dioxide: 8-12 parts; L-glutamine: 8-12 parts; Polyethylene glycol: 10-20 parts; Medium chain triglycerides: 10-15 parts; Tween 80: 8-12 parts.

[0007] The components of Yangyin Qingfei Pills are constructed based on the compatibility theory of "monarch, minister, assistant and envoy" of traditional Chinese medicine. Rehmannia root, Ophiopogon japonicus and Scrophularia ningpoensis are the main drugs, nourishing yin and moistening dryness, Fritillaria cirrhosa and white peony root work together to clear the lungs and resolve phlegm, soften the liver and relieve urgency, Paeonia suffruticosa root clears heat and cools blood, and Licorice harmonizes the drugs. In addition, the design of excipients is centered on modern pharmacy solubilization, stabilization, and enhanced bioavailability. Cyclodextrin inclusion solubilization, phosphatidylcholine and Tween 80 assist in the absorption of fat-soluble components, silicon dioxide and L-glutamine promote supramolecular assembly and crystal stability, and PEG improves the solubility of solid dispersions. The overall compatibility takes into account the combination of traditional Chinese medicine theory and modern technology.

[0008] Preferably, the extract of Rehmannia glutinosa, Ophiopogon japonicus and Scrophularia ningpoensis are subjected to ultrasonic assisted pretreatment after extraction, with an ultrasonic frequency of 20 to 40 kHz and a treatment time of 10 to 30 minutes to further release the active ingredients and improve the extraction efficiency. The cavitation effect generated by ultrasound can destroy the cell wall structure and promote the release of active ingredients in the medicinal materials.

[0009] Preferably, the cyclodextrin in the auxiliary material is β-cyclodextrin, the phosphatidylcholine is natural soybean lecithin, and the polyethylene glycol is PEG4000.

[0010] A preparation method based on the above-mentioned Yangyin Qingfei Pills comprises the following steps: S1, extracting effective ingredients from Rehmannia root, Ophiopogon japonicus, Scrophularia ningpoensis, White Peony Root, Fritillaria cirrhosa, Paeonia suffruticosa, and Licorice to obtain corresponding extracts; S2. Mix Rehmannia root extract, Fritillaria cirrhosa extract and Scrophularia ningpoensis extract with L-glutamine in proportion and assemble to form supramolecular powder; L-glutamine forms hydrogen bonds with phenolic hydroxyl groups and polysaccharide molecules in the extract by providing amino groups, and constructs supramolecular structure through intermolecular interactions (π-π stacking). Freeze drying avoids the degradation of ingredients caused by high temperature while retaining the stability of supramolecular structure. Supramolecular powder has higher solubility and absorption rate; S3, mix the Fritillaria cirrhosa extract and the Paeonia suffruticosa extract with silicon dioxide in proportion, and form a cocrystal through solvent evaporation and crystallization; the cocrystal formation promotes the interaction between the drug molecules and the excipient molecules through the surface active sites provided by silicon dioxide, forming a stable crystal structure. Cocrystallization breaks the cohesion of the Fritillaria cirrhosa alkaloids, increases its surface area, and thus significantly improves the dissolution rate; S4, dissolving the Fritillaria cirrhosa extract in medium chain triglycerides, adding phosphatidylcholine and Tween 80 to form an emulsion, and spray drying to form self-emulsifying particles; medium chain triglycerides as the oil phase, synergistically with phosphatidylcholine and Tween 80 to form a nanoemulsion structure. During the spray drying process, the emulsion is converted into solid nanoparticles with a particle size of less than 100 nm, which effectively increases the specific surface area of ​​the fat-soluble components and improves the gastrointestinal absorption efficiency.

[0011] S5. Mix the Ophiopogon japonicus extract and Scrophularia ningpoensis extract with polyethylene glycol and form a solid dispersion by spray drying. PEG disperses the active ingredients into an amorphous state through intermolecular interactions, destroys its crystal structure, and significantly increases the dissolution rate of water-soluble ingredients. At the same time, spray drying granulates the dispersion to improve the fluidity and uniformity of the finished product. S6. The supramolecular powder, eutectic, self-emulsifying particles and solid dispersion are mixed in proportion, refined honey and water are added to make pills, and the pills are coated after drying to obtain Yangyin Qingfei Pills; refined honey is used as an excipient to provide viscosity, and plays a role in stabilizing and protecting the active ingredients by appropriately coating them. The water pill drying process controls the temperature and time to avoid the decomposition of the active ingredients caused by high temperature. The coating process enhances the mechanical strength and storage stability of the water pills, while avoiding the photo-oxidative degradation of the active ingredients, and improving the appearance quality and consistency of the efficacy of the finished product.

[0012] Preferably, the amount of refined honey added is 20% to 40% of the total mass of the pill-making material. As an excipient, refined honey has good adhesion and formability, can ensure that the water pill has a stable physical structure, and at the same time give the finished product a smooth appearance.

[0013] Preferably, the extraction in S1 uses an ethanol-water mixed solvent, the ethanol volume fraction is 50% to 70%, the extraction temperature is 50 to 60°C, and the extraction time is 30 to 60 minutes. The polarity range of the ethanol-water mixed solvent can cover the dissolution requirements of polysaccharides, glycosides, alkaloids, and flavonoids in Chinese medicinal materials. The polarity is controlled by optimizing the ethanol concentration to ensure the comprehensive extraction of non-polar and polar components. The optimization of temperature and time ensures the maximum extraction of active ingredients while avoiding the decomposition of components caused by high temperature. In addition, reduced pressure concentration can remove excess solvent, concentrate the active ingredients, and provide a stable raw material basis for subsequent processes.

[0014] Preferably, the supramolecular powder assembly process in S2 is completed by stirring at 37-40°C for 1-2 hours, followed by freeze drying at 40°C. The glycosides and polysaccharide molecules in Rehmannia glutinosa and Scrophularia ningpoensis form stable supramolecular structures with L-glutamine through hydrogen bonds. This intermolecular non-covalent interaction (including π-π stacking and hydrophobic interaction) can significantly improve the stability and solubility of the ingredients and reduce the molecular aggregation effect. Freeze drying can remove moisture at low temperatures while protecting the activity of the ingredients and avoiding degradation of heat-sensitive ingredients.

[0015] Preferably, the solvent volatilization crystallization process in S3 uses an ethanol-water mixed solvent, the ethanol volume fraction is 50% to 60%, and the volatilization temperature is 60 to 70°C. As a crystal inducer, silicon dioxide can form weak intermolecular interactions with alkaloids in Fritillaria cirrhosa and phenolic substances in Paeonia suffruticosa through surface active sites, thereby stabilizing the crystal structure. During the solvent volatilization process, the local concentration of molecules in the solution increases, inducing the formation of crystal nuclei and achieving eutectic formation. After the eutectic is formed, the crystal solubility of the key components in Fritillaria cirrhosa and Paeonia suffruticosa is greatly improved, the molecular structure is more stable, and the release rate is more uniform.

[0016] Preferably, the inlet temperature of the spray drying in S4 is 120-140°C, the outlet temperature is 80-100°C, and the particle size of the obtained self-emulsifying particles is less than 100nm. Medium chain triglycerides (MCT) as the oil phase synergize with the surfactants of phosphatidylcholine and Tween 80 to form a stable nanoemulsion during stirring. The spray drying process converts the liquid emulsion into solid particles while maintaining the emulsified structure. Particles with a particle size of less than 100nm have a large specific surface area, which can significantly improve the absorption efficiency of fat-soluble alkaloids in Fritillaria cirrhosa.

[0017] Preferably, the drying temperature of the water pills in S6 is 50-60°C, the drying time is 6-8 hours, the coating temperature is 30-40°C, and the coating time is 2-4 hours. The low-temperature drying process ensures the chemical stability of the active ingredients and avoids the degradation of the ingredients caused by high temperature. The coating treatment improves the storage stability of the finished pills by covering the protective layer, preventing the external humidity and oxidative environment from affecting the drug, and improving the taking experience.

[0018] The present invention provides a Yangyin Qingfei Pill and a preparation method thereof, which has the following beneficial effects: 1. The present invention adopts supramolecular assembly technology to synergistically assemble extracts of Rehmannia glutinosa, Fritillaria cirrhosa and Scrophularia ningpoensis with L-glutamine, and forms supramolecular powders with high stability and high solubility through intermolecular hydrogen bonds and π-π stacking. Compared with the direct preparation of a single extract in the prior art, the present invention effectively avoids the aggregation effect between component molecules, greatly improves the solubility and absorption efficiency of the active ingredients, and solves the problems of slow component release rate and low bioavailability in the prior art.

[0019] 2. The present invention uses a multi-component eutectic process to induce crystallization of Fritillaria cirrhosa and Paeonia suffruticosa extracts through silicon dioxide to form eutectics, which effectively improves the crystal solubility of alkaloids and phenolic components. Compared with the simple mixing technical method in the prior art, the present invention solves the problem of low dissolution rate caused by insufficient crystal structure stability in the traditional process, and achieves the technical effect of uniform component absorption.

[0020] 3. The present invention uses self-emulsifying nanotechnology to dissolve the fat-soluble components of Fritillaria cirrhosa in medium-chain triglycerides, and combines phosphatidylcholine and Tween 80 to construct a nanoemulsion to prepare self-emulsifying particles with a particle size of less than 100 nm. Different from the defect of insufficient absorption of fat-soluble components in the preparation of traditional water pills, the present invention significantly improves the intestinal absorption rate of fat-soluble components and solves the problem of limited absorption and utilization rate in traditional formulas.

[0021] 4. The present invention uses solid dispersion technology to disperse the water-soluble components of Radix Ophiopogonis and Radix Scrophulariae with polyethylene glycol, breaking the crystalline structure of the raw material and converting it into an amorphous state, thereby greatly improving the dissolution rate. Compared with the direct crushing and mixing treatment method in the prior art, the present invention overcomes the shortcomings of low solubility and insufficient dissolution of the active ingredients in the traditional process, while optimizing the uniformity and fluidity of the particles, providing quality assurance for subsequent industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is a schematic diagram of the method flow of the present invention. DETAILED DESCRIPTION

[0023] The following will be combined with the drawings in the specification of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0024] Please refer to the attached Figure 1 , Example 1 provided by the present invention: Preparation of supramolecular powder: extract: Mix Rehmannia root, Scrophularia ningpoensis and Fritillaria cirrhosa in a mass ratio of 1:1:0.8. Add ethanol-water mixed solvent, the ethanol volume fraction is 60%, and the solid-liquid ratio is 1:8. Keep the extraction temperature at 55℃ and perform ultrasonic extraction for 40 minutes. After the extraction is completed, filter and concentrate under reduced pressure to a relative density of 1.2 (measured at 80℃) to obtain a concentrated solution. Spray dry, set the temperature to 140℃ for the inlet temperature and 90℃ for the outlet temperature to obtain an extract powder.

[0025] Assembly: L-glutamine was added at 10% of the total mass of the extract powder and mixed. The mixture was dissolved in an appropriate amount of deionized water and stirred at 37°C for 90 minutes to promote the formation of intermolecular hydrogen bonds. Subsequently, the mixture was placed in a freeze dryer at -40°C for 24 hours to obtain supramolecular powder.

[0026] Please refer to the attached Figure 1 , Example 2 provided by the present invention: Preparation of multi-component eutectic: extract: Take Fritillaria cirrhosa and Paeonia suffruticosa in proportion, with a mass ratio of 2:1. Add ethanol-water mixed solvent, with an ethanol volume fraction of 50% and a solid-liquid ratio of 1:6. Set the extraction temperature to 60°C and the extraction time to 45 minutes. After the extraction is completed, filter and concentrate under reduced pressure. Continue spray drying the concentrate with an inlet temperature of 130°C and an outlet temperature of 85°C to obtain an extract powder.

[0027] Eutectic Add silicon dioxide at 10% of the total mass of the extract powder and mix well. Dissolve in ethanol-water solvent (ethanol volume fraction is 55%), with a solid-liquid ratio of 1:5. After dissolution, keep the solution temperature at 65°C and slowly evaporate the solvent until solids precipitate. Collect the precipitated solids and dry them at 40°C for 12 hours to obtain a multi-component eutectic.

[0028] Please refer to the attached Figure 1 , Example 3 provided by the present invention: Preparation of self-emulsifying nanoparticles: extract: The extract of Fritillaria cirrhosa was prepared according to the conventional extraction process. Specifically, after the Fritillaria cirrhosa was crushed, a 70% ethanol solution was added at a solid-liquid ratio of 1:10. The extraction temperature was 50°C and the extraction time was 60 minutes. After the extract was concentrated, the extract powder was obtained by spray drying (inlet temperature 130°C, outlet temperature 85°C).

[0029] emulsification: Medium chain triglycerides were added at 20% of the total mass of the Fritillaria cirrhosa extract powder and stirred to completely dissolve. Phosphatidylcholine (10%) and Tween 80 (10%) were added in proportion and homogenized at high speed (8000 rpm) for 10 minutes at 45°C to form a stable emulsion. The emulsion was spray dried with an inlet temperature of 130°C and an outlet temperature of 85°C to prepare self-emulsifying particles. The particle size was measured and the average value was 85nm.

[0030] Please see attached Figure 1 , Example 4 provided by the present invention: Preparation of solid dispersion: extract: Take Ophiopogon japonicus and Scrophularia ningpoensis raw materials in a ratio of 1:1, crush and add 65% ethanol solution. The material-liquid ratio is 1:8, the extraction temperature is 55℃, and the extraction time is 40 minutes. The extract is filtered, concentrated under reduced pressure, and then spray-dried (inlet temperature 140℃, outlet temperature 90℃) to obtain a powder extract.

[0031] Dispersion preparation: PEG4000 was added at 30% of the total weight of the extract powder and mixed. The mixture was dissolved in an appropriate amount of deionized water and stirred evenly at 70°C. The solution was spray dried at an inlet temperature of 150°C and an outlet temperature of 90°C to obtain a solid dispersion.

[0032] Please see attached Figure 1 , Example 5 provided by the present invention: Final preparation of Yangyin Qingfei Pills: Material mixing: The supramolecular powder of Example 1, the eutectic of Example 2, the self-emulsifying particles of Example 3, and the solid dispersion of Example 4 were uniformly mixed in a ratio of 4:2:2:2.

[0033] Pill making: Add refined honey and appropriate amount of deionized water according to 30% of the total mass of the mixture, stir evenly, and make water pills. The water pills are dried at 55℃ for 6 hours.

[0034] Coating: The dried water pills were coated with a film coating solution at a coating temperature of 35°C and a coating time of 3 hours.

[0035] Comparative Example 1: Preparation of supramolecular powder (corresponding to Example 1): Extraction process: Rehmannia root, Scrophularia ningpoensis and Fritillaria cirrhosa were mixed in a ratio of 1:1:0.8, and 60% ethanol-water mixed solvent was added, with a solid-liquid ratio of 1:8, an extraction temperature of 50°C, and an extraction time of 40 minutes. The extract was filtered, concentrated under reduced pressure, and then spray-dried to obtain an extract powder.

[0036] Assembly process: L-glutamine was added at 10% of the total weight of the extract powder, and the mixture was directly freeze-dried without stirring. The drying condition was -40°C and the drying time was 24 hours, resulting in an incompletely assembled powder.

[0037] Comparative Example 2: Preparation of multi-component eutectic (corresponding to Example 2): Extraction process: Take Fritillaria cirrhosa and Paeonia suffruticosa in a mass ratio of 2:1, add 55% ethanol-water mixed solvent, the solid-liquid ratio is 1:6, the extraction temperature is 60°C, and the extraction time is 45 minutes. After filtering, the extract is concentrated under reduced pressure and spray-dried to prepare an extract powder.

[0038] Eutectic process: The extract powder was added to silicon dioxide at a ratio of 10% of the total weight and then directly dry-mixed without using an ethanol-water solvent for dissolution and evaporation. After mixing, it was dried at 40° C. for 12 hours to obtain a dry powder mixture.

[0039] Comparative Example 3: Preparation of self-emulsifying nanoparticles (corresponding to Example 3): Extraction process: 70% ethanol was added to Fritillaria cirrhosae at a solid-liquid ratio of 1:10, the extraction temperature was 55°C, and the extraction time was 45 minutes. After filtration, the mixture was concentrated under reduced pressure and spray-dried to obtain an extract powder.

[0040] Emulsification process: Medium chain triglycerides, phosphatidylcholine and Tween 80 (both 10%) were added to the total weight of the Fritillaria cirrhosa extract powder, and the mixture was directly mixed and stirred evenly without high-speed homogenization. The mixture was then spray dried with an inlet temperature of 130°C and an outlet temperature of 85°C to prepare particles. The particle size was not controlled.

[0041] Comparative Example 4: Preparation of solid dispersion (corresponding to Example 4): Extraction process: 65% ethanol was added to the mixture of Radix Ophiopogonis and Radix Scrophulariae in a ratio of 1:1 and a solid-liquid ratio of 1:8. The extraction temperature was 55°C and the extraction time was 45 minutes. The extract was filtered, concentrated under reduced pressure and then spray-dried to obtain a powder extract.

[0042] Dispersion process: PEG4000 was added at 20% of the total weight of the extract powder, and dry-mixed directly without dissolving. After dry-mixing, the mixture was spray-dried at an inlet temperature of 150°C and an outlet temperature of 90°C to obtain a dry powder.

[0043] Comparative Example 5: Final preparation of Yangyin Qingfei Pills (corresponding to Example 5): mix: The supramolecular powder (prepared in Comparative Example 1), the eutectic (prepared in Comparative Example 2), the self-emulsifying particles (prepared in Comparative Example 3), and the solid dispersion (prepared in Comparative Example 4) were uniformly mixed in a ratio of 4:2:2:2.

[0044] Pill making: Add refined honey and water according to 30% of the total mass of the mixture, stir evenly to make water pills. The water pills are dried at 50℃ for 6 hours.

[0045] Coating: The coating temperature was not controlled during the coating process, and coating was carried out at room temperature for 3 hours.

[0046] Experiment 1: Solubility test: Purpose: To verify whether the solubility of the extract can be significantly improved through the application of supramolecular assembly, multi-component co-crystals, self-emulsification and solid dispersion technology, especially under body fluid simulation conditions.

[0047] Experimental steps: Sample preparation: 1 g of each of Example 1 (supramolecular powder), Example 2 (multi-component eutectic), Example 3 (self-emulsifying particles), Example 4 (solid dispersion) and Comparative Examples 1, 2, 3, and 4 were sampled and accurately weighed.

[0048] The sample was dissolved in 50 mL of deionized water to simulate the initial dissolution of the drug in body fluids.

[0049] Test environment: The solution was placed in a constant temperature shaking water bath, set at 37°C and stirring at 100 rpm to simulate the gastrointestinal fluid environment in vivo.

[0050] Every 10 minutes, 1 mL of the solution was taken out with a sterile syringe, filtered with a 0.22 μm filter membrane, and the filtrate was collected for subsequent analysis.

[0051] Concentration determination: The absorbance value of the active ingredient in the filtrate was determined using an ultraviolet spectrophotometer at a specific wavelength (λmax = 254 nm for Fritillaria cirrhosa alkaloids).

[0052] According to the standard curve, the absorbance was converted into the concentration of dissolved active ingredient and the cumulative dissolved amount was calculated.

[0053] Data Records: The test time points were 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes and 60 minutes.

[0054] The experimental data of the cumulative dissolution rate of each group of samples are shown in the following table: Time (minutes) Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 10 21.3 19.8 24.5 18.6 12.4 13.2 10.5 9.6 20 38.7 35.2 42.1 33.8 25.5 24.8 21.4 20.3 30 49.2 47.6 56.9 45.7 34.1 32.6 29.3 27.9 40 63.4 59.1 71.2 58.2 41.3 40.7 36.4 34.5 50 72.8 66.3 82.3 67.4 48.7 47.1 41.5 39.8 60 81.5 73.6 90.2 76.1 54.2 53.8 46.2 44.5 in conclusion: The results of this experiment show that through supramolecular assembly, multi-component eutectic, self-emulsification and solid dispersion technology, the cumulative dissolution rate of Examples 1 to 4 is significantly higher than that of each corresponding comparative example. Especially after 30 minutes, Example 3 (self-emulsifying particles) shows the advantage of rapid dissolution, and its dissolution amount reaches 56.9%, far exceeding the 29.3% of Comparative Example 3. This significant difference in solubility is directly related to the high specific surface area after nano-particles. The fat-soluble Fritillaria cirrhosa alkaloids in the nanoemulsification system are fully dispersed, avoiding the problem of limited dissolution rate in the traditional system.

[0055] The performance of the supramolecular powder (Example 1) is also very outstanding, with a dissolution rate of 49.2% in 30 minutes, compared with only 34.1% in Comparative Example 1. This improvement comes from the supramolecular network formed by intermolecular hydrogen bonds and π-π stacking. The network structure significantly improves the dissolution behavior of glycosides and polysaccharide components, while giving them higher stability. In Comparative Example 1, which was not stirred and assembled, it was only a simple physical mixing, and there was a lack of interaction between molecules, so a similar dissolution effect could not be achieved.

[0056] The multi-component eutectic technology also showed good performance in Example 2, with a cumulative dissolution rate of 59.1% at 40 minutes, while Comparative Example 2 was only 40.7%. This improvement is mainly attributed to the fact that the eutectic structure breaks the lattice energy of a single molecule, allowing the crystals co-generated by the Fritillaria cirrhosa alkaloids and the peony phenol compounds to dissolve faster and more evenly in the water environment. This molecular-level structural optimization was not achieved in Comparative Example 2, resulting in its low dissolution efficiency.

[0057] The experimental data also showed that the solid dispersion technology (Example 4) performed relatively evenly in the release of water-soluble ingredients, with the cumulative dissolution rate reaching 33.8% at 20 minutes, which was about 13.5% higher than that of Comparative Example 4. The amorphous state formed by the PEG matrix at high temperature significantly increased the dissolution rate of the active ingredient, while the simple dry mixing method in Comparative Example 4 failed to destroy the crystalline structure of the drug, and thus the release efficiency decreased significantly. This fully demonstrates the key role of process parameter optimization and carrier selection in improving the solubility of active ingredients in traditional Chinese medicine.

[0058] Experiment 2: Bioavailability test: Purpose: The in vivo pharmacokinetic characteristics of the embodiments and comparative examples were compared through animal experiments to verify the effect of the present invention in improving the bioavailability of key ingredients.

[0059] Experimental steps: Experimental animals and groups: A total of 48 healthy male SD rats (180-220 g) were selected.

[0060] The mice were randomly divided into 8 groups, with 6 mice in each group, corresponding to Example 1, Example 2, Example 3, Example 4 and Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4.

[0061] Intragastric administration: The samples were prepared into suspensions with 0.5% sodium carboxymethylcellulose (CMC-Na) to ensure that each rat received an equal amount of the active ingredient (200 mg / kg).

[0062] The intragastric volume was 1 mL / 100 g body weight to ensure accurate dosing.

[0063] Blood sample collection: At five time points, 0.5 h, 1 h, 2 h, 4 h, and 6 h after intragastric administration, blood was collected through the tail vein, and 300 μL of blood samples were taken and added to anticoagulant tubes.

[0064] Plasma separation: Centrifuge at 4000 rpm for 10 minutes, take the supernatant, and store at -20°C for testing.

[0065] Target component detection: High performance liquid chromatography (HPLC) was used to detect the concentrations of target components such as Fritillaria cirrhosa alkaloids or rehmannia glutinosa in plasma.

[0066] The pharmacokinetic analysis software calculated the main parameters of each group of samples, including the maximum blood drug concentration (Cmax), peak time (Tmax) and area under the curve (AUC).

[0067] The table of blood drug concentration (ng / mL) of different samples measured over time is shown below: Time (hours) Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 0.5 102.6 87.3 115.8 94.1 56.8 60.2 51.9 50.4 1 198.7 178.5 235.6 189.7 109.4 105.7 99.3 95.2 2 172.3 152.4 205.8 162.9 90.1 86.5 84.8 80.6 4 113.4 98.3 128.9 101.2 56.3 58.1 51.2 50.7 6 64.2 55.6 71.4 59.3 30.8 31.2 28.9 27.6 in conclusion: Experimental data show that the blood drug concentration of the embodiment group is generally higher than that of the comparative example group, especially when the peak blood drug concentration (Cmax) is reached in 1 hour, the performance of embodiment 3 (self-emulsifying particles) is particularly outstanding, reaching 235.6ng / mL, which is about 2.4 times higher than that of comparative example 3. This significant difference is directly derived from the effect of the nanoemulsification system. The particle size is reduced to less than 100nm, which greatly increases the surface area of ​​the fat-soluble Fritillaria cirrhosa alkaloids and enables them to be rapidly absorbed through the intestinal membrane. In comparative example 3, the particle size that has not been homogenized and emulsified is larger, resulting in limited absorption, which is difficult to compare with the embodiment.

[0068] For Example 1, supramolecular assembly also has obvious advantages in blood drug concentration performance. The peak time (Tmax) is 1 hour, and the blood drug concentration Cmax is 198.7ng / mL, which is about 81.7% higher than 109.4ng / mL in Comparative Example 1. This advantage stems from the optimization of the supramolecular network structure. Through intermolecular hydrogen bonds and π-π stacking, the glycosides and polysaccharide components are dissolved and dispersed more evenly in the body, thereby achieving rapid absorption. In Comparative Example 1, there is a lack of molecular interaction, and it is only physical mixing, resulting in a slower release rate of the active ingredients in the body.

[0069] The performance of Example 2 (multi-component co-crystal) and Example 4 (solid dispersion) is also significantly improved compared with the comparative example, especially the AUC (area under the curve) data. The multi-component co-crystal optimizes the crystal structure to make the release more uniform, and its blood drug concentration reaches 152.4 ng / mL at 2 hours, which is about 76% higher than that of comparative example 2. The solid dispersion improves the absorption efficiency of the water-soluble components through the effect of the amorphous PEG matrix, and its blood drug concentration reaches 189.7 ng / mL at 1 hour, which is nearly 100% higher than that of comparative example 4. These results clearly show that different embodiments solve the key problems of dissolution and absorption through their own process optimization, and the problem of low absorption efficiency that is difficult to overcome in traditional processes is significantly improved in the present invention.

[0070] Experiment 3: Absorption rate test: Purpose: The in vitro simulated absorption experiment was used to evaluate the improvement effect of the solid dispersion and self-emulsifying particles in the examples on intestinal absorption rate and compare them with the comparative examples.

[0071] Experimental steps: Caco-2 cell culture: Caco-2 cells were seeded in 96-well plates at a density of 5 × 10 4 The cells were cultured in DMEM medium containing 10% fetal bovine serum at 37°C and 5% CO 2 Culture in an incubator. After the cells form a monolayer (about 21 days of culture) and the cell membrane resistance is confirmed to be >500Ω·cm², subsequent experiments can be performed.

[0072] Sample preparation: The samples of Example 3 (self-emulsifying particles), Example 4 (solid dispersion), and Comparative Examples 3 and 4 were all prepared into solutions with a concentration of 10 μg / mL of the target ingredient (Fritillaria cirrhosa alkaloids or rehmannia glycosides) to simulate the initial state of the drug in the intestine.

[0073] Absorption experiment: Each group of samples was added into the Caco-2 cell supernatant, and 3 replicate wells were set for each sample.

[0074] Sampling was performed every 15 minutes for 120 minutes, and the supernatant was collected. After filtering using a 0.22 μm filter membrane, the samples were stored at 4°C for testing.

[0075] Target component detection: The concentration of the target component in the supernatant was detected by high performance liquid chromatography (HPLC).

[0076] The absorbance at different time points was calculated (absorbance = initial concentration - residual concentration / initial concentration × 100%). The final experimental data are shown in the following table: Time (minutes) Example 3 Example 4 Comparative Example 3 Comparative Example 4 15 28.3 22.5 14.8 13.4 30 47.2 39.6 26.3 24.1 45 61.5 51.3 33.7 31.9 60 73.6 64.9 40.2 38.7 75 81.9 73.2 48.5 45.4 90 88.7 81.4 56.7 51.8 120 93.1 87.3 63.4 58.2 in conclusion: In the Caco-2 cell absorption experiment simulating the intestine, Example 3 (self-emulsifying particles) showed a very significant absorption rate advantage, with an absorption rate of 28.3% at 15 minutes, while Comparative Example 3 was only 14.8%. This difference is mainly attributed to the nano-size of the particles, which greatly increases the specific surface area of ​​the effective ingredients. At the same time, the emulsification effect reduces the aggregation of the ingredients in the intestinal fluid, forming a more stable dispersion state. This structural optimization enables the fat-soluble Fritillaria cirrhosa alkaloids to quickly penetrate the cell membrane, thereby achieving efficient absorption. However, Comparative Example 3 has not been homogenized and emulsified, the particle size is larger, the ingredients are unevenly dispersed, and the absorption is obviously slower.

[0077] The absorption rate in Example 4 (solid dispersion) is also better than that in Comparative Example 4. At 45 minutes, the absorption rate of Example 4 is 51.3%, while that of Comparative Example 4 is only 31.9%. This improvement is mainly closely related to the amorphous state of the PEG matrix. PEG dissolves the water-soluble components in Ophiopogon japonicus and Scrophularia ningpoensis, destroys the crystal structure, and forms a more uniform solution state, thereby significantly accelerating the transmembrane absorption of the active ingredients. In Comparative Example 4, due to the simple dry mixing, the drug still exists in a crystalline state, and the dissolution efficiency and absorption rate are significantly limited.

[0078] The experiment also found that at 120 minutes, the absorption rate of Example 3 reached 93.1%, close to complete absorption. In contrast, Comparative Example 3 was only 63.4%, with a significant difference. This further verifies the superiority of nanoemulsification technology in improving absorption rate. Although the absorption rate of Example 4 was slightly lower, it also reached 87.3%, significantly higher than 58.2% of Comparative Example 4. This shows that through reasonable formulation design and process optimization, the embodiments can overcome the problems of low absorption efficiency and insufficient utilization of ingredients in traditional processes, and show superior performance in a simulated intestinal environment.

[0079] Experiment 4: Finished product stability test: Purpose: By comparing the stability changes of the Yangyin Qingfei Pill samples prepared in the embodiment and the comparative example under accelerated storage conditions, the advantages of the present invention in improving the physicochemical properties and storage performance of the finished product are verified.

[0080] Experimental steps: Sample preparation: Example 5 (Yangyin Qingfei Pills prepared by standard process) and Comparative Example 5 (Yangyin Qingfei Pills prepared by non-optimized process) were selected.

[0081] 100 g of each sample was weighed and divided into 5 groups for testing at different detection time points.

[0082] Acceleration condition setting: All samples were placed in a constant temperature and humidity chamber with the conditions set at 40°C and relative humidity of 75% for 3 months.

[0083] Take samples once a month to check changes in appearance, mechanical strength and active ingredient content.

[0084] Appearance inspection: Observe the pills for color, surface smoothness, and whether there are cracks or obvious deformations.

[0085] Mechanical strength test: A pill hardness tester was used to test the breaking strength of the pills under vertical pressure. Ten pills were tested in each group and the average value was taken.

[0086] Active ingredient content detection: High performance liquid chromatography (HPLC) was used to determine the content of the target ingredient (Fritillaria cirrhosa alkaloids or rehmannia glutinosa) in the pills, and the degradation rate was calculated (degradation rate = initial content - content after storage / initial content × 100%). The final experimental data are shown in the following table: Storage time (month) Sample appearance (crack %) Hardness(N) Degradation rate of active ingredients (%) Example 51 0 95.2 1.3 Comparative 51 months 5.8 82.4 5.6 Example 52 0 94.7 2.1 Comparative Example 52 months 12.5 74.5 10.2 Example 53 0 92.3 3.6 Comparative 53 months 22.1 62.8 18.7 in conclusion: From the experimental data, the Yangyin Qingfei Pills of Example 5 showed excellent stability under accelerated storage conditions for 3 months. In terms of appearance, the sample of Example 5 always maintained a smooth surface without cracks, while the crack ratio of Comparative Example 5 was 12.5% ​​in the second month, and the crack ratio was even as high as 22.1% in the third month. This difference is obviously related to the optimization of the coating process. The film coating not only plays a role in moisture isolation, but also significantly improves the mechanical strength and crack resistance of the pills. However, Comparative Example 5 was not subjected to temperature control coating treatment, and the pills were directly exposed to a hot and humid environment, resulting in aggravated appearance degradation.

[0087] Significant differences can also be seen in the hardness test. The hardness of Example 5 still reached 92.3N after 3 months, while that of Comparative Example 5 dropped to 62.8N, a significant decrease. The fine control of temperature and time during the coating process gave the finished product of Example 5 a higher structural integrity and avoided the rapid erosion of the strength of the pills by environmental humidity. Since the pill making and drying processes of Comparative Example 5 were not optimized, the internal structure of the pills was loose, greatly affected by humidity, the hardness dropped rapidly, and the storage performance was obviously insufficient.

[0088] The degradation rate of the active ingredients also shows the technical advantages of the embodiments. After 3 months, the degradation rate of the sample in Example 5 was only 3.6%, while the degradation rate of Comparative Example 5 had reached 18.7%. This difference is mainly due to the protective effect of the coating layer on the inside of the pill. The coating not only isolates external oxygen and moisture, but also effectively reduces the destructive effect of light on the ingredients. In Comparative Example 5, due to the lack of coating treatment, the active ingredients inside the pills were exposed to a hot and humid environment and significantly degraded. This fully demonstrates that the coating process and drying parameter optimization in the present invention play a key role in improving the storage stability of Yangyin Qingfei Pills.

[0089] Experiment 5: Release performance test of water pills: Purpose: The release of ingredients of the water pills of the embodiment and the comparative example in a simulated gastrointestinal environment was compared to verify the superiority of the present invention in improving the release rate and complete release effect of the Yangyin Qingfei Pills.

[0090] Experimental steps: Sample preparation: Select the water pill samples prepared in Example 5 and Comparative Example 5, weigh 5 g of each, and record the weight accurately.

[0091] The samples were put into simulated gastric fluid and intestinal fluid for release test.

[0092] Release condition settings: Gastric fluid release: The sample was placed in 900 mL of simulated gastric fluid at pH 1.2, and oscillated in a 37°C constant temperature water bath at 100 rpm. The release time was set to 60 minutes, and samples were taken every 10 minutes.

[0093] Intestinal fluid release: The sample was transferred to 900 mL of simulated intestinal fluid at pH 6.8 and continued to be released under oscillation at 37°C with a rotation speed of 100 rpm. The release time was set to 120 minutes and samples were taken every 15 minutes.

[0094] Sample processing: Each time sampling was performed, 10 mL of solution was extracted, filtered (0.22 μm filter membrane), and an equal amount of fresh solution was added.

[0095] All filtrates were kept refrigerated for subsequent testing.

[0096] Active ingredient detection: High performance liquid chromatography (HPLC) was used to detect the concentration of target components (Fritillaria cirrhosa alkaloids or rehmannia glutinosa) in the filtrate.

[0097] Calculate the cumulative release amount and release rate (release rate = cumulative release amount / total content × 100%).

[0098] The final measured experimental data of the cumulative release rate (%) of the water pill sample in the simulated gastrointestinal fluid is shown in the following table: Time (minutes) Example 5 (Gastric Juice) Example 5 (Intestinal Juice) Comparative Example 5 (Gastric Juice) Comparative Example 5 (Intestinal Juice) 10 12.4 - 5.6 - 20 24.8 - 12.3 - 30 36.1 - 20.2 - 40 47.5 - 27.8 - 50 58.3 - 35.9 - 60 68.9 - 42.6 - 75 - 78.1 - 52.4 90 - 89.5 - 65.3 105 - 94.7 - 74.2 120 - 98.3 - 82.6 in conclusion: From the experimental data, the release performance of Example 5 in the simulated gastric juice and intestinal juice environment is quite ideal. In the gastric juice stage, the release rate reached 36.1% at 30 minutes, which is much higher than 20.2% of Comparative Example 5. This is mainly due to the optimized coating process and refined honey ratio of the present invention. The coating layer has a moderate dissolution rate in an acidic environment, which can ensure the sustained release of the active ingredients, while avoiding the premature release of the ingredients, affecting the overall efficacy. In Comparative Example 5, the coating treatment that was not strictly controlled caused the surface of the pills to be too loose, and the release in gastric juice was uneven and slow.

[0099] After entering the intestinal juice stage, the release rate of Example 5 increased rapidly, reaching 89.5% at 90 minutes, almost close to complete release. Its coating layer can be quickly decomposed in a neutral environment, and the multiple effects of internal supramolecular powder, multi-component eutectic and self-emulsifying particles ensure the complete release of the ingredients. The release rate of Comparative Example 5 at the same time point was only 65.3%, mainly due to its loose pill structure. The ingredients that were not fully released in the gastric juice stage were still released slowly in the intestinal juice, which ultimately led to incomplete release of the ingredients.

[0100] In addition, Example 5 exhibits a more stable release curve throughout the release process. In particular, the release rate in the intestinal fluid stage is smooth and uniform, which is inseparable from the synergistic effect of multiple formulation technologies. The supramolecular powder increases the release rate of water-soluble components; the eutectic structure breaks the energy barrier of the crystal, promoting a more uniform release of hydrophobic components; the nano-sized characteristics of the self-emulsifying particles further optimize the dispersion state of the hydrophobic components. The optimization of these processes enables the examples to achieve rapid, stable, and complete component release in the gastrointestinal environment, while the comparative examples cannot achieve similar effects due to the lack of the above-mentioned process optimization, and the release efficiency is significantly lower than that of the examples.

[0101] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A Yangyin Qingfei Pill, characterized in that: The composition comprises the following components in parts by weight: Rehmannia root extract: 180-220 parts; Ophiopogon japonicus extract: 100-140 parts; Scrophulariaceae extract: 150-170 parts; White peony root extract: 70-90 parts; Fritillaria cirrhosa extract: 70-90 parts; Paeonia suffruticosa root extract: 70-90 parts; Licorice extract: 35-45 parts; Excipients include: Cyclodextrin: 15-25 parts; Phosphatidylcholine: 10-20 parts; Silicon dioxide: 8-12 parts; L-glutamine: 8-12 parts; Polyethylene glycol: 10-20 parts; Medium chain triglycerides: 10-15 parts; Tween 80: 8-12 parts; Among the auxiliary materials, the cyclodextrin is β-cyclodextrin, the phosphatidylcholine is natural soybean lecithin, and the polyethylene glycol is PEG4000.

2. A Yangyin Qingfei Pill according to claim 1, characterized in that: The Rehmannia root extract, Ophiopogon japonicus extract and Scrophularia ningpoensis extract are subjected to ultrasonic assisted pretreatment after extraction, with an ultrasonic frequency of 20 to 40 kHz and a treatment time of 10 to 30 minutes, so as to further release active ingredients and improve extraction efficiency.

3. A method for preparing the Yangyin Qingfei Pills according to claim 1, characterized in that: The following steps are involved: S1, extracting effective ingredients from Rehmannia root, Ophiopogon japonicus, Scrophularia ningpoensis, White Peony Root, Fritillaria cirrhosa, Paeonia suffruticosa, and Licorice to obtain corresponding extracts; S2, mixing the Rehmannia root extract, the Fritillaria cirrhosa extract and the Scrophularia ningpoensis extract with L-glutamine in proportion to form supramolecular powder; S3, mixing the Fritillaria cirrhosa extract and the Paeonia suffruticosa extract with silicon dioxide in proportion, and forming a eutectic by crystallization through solvent evaporation; S4, dissolving the Fritillaria cirrhosa extract in medium chain triglycerides, adding phosphatidylcholine and Tween 80 to form an emulsion, and spray drying to form self-emulsifying particles; S5, mixing the Ophiopogon japonicus extract and the Scrophularia ningpoensis extract with polyethylene glycol, and forming a solid dispersion by spray drying; S6. Mix the supramolecular powder, eutectic, self-emulsifying particles and solid dispersion according to a certain proportion, add refined honey and water to make pills, dry and coat the pills to obtain Yangyin Qingfei Pills.

4. The preparation method according to claim 3, characterized in that: The amount of refined honey added is 20% to 40% of the total mass of the pill making materials.

5. The preparation method according to claim 3, characterized in that: The extraction in S1 uses an ethanol-water mixed solvent, the ethanol volume fraction is 50% to 70%, the extraction temperature is 50 to 60°C, and the extraction time is 30 to 60 minutes.

6. The preparation method according to claim 3, characterized in that: The supramolecular powder assembly process in S2 was completed by stirring at 37-40 °C for 1-2 h, followed by freeze drying at ~40 °C.

7. The preparation method according to claim 3, characterized in that: The solvent volatilization crystallization process in S3 uses an ethanol-water mixed solvent, the ethanol volume fraction is 50% to 60%, and the volatilization temperature is 60 to 70°C.

8. The preparation method according to claim 3, characterized in that: The inlet temperature of the spray drying in S4 is 120-140°C, the outlet temperature is 80-100°C, and the particle size of the obtained self-emulsifying particles is less than 100nm.

9. The preparation method according to claim 3, characterized in that: The drying temperature of S6 water pills is 50-60℃, the drying time is 6-8 hours, the coating temperature is 30-40℃, and the coating time is 2-4 hours.

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