Ambroxol hydrochloride sustained-release powder and preparation method thereof

Abstract

The invention discloses ambroxol hydrochloride sustained-release powder and a preparation method thereof. The method comprises the following steps: S1, mixing ambroxol hydrochloride and meso-porous silicon according to a mass ratio of 1: (0.8-1.5), stirring for 5-6 hours, and drying to obtain drug-loaded meso-porous silicon; s2, mixing the drug-loaded meso-porous silicon and a sustained-release material according to a mass ratio of 1: (5.5-7), dissolving, and coating to obtain skeleton powder containing the drug-loaded meso-porous silicon; s3, embedding the skeleton powder containing the drug-loaded meso-porous silicon and a wax material according to a mass ratio of 1: (2-3) to obtain prefabricated ambroxol hydrochloride sustained-release powder; and S4, adding a flavoring agent, and mixing to obtain the ambroxol hydrochloride sustained-release powder. The ambroxol hydrochloride sustained-release powder can be slowly and stably released by combining a plurality of sustained-release technologies, so that the medicine taking frequency of children is reduced, and the medication compliance is improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of sustained-release preparations, and particularly relates to a sustained-release ambroxol hydrochloride powder and a preparation method thereof. BACKGROUND

[0002] Ambroxol hydrochloride is an active N-desmethyl metabolite of bromhexine, which is a white to light yellow crystalline powder. Ambroxol hydrochloride can promote sputum dissolution and excretion, promote bronchial epithelial repair while improving dyspnea symptoms, and has synergistic effects with antibacterial drugs and anti-inflammatory and antioxidant effects. In addition, ambroxol hydrochloride has the advantages of fast oral effect, high bioavailability and the like in clinical use as an expectorant. Ambroxol hydrochloride is mainly metabolized by liver enzyme P450 CYP3A4 glucuronidation. The effectiveness and safety of ambroxol hydrochloride have been fully verified, and the incidence of adverse reactions is low. No significant drug interactions between ambroxol hydrochloride and other drugs have been reported. The clearance rate of ambroxol hydrochloride in patients with liver function damage decreases, and the plasma concentration increases, but since the therapeutic dose is large, the dose does not need to be changed. The influence of age, gender and food on the pharmacokinetics of ambroxol hydrochloride is also small.

[0003] The types of ambroxol hydrochloride preparations recorded in various pharmacopoeias mainly include oral solutions, tablets, injection solutions, capsules, sustained-release capsules and syrups. The preparation type mainly suitable for children is a liquid preparation represented by an oral solution. However, the clinical application of the liquid preparation is limited by the following factors: poor chemical stability (easily affected by environmental factors such as temperature, humidity and light to cause drug degradation), inconvenience of storage and transportation (strictly sealed and large volume), poor palatability (difficult to effectively mask the bad smell and taste) and safety hazards caused by the use of preservatives; there is also a risk of microbial contamination in multi-dose packaging preparations, and the complex production process also leads to an increase in cost. On the other hand, traditional solid preparations (such as tablets and capsules) are not suitable for children due to problems such as difficulty in swallowing, difficulty in adjusting the dose, poor palatability and poor digestion and absorption. In recent years, although ambroxol hydrochloride spray and ambroxol hydrochloride direct swallowing granules have been marketed for children, there is still no ambroxol hydrochloride sustained-release preparation for children. At present, the marketed ambroxol hydrochloride sustained-release preparations mainly include sustained-release capsules and sustained-release tablets, which are prepared by coating the sustained-release material on the pill core. However, the two dosage forms are not suitable for children, and the medication compliance of children is low. Therefore, there is a broad market demand and better research feasibility for ambroxol hydrochloride sustained-release solid preparations for children.

[0004] It should be noted that the information disclosed in the above background section is only used to strengthen the understanding of the background of the application, and therefore can include information that does not constitute prior art known to those of ordinary skill in the art. SUMMARY

[0005] To solve the above problems in the prior art, the application provides a sustained-release ambroxol hydrochloride powder and a preparation method thereof. In a first aspect, the application provides a preparation method of a sustained-release ambroxol hydrochloride powder, comprising the following steps: S1, mesoporous silica is added to an ambroxol hydrochloride solution, and after stirring for 5-6 hours, drying is performed to obtain drug-loaded mesoporous silica; wherein the mass ratio of the ambroxol hydrochloride to the mesoporous silica is 1:(0.8-1.5); S2, the drug-loaded mesoporous silica is mixed with a sustained-release material at a mass ratio of 1:(5.5-7), and after dissolution by adding a first solvent, coating is performed, and after the coating is completed, the solvent is removed and crushing is performed to obtain a skeleton powder containing the drug-loaded mesoporous silica; S3, the skeleton powder containing the drug-loaded mesoporous silica is added to a wax material in a molten state, embedding is performed while the wax material is kept in a molten state, and after the embedding is completed, cooling and solidification are performed and crushing is performed to obtain a pre-prepared sustained-release ambroxol hydrochloride powder; wherein the mass ratio of the skeleton powder containing the drug-loaded mesoporous silica to the wax material is 1:(2-3); S4, the pre-prepared sustained-release ambroxol hydrochloride powder is mixed with a flavoring agent to obtain a sustained-release ambroxol hydrochloride powder.

[0006] In an embodiment of the application, in step S1, the mass ratio of the ambroxol hydrochloride to the mesoporous silica is 1:1; In step S2, the mass ratio of the drug-loaded mesoporous silica to the sustained-release material is 1:6; In step S3, the mass ratio of the skeleton powder containing the drug-loaded mesoporous silica to the wax material is 1:2.5.

[0007] In an embodiment of the application, in step S1, the pore size of the mesoporous silica is 2-5 nm.

[0008] In an embodiment of the application, in step S2, the first solvent is ethanol or acetone; the coating condition is stirring at 40-60°C for 25-35 min; and the particle size of the skeleton powder containing the drug-loaded mesoporous silica is less than 180 μm.

[0009] In an embodiment of the application, in step S3, the embedding condition is performed within the melting temperature range of the wax material, and the stirring time is 25-35 min; the cooling and solidification time is 3-6 h; and the particle size of the pre-prepared sustained-release ambroxol hydrochloride powder is less than 125 μm.

[0010] In an embodiment of the application, the preparation method of the ambroxol hydrochloride solution is to dissolve ambroxol hydrochloride in a second solvent. The second solvent is water, or a mixed solution of water and ethanol in a volume ratio of 8:2.

[0011] In one embodiment of the present application, in step S4, the mass ratio of the pre-prepared ambroxol hydrochloride sustained-release powder to the flavoring agent is 100: (0.3-5.5).

[0012] In one embodiment of the present application, in step S1, the mesoporous silica is Syloid® 244FP; In step S2, the sustained-release material is one or more of ethyl cellulose, Eudragit RL, and Eudragit RS; In step S3, the waxy material is a combination of at least two of stearic acid, stearyl alcohol, and carnauba wax; In step S4, the flavoring agent is selected from one or more of sucralose, xylitol, erythritol, strawberry flavor, orange flavor, and peppermint flavor.

[0013] In one embodiment of the present application, the waxy material is a combination of stearic acid and stearyl alcohol, wherein the mass ratio of stearic acid to stearyl alcohol is 2.6:100; or the waxy material is a combination of stearyl alcohol and carnauba wax, wherein the mass ratio of stearyl alcohol to carnauba wax is 4:100.

[0014] In a second aspect, the present application provides a sustained-release ambroxol hydrochloride powder, which is obtained by the above preparation method.

[0015] Compared with the prior art, the present application has the following beneficial effects: 1. In the preparation method of the sustained-release ambroxol hydrochloride powder provided by the present application, the synergistic effect of "mesoporous adsorption-sustained-release skeleton controlled release-waxy barrier" realizes multi-level regulation of the drug release rate. First, mesoporous silica as the core of drug loading realizes efficient drug loading; at the same time, it reduces the adhesion between particles and improves the flowability of the powder. Second, the insoluble material is used as the sustained-release material, which is further wrapped outside the drug-loaded mesoporous silica to further regulate the release rate of the drug. Finally, the waxy material is used for embedding to form a continuous hydrophobic protective barrier to delay the release of the drug. In addition, the combination of multiple sustained-release technologies improves the stability of the preparation, facilitating storage and transportation.

[0016] 2. The present application synergistically adjusts the ratio of parameters in the processes of mesoporous silica loading, sustained-release material coating, and waxy material embedding to synergistically realize the sustained-release effect of the prepared powder, so that the prepared sustained-release ambroxol hydrochloride powder can be slowly and smoothly released within 24 hours, the blood drug concentration is maintained within the effective concentration range for a long time window, and the number of drug administrations is reduced.

[0017] 3. The sustained-release powder formulation fully considers the needs of children, allowing for flexible dosage adjustment. It is suitable for children of different weights and ages, and avoids the swallowing difficulties of capsules and the inconvenience of refrigerated storage required for liquid preparations, thus enhancing the drug's practicality and market application value. Simultaneously, the addition of flavoring agents effectively improves the bitter taste of ambroxol hydrochloride, increasing children's compliance and providing a new medication option for the long-term treatment of respiratory diseases in children.

[0018] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0019] Figure 1a This is a SEM characterization image of mesoporous silica before drug loading in Embodiment 1 of the present invention; Figure 1b This is an SEM characterization image of the drug-loaded mesoporous silica prepared in step S1 of Embodiment 1 of the present invention. Figure 2a This is an SEM characterization image (scale bar is 1:1μm) of the drug-loaded mesoporous silica framework powder prepared in step S2 of Embodiment 1 of the present invention. Figure 2b This is an SEM characterization image (scale bar is 1:10 μm) of the drug-loaded mesoporous silica framework powder prepared in step S2 of Embodiment 1 of the present invention. Figure 3 This is a SEM characterization image (scale bar 1:2μm) of the pre-prepared ambroxol hydrochloride sustained-release agent prepared in step S3 of Embodiment 1 of the present invention. Figure 4 This is a SEM characterization image (scale bar 1:10 μm) of the pre-prepared ambroxol hydrochloride sustained-release powder prepared in step S3 of Example 1 of the present invention. Figure 5 This is a schematic diagram of the in vitro release rate test results of ambroxol hydrochloride sustained-release powder in one embodiment of the present invention; Figure 6 This is a characterization diagram of the particle size detection results of ambroxol hydrochloride sustained-release dispersant in one embodiment of the present invention; Figure 7 This is a schematic diagram illustrating the in vivo blood concentration detection results of ambroxol hydrochloride sustained-release powder in one embodiment of the present invention. Detailed Implementation

[0020] To further illustrate the technical means and effects adopted by the present invention to achieve the intended purpose, the following detailed description, in conjunction with the accompanying drawings and specific embodiments, provides a method for preparing an ambroxol hydrochloride sustained-release powder and the preparation thereof based on the present invention.

[0021] The foregoing and other technical contents, features, and effects of the present invention will be clearly presented in the following detailed description of specific embodiments in conjunction with the accompanying drawings. Through the description of the specific embodiments, a more in-depth and concrete understanding can be gained of the technical means and effects adopted by the present invention to achieve its intended purpose. However, the accompanying drawings are for reference and illustration only and are not intended to limit the technical solutions of the present invention.

[0022] It should be noted that, in this document, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, the terms "comprising," "including," or any other variations are intended to cover non-exclusive inclusion, such that an article or apparatus comprising a list of elements includes not only those elements but also other elements not expressly listed.

[0023] This invention provides an ambroxol hydrochloride sustained-release dispersant and a method for preparing the sustained-release dispersant. The method for preparing the ambroxol hydrochloride sustained-release dispersant includes the following steps S1-S4. Specifically, it includes: S1. Add mesoporous silica to an ambroxol hydrochloride solution, stir for 5–6 h, and then dry to obtain drug-loaded mesoporous silica; wherein the mass ratio of ambroxol hydrochloride to mesoporous silica is 1:(0.8–1.5). In this step, if too much mesoporous silica is added, the loading efficiency of ambroxol hydrochloride on the mesoporous silica will decrease, resulting in an excessively rapid release rate. If too little mesoporous silica is added, the prepared sustained-release powder may be incompletely released, affecting the blood drug concentration in vivo.

[0024] In one example, the ambroxol hydrochloride solution is obtained by dissolving ambroxol hydrochloride in a second solvent; wherein the second solvent can be water, or the second solvent can be a mixture of water and ethanol in a volume ratio of 8:2.

[0025] In one example, the mesoporous silica can be Syloid®244FP, which has excellent specific surface area, pore size distribution, and drug loading capacity. It is understood that in this embodiment, other mesoporous silica with a particle size of 2–5 nm can also be selected.

[0026] In some examples, the mass ratio of ambroxol hydrochloride to mesoporous silica can be 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5, etc. Preferably, the mass ratio of ambroxol hydrochloride to mesoporous silica is 1:1.

[0027] S2. Mix drug-loaded mesoporous silica and sustained-release material at a mass ratio of 1: (5.5~7), add the first solvent to dissolve and then coat the mixture. After coating, remove the solvent and pulverize the mixture to obtain a framework powder containing drug-loaded mesoporous silica.

[0028] In one example, the first solvent is ethanol or acetone. Using ethanol or acetone as a solvent is inexpensive and relatively easy to remove by rotary evaporation.

[0029] In one example, the coating conditions were a stirred reaction at 40–60°C for 25–35 min.

[0030] In one example, the particle size of the drug-loaded mesoporous silica framework powder is less than 180 μm. For instance, the coated solid product can be pulverized and passed through an 80-mesh sieve (approximately 180 μm pore size) to obtain a drug-loaded mesoporous silica framework powder with a particle size less than 180 μm.

[0031] In one example, the sustained-release material is one or more of ethyl cellulose, Eudragit RL, and Eudragit RS.

[0032] In some examples, the mass ratio of drug-loaded mesoporous silica to sustained-release material can be 1:5.5, 1:5.7, 1:5.9, 1:6, 1:6.2, 1:6.4, 1:6.6, 1:6.8, or 1:7.0. Preferably, the mass ratio of drug-loaded mesoporous silica to sustained-release material is 1:6.

[0033] S3. Add the drug-loaded mesoporous silica framework powder to the molten wax material, keep the wax material in the molten state for encapsulation, cool and solidify after encapsulation, and then pulverize to obtain a pre-prepared ambroxol hydrochloride sustained-release dispersant. The mass ratio of the drug-loaded mesoporous silica framework powder to the wax material is 1:(2-3).

[0034] In one example, the wax material is a combination of at least two of stearyl alcohol, carnauba wax, and stearic acid.

[0035] In one example, the wax material is a composition of stearic acid and stearyl alcohol, or a composition of stearyl alcohol and carnauba wax. Further, in the composition of stearic acid and stearyl alcohol, the mass ratio of stearic acid to stearyl alcohol is 2.6:100; in the composition of stearyl alcohol and carnauba wax, the mass ratio of stearyl alcohol to carnauba wax is 4:100.

[0036] In one example, the embedding reaction is carried out within the melting temperature range of the wax material, and the reaction time is 25–35 min. For example, a composition of stearic acid and stearyl alcohol can be used at a melting temperature of 70°C; a composition of stearyl alcohol and carnauba wax can be used at a melting temperature of 90°C.

[0037] In one example, the time for cooling and solidification after the embedding reaction was 3–6 h.

[0038] In one example, the pre-formulated ambroxol hydrochloride sustained-release dispersant has a particle size of less than 125 μm. For instance, the obtained solid product can be pulverized after encapsulation and passed through a 120-mesh sieve (approximately 125 μm pore size) to obtain the pre-formulated ambroxol hydrochloride sustained-release dispersant.

[0039] In some examples, the mass ratio of the drug-loaded mesoporous silica framework powder to the wax material can be 1:2, 1:2.2, 1:2.4, 1:2.5, 1:2.6, 1:2.8, or 1:3. Preferably, the mass ratio of the drug-loaded mesoporous silica framework powder to the wax material is 1:2.5.

[0040] S4. Mix the pre-prepared ambroxol hydrochloride sustained-release powder with the flavoring agent to obtain the ambroxol hydrochloride sustained-release powder.

[0041] In one example, the mass ratio of pre-prepared ambroxol hydrochloride sustained-release powder to flavoring agent is 100:(0.3-5.5).

[0042] In one example, the flavoring agent is selected from one or more of sucralose, xylitol, erythritol, strawberry flavor, orange flavor, and peppermint flavor. For example, the flavoring agent may be a combination of sucralose, xylitol, and strawberry flavor, or a combination of sucralose and orange flavor, etc.

[0043] Preferably, the amount of flavoring agent added to the pre-prepared ambroxol hydrochloride sustained-release powder is 0.2%~0.3% sucralose, 3%~5% xylitol, and 0.1%~0.2% flavoring.

[0044] The preparation method of ambroxol hydrochloride sustained-release powder provided by the present invention achieves stable, efficient and slow drug release by constructing a multi-layer sustained-release system comprising "mesoporous silica support + sustained-release material skeleton + wax material embedding". This overcomes the defects of traditional ambroxol hydrochloride liquid preparations, such as poor stability, inconvenience in carrying, strong bitterness and capsules or tablets being unsuitable for children to swallow.

[0045] The ambroxol hydrochloride sustained-release powder provided by this invention uses mesoporous silica as a drug carrier. Utilizing its high specific surface area and mesoporous structure, ambroxol hydrochloride is efficiently loaded through physical adsorption, forming a solid dispersion. Subsequently, sustained-release materials and waxy materials are used to coat and embed the drug-loaded mesoporous silica. By adjusting the ratio of sustained-release materials and waxy materials, the drug release rate is effectively controlled, enabling the drug to be slowly released in vivo over 24 hours, maintaining a stable blood drug concentration, improving therapeutic efficacy, and reducing the frequency of administration. The ambroxol hydrochloride sustained-release powder achieves multi-level regulation of the drug release rate through the synergistic effect of "mesoporous adsorption - sustained-release framework controlled release - waxy barrier". First, mesoporous silica, as the core of drug loading, achieves efficient drug loading while reducing interparticle adhesion and improving the flowability of the powder. Second, the sustained-release material is an insoluble material that forms a three-dimensional network structure to wrap around the drug-loaded mesoporous silica, further regulating the drug release rate. Finally, the waxy material is used for embedding, forming a continuous hydrophobic protective barrier to delay drug release. Thus, the release rate of ambroxol hydrochloride is controlled in multiple stages through a multi-stage sustained-release technology. The first stage (waxy material): After administration, the hydrophobicity of the waxy layer initially restricts the entry of the drug release medium into the powder and controls the drug diffusion path, gradually slowing drug release. The second stage: When water penetrates the waxy material or the waxy material is partially dissolved, the sustained-release matrix formed by the sustained-release material is a water-insoluble polymer, controlling the penetration of the drug release medium. When media from the body's internal environment (such as digestive fluids, intestinal fluids, etc.) come into contact with the sustained-release matrix (ethyl cellulose and / or acrylic resin matrix), the sustained-release matrix material (polymer material) begins to absorb water and swell, and the drug begins to diffuse through the complex pores; the second stage constitutes the main stage of drug release. The third stage: The drug particles released from the sustained-release matrix are still loaded with mesoporous silica, meaning the drug needs to be released from the mesoporous silica to be absorbed. This is mainly determined by the diffusion of residual drug within the particles until the drug is completely released.

[0046] In terms of preparation process, this invention has the advantage of a simple process flow. The preparation process mainly includes mixing and adsorption of drug solution and carrier, preparation of framework, and melt embedding. The process conditions are mild, safe, and easy to control in terms of quality. The resulting powder has a moderate particle size and good flowability, and can be directly packaged or dispensed into single-dose formulations, which is convenient for storage, transportation, and use.

[0047] In terms of practicality, this invention fully considers the needs of children's medication. The powder dosage form allows for flexible dosage adjustment, making it suitable for children of different weights and ages. It also avoids the swallowing difficulties of capsules and the inconvenience of refrigerated storage required for liquid preparations, thus enhancing the drug's practicality and market application value. Simultaneously, the addition of a flavoring agent effectively improves the bitter taste of ambroxol hydrochloride, increasing children's compliance with medication.

[0048] The present invention will be further described in detail below with reference to specific embodiments.

[0049] Example 1 0.5 g of mesoporous silica Syloid® 244FP was weighed and added to 25 ml of ambroxol hydrochloride solution with a concentration of 20 mg / ml. The solution was stirred at a constant temperature (25℃) for 8 h. Samples were taken and filtered at different time points. Using a UV-Vis spectrophotometer, the absorbance of the drug solution before and after drug loading was measured at its maximum absorption wavelength (λmax = 244 nm), and the drug concentration at each time point was calculated to determine the drug loading status. The drug adsorption rate (E) was calculated using the formula: E = C0 - C e / C0; The formula for calculating drug loading (L) is: L = (C0 - C e ) V / M. Where C0 is the initial concentration of the drug solution before loading (mg / mL or g / L), C e V is the concentration of the drug solution after loading (mg / mL or g / L), V is the volume of the drug solution (mL or L), and M is the mass of the mesoporous silica (mg or g).

[0050] Table 1. Comparison of drug loading and drug adsorption rate at different time points

[0051] According to the test results in Table 1, the mesoporous silica and ambroxol hydrochloride solution reached adsorption equilibrium after 6 hours of mixing and stirring. The equilibrium drug loading was 0.90 g / g, and the drug adsorption rate was 90%, both reaching high levels. Stirring for another hour had little effect on the drug loading and adsorption rate, but instead increased the process cost.

[0052] Example 2 S1. Preparation of drug-loaded mesoporous silica Dissolve 5 g of ambroxol hydrochloride in 250 ml of 20% ethanol, suspend 5 g of mesoporous silica Syloid® 244FP in the solution, and stir for 6 h. Decantation separates the drug-loaded particles, free drug is removed with water, and the solution is dried at 40°C to obtain drug-loaded mesoporous silica. Figure 1b The image shown is a scanning electron microscope (SEM) characterization image of the drug-loaded mesoporous silica prepared in Example 2. Figure 1a and Figure 1b As can be seen, the mesoporous silica particles before and after drug loading are rough and irregular, with virtually no difference in appearance. This is likely because the drug primarily fills the voids within the pores after loading, rather than covering the particle surface. Therefore, the morphology (such as shape and surface roughness) of the particles does not show significant changes in the electron microscope images.

[0053] S2, Coating of sustained-release materials 12 g of ethyl cellulose was dissolved in ethanol at 40°C, and 2 g of drug-loaded mesoporous silica from step S1 was added. After stirring for 30 min, the solvent ethanol was removed by rotary evaporation. After aging at 50°C for 12 h, the mixture was pulverized through an 80-mesh sieve to obtain a framework powder containing drug-loaded mesoporous silica. Figure 2a and Figure 2b The image shown is a SEM characterization image of the drug-loaded mesoporous silica framework powder prepared in Example 2. Figure 2a and Figure 2b As can be seen, the particles of the drug-loaded mesoporous silica framework powder exhibit an irregular shape, with only a small portion having a slightly larger particle size. The majority of the particles are relatively uniformly distributed. However, the coating does not completely block the mesoporous silica to form a uniform and continuous film structure; it only forms a partial coating layer. The particle surface shows obvious porous structures, requiring wax encapsulation to further seal the open pores and slow down the release rate.

[0054] S3, embedding of wax materials 6.3 g of waxy material (stearyl alcohol containing 2.6% stearic acid) was melted at 70°C. While stirring, 2.5 g of the skeleton powder prepared in step S2 was added. After stirring for 30 min to mix evenly, the mixture was quickly poured into a cooled iron plate and refrigerated for 6 h to solidify. The mixture was then pulverized through a 120-mesh sieve to obtain a pre-prepared ambroxol hydrochloride sustained-release dispersant. Figure 3 and Figure 4 The image shows the SEM characterization of the pre-prepared ambroxol hydrochloride sustained-release powder obtained in Example 2. Compared to the rough, porous skeletal powder before encapsulation, the encapsulated particle surface is smoother, and the pores are largely covered, indicating that the waxy encapsulation layer forms a more continuous barrier. The encapsulated surface barrier reduces the direct contact area with the drug, decreases the specific surface area, and significantly delays drug dissolution. The smooth, dense surface contributes to the sustained-release effect.

[0055] S4, tasteful Take the pre-prepared ambroxol hydrochloride sustained-release powder from step S3, add sucralose, xylitol, and strawberry flavoring for flavoring, and mix well to obtain the ambroxol hydrochloride sustained-release powder. Wherein, sucralose is 0.3% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder, xylitol is 3% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder, and strawberry flavoring is 0.2% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder. The ambroxol hydrochloride sustained-release powder prepared in Example 2 is defined as sustained-release powder 1.

[0056] Performance testing was conducted on sustained-release powder 1: (1) In vitro release rate test of ambroxol hydrochloride sustained-release powder In vitro dissolution testing is a core tool for sustained-release formulation design and quality control. By analyzing release behavior, it optimizes formulations, provides scientific evidence for batch-to-batch consistency verification and in vitro-in vivo correlation, and ensures efficacy and safety.

[0057] The sustained-release powder 1 prepared in Example 2 was used as the test sample. The dissolution and release rate were determined according to the method of determination of dissolution and release rate (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). 1000 ml of pH 7.4 phosphate buffer (27.2 g of potassium dihydrogen phosphate was added to 395 ml of 0.1 mol / L sodium hydroxide solution and diluted with water to 1000 ml) was used as the release medium. The rotation speed was 50 r / min. The procedure was followed. 10 mL of the dissolution was collected after 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h, and release medium of the same temperature and volume was added immediately. Specifically: Take the dissolution solutions from 0.5 h and 1 h, filter, discard 3 mL of the initial filtrate, and use the subsequent filtrate as the test solution; for dissolution solutions from other time periods, filter, discard 3 mL of the initial filtrate, accurately measure 2 mL of the subsequent filtrate, place it in a 10 mL volumetric flask, dilute to the mark with the release medium, and shake well to obtain the test solution. Accurately weigh ambroxol hydrochloride reference standard, dissolve it in the release medium, and quantitatively dilute it to prepare a solution containing approximately 15 μg per mL as the reference solution. Take the test solution and the reference solution, and measure the absorbance at a wavelength of 244 nm using ultraviolet-visible spectrophotometry (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0401), and calculate the dissolution amount at different times. Perform six parallel experiments on the sample.

[0058] Commercially available sustained-release capsules A (Lepu Pharmaceutical Co., Ltd., Ambroxol Hydrochloride Sustained-Release Capsules, 75mg / capsule), B (Heumann Pharma GmbH & Co. Generica KG, Ambroxol Hydrochloride Sustained-Release Capsules, 75mg / capsule), and C (Boehringer ingelheim Pharma GmbH & Co. KG, Ambroxol Hydrochloride Sustained-Release Capsules, 75mg / capsule) were used as positive controls. The in vitro release rate of these three positive control sustained-release capsules was determined using the same detection method described above. Commercially available sustained-release formulations of ambroxol hydrochloride mainly include sustained-release tablets and sustained-release capsules. The release rate of these three commercially available sustained-release capsules (A, B, and C) was determined using the same method as a reference. The experimental results are shown below. Figure 5 And Table 2. Among them, Figure 5 In the text, A represents sustained-release capsule A, B represents sustained-release capsule B, C represents sustained-release capsule C, and Homemade preparation represents sustained-release powder 1 prepared in Example 2.

[0059] Table 2. Release rates of ambroxol hydrochloride sustained-release powder at different time points

[0060] According to Table 2 and Figure 5The measurement results showed that the early release (before 2 hours) of the sustained-release powder 1 prepared in Example 2 was consistent with the early release of sustained-release capsule A, while the mid-to-late release of sustained-release powder 1 was more similar to that of sustained-release capsule C. f 2. Similarity factor calculation: The in vitro release of sustained-release powder 1 prepared in Example 2 is quite consistent with that of sustained-release capsule C. f The value of 2 is 62.35, which shows a more significant sustained-release effect compared to sustained-release capsules A and B, indicating that the sustained-release powder prepared by the preparation method provided by this invention has a better sustained-release effect.

[0061] (2) Stability test of ambroxol hydrochloride sustained-release powder The sustained-release agent 1 prepared in Example 2 was subjected to high temperature, high humidity, light exposure, and long-term experiments. The results showed that at 40℃, 75% humidity, an illuminance of 5000 lx, and an ultraviolet radiation illuminance of 90 μw / cm², the reaction conditions were optimal. 2 Under the given conditions, the drug content, related substances, and dissolution did not change significantly, and the particle size, properties, and appearance uniformity all met the requirements for powders, indicating that the ambroxol hydrochloride sustained-release powder has good stability.

[0062] (3) Particle size determination Particle size and distribution are essential for formulations to meet the requirements of powders and achieve sustained-release performance. The particle size of sustained-release powder 1 was determined using laser diffraction (dry injection). For example... Figure 6 The particle size distribution results shown are as follows: Sustained-release powder 1 has a particle size distribution of D10 = 16.12 μm, D50 = 21.43 μm, D90 = 27.77 μm, and a Span of 0.543. These results indicate that sustained-release powder 1 exhibits high uniformity in particle size distribution, with consistent powder size. Both the particle size distribution range and uniformity meet the requirements for powders in the Chinese Pharmacopoeia, contributing to consistent distribution during use and preventing dosage deviations due to excessively large or small powder particles.

[0063] (4) Drug metabolism kinetics experiment in rats Pharmacokinetic studies can assess the bioavailability of a drug, that is, the extent and rate at which a drug is absorbed into the systemic circulation, and can verify whether sustained-release or controlled-release formulations can maintain a stable blood drug concentration.

[0064] The pharmacokinetic experiment included an experimental group (ambroxol hydrochloride sustained-release powder) and a control group (ambroxol hydrochloride granules, Tianjin Meihua Biomedical Technology Co., Ltd., 15 mg / bag), with 6 SD rats in each group.

[0065] Experimental group treatment: At hour 0, each SD rat was orally administered ambroxol hydrochloride sustained-release powder at a dose of 7.875 mg / kg (drug / rat body weight). Blood samples were collected from the orbital cavity at 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 8 h, 12 h, and 24 h post-administration. Blood drug concentrations were measured at each time point. Results are shown below. Figure 7 .

[0066] Control group treatment: At hour 0, each SD rat was orally administered ambroxol hydrochloride granules at a dose of 7.875 mg / kg (drug / rat body weight). Blood samples were collected from the orbital cavity at 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 8 h, 12 h, and 24 h post-administration. Blood drug concentrations were measured at each time point. Results are shown below. Figure 7 .

[0067] The results showed that, compared with ambroxol hydrochloride granules, the sustained-release powder 1 prepared in Example 2 had a significant sustained-release effect, and the drug could still be detected in blood samples after 24 hours, maintaining a relatively stable blood drug concentration. In contrast, the main component of ambroxol hydrochloride granules was almost undetectable after 12 hours.

[0068] Example 3 S1. Preparation of drug-loaded mesoporous silica 2 g of ambroxol hydrochloride was dissolved in 100 ml of water, and 2 g of mesoporous silica Syloid® 244FP was suspended in the solution and stirred for 6 h. The drug-loaded particles were separated by decantation, and the free drug was removed with a solvent. The mixture was then dried at 50 °C to obtain drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica prepared in this step is shown below. Figure 1b resemblance.

[0069] S2, Coating of sustained-release materials 6 g of ethyl cellulose was dissolved in ethanol at 60 °C, and 1 g of drug-loaded mesoporous silica from step S1 was added. After stirring for 30 min, the solvent ethanol was removed by rotary evaporation. After aging at 50 °C for 12 h, the mixture was pulverized and passed through an 80-mesh sieve to obtain a framework powder containing drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica framework powder obtained in this step is shown below. Figure 2a and Figure 2b resemblance.

[0070] S3, embedding of wax materials 5 g of waxy material (stearyl alcohol containing 2.6% stearic acid) was melted at 70°C. While stirring, 2.5 g of the skeleton powder prepared in step S2 was added. After stirring for 30 min to mix evenly, the mixture was quickly poured into a cooled iron plate and refrigerated for 3 h to solidify. The mixture was then pulverized through a 120-mesh sieve to obtain a pre-prepared ambroxol hydrochloride sustained-release dispersant. The SEM characterization image of the pre-prepared ambroxol hydrochloride sustained-release dispersant obtained in this step is shown below. Figure 3 resemblance.

[0071] S4, tasteful Take the pre-prepared ambroxol hydrochloride sustained-release powder from step S3, add sucralose, xylitol, and strawberry flavoring for flavoring, and mix well to obtain the ambroxol hydrochloride sustained-release powder. Wherein, sucralose is 0.2% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder, xylitol is 4% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder, and strawberry flavoring is 0.1% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder. The ambroxol hydrochloride sustained-release powder prepared in Example 3 is defined as sustained-release powder 2.

[0072] The performance of sustained-release powder 2 was tested using the same method as that used for sustained-release powder 1. In the in vitro experiment of sustained-release powder 2, the drug release of sustained-release powder 2 was 98.2% within 24 hours; the performance of sustained-release powder 2 was stable in high temperature, high humidity, light exposure and long-term experiments, and the particle size, properties and appearance uniformity all met the requirements of powder.

[0073] The particle size of the sustained-release powder 2 was measured to be D10=14.72 μm, D50=21.92 μm, D90=28.26 μm, and Span=0.616.

[0074] Example 4 S1. Preparation of drug-loaded mesoporous silica 2 g of ambroxol hydrochloride was dissolved in 100 ml of water, and 2 g of mesoporous silica Syloid® 244FP was suspended in the solution and stirred for 6 h. The drug-loaded particles were separated by decantation, and the free drug was removed with a solvent. The mixture was then dried at 50 °C to obtain drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica prepared in this step is shown below. Figure 1b resemblance.

[0075] S2, Coating of sustained-release materials 6 g of Eudragit RS was dissolved in ethanol at 40 °C, and 1 g of the drug-loaded mesoporous silica from step S1 was added. After stirring for 30 min, the solvent ethanol was removed by rotary evaporation. After aging at 50 °C for 12 h, the mixture was pulverized and passed through an 80-mesh sieve to obtain a framework powder containing drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica framework powder obtained in this step is shown below. Figure 2a and Figure 2b resemblance.

[0076] S3, embedding of wax materials 6.3 g of waxy material (stearyl alcohol containing 2.6% stearic acid) was melted at 70°C. While stirring, 2.5 g of the skeleton powder prepared in step S2 was added. After stirring for 30 min to mix evenly, the mixture was quickly poured into a cooled iron plate and refrigerated for 3 h to solidify. The mixture was then pulverized and passed through a 120-mesh sieve to obtain a pre-prepared ambroxol hydrochloride sustained-release dispersant. The SEM characterization image of the pre-prepared ambroxol hydrochloride sustained-release dispersant obtained in this step is shown below. Figure 3 resemblance.

[0077] S4, tasteful Take the pre-prepared ambroxol hydrochloride sustained-release powder from step S3, add sucralose, erythritol, and peppermint flavoring, and mix well to obtain the ambroxol hydrochloride sustained-release powder. The sucralose is 0.3% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder, the erythritol is 5% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder, and the peppermint flavoring is 0.1% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder. The ambroxol hydrochloride sustained-release powder prepared in Example 4 is defined as sustained-release powder 3.

[0078] The performance of sustained-release powder 3 was tested using the same method as that used for sustained-release powder 1. In the in vitro experiment of sustained-release powder 3, the drug release of sustained-release powder 3 was 97.6% within 24 hours; the performance of sustained-release powder 3 was stable in high temperature, high humidity, light exposure and long-term experiments, and the particle size, properties and appearance uniformity all met the requirements of powder.

[0079] The particle size measurements of the sustained-release powder were D10=16.36 μm, D50=21.41 μm, D90=27.65 μm, and Span=0.630.

[0080] Example 5 S1. Preparation of drug-loaded mesoporous silica 5 g of ambroxol hydrochloride was dissolved in 250 ml of 20% ethanol, and 5 g of mesoporous silica Syloid® 244FP was suspended in the solution and stirred for 6 h. The drug-loaded particles were separated by decantation, and the free drug was removed with a solvent. The mixture was then dried at 40 °C to obtain drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica prepared in this step is shown below. Figure 1b resemblance.

[0081] S2, Coating of sustained-release materials 12 g of ethyl cellulose was dissolved in ethanol at 40 °C, and 2 g of drug-loaded mesoporous silica from step S1 was added. After stirring for 30 min, the solvent ethanol was removed by rotary evaporation. After aging at 50 °C for 12 h, the mixture was pulverized and passed through an 80-mesh sieve to obtain a framework powder containing drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica framework powder obtained in this step is shown below. Figure 2a and Figure 2b resemblance.

[0082] S3, embedding of wax materials 6.3 g of waxy material (carnauba wax containing 4% stearyl alcohol) was melted at 90℃. While stirring, 2.5 g of the skeleton powder prepared in step S2 was added. After stirring for 30 min to mix evenly, the mixture was quickly poured into a cooled iron plate and refrigerated for 6 h to solidify. The mixture was then pulverized through a 120-mesh sieve to obtain a pre-prepared ambroxol hydrochloride sustained-release dispersant. The SEM characterization image of the pre-prepared ambroxol hydrochloride sustained-release dispersant obtained in this step is shown below. Figure 3 resemblance.

[0083] S4, tasteful Take the pre-prepared ambroxol hydrochloride sustained-release dispersant from step S3, add sucralose, xylitol, and strawberry flavoring for flavoring, and mix well to obtain the ambroxol hydrochloride sustained-release dispersant. Wherein, sucralose is 0.3% of the mass of the pre-prepared ambroxol hydrochloride sustained-release dispersant, xylitol is 3% of the mass of the pre-prepared ambroxol hydrochloride sustained-release dispersant, and strawberry flavoring is 0.2% of the mass of the pre-prepared ambroxol hydrochloride sustained-release dispersant. The ambroxol hydrochloride sustained-release dispersant prepared in Example 5 is defined as sustained-release dispersant 4.

[0084] The performance of sustained-release powder 4 was tested using the same method as that used for sustained-release powder 1. In the in vitro experiment of sustained-release powder 4, the drug release of sustained-release powder 4 was 99.3% within 24 hours; the performance of sustained-release powder 4 was stable in high temperature, high humidity, light exposure and long-term experiments, and the particle size, properties and appearance uniformity all met the requirements of powder.

[0085] The particle size measurements of the sustained-release powder 4 were D10=14.29 μm, D50=21.53 μm, D90=27.75 μm, and Span=0.577.

[0086] Example 6 S1. Preparation of drug-loaded mesoporous silica 5 g of ambroxol hydrochloride was dissolved in 250 mL of water, and 4 g of mesoporous silica Syloid® 244FP was suspended in the solution. The mixture was stirred for 5 h. The drug-loaded particles were separated by decantation, and the free drug was removed with a solvent. The product was then dried at 40 °C to obtain drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica prepared in this step is shown below. Figure 1b resemblance.

[0087] S2, Coating of sustained-release materials 11 g of Eudragit RL was dissolved in acetone at 45°C, and 2 g of the drug-loaded mesoporous silica from step S1 was added. After stirring for 35 min, the solvent acetone was removed by rotary evaporation. After aging at 50°C for 12 h, the mixture was pulverized and passed through an 80-mesh sieve to obtain a framework powder containing drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica framework powder obtained in this step is shown below. Figure 2a and Figure 2b resemblance.

[0088] S3, embedding of wax materials 7.5 g of waxy material (carnauba wax containing 4% stearyl alcohol) was melted at 90℃. While stirring, 2.5 g of the skeleton powder prepared in step S2 was added. After stirring for 35 min to mix evenly, the mixture was quickly poured into a cooled iron plate and refrigerated for 5 h to solidify. The mixture was then pulverized through a 120-mesh sieve to obtain a pre-prepared ambroxol hydrochloride sustained-release dispersant. The SEM characterization image of the pre-prepared ambroxol hydrochloride sustained-release dispersant obtained in this step is shown below. Figure 3 resemblance.

[0089] S4, tasteful Take the pre-prepared ambroxol hydrochloride sustained-release powder from step S3, add sucralose, and obtain ambroxol hydrochloride sustained-release powder. Sucralose is 0.3% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder. Define the ambroxol hydrochloride sustained-release powder prepared in Example 6 as sustained-release powder 5.

[0090] The performance of sustained-release powder 5 was tested using the same method as that used for sustained-release powder 1. In in vitro experiments, the drug release of sustained-release powder 5 was 97.2% within 24 hours; its performance was stable under high temperature, high humidity, light, and long-term testing, and its particle size, properties, and appearance uniformity all met the requirements for powders.

[0091] The particle size measurements of the sustained-release powder 5 were D10=15.92 μm, D50=21.07 μm, D90=29.94 μm, and Span=0.717.

[0092] Example 7 S1. Preparation of drug-loaded mesoporous silica 5 g of ambroxol hydrochloride was dissolved in 250 ml of 20% ethanol, and 6 g of mesoporous silica Syloid® 244FP was suspended in the solution. The mixture was stirred for 6 h. The drug-loaded particles were separated by decantation, and the free drug was removed with a solvent. The mixture was then dried at 40 °C to obtain drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica prepared in this step is shown below. Figure 1b resemblance.

[0093] S2, Coating of sustained-release materials 11.6 g of ethyl cellulose was dissolved in ethanol at 55°C, and 2 g of drug-loaded mesoporous silica from step S1 was added. After stirring for 25 min, the solvent ethanol was removed by rotary evaporation. After aging at 50°C for 12 h, the mixture was pulverized and passed through an 80-mesh sieve to obtain a framework powder containing drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica framework powder obtained in this step is shown below. Figure 2a and Figure 2b resemblance.

[0094] S3, embedding of wax materials 5 g of waxy material (carnauba wax containing 4% stearyl alcohol) was melted at 90℃. While stirring, 2.5 g of the skeleton powder prepared in step S2 was added. After stirring for 30 min to mix evenly, the mixture was quickly poured into a cooled iron plate and refrigerated for 4.5 h to solidify. The mixture was then pulverized through a 120-mesh sieve to obtain a pre-prepared ambroxol hydrochloride sustained-release dispersant. The SEM characterization image of the pre-prepared ambroxol hydrochloride sustained-release dispersant obtained in this step is shown below. Figure 3 resemblance.

[0095] S4, tasteful Take the pre-prepared ambroxol hydrochloride sustained-release powder from step S3, add xylitol, erythritol, and orange flavoring for flavoring, and mix well to obtain the ambroxol hydrochloride sustained-release powder. Xylitol accounts for 0.8% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder, erythritol accounts for 1.5% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder, and orange flavoring accounts for 0.2% of the mass of the pre-prepared ambroxol hydrochloride sustained-release powder. The ambroxol hydrochloride sustained-release powder prepared in Example 7 is defined as sustained-release powder 6.

[0096] The performance of sustained-release powder 6 was tested using the same method as that used for sustained-release powder 1: In in vitro experiments, the drug release of sustained-release powder 6 was 98.6% within 24 hours. The performance of sustained-release powder 6 was stable under high temperature, high humidity, light exposure, and long-term experiments, and the particle size, properties, and appearance uniformity all met the requirements for powders.

[0097] The particle size measurements of the sustained-release powder 6 were D10=15.16 μm, D50=20.84 μm, D90=27.27 μm, and Span=0.634.

[0098] Example 8 S1. Preparation of drug-loaded mesoporous silica 2 g of ambroxol hydrochloride was dissolved in 100 ml of 20% ethanol, and 1.8 g of mesoporous silica Syloid® 244FP was suspended in the solution and stirred for 6 h. The drug-loaded particles were separated by decantation, and the free drug was removed with a solvent. The mixture was then dried at 40 °C to obtain drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica prepared in this step is shown below. Figure 1b resemblance.

[0099] S2, Coating of sustained-release materials 6 g of Eudragit RS was dissolved in acetone at 40°C, and 1 g of the drug-loaded mesoporous silica from step S1 was added. After stirring for 25 min, the solvent acetone was removed by rotary evaporation. After aging at 50°C for 12 h, the mixture was pulverized and passed through an 80-mesh sieve to obtain a framework powder containing drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica framework powder obtained in this step is shown below. Figure 2a and Figure 2b resemblance.

[0100] S3, embedding of wax materials 7.5 g of waxy material (stearyl alcohol containing 2.6% stearic acid) was melted at 70°C. While stirring, 2.5 g of the skeleton powder prepared in step S2 was added. After stirring for 25 min to mix evenly, the mixture was quickly poured into a cooled iron plate and refrigerated for 4 h to solidify. The mixture was then pulverized and passed through a 120-mesh sieve to obtain a pre-prepared ambroxol hydrochloride sustained-release dispersant. The SEM characterization image of the pre-prepared ambroxol hydrochloride sustained-release dispersant obtained in this step is shown below. Figure 3 resemblance.

[0101] S4, tasteful Take the pre-prepared ambroxol hydrochloride sustained-release dispersant from step S3, add sucralose and xylitol for flavoring, and mix well to obtain the ambroxol hydrochloride sustained-release dispersant. The sucralose is 0.3% of the mass of the pre-prepared ambroxol hydrochloride sustained-release dispersant, and the xylitol is 0.7% of the mass of the pre-prepared ambroxol hydrochloride sustained-release dispersant. The ambroxol hydrochloride sustained-release dispersant prepared in Example 8 is defined as sustained-release dispersant 7.

[0102] The performance of sustained-release powder 7 was tested using the same method as that used for sustained-release powder 1: In in vitro experiments, the drug release of sustained-release powder 7 was 98.9% within 24 hours. The performance of sustained-release powder 7 was stable under high temperature, high humidity, light, and long-term experiments, and the particle size, properties, and appearance uniformity all met the requirements for powders.

[0103] The particle size of the sustained-release powder 7 was measured to be D10=16.34 μm, D50=21.87 μm, D90=28.18 μm, and Span=0.530.

[0104] Example 9 S1. Preparation of drug-loaded mesoporous silica 2 g of ambroxol hydrochloride was dissolved in 250 ml of water, and 3 g of mesoporous silica Syloid® 244FP was suspended in the solution. The mixture was stirred for 6 h. The drug-loaded particles were separated by decantation, and the free drug was removed with a solvent. The product was then dried at 40 °C to obtain drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica prepared in this step is shown below. Figure 1b resemblance.

[0105] S2, Coating of sustained-release materials 5.6 g of ethyl cellulose was dissolved in ethanol at 40 °C, and 1 g of drug-loaded mesoporous silica from step S1 was added. After stirring for 35 min, the solvent ethanol was removed by rotary evaporation. After aging at 50 °C for 12 h, the mixture was pulverized and passed through an 80-mesh sieve to obtain a framework powder containing drug-loaded mesoporous silica. The SEM characterization image of the drug-loaded mesoporous silica framework powder obtained in this step is shown below. Figure 2a and Figure 2b resemblance.

[0106] S3, embedding of wax materials 6.3 g of waxy material (stearyl alcohol containing 2.6% stearic acid) was melted at 70°C. While stirring, 2.5 g of the skeleton powder prepared in step S2 was added. After stirring for 30 min to mix evenly, the mixture was quickly poured into a cooled iron plate and refrigerated for 5 h to solidify. The mixture was then pulverized and passed through a 120-mesh sieve to obtain a pre-prepared ambroxol hydrochloride sustained-release dispersant. The SEM characterization image of the pre-prepared ambroxol hydrochloride sustained-release dispersant obtained in this step is shown below. Figure 3 Figure 1b Figure 2a Figure 2b Figure 3 resemblance.

[0107] S4, tasteful Take the pre-prepared ambroxol hydrochloride sustained-release dispersant from step S3, add sucralose, xylitol, erythritol, and strawberry flavoring for flavoring, and mix well to obtain the ambroxol hydrochloride sustained-release dispersant. Wherein, sucralose is 0.3% of the mass of the pre-prepared ambroxol hydrochloride sustained-release dispersant, xylitol is 4% of the mass of the pre-prepared ambroxol hydrochloride sustained-release dispersant, erythritol is 1% of the mass of the pre-prepared ambroxol hydrochloride sustained-release dispersant, and strawberry flavoring is 0.2% of the mass of the pre-prepared ambroxol hydrochloride sustained-release dispersant. The ambroxol hydrochloride sustained-release dispersant prepared in Example 9 is defined as sustained-release dispersant 8.

[0108] The performance of sustained-release powder 8 was tested using the same method as that used for sustained-release powder 1: In in vitro experiments, the drug release of sustained-release powder 8 was 99.2% within 24 hours. In high temperature, high humidity, light exposure, and long-term experiments, the performance of sustained-release powder 8 was stable, and the particle size, properties, and appearance uniformity all met the requirements for powders.

[0109] The particle size measurements of the sustained-release powder were D10=16.30 μm, D50=21.55 μm, D90=28.04 μm, and Span=0.660.

[0110] Comparative Example 1 Compared with Example 2, the difference lies in step S1, where the mass of ambroxol hydrochloride is 5 g and the mass of mesoporous silica Syloid® 244FP is 12.5 g. The other steps are the same as in Example 2. The ambroxol hydrochloride sustained-release powder prepared in Comparative Example 1 is designated as sustained-release powder 01.

[0111] The in vitro release rate of sustained-release powder 01 was tested using the same method as that used for sustained-release powder 1. The results are shown in Table 3. Sustained-release powder 01 was almost completely released within 6 hours, but 61.2% was released within 1 hour, indicating that the release was too rapid in the early stage.

[0112] Comparative Example 2 Compared with Example 2, the difference lies in step S1, where the mass of ambroxol hydrochloride is 5 g and the mass of mesoporous silica Syloid® 244FP is 2.5 g. The other steps are the same as in Example 2. The ambroxol hydrochloride sustained-release powder prepared in Comparative Example 2 is designated as sustained-release powder O2.

[0113] The in vitro release rate of sustained-release powder 02 was tested using the same method as that used for sustained-release powder 1. The results are shown in Table 3. The release rate of sustained-release powder 02 was 22.1% at 1 h and 75.4% at 24 h, indicating incomplete release.

[0114] Comparative Example 3 Compared with Example 2, the difference lies in step S2, where the mass of the drug-loaded mesoporous silica is 1 g and the mass of ethyl cellulose is 4 g. The other steps are the same as in Example 2. The ambroxol hydrochloride sustained-release powder prepared in Comparative Example 3 is designated as sustained-release powder 03.

[0115] The in vitro release rate of sustained-release powder 03 was tested using the same method as that used for sustained-release powder 1. The results are shown in Table 3. The 1-hour release rate of sustained-release powder 03 was 54.5%, indicating a burst release phenomenon.

[0116] Comparative Example 4 Compared with Example 2, the difference lies in step S2, where the mass of the drug-loaded mesoporous silica is 1 g and the mass of ethyl cellulose is 8 g. The other steps are the same as in Example 2. The ambroxol hydrochloride sustained-release powder prepared in Comparative Example 4 is designated as sustained-release powder O4.

[0117] The in vitro release rate of sustained-release powder 04 was tested using the same method as that used for sustained-release powder 1. The results are shown in Table 3. The 1-hour release of sustained-release powder 04 was 30.2%, but the 24-hour release was 90.2%, indicating that the drug was not completely released.

[0118] Comparative Example 5 Compared with Example 2, the difference lies in step S3, where the mass of the skeleton powder is 2.5 g and the mass of the wax material is 2.5 g. The other steps are the same as in Example 2. The ambroxol hydrochloride sustained-release powder prepared in Comparative Example 5 is designated as sustained-release powder 05.

[0119] The in vitro release rate of sustained-release powder 05 was tested using the same method as that used for sustained-release powder 1. The results are shown in Table 3. The 1-hour release rate of sustained-release powder 05 was 78.8%, indicating a significant burst release effect.

[0120] Comparative Example 6 Compared with Example 2, the difference lies in step S3, where the mass of the skeleton powder is 2.5 g and the mass of the wax material is 10 g. The other steps are the same as in Example 2. The ambroxol hydrochloride sustained-release powder prepared in Comparative Example 6 is designated as sustained-release powder 06.

[0121] Using the same method as for the performance testing of sustained-release powder 1, the in vitro release rate of sustained-release powder 05 is shown in Table 3. The 1-hour release rate of sustained-release powder 06 is 31.8%, and the 24-hour release rate is 97.9%, which is similar to the release rate of sustained-release powder 1.

[0122] Table 3. In vitro release test results of the sustained-release powders prepared in the comparative examples

[0123] Example Result Analysis: Example 1 shows that mesoporous silica, as a drug loading medium for ambroxol hydrochloride, has superior drug loading capacity.

[0124] Performance tests of sustained-release powders 1 to 8 prepared in Examples 2 to 9 show that, within the parameter range disclosed in the preparation method provided by this invention, powders with good drug release rate, stable performance, highly concentrated particle size distribution, and good particle uniformity can be obtained.

[0125] Compared with Example 1, Comparative Example 1 used an excess of mesoporous silica. The in vitro release results showed that as the amount of mesoporous silica increased, the release rate of ambroxol hydrochloride increased. Excess mesoporous silica was not conducive to achieving a sustained release effect. This is because mesoporous materials have the characteristics of high specific surface area and high porosity. Their structure allows the solvent to penetrate rapidly, resulting in an increased rate of drug dissolution and diffusion, especially in the early stage of release, which manifests as a burst release phenomenon.

[0126] Compared with Example 1, Comparative Example 2 used a smaller amount of mesoporous silica. The in vitro release results showed that too little mesoporous silica was not conducive to the later release, resulting in incomplete release. This was related to the reduction in the comparison area caused by the reduction in the amount of mesoporous silica.

[0127] Compared with Example 1, Comparative Example 3 used a smaller amount of sustained-release material. The in vitro release results showed that the smaller amount of sustained-release material was insufficient to completely encapsulate the drug to form a continuous and dense sustained-release framework, resulting in an unsatisfactory sustained-release effect.

[0128] Compared with Example 1, Comparative Example 4 used an excessive amount of sustained-release material. The in vitro release results showed that when there was too much sustained-release material, the path of drug diffusion from the inside of the pores to the outside was prolonged. For drugs that were already deeply encapsulated, the diffusion time would be too long, or even completely blocked, resulting in incomplete drug release.

[0129] Compared with Example 1, Comparative Example 5 used a smaller amount of wax material. The in vitro release results showed that it could not play a significant blocking effect because the small amount of wax material could not completely cover the defects of the sustained-release material coating layer.

[0130] Compared with Example 1, Comparative Example 6 used an excessive amount of wax material. The in vitro release results showed that the excessive wax had little effect on the sustained-release effect, but the excessive wax would increase the corresponding raw material cost.

[0131] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. It should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered within the scope of protection of the present invention.

Claims

1. A method for preparing an ambroxol hydrochloride sustained-release powder, characterized in that, Includes the following steps: S1. Add mesoporous silica to ambroxol hydrochloride solution, stir for 5-6 hours and then dry to obtain drug-loaded mesoporous silica; wherein the mass ratio of ambroxol hydrochloride to mesoporous silica is 1:(0.8-1.5). S2. The drug-loaded mesoporous silica and the sustained-release material are mixed at a mass ratio of 1: (5.5~7), dissolved in the first solvent, and then coated. After coating, the solvent is removed and the mixture is pulverized to obtain a skeleton powder containing drug-loaded mesoporous silica. S3. The drug-loaded mesoporous silica framework powder is added to the wax material in a molten state, and the wax material is kept in a molten state for encapsulation. After encapsulation, it is cooled and solidified and then pulverized to obtain a pre-made ambroxol hydrochloride sustained-release powder. The mass ratio of the drug-loaded mesoporous silica framework powder to the wax material is 1:(2-3); S4. Mix the pre-prepared ambroxol hydrochloride sustained-release powder with a flavoring agent to obtain ambroxol hydrochloride sustained-release powder.

2. The method for preparing the ambroxol hydrochloride sustained-release powder according to claim 1, characterized in that, In step S1, the mass ratio of ambroxol hydrochloride to mesoporous silica is 1:1; In step S2, the drug-loaded mesoporous silica and the sustained-release material are in a mass ratio of 1:6; In step S3, the mass ratio of the drug-loaded mesoporous silica framework powder to the wax material is 1:2.

5.

3. The method for preparing the ambroxol hydrochloride sustained-release powder according to claim 1, characterized in that, In step S1, the pore size of the mesoporous silicon is 2 to 5 nm.

4. The method for preparing the ambroxol hydrochloride sustained-release powder according to claim 1, characterized in that, In step S2, the first solvent is ethanol or acetone; the coating conditions are stirring at 40–60°C for 25–35 min; and the particle size of the drug-loaded mesoporous silica framework powder is less than 180 μm.

5. The method for preparing the ambroxol hydrochloride sustained-release powder according to claim 1, characterized in that, In step S3, the embedding conditions are as follows: the embedding is carried out within the melting temperature range of the wax material, and the stirring time is 25-35 min; the cooling and solidification time is 3-6 h; and the particle size of the pre-prepared ambroxol hydrochloride sustained-release agent is less than 125 μm.

6. The method for preparing the ambroxol hydrochloride sustained-release powder according to claim 1, characterized in that, The method for preparing the ambroxol hydrochloride solution is to dissolve ambroxol hydrochloride in a second solvent; The second solvent is water, or a mixed solution of water and ethanol in a volume ratio of 8:

2.

7. The method for preparing the ambroxol hydrochloride sustained-release powder according to claim 1, characterized in that, In step S4, the mass ratio of the pre-prepared ambroxol hydrochloride sustained-release powder to the flavoring agent is 100:(0.3-5.5).

8. The method for preparing the ambroxol hydrochloride sustained-release powder according to claim 1, characterized in that, In step S1, the mesoporous silicon is Syloid®244FP; In step S2, the sustained-release material is one or more of ethyl cellulose, Eudragit RL, and Eudragit RS; In step S3, the wax material is a combination of at least two of stearic acid, stearyl alcohol, and carnauba wax; In step S4, the flavoring agent is selected from one or more of sucralose, xylitol, erythritol, strawberry flavor, orange flavor, and peppermint flavor.

9. The method for preparing the ambroxol hydrochloride sustained-release powder according to claim 1, characterized in that, The waxy material is a composition of stearic acid and stearyl alcohol, wherein the mass ratio of stearic acid to stearyl alcohol is 2.6:100; Alternatively, the wax material may be a combination of stearyl alcohol and carnauba wax, wherein the mass ratio of stearyl alcohol to carnauba wax is 4:

100.

10. A sustained-release powder of ambroxol hydrochloride, characterized in that, The ambroxol hydrochloride sustained-release powder is obtained by the preparation method provided in any one of claims 1-9.

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