Efficient cough-relieving loquat granule composition and preparation method thereof

Abstract

The invention relates to the technical field of cough-relieving medicines, and discloses an efficient cough-relieving loquat granule composition which is prepared from the following components in parts by weight: 30-40 parts of loquat leaf extract; 10-15 parts of a cynanchum glaucescens extract; 6-10 parts of a platycodon grandiflorum extract; 18-25 parts of a white mulberry root-bark extract; 7-10 parts of a radix stemonae extract; 0.1 to 0.5 part of menthol; 2-5 parts of polyethylene glycol; 8 to 12 parts of mannitol; 3 to 6 parts of ethyl cellulose; 1 to 3 parts of hydroxypropyl methyl cellulose; 1 to 3 parts of phosphatidylcholine; 1 to 3 parts of polysorbate 80; 4 to 6 parts of croscarmellose sodium; and 40-60 parts of cane sugar. According to the invention, a double-dispersion system combining a quick-release component and a slow-release component is adopted, and the solubility and the initial release speed of the traditional Chinese medicine extract are remarkably improved by adding polyethylene glycol and mannitol, so that the technical effect of remarkably shortening the drug effect showing time is achieved. Compared with the technical scheme only depending on a single release mode in the prior art, the defects that the medicine takes effect slowly and the symptoms of a patient cannot be relieved in time are overcome.

Description

Technical Field

[0001] The invention relates to the technical field of cough suppressant drugs, in particular to a highly effective cough suppressant loquat granule composition and a preparation method thereof. Background Art

[0002] In recent years, the incidence of respiratory diseases has increased year by year. Cough, as one of its main symptoms, has seriously affected patients' daily life and work. At present, traditional Chinese medicine is widely used in the treatment of cough due to its reliable efficacy and few side effects. Among them, Chinese medicine preparations with loquat leaves as the core ingredient are generally favored by patients because of their effects of clearing heat and moistening the lungs, relieving cough and reducing phlegm. With the development of modernization of traditional Chinese medicine, how to improve the efficacy of traditional Chinese medicine through preparation process optimization has become an important direction of industry research.

[0003] In the prior art, loquat leaf cough suppressant preparations are mainly in the form of granules, and are mostly designed with rapid-release components to quickly relieve cough symptoms by rapidly releasing effective substances. However, these preparations have limitations in design, mainly reflected in the lack of control over the drug release process, resulting in rapid release of active ingredients in a short period of time, a short duration of efficacy, and the need for frequent dosing. In addition, due to process problems, some preparations have poor particle uniformity and solubility, which further affects the absorption and efficacy of the drug and limits the patient's medication experience.

[0004] The main problem with the existing technology is that the drug release process is not stable enough, resulting in a short duration of drug effect, making it difficult to achieve a combination of rapid onset and long-term effect. This not only reduces patient compliance, but also has an adverse effect on the overall efficacy of the drug. Therefore, there is an urgent need for an efficient cough suppressant preparation that can achieve rapid onset of drug effect and stable release to better meet the treatment needs of patients. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present invention provides a highly effective cough-relieving loquat granule composition and a preparation method thereof, and solves the problems of unstable release of the efficacy and short duration of the existing cough-relieving preparations.

[0006] To achieve the above objectives, the present invention is implemented by the following technical scheme: a highly effective cough-relieving loquat granule composition, comprising the following components by weight: 30-40 parts of loquat leaf extract; 10-15 parts of white scutellaria extract; 6-10 parts of platycodon grandiflorum extract; 18-25 parts of mulberry bark extract; 7-10 parts of stemonae extract; 0.1-0.5 parts of menthol; 2-5 parts of polyethylene glycol; 8-12 parts of mannitol; 3-6 parts of ethyl cellulose; 1-3 parts of hydroxypropyl methylcellulose; 1-3 parts of phosphatidylcholine; 1-3 parts of polysorbate 80; 4-6 parts of cross-linked sodium carboxymethyl cellulose; and 40-60 parts of sucrose.

[0007] Preferably, the weight ratio of polyethylene glycol to mannitol is 1:4 to 1:2.

[0008] Preferably, the amount of cross-linked sodium carboxymethyl cellulose added is 5% of the total mass of the composition.

[0009] Preferably, the sucrose addition ratio is 40-50%.

[0010] A method for preparing a highly effective cough-relieving loquat granule composition comprises the following steps: Step 1, raw material processing: crush loquat leaves, white scutellaria, platycodon, mulberry bark and stemona to 40-60 mesh, add 10-12 times of water, extract at 85-95°C, extract for 1.5-2 hours, extract 2-3 times, combine the extracts, and concentrate under reduced pressure to a relative density of 1.30-1.35 to obtain a clear paste; Step 2, preparation of quick-acting component: adding 2-5% polyethylene glycol and 8-12% mannitol to the clear paste, heating to 60-70°C and stirring evenly to form a quick-acting component; Step 3, preparation of sustained-release component: mixing the clear paste with 3-6% ethyl cellulose and 1-3% hydroxypropyl methyl cellulose in a ratio of 4:1:1, and coating by spray drying, wherein the inlet temperature of the spray drying is 120-130°C, the outlet temperature is 65-75°C, and the spray pressure is 0.5-1.0 MPa, to obtain sustained-release particles with a particle size range of 50-80 μm; Step 4, wet granulation: the fast-acting component and the sustained-release granules are mixed in proportion, 40-60% sucrose and 4-6% cross-linked sodium carboxymethyl cellulose are added, the slurry viscosity is adjusted, and wet granulation is performed, and the particle size is controlled at 0.5-1.0 mm; Step 5: Drying: Place the wet granules in a fluidized bed dryer at a drying temperature of 50-60°C for 2-3 hours; Step 6. Adding menthol: Add 0.1-0.5% menthol to the dry granules and mix well to obtain the target granules.

[0011] Preferably, in step 2, the weight ratio of polyethylene glycol to mannitol is 1:4 to 1:2, the stirring speed is 300-500 rpm, and the stirring time is 20-40 minutes.

[0012] Preferably, the solid-liquid ratio of the slurry in the wet granulation in step 4 is 1:2 to 1:3, the granulation pressure is 0.6-0.8 MPa, and the rotation speed of the granulator drum is 20-50 rpm.

[0013] The present invention provides a highly effective cough-relieving loquat granule composition and a preparation method thereof. The composition has the following beneficial effects: 1. The present invention adopts a double dispersion system combining a quick-release component and a sustained-release component, and significantly improves the solubility and initial release rate of the Chinese medicine extract by adding polyethylene glycol and mannitol, achieving the technical effect of significantly shortening the time for the drug effect to appear. Compared with the technical solution in the prior art that only relies on a single release method, it solves the problem of slow drug onset and inability to relieve patient symptoms in a timely manner.

[0014] 2. The present invention uses ethyl cellulose and hydroxypropyl methylcellulose as the sustained-release matrix in the sustained-release component and forms the sustained-release particles through a spray drying process, thereby achieving the technical effect of stable release of the drug effect within 6-8 hours and longer duration of the therapeutic effect. Compared with the technical solution in the prior art that relies on rapid release of a single dose, it solves the problem of short duration of drug efficacy and the need for frequent medication.

[0015] 3. The present invention uses phosphatidylcholine and polysorbate 80 as absorption enhancers, combined with the optimized design of rapid-release and sustained-release particles, to improve the absorption efficiency of active drug ingredients in the gastrointestinal tract, achieving a technical effect of significantly improving bioavailability. Compared with the technical solution of traditional particles in the prior art that do not add absorption-enhancing excipients, it solves the problems of low drug absorption rate and serious waste of active ingredients.

[0016] 4. The present invention retains the active ingredients of traditional Chinese medicine through multiple extractions and vacuum concentration processes during the preparation process, and combines the technical solutions of wet granulation and fluidized bed drying to ensure the uniformity of the particles and the precise control of the water content, achieving the technical effect of low degradation rate of active ingredients and good product stability during the storage period. Compared with the technical solutions in the prior art where the particles are not fully dried or have poor storage stability, the problem of difficult to ensure product quality and short shelf life is solved. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is a schematic diagram of the method flow of the present invention. DETAILED DESCRIPTION

[0018] 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.

[0019] Embodiment 1: Please see attached Figure 1 The embodiment of the present invention provides a highly effective cough-relieving loquat granule composition and a preparation method thereof, comprising: Formula composition (by weight): Loquat leaf extract: 35 parts; Whitehead extract: 12 parts; Platycodon grandiflorum extract: 8 parts; Morus alba extract: 20 parts; Stemona extract: 8 parts; Menthol: 0.2 parts; Polyethylene glycol (PEG4000): 3 parts; Mannitol: 10 parts; Ethyl cellulose (EC): 5 parts; Hydroxypropyl methylcellulose (HPMC): 2 parts; Phosphatidylcholine: 2 parts; Polysorbate 80 (Tween-80): 2 parts; Cross-linked carboxymethyl cellulose sodium (CCMC-Na): 5 parts; Sucrose: 50 parts; Preparation steps and process parameters: (1) Extraction and concentration Grind loquat leaves, radix scutellariae, platycodon grandiflorum, mulberry bark and stemonae to 40-mesh coarse powder; Add 10 times the amount of water, extract at 90°C for 2 hours, and repeat the extraction 3 times; The extracts were combined and concentrated under reduced pressure to a relative density of 1.32 (70°C) to prepare a clear paste.

[0020] (2) Preparation of immediate-release components Add 3% PEG4000 and 10% mannitol to the clear ointment; Stir evenly at 60°C to form a quick-release component.

[0021] (3) Preparation of sustained-release components Mix the clear paste with ethyl cellulose and HPMC in a ratio of 4:1:1; The packaging was carried out in a spray dryer with a spray drying inlet temperature of 130°C, an outlet temperature of 70°C and a spray pressure of 1.0 MPa to obtain sustained-release particles.

[0022] (4) Wet granulation The immediate-release component and the sustained-release granules were mixed at a ratio of 1:1, and 50% sucrose and 5% CCMC-Na were added to adjust the slurry solid-liquid ratio to 1:3; The wet granulator was used to granulate the particles, and the particle size was controlled at 0.8 mm.

[0023] (5) Drying and adding menthol The wet granules were dried in a fluidized bed at 50°C for 2 hours until the granule moisture content was ≤5%; Add 0.2% menthol and mix well to obtain the target particles.

[0024] This embodiment uses a dual dispersion system combining rapid release and sustained release to shorten the drug effect to within 15 minutes, and the drug effect lasts for 6-8 hours. PEG4000 and mannitol in the rapid release component improve solubility and accelerate the drug effect; the sustained release particles use ethyl cellulose and HPMC to control the drug release rate and extend the duration of drug effect. Compared with the prior art, it solves the problems of slow drug onset and short-lasting efficacy.

[0025] Example 2: Preparation method of highly effective cough-relieving loquat granules combining absorption promotion and release regulation 1. Formula composition (by weight): Loquat leaf extract: 38 parts; Whitehead extract: 13 parts; Platycodon grandiflorum extract: 7 parts; Morus alba extract: 22 parts; Stemona extract: 9 parts; Menthol: 0.3 parts; Polyethylene glycol (PEG4000): 4 parts; Mannitol: 8 parts; Ethyl cellulose (EC): 4 parts; Hydroxypropyl methylcellulose (HPMC): 3 parts; Phosphatidylcholine: 3 parts; Polysorbate 80 (Tween-80): 3 parts Cross-linked carboxymethylcellulose; Sodium (CCMC-Na): 6 parts; Sucrose: 45 parts 2. Preparation steps and process parameters: (1) Extraction and concentration Grind the herbs to 60 mesh and add 12 times the amount of water; Extraction was performed at 85°C for 1.5 h and repeated twice; After combining the extracts, the extracts were concentrated under reduced pressure to a relative density of 1.33 (75°C) to obtain a clear paste.

[0026] (2) Preparation of immediate-release components Add 4% PEG4000 and 8% mannitol to the clear ointment; Stir evenly at 65°C to form a quick-release component.

[0027] (3) Preparation of sustained-release components Mix the clear paste with ethyl cellulose (4%) and HPMC (3%) in a ratio of 5:1:1; The mixture was dried in a spray dryer with an inlet temperature of 125°C, an outlet temperature of 65°C and a spray pressure of 0.8 MPa to obtain sustained-release particles.

[0028] (4) Wet granulation Mix the immediate-release component with the sustained-release granules in a 2:1 ratio; Sucrose 45% and CCMC-Na 6% were added to adjust the solid-liquid ratio of the slurry to 1:2, and the granules were made using a wet granulator, and the particle size was controlled at 1.0 mm.

[0029] (5) Drying and adding menthol The wet granules were dried in a fluidized bed at 55°C for 2.5 hours until the granule moisture content was ≤5%; Add 0.3% menthol and mix well to obtain the finished product.

[0030] This example improves the gastrointestinal absorption efficiency of the drug by increasing the ratio of absorption enhancers (phosphatidylcholine and polysorbate 80), and the bioavailability is further improved compared to Example 1. While the absorption efficiency is improved, the release regulation design makes the drug effect more stable. Due to the increase in the content of the absorption enhancer, the drug effect manifestation time is slightly longer than that of Example 1, but the peak drug concentration is higher, which is suitable for patients who need rapid relief and optimized absorption efficiency.

[0031] Example 3: Preparation method of highly stable and shelf-life-extended high-efficiency cough-relieving loquat granules 1. Formula composition (by weight): Loquat leaf extract: 36 parts; Whitehead extract: 11 parts; Platycodon grandiflorum extract: 9 parts; Morus alba extract: 19 parts; Stemona extract: 8 parts; Menthol: 0.1 parts; Polyethylene glycol (PEG4000): 2 parts; Mannitol: 9 parts; Ethyl cellulose (EC): 5 parts; Hydroxypropyl methylcellulose (HPMC): 2 parts; Phosphatidylcholine: 2 parts; Polysorbate 80 (Tween-80): 2 parts; Cross-linked carboxymethyl cellulose sodium (CCMC-Na): 4 parts; Sucrose: 50 parts; 2. Preparation steps and process parameters: (1) Extraction and concentration The medicinal materials were crushed into 50 mesh, and 10 times the amount of water was added. The extraction was carried out at 90°C for 2 hours, and the extraction was repeated 3 times. The extracts were combined and concentrated under reduced pressure to a relative density of 1.31 (70°C) to prepare a clear paste.

[0032] (2) Preparation of immediate-release components Add 2% PEG4000 and 9% mannitol to the clear ointment; The mixture was stirred evenly at 60°C to form a quick-release component.

[0033] (3) Preparation of sustained-release components Mix the clear paste with ethyl cellulose and HPMC in a ratio of 4:1:1; The packaging was carried out in a spray dryer with a spray drying inlet temperature of 130°C, an outlet temperature of 70°C and a spray pressure of 1.0 MPa to obtain sustained-release particles.

[0034] (4) Wet granulation and drying The immediate-release component and the sustained-release granules were mixed in a ratio of 1:1, and 50% sucrose and 4% CCMC-Na were added to adjust the slurry solid-liquid ratio to 1:3; Dry in a fluidized bed at 50°C for 2 hours and control the moisture content to ≤4%.

[0035] (5) Menthol addition and packaging Add 0.1% menthol, mix well and pack in vacuum aluminum foil.

[0036] This embodiment takes high stability as the core design goal, and significantly improves the stability of the particles under high temperature and high humidity conditions by reducing the proportion of absorption enhancers and accurately controlling the moisture content. Storage tests show that the degradation rate of the active ingredient is less than 2% within 3 months at 40°C and 75% humidity. Compared with Examples 1 and 2, the drug effect is slightly slower to appear, but the stability is significantly enhanced, and it is suitable for use in situations where long-term storage and transportation are required.

[0037] Several comparative examples are provided below, which are mainly compared by adjusting the data to be similar to the prior art.

[0038] Comparative Example 1: In Comparative Example 1, no sustained-release design was adopted, and only a single rapid-release component was relied upon to release the active ingredient, which is in contrast to the rapid-release and sustained-release combined technical solution in Example 1.

[0039] Preparation process: Raw material processing and extraction According to the extraction method of Example 1, loquat leaves, white radix, platycodon, mulberry bark and stemonae were crushed into 40 mesh coarse powder; Add 10 times the amount of water, extract at 90°C for 2 hours, repeat the extraction 3 times, combine the extracts and concentrate under reduced pressure to a relative density of 1.32 (70°C) to prepare a clear paste.

[0040] Preparation of immediate release components Add 3% PEG4000 and 10% mannitol to the clear paste, stir evenly at 60°C to directly form rapid-release granules.

[0041] Wet granulation 50% sucrose and 5% CCMC-Na were added to adjust the solid-liquid ratio of the slurry to 1:3, and the granules were prepared using a wet granulator, with the particle size controlled at 0.8 mm.

[0042] Dried with menthol added The wet granules were dried in a fluidized bed at 50°C for 2 hours until the granule moisture content was ≤5%; Add 0.2% menthol and mix well to obtain the finished product.

[0043] This comparative example does not adopt the design of sustained-release particles, and the release of drug efficacy completely relies on the rapid-release component.

[0044] Comparative Example 2 Comparison content: In Comparative Example 2, absorption enhancers such as phosphatidylcholine and polysorbate 80 were not used, which is in contrast to the absorption enhancement design in Example 2.

[0045] Preparation process: Raw material processing and extraction According to the extraction method of Example 2, loquat leaves, white scutellaria, platycodon, mulberry bark and stemona were crushed to 60 mesh; 12 times the amount of water was added, and the mixture was extracted at 85°C for 1.5 hours. The extraction was repeated twice, and the extracts were combined and concentrated under reduced pressure to a relative density of 1.33 (75°C) to obtain a clear paste.

[0046] Preparation of rapid-release components: Add 4% PEG4000 and 8% mannitol to the clear paste, stir evenly at 65°C to form rapid-release components.

[0047] Preparation of sustained-release components The clear paste was mixed with ethylcellulose (4%) and HPMC (3%) in a ratio of 5:1:1; The packaging was carried out in a spray dryer with a spray drying inlet temperature of 125°C, an outlet temperature of 65°C and a spray pressure of 0.8 MPa to obtain sustained-release particles.

[0048] Wet granulation Mix the immediate-release component with the sustained-release granules in a 2:1 ratio; 45% sucrose and 6% CCMC-Na were added to adjust the solid-liquid ratio of the slurry to 1:2, and the granules were prepared using a wet granulator, with the particle size controlled at 1.0 mm.

[0049] Dried with menthol added The wet granules were dried in a fluidized bed at 55°C for 2.5 hours until the granule moisture content was ≤5%; Add 0.3% menthol and mix well to obtain the finished product.

[0050] Difference: This comparative example did not use absorption enhancers (phosphatidylcholine and polysorbate 80), and the absorption enhancement ability was weakened.

[0051] Comparative Example 3: Comparison content: In Comparative Example 3, the moisture content was not strictly controlled during the drying process, in contrast to the strict drying conditions of Example 3.

[0052] Preparation process: Raw material processing and extraction According to the extraction method of Example 3, the medicinal materials were crushed into 50 meshes; Add 10 times the amount of water, extract at 90°C for 2 hours, repeat the extraction 3 times, combine the extracts and concentrate under reduced pressure to a relative density of 1.31 (70°C) to prepare a clear paste.

[0053] Preparation of immediate release components Add 2% PEG4000 and 9% mannitol to the clear ointment and stir evenly at 60°C to form a quick-release component.

[0054] Preparation of sustained-release components Mix the clear paste with ethyl cellulose and HPMC in a ratio of 4:1:1; The packaging was carried out in a spray dryer with a spray drying inlet temperature of 130°C, an outlet temperature of 70°C and a spray pressure of 1.0 MPa to obtain sustained-release particles.

[0055] Wet granulation and drying The immediate-release component and the sustained-release granules were mixed in a ratio of 1:1, and 50% sucrose and 4% CCMC-Na were added to adjust the slurry solid-liquid ratio to 1:3; The particles were dried in a fluidized bed at 50°C for 2 hours without strict control of the moisture content, and dried to a moisture content of approximately 6%.

[0056] Menthol Addition and Packaging Add 0.1% menthol, mix well and pack directly.

[0057] Difference: This comparative example does not strictly control the moisture content of the particles during the drying process, which may affect the stability of the particles.

[0058] Comparative Example 4: Comparison content: In Comparative Example 4, the ratio of functional excipients was adjusted, and the ratio of PEG4000 to mannitol was reduced, which was compared with Example 1.

[0059] Preparation process: Raw material processing and extraction According to the extraction method of Example 1, loquat leaves, white radix, platycodon, mulberry bark and stemonae were crushed into 40 mesh coarse powder; Add 10 times the amount of water, extract at 90°C for 2 hours, repeat the extraction 3 times, combine the extracts and concentrate under reduced pressure to a relative density of 1.32 (70°C) to prepare a clear paste.

[0060] Preparation of immediate release components Add 1% PEG4000 and 5% mannitol to the clear ointment and stir evenly at 60°C to form a quick-release component.

[0061] Preparation of sustained-release components Mix the clear paste with ethyl cellulose and HPMC in a ratio of 4:1:1; The packaging was carried out in a spray dryer with a spray drying inlet temperature of 130°C, an outlet temperature of 70°C and a spray pressure of 1.0 MPa to obtain sustained-release particles.

[0062] Wet granulation The immediate-release component and the sustained-release granules were mixed in a ratio of 1:1, 50% sucrose and 5% CCMC-Na were added, the solid-liquid ratio of the slurry was adjusted to 1:3, and the granules were made using a wet granulator, and the particle size was controlled at 0.8 mm.

[0063] Dried with menthol added The wet granules were dried in a fluidized bed at 50°C for 2 hours until the granule moisture content was ≤5%; Add 0.2% menthol and mix well to obtain the finished product.

[0064] This comparative example reduces the ratio of PEG4000 to mannitol, which may affect the solubility and initial release efficiency of the immediate-release component.

[0065] Experiment 1: Drug effect manifestation time test The purpose of this experiment is to test the difference in drug efficacy manifestation time between Example 1 (rapid-release and sustained-release combination design) and Comparative Example 1 (no sustained-release design) through in vitro dissolution experiments, and to verify the significant effect of the rapid-release and sustained-release combination design of the present invention.

[0066] Experimental procedures Experimental equipment and dissolution conditions Dissolution equipment: six-paddle dissolution apparatus.

[0067] Dissolution medium: 900 mL simulated gastric fluid (pH 1.2, enzyme-free).

[0068] Temperature: 37±0.5℃.

[0069] Rotation speed: 100rpm.

[0070] Sample preparation: Take the particles of Example 1 and Comparative Example 1, and weigh samples equivalent to 100 mg of the active ingredient (calculated as ursolic acid) respectively.

[0071] Three parallel samples were set up in each group.

[0072] Sampling and testing: Place the particle samples separately in the dissolution medium and take samples at regular intervals, with 2 mL sampled every 5 minutes (add an equal amount of fresh medium after sampling to keep the dissolution volume unchanged).

[0073] The concentration of active ingredient (ursolic acid) in the sample solution was detected using a UV spectrophotometer at a wavelength of 210 nm.

[0074] The cumulative release amount of ursolic acid in the dissolution solution was determined, and the cumulative dissolution curve was drawn.

[0075] Data analysis: The time required for the sample to release 50% of the active ingredient (T50%) was used as an indicator of the drug effect manifestation time to compare the differences between Example 1 and Comparative Example 1.

[0076] Time (min) Example 1 Group 1 (%) Example 1 Group 2 (%) Example 1 Group 3 (%) Comparative Example 1 Group 1 (%) Comparative Example 1 Group 2 (%) Comparative Example 1 Group 3 (%) 0 0 0 0 0 0 0 5 15.3 13.8 16.1 9.2 8.7 9.8 10 38.6 36.9 39.4 22.4 21.8 23.1 15 50.7 48.9 52.3 32.9 31.4 33.2 20 63.2 61.4 65 45.6 44.2 46 30 80.8 79.3 82.2 62.7 61.5 63.2 45 90.5 88.9 91.8 81.3 80.2 82 The experimental data show that the release rate of the active ingredient in Example 1 is significantly higher than that in Comparative Example 1, especially in the first 15 minutes. This phenomenon is due to the synergistic effect of the combination of rapid release and sustained release. Polyethylene glycol (PEG4000) and mannitol are added to the rapid release granules. These excipients effectively reduce the interfacial tension of the active ingredient and increase the dissolution rate. In the first 5 minutes, the release rate of Example 1 is significantly accelerated, which to a certain extent explains the shortening of the time for the drug effect to appear.

[0077] In contrast, comparative example 1 did not introduce sustained-release particles, and the release was completely dependent on the rapid-release component. Although the initial release increased, the release rate gradually decreased thereafter. The limitation of rapid-release particles is that the dissolution is limited by the surface area of ​​the particles, making it difficult for the active ingredients to be released continuously. Therefore, its cumulative dissolution at 15 minutes is much lower than that of Example 1. The combination of rapid-release and sustained-release solves this problem well. The sustained-release particles are gradually released after the rapid-release ends, effectively maintaining a stable release rate.

[0078] It is worth noting that the inter-group differences in the dissolution data of Example 1 are small, which indicates that the preparation process of the sustained-release granules performs well in uniformity. However, the inter-group differences in Comparative Example 1 are slightly larger, which may be due to the randomness of granule dissolution. It can be seen that the sustained-release technology not only improves the time for drug efficacy to appear, but also significantly optimizes the dissolution stability of the granules.

[0079] Experiment 2: Bioavailability test The purpose of this experiment is to compare the difference in bioavailability of active ingredients between Example 2 (containing absorption enhancer) and Comparative Example 2 (without absorption enhancer) through animal experiments, and to verify the effect of absorption enhancers (phosphatidylcholine and polysorbate 80).

[0080] Experimental procedures Experimental subjects and groups Experimental animals: healthy male SD rats, weighing 180-200 g, were fed adaptively for 7 days.

[0081] Grouping: Randomly divided into 2 groups, 8 in each group, corresponding to Example 2 and Comparative Example 2, respectively.

[0082] Sample preparation and dosing The particle samples were prepared according to Example 2 and Comparative Example 2.

[0083] The samples were taken and made into uniform suspensions with equal amount of deionized water. Each animal was given the drug by gavage at a dose of 200 mg / kg (calculated as the active ingredient ursolic acid).

[0084] Blood sample collection and processing 0.5 mL of blood was collected from the orbital vein at 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours after administration.

[0085] The blood samples were immediately centrifuged (3000 rpm, 10 min), and the supernatant plasma was stored at -20°C for future use.

[0086] Plasma sample testing The concentration of ursolic acid in plasma was determined by high performance liquid chromatography (HPLC) and quantified by internal standard method.

[0087] Chromatographic conditions: the mobile phase was methanol-water (70:30), and the detection wavelength was 210 nm.

[0088] Data analysis A curve was drawn based on the blood drug concentration-time data, and the maximum blood drug concentration (Cmax) and the area under the curve (AUC) were calculated as bioavailability indicators.

[0089] Time (h) Example 2 Group 1 (μg / mL) Example 2 Group 2 (μg / mL) Example 2 Group 3 (μg / mL) Comparative Example 2 Group 1 (μg / mL) Comparative Example 2 Group 2 (μg / mL) Comparative Example 2 Group 3 (μg / mL) 0.5 3.62 3.51 3.75 1.94 2.02 1.88 1 5.83 5.95 5.74 3.44 3.32 3.56 2 6.91 6.88 7.02 4.52 4.41 4.38 4 5.34 5.21 5.4 3.6 3.68 3.55 6 3.24 3.36 3.3 2.08 2.12 2.04 8 1.43 1.32 1.41 0.98 1.02 1.03 From the data, the Cmax of Example 2 is nearly double that of Comparative Example 2, especially at about 1 hour, the curve is significantly steeper. This is because of the synergistic effect of phosphatidylcholine and polysorbate 80, which help the active ingredients to quickly pass through the gastrointestinal membrane and improve the initial absorption efficiency. These two excipients simulate the phospholipid structure of the cell membrane, enhance the permeability of the drug, and play a key role in improving bioavailability. In contrast, in Comparative Example 2, due to the lack of absorption enhancers, the absorption efficiency of the active ingredient is low, and the blood drug concentration is always low.

[0090] In Example 2, not only the Cmax is high, but the AUC is also greater, indicating that the total amount absorbed is significantly improved. The presence of sustained-release particles may be another reason. It ensures the continuous release of the active ingredient in the gastrointestinal tract, which complements the immediate-release particles. Although Comparative Example 2 also contains sustained-release particles, the design advantages of sustained release cannot be fully utilized due to insufficient absorption of the active ingredient. The sustained-release particles are more fully stimulated in Example 2.

[0091] After 6 hours, the concentration of Example 2 also decreases more slowly, and the bilayer structure of phosphatidylcholine can form a protective barrier in the gastrointestinal tract to prevent the rapid degradation of the active ingredients, which is an additional benefit to the stability of the drug effect.

[0092] Experiment 3: Drug effect duration test Purpose This experiment compared the difference in duration of drug effect between Example 1 (combination of rapid release and sustained release design) and Comparative Example 1 (no sustained release design) through in vitro release experiments, and verified the contribution of sustained-release particles in prolonging drug effect.

[0093] Experimental procedures Experimental equipment and conditions Dissolution equipment: six-paddle dissolution apparatus.

[0094] Dissolution medium: 900 mL simulated intestinal fluid (pH 6.8, enzyme-free).

[0095] Temperature: 37±0.5℃.

[0096] Rotation speed: 100rpm.

[0097] Detection wavelength: 210nm (determination of ursolic acid).

[0098] Sample preparation The granule samples of Example 1 and Comparative Example 1 were respectively taken, and the amount equivalent to 100 mg of the active ingredient (ursolic acid) was weighed.

[0099] There were 3 parallel samples in each group.

[0100] Sampling and testing Place the samples in the dissolution apparatus respectively and take samples according to the set time points (0.5h, 1h, 2h, 4h, 6h, 8h, 12h).

[0101] 2 mL of sample was taken each time, and an equal amount of fresh medium was added to keep the dissolution volume constant.

[0102] The concentration of ursolic acid in the sample solution was detected by UV spectrophotometer, the cumulative release amount was calculated, and the cumulative release curve was drawn.

[0103] Data analysis The cumulative release amounts at different time points were compared, and the drug release amounts at 6 hours and 12 hours and the stability of the release curve were used as the basis for judging the duration of drug efficacy.

[0104] Time (h) Example 1 Group 1 (%) Example 1 Group 2 (%) Example 1 Group 3 (%) Comparative Example 1 Group 1 (%) Comparative Example 1 Group 2 (%) 0.5 12.5 11.8 13 18.9 18.5 1 22.3 23.1 21.5 32.7 31.9 2 40.4 39.1 41.6 50.1 51.3 4 63.5 62.2 64.7 79.4 80.2 6 79.8 80.4 78.9 93.2 94 8 88.3 89.2 87.4 97.1 96.8 12 97.2 96.7 97.8 98.8 98.9 The experimental data show that there are some differences in the release performance of Example 1 and Comparative Example 1 in the first hour. Comparative Example 1 has a faster initial release, and the rapid release particles release quickly, but after 2 hours, the release curve tends to be flat. The drug is almost completely released at 4 hours. This rapid release feature determines that its drug effect duration is relatively limited. Without the design of sustained-release particles, the active ingredient has almost no power to push in the middle and late stages of release. This is a significant defect of Comparative Example 1.

[0105] In Example 1, under the action of the sustained-release particles, the release showed a long-term stability. Between 6 hours and 12 hours, the release curve gradually approached a platform. The sustained-release matrix of ethyl cellulose and hydroxypropyl methylcellulose played a good regulatory role. They gradually swelled and dissolved in the simulated intestinal fluid, controlling the release rate of the active ingredient. This gradual release mechanism is the key to the sustained efficacy. The quick-release particles release the initial efficacy, while the sustained-release particles extend the duration of action.

[0106] In addition, the curve stability of Example 1 is higher. The consistency of data between groups is good, indicating that the uniformity of its process is better than that of Comparative Example 1. In contrast, the release rate of Comparative Example 1 varies greatly in the later period, which may be caused by the low physical dispersibility of the immediate-release particles. These data clearly show that the introduction of sustained-release particles not only prolongs the efficacy time, but also improves the controllability and uniformity of release, providing patients with a more stable medication experience.

[0107] Experiment 4: Particle stability test Purpose The stability differences of the particles of Example 3 (strict moisture control) and Comparative Example 3 (no strict moisture control) under different storage conditions were tested to verify the effect of moisture content control on the long-term storage performance of the particles.

[0108] Experimental procedures Experimental conditions Storage environment: 40°C, 75% relative humidity (accelerated aging test).

[0109] Experimental time: Storage for 3 months, sampling once a month to test stability indicators.

[0110] Sample preparation Sample setup: Take 30 g of the particles of Example 3 and Comparative Example 3, respectively, put them into aluminum foil bags, seal them and place them in an accelerated aging box.

[0111] Test indicators and methods Appearance changes: record the clumping of particles, color changes, etc.

[0112] Moisture content: The moisture content (%) of the particles was measured using a Karl Fischer moisture meter.

[0113] Active ingredient content: High performance liquid chromatography (HPLC) was used to determine the ursolic acid content, and the degradation rate was calculated.

[0114] Chromatographic conditions: the mobile phase was methanol-water (70:30), and the detection wavelength was 210 nm.

[0115] Test frequency Samples from each group were taken after 1 month, 2 months and 3 months of storage, and the above-mentioned indexes were tested.

[0116] Storage time (months) Example 3 Group 1 Moisture content (%) Example 3 Group 2 Moisture content (%) Example 3 Group 3 Moisture content (%) Comparative Example 3 Group 1 Moisture content (%) Comparative Example 3 Group 2 Moisture content (%) Comparative Example 3 Group 3 Moisture content (%) 0 3.9 4.1 4 6.1 6.3 6 1 4.2 4.5 4.3 7.2 7.1 7.5 2 4.7 4.8 4.9 8.5 8.3 8.6 3 5.1 5.2 5.3 9.4 9.2 9.6 Storage time (months) Example 3 Group 1 Degradation rate (%) Example 3 Group 2 Degradation rate (%) Example 3 Group 3 Degradation rate (%) Comparative Example 3 Group 1 Degradation rate (%) Comparative Example 3 Group 2 Degradation Rate (%) Comparative Example 3 Group 3 Degradation rate (%) 0 0 0 0 0 0 0 1 0.81 0.74 0.79 3.02 2.85 3.14 2 1.34 1.28 1.31 5.89 5.62 6.03 3 1.92 2.01 1.85 8.92 9.1 9.25 The experimental data show that the moisture content of Example 3 is always kept within a reasonable range during storage, and the increase is small, while the moisture content of Comparative Example 3 is significantly higher. This phenomenon can be explained from the internal structure of the particles. In Example 3, the drying process is strictly controlled to make the initial moisture content of the particles ≤4%, and a denser structure is formed on the surface of the particles, preventing the intrusion of environmental moisture. However, since the moisture content of Comparative Example 3 is not strictly controlled (about 6%), the moisture content inside the particles is high, and it is easy to absorb moisture in the environment, resulting in a rapid increase in moisture content during storage.

[0117] The difference in the degradation rate of the active ingredient is also very significant. The degradation rate of Example 3 is only slightly higher than 2% after 3 months, showing excellent stability. The degradation rate of Comparative Example 3 is close to 9% under the same conditions, indicating that the higher water content accelerates the degradation reaction of the active ingredient. This is because the presence of water will cause the humidity of the internal environment of the particles to increase, thereby catalyzing oxidation and hydrolysis reactions and reducing the content of the active ingredient. Strict moisture control is obviously the key to improving product stability.

[0118] The appearance of Example 3 remained basically unchanged during storage, and the surface of the particles was dry and uniform, with no obvious caking or color change. However, the particles of Comparative Example 3 began to cake slightly after 1 month of storage, and the caking phenomenon became more serious after 3 months. This phenomenon is directly related to the high moisture content. The presence of moisture causes the particles to absorb moisture and soften, thereby sticking and caking. This instability of physical properties also further reduces the usability and market competitiveness of the product.

[0119] Experiment 5: Solubility test Purpose Through simulated dissolution experiments, the dissolution properties of the particles of Example 1 (optimization of the ratio of functional excipients) and Comparative Example 4 (adjustment of the ratio of excipients) were tested to verify the effect of the optimization of the ratio of functional excipients (PEG4000 and mannitol) on the rapid dissolution ability of the particles.

[0120] Experimental procedures Experimental conditions Equipment: Solubility tester.

[0121] Dissolution medium: 900 mL simulated saliva (pH 7.0).

[0122] Temperature: 37±0.5℃.

[0123] Rotation speed: 50rpm.

[0124] Sample preparation Sample setup: Take 10 g of the particles of Example 1 and Comparative Example 4 respectively and place them in a solubility tester for testing.

[0125] Sampling and testing At the beginning of the experiment, start the solubility tester, observe the dissolution of the particles every 2 minutes, and record the time required for the particles to be completely dissolved (the particles are not visible to the naked eye).

[0126] Sample No. Dissolution time (group 1, s) Dissolution time (Group 2, s) Dissolution time (Group 3, s) Example 1 78 82 76 Comparative Example 4 121 118 125 Table 5: Simulated saliva dissolution time data of Example 1 and Comparative Example 4 (seconds) The experimental results show that the dissolution time of the particles of Example 1 in simulated saliva is significantly shorter than that of Comparative Example 4. This is closely related to the optimized ratio of functional excipients. In Example 1, the addition amounts of PEG4000 and mannitol are 3% and 10% respectively. The synergistic effect of these two excipients enhances the hydrophilicity of the particles. PEG4000 reduces the surface tension of the particles, allowing water to penetrate into the particles faster, while mannitol has excellent solubility and lubricity, further accelerating the disintegration and dissolution of the particles. This dual effect is the key to significantly improving the dissolution performance of the particles.

[0127] The dissolution time of Comparative Example 4 is significantly longer, probably because the addition amount of PEG4000 and mannitol is reduced to 1% and 5%. The lower excipient ratio is not enough to effectively improve the hydrophilicity of the particles, resulting in a slower disintegration rate of the particles and a longer time for water to penetrate into the core of the particles. At the same time, the reduction of mannitol weakens the lubrication effect, making the contact between the particle surface and the solution less uniform. This shows that the optimization of the excipient ratio has a significant effect on the dissolution behavior of the particles.

[0128] The rapid dissolution ability of particles is particularly important for the onset time of the drug. The design of Example 1 not only improves the dissolution efficiency of the particles, but also improves the dissolution stability of the particles through uniform disintegration, and the difference in dissolution time between groups is small. However, due to the unreasonable ratio of excipients in Comparative Example 4, the dissolution performance is unstable and the data fluctuations between groups are large. This unevenness may lead to inconsistent absorption effects of particles during patient use. In general, the optimization of dissolution performance in Example 1 fully reflects the core value of functional excipients, and further verifies the importance of ratio adjustment.

[0129] 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 highly effective cough-relieving loquat granule composition, characterized in that: It is composed of the following components by weight: 30-40 parts of loquat leaf extract; 10-15 parts of white scutellaria extract; 6-10 parts of platycodon grandiflorum extract; 18-25 parts of mulberry bark extract; 7-10 parts of stemonae extract; 0.1-0.5 parts of menthol; 2-5 parts of polyethylene glycol; 8-12 parts of mannitol; 3-6 parts of ethyl cellulose; 1-3 parts of hydroxypropyl methylcellulose; 1-3 parts of phosphatidylcholine; 1-3 parts of polysorbate 80; 4-6 parts of cross-linked sodium carboxymethyl cellulose; and 40-60 parts of sucrose.

2. The highly effective cough-relieving loquat granule composition according to claim 1, characterized in that: The weight ratio of the polyethylene glycol to mannitol is 1:4 to 1:

2.

3. The highly effective cough-relieving loquat granule composition according to claim 1, characterized in that: The added amount of the cross-linked sodium carboxymethyl cellulose is 5% of the total mass of the composition.

4. The highly effective cough-relieving loquat granule composition according to claim 1, characterized in that: The sucrose adding ratio is 40-50%.

5. A method for preparing a highly effective cough-relieving loquat granule composition, according to the highly effective cough-relieving loquat granule composition according to any one of claims 1 to 4, characterized in that: The following steps are involved: Step 1, raw material processing: crush loquat leaves, white scutellaria, platycodon, mulberry bark and stemona to 40-60 mesh, add 10-12 times of water, extract at 85-95°C, extract for 1.5-2 hours, extract 2-3 times, combine the extracts, and concentrate under reduced pressure to a relative density of 1.30-1.35 to obtain a clear paste; Step 2, preparation of quick-acting component: adding 2-5% polyethylene glycol and 8-12% mannitol to the clear paste, heating to 60-70°C and stirring evenly to form a quick-acting component; Step 3, preparation of sustained-release component: mixing the clear paste with 3-6% ethyl cellulose and 1-3% hydroxypropyl methyl cellulose in a ratio of 4:1:1, and coating by spray drying, wherein the inlet temperature of the spray drying is 120-130°C, the outlet temperature is 65-75°C, and the spray pressure is 0.5-1.0 MPa, to obtain sustained-release particles with a particle size range of 50-80 μm; Step 4, wet granulation: the fast-acting component and the sustained-release granules are mixed in proportion, 40-60% sucrose and 4-6% cross-linked sodium carboxymethyl cellulose are added, the slurry viscosity is adjusted, and wet granulation is performed, and the particle size is controlled at 0.5-1.0 mm; Step 5: Drying: Place the wet granules in a fluidized bed dryer at a drying temperature of 50-60°C for 2-3 hours; Step 6. Adding menthol: Add 0.1-0.5% menthol to the dry granules and mix well to obtain the target granules.

6. The method for preparing a highly effective cough-relieving loquat granule composition according to claim 5, characterized in that: In step 2, the weight ratio of polyethylene glycol to mannitol is 1:4 to 1:2, the stirring speed is 300-500 rpm, and the stirring time is 20-40 minutes.

7. The method for preparing a highly effective cough-relieving loquat granule composition according to claim 5, characterized in that: In the step 4, the solid-liquid ratio of the slurry in the wet granulation is 1:2 to 1:3, the granulation pressure is 0.6-0.8 MPa, and the rotation speed of the granulator drum is 20-50 rpm.

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