Efficient cough-relieving loquat granule composition and preparation method thereof

Abstract

The application relates to the technical field of cough-relieving medicines, and discloses a high-efficiency cough-relieving loquat particle composition which is composed of the following components in parts by weight: loquat leaf extract 30-40 parts; white front extract 10-15 parts; platycodon grandiflorum extract 6-10 parts; white mulberry bark extract 18-25 parts; stemona sessiliflora extract 7-10 parts; menthol 0.1-0.5 part; polyethylene glycol 2-5 parts; mannitol 8-12 parts; ethyl cellulose 3-6 parts; hydroxypropyl methyl cellulose 1-3 parts; phosphatidylcholine 1-3 parts; polysorbate 80 1-3 parts; cross-linked sodium carboxymethyl cellulose 4-6 parts; and sucrose 40-60 parts. The double dispersion system combining the immediate-release component and the sustained-release component is adopted, the solubility and the initial release speed of the traditional Chinese medicine extract are remarkably improved through the addition of polyethylene glycol and mannitol, and the technical effect that the drug effect appearing time is remarkably shortened is achieved. Compared with the technical scheme relying on only a single release mode in the prior art, the deficiency that the drug effect is slow and the symptoms of the patient cannot be timely relieved is solved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of cough-relieving medicines, in particular to a high-efficiency cough-relieving loquat granule composition and a preparation method thereof. BACKGROUND

[0002] In recent years, the incidence of respiratory diseases has been increasing year by year, and cough, as one of the main symptoms, has seriously affected the daily life and work of patients. At present, traditional Chinese medicines are widely used in the treatment of cough due to their reliable efficacy and small side effects. Among them, the traditional Chinese medicine preparations with loquat leaf as the core component are favored by patients due to their effects of clearing heat and moistening lung, relieving cough and reducing phlegm. With the development of modernization of traditional Chinese medicines, how to optimize the preparation process to improve the efficacy of traditional Chinese medicines has become an important direction of industry research.

[0003] In the prior art, loquat leaf cough-relieving preparations mainly exist in the form of granules, and most of them are designed with immediate-release components to quickly relieve cough symptoms by releasing the effective substances quickly. However, these preparations have limitations in design, mainly in that the release process of the drug lacks control, resulting in rapid release of the effective components in a short time, short duration of drug efficacy, and the need for frequent administration. In addition, due to process problems, the uniformity and dissolution performance of some preparations are poor, which further affects the absorption and efficacy of the drug and limits the patient's medication experience.

[0004] The main problem existing in the prior art is that the release process of the drug is not stable, resulting in short duration of drug efficacy, and it is difficult to achieve the combination of rapid onset and long-acting effect. This not only reduces the patient's compliance, but also has an adverse effect on the overall efficacy of the drug. Therefore, there is an urgent need for a high-efficiency cough-relieving preparation that can achieve rapid appearance and stable release of drug efficacy to better meet the treatment needs of patients. SUMMARY

[0005] In view of the deficiencies of the prior art, the present application provides a high-efficiency cough-relieving loquat granule composition and a preparation method thereof, which solves the problems of unstable release of drug efficacy and short duration of existing cough-relieving preparations.

[0006] To achieve the above purpose, the present application realizes the following technical scheme: a high-efficiency cough-relieving loquat granule composition, which is composed of the following components in parts by weight:

[0007] Loquat leaf extract 30-40 parts; white front extract 10-15 parts; Anemarrhena asphodeloides Bunge extract 6-10 parts; mulberry bark extract 18-25 parts; stemona root extract 7-10 parts; menthol 0.1-0.5 parts; polyethylene glycol 2-5 parts; mannitol 8-12 parts; ethyl cellulose 3-6 parts; hydroxypropyl methyl cellulose 1-3 parts; phosphatidylcholine 1-3 parts; polysorbate 80 1-3 parts; cross-linked sodium carboxymethyl cellulose 4-6 parts; sucrose 40-60 parts.

[0008] Preferably, the weight ratio of the polyethylene glycol and mannitol is 1:4 to 1:2.

[0009] Preferably, the amount of sodium croscarmellose added is 5% of the total mass of the composition.

[0010] Preferably, the addition ratio of sucrose is 40-50%.

[0011] A preparation method of a high-efficiency cough-relieving loquat particle composition, comprising the following steps:

[0012] Step one, raw material processing: grind loquat leaves, baiqian, jiegeng, mulberry bark, and baido to 40-60 mesh, add 10-12 times the amount of water, extract at a temperature of 85-95°C for 1.5-2 hours, extract 2-3 times, combine the extract, and reduce pressure to concentrate to a relative density of 1.30-1.35 to obtain a clear paste;

[0013] Step two, preparation of quick-acting components: add 2-5% polyethylene glycol and 8-12% mannitol to the clear paste, heat to 60-70°C, and stir uniformly to form quick-acting components;

[0014] Step three, preparation of sustained-release components: mix the clear paste with 3-6% ethyl cellulose and 1-3% hydroxypropyl methyl cellulose at a ratio of 4:1:1, use spray drying to coat, the inlet temperature of spray drying is 120-130°C, the outlet temperature is 65-75°C, the spray pressure is 0.5-1.0 MPa, and the sustained-release particles with a particle size range of 50-80 μm are prepared;

[0015] Step four, wet granulation: mix the quick-acting components with the sustained-release particles in proportion, add 40-60% sucrose and 4-6% sodium croscarmellose, adjust the slurry viscosity, and wet granulate, with the particle size controlled at 0.5-1.0 mm;

[0016] Step five, drying: place the wet particles in a fluidized bed dryer, dry at a temperature of 50-60°C for 2-3 hours;

[0017] Step six, menthol addition: add 0.1-0.5% menthol to the dried particles, mix uniformly, and obtain the target particles.

[0018] Preferably, in step two, the weight ratio of the polyethylene glycol and mannitol is 1:4 to 1:2, the stirring speed is 300-500 rpm, and the stirring time is 20-40 minutes.

[0019] Preferably, in step four, the solid-liquid ratio of the slurry for wet granulation is 1:2 to 1:3, the granulation pressure is 0.6-0.8 MPa, and the roller speed of the granulator is 20-50 rpm.

[0020] This invention provides a highly effective cough-relieving loquat granule composition and its preparation method. It possesses the following beneficial effects:

[0021] 1. This invention employs a dual-dispersion system combining immediate-release and sustained-release components. The addition of polyethylene glycol and mannitol significantly enhances the solubility and initial release rate of the traditional Chinese medicine extract, resulting in a significantly shortened time to drug efficacy. Compared to existing technologies relying solely on a single release mechanism, this invention overcomes the shortcomings of slow drug onset and delayed symptom relief.

[0022] 2. This invention achieves stable drug release within 6-8 hours and a longer duration of therapeutic effect by using ethyl cellulose and hydroxypropyl methylcellulose as the sustained-release matrix in the sustained-release component and forming sustained-release particles through a spray drying process. Compared with existing technologies that rely on rapid release from a single dose, this invention solves the problems of short duration of drug effect and the need for frequent medication.

[0023] 3. This invention uses phosphatidylcholine and polysorbate 80 as absorption enhancers, combined with the optimized design of immediate-release and sustained-release granules, to improve the absorption efficiency of the active pharmaceutical ingredient in the gastrointestinal tract, achieving a significant improvement in bioavailability. Compared to existing technologies that do not include absorption-enhancing excipients in traditional granules, this invention solves the problems of low drug absorption rate and significant waste of active ingredients.

[0024] 4. This invention preserves the active ingredients of traditional Chinese medicine through multiple extractions and vacuum concentration processes during preparation. Combined with wet granulation and fluidized bed drying, it ensures particle uniformity and precise control of moisture content, achieving low degradation rate of active ingredients and good product stability during storage. Compared to existing technologies with insufficient particle drying or poor storage stability, this invention solves the problems of unreliable product quality and short shelf life. Attached Figure Description

[0025] Figure 1 This is a schematic diagram of the method flow of the present invention. Detailed Implementation

[0026] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0027] Example 1:

[0028] Please see the appendix Figure 1 This invention provides a highly effective cough-relieving loquat granule composition and its preparation method, comprising:

[0029] Formula composition (by weight):

[0030] Loquat leaf extract: 35 parts; Cynanchum paniculatum extract: 12 parts; Platycodon grandiflorus extract: 8 parts; Morus alba root bark extract: 20 parts; Stemona japonica 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; Croscarmellose sodium carboxymethyl cellulose (CCMC-Na): 5 parts; Sucrose: 50 parts;

[0031] Preparation steps and process parameters: (1) Extraction and concentration

[0032] Powder the loquat leaves, cynanchum paniculatum, platycodon grandiflorum, mulberry bark, and stemona japonica into a coarse powder of 40 mesh.

[0033] Add 10 times the amount of water and extract at 90℃ for 2 hours. Repeat the extraction 3 times.

[0034] Combine the extracts and concentrate under reduced pressure to a relative density of 1.32 (70℃) to prepare a clear extract.

[0035] (2) Preparation of immediate-release components

[0036] Add 3% PEG4000 and 10% mannitol to the ointment;

[0037] Stir until homogeneous at 60°C to form an immediate-release component.

[0038] (3) Preparation of sustained-release components

[0039] Mix the extract with ethyl cellulose and HPMC in a 4:1:1 ratio;

[0040] Encapsulation was performed in a spray dryer with an inlet temperature of 130°C, an outlet temperature of 70°C, and a spray pressure of 1.0 MPa to obtain slow-release granules.

[0041] (4) Wet granulation

[0042] Mix the immediate-release component with the slow-release granules at a ratio of 1:1, add 50% sucrose and 5% CCMC-Na, and adjust the solid-liquid ratio of the slurry to 1:3.

[0043] Wet granulation was used to granulate the particles, with the particle size controlled at 0.8 mm.

[0044] (5) Drying and Menthol Addition

[0045] The wet granules were dried in a fluidized bed at 50°C for 2 hours until the moisture content of the granules was ≤5%.

[0046] Add 0.2% menthol and mix well to obtain the target granules.

[0047] This embodiment utilizes a dual dispersion system combining immediate and sustained release, shortening the time to drug efficacy to less than 15 minutes and extending the efficacy to 6-8 hours. In the immediate-release component, PEG4000 and mannitol enhance solubility and accelerate drug efficacy; the sustained-release granules employ ethyl cellulose and HPMC to control the drug release rate, prolonging the duration of efficacy. Compared to existing technologies, this overcomes the shortcomings of slow onset and short-lasting therapeutic effects.

[0048] Example 2: Preparation method of highly effective antitussive loquat granules combining absorption promotion and release regulation

[0049] 1. Formula composition (by weight):

[0050] Loquat leaf extract: 38 parts; Cynanchum paniculatum extract: 13 parts; Platycodon grandiflorus extract: 7 parts; Morus alba root bark extract: 22 parts; Stemona japonica 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; Crosslinked carboxymethyl cellulose; Sodium (CCMC-Na): 6 parts; Sucrose: 45 parts

[0051] 2. Preparation steps and process parameters:

[0052] (1) Extraction and Concentration

[0053] Grind the medicinal materials to 60 mesh and add 12 times the amount of water;

[0054] Extract at 85℃ for 1.5 hours, and repeat the extraction twice;

[0055] The combined extracts were concentrated under reduced pressure to a relative density of 1.33 (75°C) to obtain a clear extract.

[0056] (2) Preparation of immediate-release components

[0057] Add 4% PEG4000 and 8% mannitol to the ointment;

[0058] Stir thoroughly at 65°C to form an immediate-release component.

[0059] (3) Preparation of sustained-release components

[0060] Mix the extract with ethyl cellulose (4%) and HPMC (3%) in a ratio of 5:1:1;

[0061] The product is 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 slow-release granules.

[0062] (4) Wet granulation

[0063] Mix the immediate-release component with the sustained-release granules in a 2:1 ratio;

[0064] Add 45% sucrose and 6% CCMC-Na, adjust the solid-liquid ratio of the slurry to 1:2, and granulate using a wet granulation machine, controlling the particle size to 1.0 mm.

[0065] (5) Drying and Menthol Addition

[0066] The wet granules were dried in a fluidized bed at 55°C for 2.5 hours until the moisture content of the granules was ≤5%.

[0067] Add 0.3% menthol, mix well, and you have the finished product.

[0068] This embodiment improves the gastrointestinal absorption efficiency of the drug by increasing the proportion of absorption enhancers (phosphatidylcholine and polysorbate 80), resulting in further enhanced bioavailability compared to Example 1. While improving absorption efficiency, the release regulation design makes the drug effect more stable. Due to the increased content of absorption enhancers, the onset of drug effect is slightly longer than in Example 1, but the peak drug concentration is higher, making it suitable for patients requiring rapid relief and optimized absorption efficiency.

[0069] Example 3: Preparation method of highly stable and long-shelf-life loquat granules for cough relief

[0070] 1. Formula composition (by weight):

[0071] Loquat leaf extract: 36 parts; Cynanchum paniculatum extract: 11 parts; Platycodon grandiflorus extract: 9 parts; Morus alba root bark extract: 19 parts; Stemona japonica 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; Croscarmellose sodium carboxymethyl cellulose (CCMC-Na): 4 parts; Sucrose: 50 parts;

[0072] 2. Preparation steps and process parameters:

[0073] (1) Extraction and Concentration

[0074] The medicinal materials are pulverized to 50 mesh, 10 times the amount of water is added, and the mixture is extracted at 90℃ for 2 hours. The extraction is repeated 3 times.

[0075] The combined extracts were concentrated under reduced pressure to a relative density of 1.31 (70℃) to prepare a clear extract.

[0076] (2) Preparation of immediate-release components

[0077] Add 2% PEG4000 and 9% mannitol to the ointment;

[0078] Stir at 60°C to form an immediate-release component.

[0079] (3) Preparation of sustained-release components

[0080] Mix the extract with ethyl cellulose and HPMC in a 4:1:1 ratio;

[0081] Encapsulation was performed in a spray dryer with an inlet temperature of 130°C, an outlet temperature of 70°C, and a spray pressure of 1.0 MPa to obtain slow-release granules.

[0082] (4) Wet granulation and drying

[0083] Mix the immediate-release component with the slow-release granules in a 1:1 ratio, add 50% sucrose and 4% CCMC-Na, and adjust the solid-liquid ratio of the slurry to 1:3.

[0084] The sample was dried in a fluidized bed at 50°C for 2 hours, with the moisture content controlled at ≤4%.

[0085] (5) Menthol Addition and Packaging

[0086] Add 0.1% menthol, mix well, and then vacuum-pack with aluminum foil.

[0087] This embodiment prioritizes high stability in its design. By reducing the proportion of absorption enhancers and precisely controlling moisture content, the stability of the particles under high temperature and humidity conditions is significantly improved. 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 efficacy is slightly slower to appear, but the stability is significantly enhanced, making it suitable for use in situations requiring long-term storage and transportation.

[0088] The following provides several comparative examples, which are mainly compared by adjusting the data to be similar to existing technologies.

[0089] Comparative Example 1:

[0090] In Comparative Example 1, no sustained-release design was used; the active ingredient was released by relying solely on a single immediate-release component, in contrast to the combined immediate-release and sustained-release technology in Example 1.

[0091] Preparation process:

[0092] Raw material processing and extraction

[0093] Following the extraction method of Example 1, loquat leaves, Cynanchum paniculatum, Platycodon grandiflorus, mulberry bark, and Stemona japonica were pulverized into 40-mesh coarse powder;

[0094] Add 10 times the amount of water and extract at 90℃ for 2 hours. Repeat the extraction 3 times. Combine the extracts and concentrate under reduced pressure to a relative density of 1.32 (70℃) to prepare a clear extract.

[0095] Preparation of immediate-release components

[0096] Add 3% PEG4000 and 10% mannitol to the extract, stir evenly at 60°C, and directly form immediate-release granules.

[0097] wet granulation

[0098] Add 50% sucrose and 5% CCMC-Na, adjust the solid-liquid ratio of the slurry to 1:3, and granulate using a wet granulation machine, controlling the particle size to 0.8 mm.

[0099] Drying and menthol addition

[0100] The wet granules were dried in a fluidized bed at 50°C for 2 hours until the moisture content of the granules was ≤5%.

[0101] Add 0.2% menthol, mix well, and you have the finished product.

[0102] This comparative example did not use a sustained-release particle design; the drug efficacy release relied entirely on the immediate-release component.

[0103] Comparative Example 2

[0104] Comparison: In Comparative Example 2, absorption enhancers such as phosphatidylcholine and polysorbate 80 were not used, which contrasts with the absorption-enhancing design in Example 2.

[0105] Preparation process:

[0106] Raw material processing and extraction

[0107] According to the extraction method in Example 2, loquat leaves, cynanchum paniculatum, platycodon grandiflorum, mulberry bark and stemona japonica were pulverized 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 extract.

[0108] Preparation of immediate-release component: Add 4% PEG4000 and 8% mannitol to the clear extract and stir evenly at 65°C to form the immediate-release component.

[0109] Preparation of sustained-release components

[0110] Mix the extract with ethyl cellulose (4%) and HPMC (3%) in a ratio of 5:1:1;

[0111] Encapsulation was performed 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 slow-release granules.

[0112] wet granulation

[0113] Mix the immediate-release component with the sustained-release granules in a 2:1 ratio;

[0114] Add 45% sucrose and 6% CCMC-Na, adjust the solid-liquid ratio of the slurry to 1:2, and granulate using a wet granulation machine, controlling the particle size to 1.0 mm.

[0115] Drying and menthol addition

[0116] The wet granules were dried in a fluidized bed at 55°C for 2.5 hours until the moisture content of the granules was ≤5%.

[0117] Add 0.3% menthol, mix well, and you have the finished product.

[0118] Difference: This comparative example did not use absorption enhancers (phosphatidylcholine and polysorbate 80), resulting in a weakened absorption-enhancing ability.

[0119] Comparative Example 3:

[0120] Comparison: In Comparative Example 3, the moisture content was not strictly controlled during the drying process, which contrasts with the strict drying conditions in Example 3.

[0121] Preparation process:

[0122] Raw material processing and extraction

[0123] The medicinal materials were pulverized to 50 mesh according to the extraction method of Example 3;

[0124] Add 10 times the amount of water and extract at 90℃ for 2 hours. Repeat the extraction 3 times. Combine the extracts and concentrate under reduced pressure to a relative density of 1.31 (70℃) to prepare a clear extract.

[0125] Preparation of immediate-release components

[0126] Add 2% PEG4000 and 9% mannitol to the extract and stir evenly at 60°C to form an immediate-release component.

[0127] Preparation of sustained-release components

[0128] Mix the extract with ethyl cellulose and HPMC in a 4:1:1 ratio;

[0129] Encapsulation was performed in a spray dryer with an inlet temperature of 130°C, an outlet temperature of 70°C, and a spray pressure of 1.0 MPa to obtain slow-release granules.

[0130] Wet granulation and drying

[0131] Mix the immediate-release component and the slow-release granules in a 1:1 ratio, add 50% sucrose and 4% CCMC-Na, and adjust the solid-liquid ratio of the slurry to 1:3.

[0132] The particles were dried in a fluidized bed at 50°C for 2 hours, but the moisture content of the particles was not strictly controlled, and the moisture content was dried to about 6%.

[0133] Menthol Addition and Packaging

[0134] Add 0.1% menthol, mix well, and then package directly.

[0135] Difference: This comparison ratio does not strictly control the moisture content of the particles during the drying process, which may affect the stability of the particles.

[0136] Comparative Example 4:

[0137] Comparison content: In Comparative Example 4, the proportion of functional excipients was adjusted, and the proportion of PEG4000 and mannitol was reduced, to form a comparison with Example 1.

[0138] Preparation process:

[0139] Raw material processing and extraction

[0140] Following the extraction method of Example 1, loquat leaves, Cynanchum paniculatum, Platycodon grandiflorus, mulberry bark, and Stemona japonica were pulverized into 40-mesh coarse powder;

[0141] Add 10 times the amount of water and extract at 90℃ for 2 hours. Repeat the extraction 3 times. Combine the extracts and concentrate under reduced pressure to a relative density of 1.32 (70℃) to prepare a clear extract.

[0142] Preparation of immediate-release components

[0143] Add 1% PEG4000 and 5% mannitol to the extract and stir evenly at 60°C to form an immediate-release component.

[0144] Preparation of sustained-release components

[0145] Mix the extract with ethyl cellulose and HPMC in a 4:1:1 ratio;

[0146] Encapsulation was performed in a spray dryer with an inlet temperature of 130°C, an outlet temperature of 70°C, and a spray pressure of 1.0 MPa to obtain slow-release granules.

[0147] wet granulation

[0148] 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. The solid-liquid ratio of the slurry was adjusted to 1:3, and granulation was performed using a wet granulation machine, with the particle size controlled at 0.8 mm.

[0149] Drying and menthol addition

[0150] The wet granules were dried in a fluidized bed at 50°C for 2 hours until the moisture content of the granules was ≤5%.

[0151] Add 0.2% menthol, mix well, and you have the finished product.

[0152] This comparative example reduced the ratio of PEG4000 to mannitol, which may affect the solubility and initial release efficiency of the immediate-release component.

[0153] Experiment 1: Test of drug efficacy manifestation time

[0154] This experiment aims to test the difference in the time of drug efficacy between Example 1 (combined immediate-release and sustained-release design) and Comparative Example 1 (no sustained-release design) through in vitro dissolution experiments, and to verify the significant effect of the combined immediate-release and sustained-release design of the present invention.

[0155] Experimental steps

[0156] Experimental equipment and dissolution conditions

[0157] Dissolution equipment: Six-paddle dissolution apparatus.

[0158] Dissolution medium: 900 mL simulated gastric juice (pH 1.2, enzyme-free).

[0159] Temperature: 37±0.5℃.

[0160] Speed: 100 rpm.

[0161] Sample preparation: Take the granules from Example 1 and Comparative Example 1, and weigh out samples equivalent to 100 mg of active ingredient (calculated as ursolic acid).

[0162] Each group has 3 parallel samples.

[0163] Sampling and testing: Place the particle samples in the dissolution medium and take samples at regular intervals, taking 2 mL of sample every 5 minutes (replenish with an equal amount of fresh medium after sampling to keep the dissolution volume constant).

[0164] The concentration of the active ingredient (ursolic acid) in the sample solution was detected using a UV spectrophotometer at a wavelength of 210 nm.

[0165] The cumulative release of ursolic acid in the dissolution solution was determined, and a cumulative dissolution curve was plotted.

[0166] Data analysis: The time required for the sample to release 50% of the active ingredient (T50%) was used as the indicator of the time for the drug effect to appear, and the differences between Example 1 and Comparative Example 1 were compared.

[0167] 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 exhibiting a faster release rate in the first 15 minutes. This phenomenon stems from the synergistic effect of the combined immediate-release and sustained-release design. The immediate-release granules contain polyethylene glycol (PEG4000) and mannitol, which effectively reduce the interfacial tension of the active ingredient and improve the dissolution rate. In the first 5 minutes, the release rate of Example 1 is significantly accelerated, which to some extent explains the shortened time to drug efficacy.

[0168] In contrast, Comparative Example 1 did not introduce sustained-release particles, and release relied entirely on the immediate-release component. Although the initial release increased, the release rate gradually decreased thereafter. The limitation of immediate-release particles is that dissolution is restricted by the particle surface area, making it difficult to sustain the release of the active ingredient. Therefore, its cumulative dissolution at 15 minutes was much lower than that of Example 1. The combined immediate-release and sustained-release scheme effectively solves this problem, with the sustained-release particles gradually released after the immediate release has ended, effectively maintaining a stable release rate.

[0169] It is particularly noteworthy that the dissolution data in Example 1 showed relatively small differences between groups, indicating that the preparation process of the sustained-release granules exhibited excellent uniformity. In contrast, Comparative Example 1 showed slightly larger differences between groups, possibly due to the randomness of granule dissolution. Therefore, sustained-release technology not only improves the time to drug efficacy but also significantly optimizes the dissolution stability of the granules.

[0170] Experiment 2: Bioavailability Test

[0171] This experiment aims to compare the differences in bioavailability of active ingredients between Example 2 (containing the absorption enhancer) and Comparative Example 2 (without the absorption enhancer) through animal experiments, and to verify the effect of the absorption enhancer (phosphatidylcholine and polysorbate 80).

[0172] Experimental steps

[0173] Experimental subjects and groups

[0174] Experimental animals: Healthy male SD rats, weighing 180-200g, were acclimatized for 7 days.

[0175] Grouping: The animals were randomly divided into two groups of eight each. These correspond to Example 2 and Comparative Example 2, respectively.

[0176] Sample preparation and administration

[0177] The particulate samples were prepared according to Example 2 and Comparative Example 2.

[0178] Each sample was prepared into a homogeneous suspension using an equal volume of deionized water. The animal was administered the drug via gavage at a dose of 200 mg / kg (calculated based on the active ingredient, ursolic acid).

[0179] Blood sample collection and processing

[0180] 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.

[0181] Centrifuge the blood sample immediately (3000 rpm, 10 minutes), and store the supernatant plasma at -20℃ for later use.

[0182] plasma sample testing

[0183] The concentration of ursolic acid in plasma was determined by high performance liquid chromatography (HPLC), and quantification was performed using the internal standard method.

[0184] Chromatographic conditions: mobile phase was methanol-water (70:30), detection wavelength was 210 nm.

[0185] Data Analysis

[0186] Based on the blood drug concentration-time data, a curve was plotted, and the maximum blood drug concentration (Cmax) and the area under the curve (AUC) were calculated as indicators of bioavailability.

[0187] Time (h) Example 2 Group 1 (pg / mL) Example 2 Group 2 (pg / mL) Example 2 Group 3 (pg / mL) Comparative Example 2 Group 1 (pg / mL) Comparative Example 2 Group 2 (pg / mL) Comparative Example 2 Group 3 (pg / 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 The data show that the Cmax of Example 2 was nearly twice that of Comparative Example 2, especially around 1 hour, where the curve was significantly steeper. This is due to the synergistic effect of phosphatidylcholine and polysorbate 80, which help the active ingredient quickly cross the gastrointestinal membrane, improving initial absorption efficiency. These two excipients mimic the phospholipid structure of cell membranes, enhancing drug permeability and playing a key role in improving bioavailability. In contrast, Comparative Example 2, lacking absorption enhancers, showed low absorption efficiency of the active ingredient, resulting in consistently low blood drug concentrations.

[0188] Example 2 not only showed a higher Cmax but also a larger AUC, indicating a significant increase in total absorption. The presence of sustained-release particles may be another reason. It ensures the continuous release of the active ingredient in the gastrointestinal tract, complementing the immediate-release particles. Although Comparative Example 2 also contained sustained-release particles, the absorption of the active ingredient itself was insufficient, preventing the full utilization of the sustained-release design advantages. In Example 2, the sustained-release particles were more fully activated to achieve their effect.

[0189] After 6 hours, the concentration of Example 2 decreased at a slower rate, indicating that the bilayer structure of phosphatidylcholine can form a protective barrier in the gastrointestinal tract, preventing rapid degradation of the active ingredient. This is an additional benefit to the stability of the drug's efficacy.

[0190] Experiment 3: Duration of Drug Effect Test

[0191] Experimental Objective

[0192] This experiment compares the differences in duration of drug effect between Example 1 (combined immediate and sustained release design) and Comparative Example 1 (no sustained release design) through in vitro release experiments, verifying the contribution of sustained-release particles to prolonging drug effect.

[0193] Experimental steps

[0194] Experimental equipment and conditions

[0195] Dissolution equipment: Six-paddle dissolution apparatus.

[0196] Dissolution medium: 900 mL simulated intestinal fluid (pH 6.8, enzyme-free).

[0197] Temperature: 37±0.5℃.

[0198] Speed: 100 rpm.

[0199] Detection wavelength: 210nm (for ursolic acid determination).

[0200] Sample preparation

[0201] Take the particle samples from Example 1 and Comparative Example 1 respectively, and weigh the amount equivalent to 100 mg of active ingredient (ursolic acid).

[0202] Each group has 3 parallel samples.

[0203] Sampling and Testing

[0204] The samples were placed in the dissolution apparatus and sampled at the set time points (0.5h, 1h, 2h, 4h, 6h, 8h, 12h).

[0205] Take 2 mL of sample each time, and add an equal amount of fresh medium at the same time to keep the dissolution volume constant.

[0206] The concentration of ursolic acid in the sample solution was detected using a UV spectrophotometer, the cumulative release was calculated, and the cumulative release curve was plotted.

[0207] Data Analysis

[0208] The cumulative release at different time points was compared, and the release amount at 6 hours and 12 hours and the stability of the release curve were used as the basis for judging the duration of drug effect.

[0209] 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 Experimental data showed some differences in release performance between Example 1 and Comparative Example 1 in the first hour. Comparative Example 1 exhibited faster initial release, with rapid release from the immediate-release granules, but the release curve flattened after 2 hours. The drug was nearly completely released by 4 hours. This rapid release characteristic determines its relatively limited duration of efficacy. Without the design of sustained-release granules, the active ingredient lacks almost no propulsion in the later stages of release. This is a significant drawback of Comparative Example 1.

[0210] In Example 1, the sustained-release granules demonstrated long-term stability in drug release. Between 6 and 12 hours, the release curve gradually plateaued. The sustained-release matrix of ethyl cellulose and hydroxypropyl methylcellulose played a significant moderating role. They gradually swelled and dissolved in simulated intestinal fluid, controlling the release rate of the active ingredient. This gradual release mechanism is key to sustained efficacy. While immediate-release granules release the initial drug effect, sustained-release granules prolong the duration of action.

[0211] Furthermore, Example 1 exhibited higher curve stability. The good consistency between groups indicated that its process uniformity was superior to Comparative Example 1. In contrast, Comparative Example 1 showed greater variation in release rate in the later stages, which may be due to the lower physical dispersibility of the immediate-release particles. These data clearly demonstrate that the introduction of sustained-release particles not only prolongs the duration of drug effect but also improves the controllability and uniformity of release, providing patients with a more stable medication experience.

[0212] Experiment 4: Particle stability test

[0213] Experimental Objective

[0214] The stability differences between Example 3 (strict moisture control) and Comparative Example 3 (no strict moisture control) particles under different storage conditions were tested to verify the impact of moisture content control on the long-term storage performance of the particles.

[0215] Experimental steps

[0216] Experimental conditions

[0217] Storage environment: 40℃, 75% relative humidity (accelerated aging test).

[0218] Experimental period: 3 months of storage, with monthly sampling to test stability indicators.

[0219] Sample preparation

[0220] Sample setup: Take 30g of each of the particles from Example 3 and Comparative Example 3, put them into aluminum foil bags, seal them, and place them in an accelerated aging chamber.

[0221] Test metrics and methods

[0222] Appearance changes: Record phenomena such as particle clumping and color changes.

[0223] Moisture content: The moisture content (%) of the particles was determined using a Karl Fischer moisture analyzer.

[0224] Active ingredient content: The content of ursolic acid was determined by high performance liquid chromatography (HPLC), and the degradation rate was calculated.

[0225] Chromatographic conditions: mobile phase was methanol-water (70:30), detection wavelength was 210 nm.

[0226] Test frequency

[0227] Samples were taken from each group of samples after 1 month, 2 months, and 3 months of storage, and the above-mentioned indicators were tested.

[0228] 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 Experimental data show that the moisture content of Example 3 remained within a reasonable range throughout storage, with only a small increase, while the moisture content of Comparative Example 3 was significantly higher. This phenomenon can be explained by the internal structure of the particles. In Example 3, the drying process was strictly controlled, ensuring that the initial moisture content of the particles was ≤4%, resulting in a denser structure on the particle surface that prevented the intrusion of environmental moisture. In contrast, Comparative Example 3, due to the lack of strict control over the moisture content (approximately 6%), had a higher internal moisture content in the particles, making them more susceptible to absorbing moisture from the environment, leading to a rapid increase in moisture content during storage.

[0229] The degradation rates of the active ingredients also differed significantly. Example 3 showed a degradation rate only slightly above 2% after 3 months, demonstrating excellent stability. In contrast, Comparative Example 3 showed a degradation rate close to 9% under the same conditions, indicating that higher moisture content accelerated the degradation reaction of the active ingredients. This is because the presence of moisture increases the humidity inside the particles, thereby catalyzing oxidation and hydrolysis reactions and reducing the content of the active ingredients. Strict moisture control is clearly key to improving product stability.

[0230] The appearance of the particles in Example 3 remained essentially unchanged during storage; the particle surface was dry and uniform, with no obvious clumping or color change. In contrast, the particles in Comparative Example 3 began to show slight clumping after one month of storage, and the clumping became more severe after three months. This phenomenon is directly related to the high moisture content; the presence of moisture causes the particles to absorb moisture, soften, and thus clump together. This instability in physical properties further reduces the product's usability and market competitiveness.

[0231] Experiment 5: Solubility Test

[0232] Experimental Objective

[0233] The dissolution performance of the particles from Example 1 (optimized ratio of functional excipients) and Comparative Example 4 (adjusted ratio of excipients) was tested through simulated dissolution experiments to verify the effect of optimizing the ratio of functional excipients (PEG4000 and mannitol) on the rapid dissolution ability of the particles.

[0234] Experimental steps

[0235] Experimental conditions

[0236] Equipment: Solubility meter.

[0237] Dissolving medium: 900 mL of simulated saliva (pH 7.0).

[0238] Temperature: 37±0.5℃.

[0239] Rotation speed: 50 rpm.

[0240] Sample preparation

[0241] Sample setup: Take 10g of each of the particles from Example 1 and Comparative Example 4 and place them in a solubility analyzer for testing.

[0242] Sampling and Testing

[0243] Start the solubility meter at the beginning of the experiment and observe the dissolution of the particles every 2 minutes. Record the time required for the particles to completely dissolve (the particles are not visible to the naked eye).

[0244] 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

[0245] Table 5: Simulated saliva dissolution time data (seconds) for Example 1 and Comparative Example 4

[0246] Experimental results showed that the particles of Example 1 dissolved in simulated saliva in a significantly shorter time than those of Comparative Example 4. This is closely related to the optimized formulation of the functional excipients. In Example 1, the addition amounts of PEG4000 and mannitol were 3% and 10%, respectively. The synergistic effect of these two excipients enhanced the hydrophilicity of the particles. PEG4000 reduced the surface tension of the particles, allowing water to penetrate into the particles more quickly, while mannitol, with its excellent solubility and lubricity, further accelerated the disintegration and dissolution of the particles. This dual effect is the key to the significant improvement in particle dissolution performance.

[0247] The significantly longer dissolution time in Comparative Example 4 is likely due to the reduced addition levels of PEG4000 and mannitol to 1% and 5%, respectively. The lower excipient ratio is insufficient to effectively improve the hydrophilicity of the particles, leading to a slower particle disintegration rate and a prolonged time for water to penetrate the particle core. Simultaneously, the reduction in mannitol weakens the lubrication effect, resulting in less uniform contact between the particle surface and the solution. This indicates that optimizing the excipient ratio has a significant impact on the particle dissolution behavior.

[0248] The rapid dissolution of granules is crucial for the onset time of drug action. Example 1 not only improved the dissolution efficiency of the granules but also enhanced their dissolution stability through uniform disintegration, resulting in minimal differences in dissolution time between groups. In contrast, Comparative Example 4, due to an unreasonable excipient ratio, exhibited unstable dissolution performance and significant fluctuations in data between groups. This inhomogeneity may lead to inconsistent absorption of the granules during patient use. In summary, the optimization of dissolution performance in Example 1 fully demonstrates the core value of functional excipients and further validates the importance of ratio adjustment.

[0249] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A highly effective cough-relieving loquat granule composition, characterized in that, Composed of the following components in parts by weight: The ingredients are: 30-40 parts loquat leaf extract; 10-15 parts Cynanchum paniculatum extract; 6-10 parts Platycodon grandiflorus extract; 18-25 parts mulberry bark extract; 7-10 parts Stemona japonica extract; 0.1-0.5 parts menthol; 2-5 parts polyethylene glycol; 8-12 parts mannitol; 3-6 parts ethyl cellulose; 1-3 parts hydroxypropyl methylcellulose; 1-3 parts phosphatidylcholine; 1-3 parts polysorbate 80; 4-6 parts croscarmellose sodium; and 40-60 parts sucrose. The weight ratio of polyethylene glycol to mannitol is 1:4 to 1:

2. The composition is prepared by a method comprising the following steps: Step 1: Raw material processing: Pulverize loquat leaves, cynanchum paniculatum, platycodon grandiflorum, mulberry bark, and stemona japonica to 40-60 mesh, add 10-12 times the amount of water, extract at 85-95℃ 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 extract; Step 2, Preparation of fast-acting components: Add 2-5% polyethylene glycol and 8-12% mannitol to the ointment, heat to 60-70℃ and stir evenly to form fast-acting components; Step 3: Preparation of sustained-release components: Mix the extract with 3-6% ethyl cellulose and 1-3% hydroxypropyl methyl cellulose in a ratio of 4:1:1, and encapsulate using spray drying. The inlet temperature of the spray dryer is 120-130℃, the outlet temperature is 65-75℃, and the spray pressure is 0.5-1.0MPa to obtain sustained-release particles with a particle size range of 50-80μm. Step 4, wet granulation: Mix the fast-acting component with the slow-release granules in a certain proportion, add 40-60% sucrose and 4-6% croscarmellose sodium, adjust the slurry viscosity, and wet granulate, controlling the particle size to 0.5-1.0 mm. Step 5: Drying: Place the wet granules in a fluidized bed dryer at a temperature of 50-60℃ for 2-3 hours until the moisture content of the granules is ≤5%. Step 6: Add menthol: Add 0.1-0.5% menthol to the dried granules, mix well, and obtain the target granules.

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

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

4. The highly effective cough-relieving loquat granule composition according to claim 1, characterized in that, In step two, 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.

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

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