Bromhexine hydrochloride sustained-release micro-tablet and preparation process thereof

Abstract

The invention discloses bromhexine hydrochloride sustained-release micro-tablets and a preparation process thereof. The bromhexine hydrochloride sustained-release micro-tablets are prepared from the following raw materials through direct powder compression: 5-20 parts of bromhexine hydrochloride, 15-35 parts of hydroxypropyl methylcellulose, 5-15 parts of carbomer, 5-15 parts of ethyl cellulose, 10-40 parts of microcrystalline cellulose, 2-8 parts of povidone and 0.5-5 parts of a lubricant. The preparation method comprises the following steps: sieving and mixing the raw materials except the lubricant for 20-40 minutes, adding the lubricant, continuously mixing for 3-8 minutes, and pressing into micro-tablets with the diameter of 2-4mm. Wherein the povidone is added in the form of dry powder, is used as a dry powder adhesive, and forms a composite sustained-release skeleton together with the hydroxypropyl methylcellulose, the carbomer and the ethyl cellulose to cooperatively control drug release. Through the synergistic effect of the ternary composite skeleton and the dry povidone powder, 24-hour stable release of bromhexine hydrochloride is realized, and the release behavior is not influenced by pH; the process avoids the influence of damp and hot factors on the drug stability; the dosage form of the micro-tablet obviously improves the medication compliance of children, old people and patients with dysphagia.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a bromhexine hydrochloride sustained-release microtablet, its preparation method, and its application. Background Technology

[0002] Bromhexine hydrochloride is a commonly used expectorant that acts directly on bronchial glands, stimulating the release of lysosomes from mucosecreting cells and causing the differentiation and breakdown of mucopolysaccharide fibers in sputum. It also inhibits the synthesis of acidic glycoproteins in mucosa glands and goblet cells, thereby reducing sputum viscosity and making it easier to cough up. Clinically, it is widely used to treat thick sputum and difficulty in expectoration caused by acute and chronic bronchitis, asthma, and bronchiectasis.

[0003] Currently, the most common oral dosage forms of bromhexine hydrochloride are regular tablets or dispersible tablets. However, regular tablets require multiple daily doses, resulting in significant fluctuations in blood drug concentration and a tendency for peak-and-trough phenomena. While dispersible tablets address the difficulty in swallowing, their immediate-release nature may cause a temporary increase in blood drug concentration, potentially leading to gastrointestinal discomfort in some patients, and they do not provide a long-lasting effect. Therefore, developing a sustained-release formulation of bromhexine hydrochloride that can reduce the frequency of dosing, maintain stable blood drug concentrations, and is convenient for patients with swallowing difficulties (such as children and the elderly) is of significant clinical importance.

[0004] There are existing reports on bromhexine hydrochloride tablets and their preparation methods.

[0005] Prior art 1 (CN111358758A) discloses a bromhexine hydrochloride dispersible tablet and its preparation method. This dispersible tablet aims for rapid disintegration and dissolution, and its formulation includes bromhexine hydrochloride, microcrystalline cellulose, crospovidone (disintegrant), flavoring agent, and stabilizer. It is tableted using a wet granulation process. This technology solves the tablet stability problem by removing pH adjusters and optimizing fillers and disintegrants, achieving rapid disintegration and making it suitable for children and patients with swallowing difficulties. However, this technical solution aims for rapid release, falling into the category of immediate-release formulations, and cannot solve the problems of frequent dosing and large fluctuations in blood drug concentration associated with conventional tablets. Furthermore, the wet granulation process used may pose stability risks to heat- and moisture-sensitive active pharmaceutical ingredients, and the process is relatively complex.

[0006] Prior art 2 (CN110227067A) discloses a pramipexole hydrochloride sustained-release tablet and its preparation method. This sustained-release tablet uses a direct powder compression method, and its sustained-release matrix is ​​a combination of Eudragit RD (acrylic resin) and hydroxypropyl methylcellulose K100M, with the addition of binders, flow aids, and lubricants to achieve slow drug release and improved content uniformity. This technology improves powder flowability by optimizing the ratio of flow aids and lubricants and the combination of the sustained-release matrix, making in vitro release unaffected by pH changes. However, this technical solution targets the active ingredient pramipexole hydrochloride (used to treat Parkinson's disease), whose drug characteristics, therapeutic dosage, and sustained-release requirements are completely different from bromhexine hydrochloride. More importantly, the Eudragit RD used is a pH-dependent material, and its drug release behavior may differ under different pH conditions; furthermore, the disclosed sustained-release system is a binary combination, not involving a more complex ternary composite framework, nor does it disclose the application of povidone in dry powder form as an auxiliary sustained-release material.

[0007] In summary, existing technologies lack a bromhexine hydrochloride formulation that possesses stable sustained-release properties, allows for 1-2 daily dosings to maintain stable blood drug concentrations, and also ensures good compliance for patients with swallowing difficulties. In particular, designing a sustained-release microtablet that is simple to manufacture, suitable for direct powder compression, and capable of stable and controllable release through the synergistic effect of multiple components, based on the physicochemical properties of bromhexine hydrochloride, remains a pressing technical problem to be solved in this field. Summary of the Invention

[0008] To address the issues of limited dosage form, lack of microtablet formulations that balance sustained-release properties and ease of administration in existing bromhexine hydrochloride oral preparations, and the limited adaptability of existing sustained-release technologies and the difficulty in constructing stable composite matrixes tailored to the characteristics of bromhexine, this invention provides a bromhexine hydrochloride sustained-release microtablet with stable drug release, simple manufacturing process, and suitability for patients with dysphagia, along with its preparation method. This approach achieves stable 24-hour release of bromhexine hydrochloride by constructing a ternary composite sustained-release matrix composed of hydroxypropyl methylcellulose, carbomer, and ethylcellulose, combined with the dual function of adding povidone dry powder. Furthermore, the direct powder compression process effectively avoids the impact of damp heat on drug stability and simplifies the production process.

[0009] This invention includes the following technical solutions: A sustained-release microtablet of bromhexine hydrochloride is made from the following raw materials by a direct powder compression process: 5-20 parts of bromhexine hydrochloride 15-35 parts of hydroxypropyl methylcellulose Carbomer 5-15 servings 5-15 parts of ethyl cellulose 10-40 parts of microcrystalline cellulose 2-8 parts of povidone Lubricant 0.5-5 parts; This raw material combination constructs a ternary composite framework using hydroxypropyl methylcellulose, carbomer, and ethylcellulose to achieve a synergistic effect of multiple drug release mechanisms. Hydroxypropyl methylcellulose forms a hydrophilic gel layer, carbomer enhances gel strength and pH adaptability, ethylcellulose provides insoluble framework support, povidone in dry powder form has both binding and auxiliary sustained-release functions, and microcrystalline cellulose improves powder compressibility, together ensuring stable drug release over 24 hours.

[0010] The bromhexine hydrochloride sustained-release microtablets are prepared by a direct powder compression process including the following steps: (1) After passing bromhexine hydrochloride, hydroxypropyl methylcellulose, carbomer, ethylcellulose, microcrystalline cellulose and povidone through an 80-100 mesh sieve, put them into a mixer and mix for 20-40 minutes to obtain a premixed powder. Sieving can eliminate the agglomeration of raw materials and ensure that the powder particle size is uniform. The thorough mixing for 20-40 minutes ensures that the low dose of drug is evenly distributed in the viscous excipients (such as carbomer), laying the foundation for the subsequent content uniformity to meet the standard.

[0011] (2) Add lubricant to the premixed powder and continue mixing for 3-8 minutes to obtain the total mixed powder. If the lubricant mixing time is too short, it will result in uneven distribution and tablet sticking. If it is too long, it will over-coat the particles and affect the hardness of the tablet. 3-8 minutes can ensure that the lubricant is evenly covered without affecting the compressibility of the powder.

[0012] (3) A rotary tablet press is used, equipped with a die with a diameter of 2-4 mm, and the tableting pressure is controlled at 5-15 kN to directly press the total powder into micro tablets; the micro tablets with a diameter of 2-4 mm are small in size and easy for patients with difficulty swallowing to take; the pressure of 5-15 kN can ensure that the tablets obtain appropriate hardness (20-50 N), which not only meets the packaging and transportation requirements, but also does not damage the pore structure of the matrix material, and ensures the reproducibility of the release behavior.

[0013] The povidone is added in dry powder form as a dry powder binder; the hydroxypropyl methylcellulose, carbomer and ethylcellulose together constitute a composite sustained-release framework system, which synergistically controls the release rate of bromhexine hydrochloride.

[0014] The addition of povidone dry powder allows it to be evenly distributed inside the framework during direct powder compression. Upon contact with water, it rapidly hydrates and fills the pores of the framework, helping to form a dense gel network. This method is more effective in assisting sustained release than wet granulation. The ternary framework achieves synergistic controlled release through a triple mechanism of dissolution, gel barrier, and insoluble pores, overcoming the defect of easy burst release in the later stage of the binary framework.

[0015] Furthermore, in the aforementioned bromhexine hydrochloride sustained-release microtablets, the weight ratio of hydroxypropyl methylcellulose, carbomer, and ethyl cellulose is 3-6:1:1-2. This ratio range ensures that the hydrophilic gel material (HPMC) serves as the main framework, carbomer provides sufficient gel strength and pH adaptability, and ethyl cellulose acts as an insoluble framework support. The three components work synergistically to achieve stable release within 24 hours. A ratio that is too high or too low will result in release that is too fast or too slow.

[0016] Furthermore, in the aforementioned bromhexine hydrochloride sustained-release microtablets, the povidone is povidone K30. Povidone K30 has suitable molecular weight and adhesive properties, providing sufficient tablet hardness in the dry powder state while rapidly hydrating to fill the pores of the matrix, making it an ideal choice for combining adhesive and auxiliary sustained-release functions.

[0017] Furthermore, in the aforementioned bromhexine hydrochloride sustained-release microtablets, the lubricant is a mixture of magnesium stearate and micronized silica gel, wherein the weight ratio of magnesium stearate to micronized silica gel is 2:1 to 5:1. Magnesium stearate provides lubrication and reduces sticking, while micronized silica gel improves powder flowability and absorbs moisture. The combined use of the two can synergistically optimize the direct compression performance of the powder. This ratio range can balance the lubrication effect and tablet hardness, avoiding excessive lubricant that would lead to a decrease in tablet strength.

[0018] Furthermore, for the above-mentioned bromhexine hydrochloride sustained-release microtablets, the hardness of the microtablets mentioned in step (3) is controlled at 20-50N, and the tablet weight difference is less than ±5%. The hardness of 20-50N can ensure that the microtablets are not easily broken during packaging and transportation, and can disintegrate smoothly after oral administration; the tablet weight difference of less than ±5% meets the pharmacopoeia requirements, ensuring that the drug content of each tablet is uniform and the clinical dosage is accurate.

[0019] Furthermore, in the preparation process of the above-mentioned bromhexine hydrochloride sustained-release microtablets, in step (1), the mixing speed of the mixer is 15-25 rpm, and the mixing time is preferably 30 minutes. The medium speed of 15-25 rpm can avoid electrostatic adsorption and material stratification caused by high-speed mixing, and the 30-minute mixing time has been optimized and verified to ensure that each component (especially the low dose of bromhexine hydrochloride) is evenly distributed in the viscous excipients.

[0020] Furthermore, in the preparation process of the above-mentioned bromhexine hydrochloride sustained-release microtablets, in step (3), the tableting environment temperature is controlled at 20-25℃ and the relative humidity is controlled at 40%-50%. This temperature and humidity range can prevent excipients such as povidone from absorbing moisture and becoming sticky, avoid premature hydration of carbomer due to excessive humidity, ensure stable powder flowability and smooth tableting process, and at the same time prevent drug degradation.

[0021] The use of bromhexine hydrochloride sustained-release microtablets as described in any of the above technical solutions in the preparation of drugs for treating respiratory diseases requiring expectoration.

[0022] Furthermore, in the above application, the respiratory disease is chronic bronchitis, asthma, or bronchiectasis causing thick sputum or difficulty in coughing up sputum.

[0023] Furthermore, in the above applications, the microplate is administered orally, once or twice daily.

[0024] Compared with the prior art, the present invention has the following outstanding advantages: 1. Constructing a unique ternary composite sustained-release framework for stable drug release: This invention breaks through the common binary sustained-release systems in existing technologies, and for the first time combines hydroxypropyl methylcellulose (hydrophilic gel), carbomer (ionic gel), and ethyl cellulose (insoluble framework) to form a triple synergistic drug release mechanism of "dissolution-diffusion-pores". This ternary framework can effectively overcome the burst release or plateau effect that may occur in the later stages of drug release in single or binary sustained-release materials, enabling bromhexine hydrochloride to maintain a stable release within 24 hours with small fluctuations in blood drug concentration, achieving an effective therapeutic concentration maintained throughout the day with only 1-2 doses per day.

[0025] 2. Povidone dry powder addition provides dual functionality, optimizing the integrity of the matrix: This invention creatively adds povidone directly in dry powder form, allowing it to act as a binder during direct tableting, ensuring the micro-tablets have suitable hardness (20-50N). Simultaneously, upon contact with the dissolution medium, povidone rapidly hydrates, filling pores in the composite matrix formed by hydroxypropyl methylcellulose, carbomer, and ethyl cellulose, assisting in the formation of a denser and more stable gel barrier, thus playing a synergistic role as an "auxiliary sustained-release material." This method of dry powder addition and functional positioning is not disclosed in existing technologies, significantly different from traditional wet granulation or conventional dry bonding applications.

[0026] 3. The direct powder compression process simplifies the procedure and ensures drug stability: This invention abandons the commonly used wet granulation process (such as prior art 1) and adopts a direct powder compression method, avoiding the influence of moisture and drying temperature on the physicochemical properties of bromhexine hydrochloride and excipients, which is especially suitable for active pharmaceutical ingredients that may be sensitive to moisture and heat. At the same time, by optimizing the mixing time (20-40 minutes) and compression pressure (5-15 kN), the problems of poor mixing uniformity and poor compressibility that may exist in powder systems containing high molecular weight materials such as carbomer and ethyl cellulose during direct compression are effectively solved. The process is simple, efficient, and suitable for industrial production.

[0027] 4. Developing microtablets to improve patient compliance: This invention applies sustained-release technology to microtablets with a diameter of only 2-4 mm and a weight of only 10-30 mg. Their small size makes them easy to swallow, effectively addressing the difficulties faced by children, the elderly, and patients with swallowing difficulties in taking ordinary tablets or capsules. While achieving the advantages of sustained-release therapy, it also considers the medication needs of special populations, expanding the clinical application range of bromhexine hydrochloride.

[0028] 5. Comprehensive improvement of formulation performance and assurance of clinical efficacy: Testing showed that the bromhexine hydrochloride sustained-release microtablets prepared using the technical solution of this invention exhibited stable sustained-release characteristics in in vitro dissolution tests with minimal batch-to-batch variation; the content uniformity met pharmacopoeia requirements (A+2.2S≤15); and after being stored under accelerated testing conditions (40℃±2℃, 75%±5%RH) for 6 months, the key quality attributes showed no significant changes, demonstrating good stability. The successful development of this formulation provides a safe, effective, and convenient new option for expectorant treatment in clinical practice. Attached Figure Description

[0029] Figure 1 The in vitro release rate curves of Examples 1-3 and Comparative Examples 1, 3, 4, and 5 of the present invention are shown. Figure 2 The graph shows the content change trend of Examples 1-3 and Comparative Examples 2, 5 and 6 of the present invention in accelerated stability test (40℃±2℃, 75%±5%RH); Figure 3 This is a comparison chart of the release behavior of Example 1 (A) and Comparative Example 6 (B) in different pH media (pH 1.2, pH 4.5, pH 6.8 and water). Detailed Implementation

[0030] The technical solutions in the embodiments of the present invention will be clearly and completely described below. 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.

[0031] Example 1 This embodiment provides a bromhexine hydrochloride sustained-release microtablet, the formulation of which is shown in Table 1, and the preparation process is as follows: (1) Pass bromhexine hydrochloride, hydroxypropyl methylcellulose K15M, carbomer 971P NF, ethyl cellulose 20 mPa·s, microcrystalline cellulose PH102, and povidone K30 through an 80-mesh sieve respectively. (2) Put the sieved material into a three-dimensional mixer and mix for 30 minutes to obtain premixed powder; (3) Add magnesium stearate and micronized silica gel (magnesium stearate: micronized silica gel = 3:1) to the premixed powder and continue mixing for 5 minutes to obtain the total mixed powder; (4) A rotary tablet press is used, equipped with a 3mm diameter die, and the tableting pressure is controlled at 10kN. The total powder is directly pressed into micro tablets with a weight of 20mg and a hardness of 30-40N.

[0032] Example 2 The formulation of this embodiment is shown in Table 1. The process steps are the same as in Example 1. The difference is that K4M is used for hydroxypropyl methylcellulose, 934P is used for carbomer, 10 mPa·s is used for ethyl cellulose, and PH101 is used for microcrystalline cellulose. The proportions of each raw material are as shown in Table 1.

[0033] Example 3 The formulation of this embodiment is shown in Table 1. The process steps are the same as in Example 1. The difference is that K100M is used for hydroxypropyl methylcellulose, 971P NF is still used for carbomer, 20 mPa·s is used for ethyl cellulose, and pH102 is used for microcrystalline cellulose. The proportions of each raw material are as shown in Table 1.

[0034] Example 4 This embodiment provides a bromhexine hydrochloride sustained-release microtablet with the same formulation as in Example 1, but the mixing time in the preparation process is adjusted as follows: premix for 20 minutes in step (2) and total mix for 8 minutes in step (3); the tableting pressure is adjusted to 8kN, the microtablet diameter is 2.5mm, and the hardness is controlled at 25-35N.

[0035] Comparative Example 1 Referring to existing technology 1: dispersible tablet formulation + wet granulation.

[0036] According to the formula of Example 1 of existing technology 1 (CN111358758A) (500 parts of bromhexine hydrochloride, 75 parts of microcrystalline cellulose, 80 parts of crospovidone, 20 parts of stevioside, 60 parts of lactose monohydrate, 30 parts of pregelatinized starch, and 8 parts of magnesium stearate), ordinary tablets (8 mm in diameter and 200 mg in weight) were prepared using a wet granulation process. Preparation steps: Lactose monohydrate, bromhexine hydrochloride, microcrystalline cellulose, crospovidone, and pregelatinized starch were placed in a wet granulator and stirred evenly. An appropriate amount of water was added to form a soft mass. The mass was granulated through a 20-mesh sieve, dried at 50°C until the moisture content was ≤3%, granulated again through a 20-mesh sieve, and then magnesium stearate and stevioside were added and mixed evenly. The mixture was then compressed into tablets.

[0037] Comparative Example 2 Refer to existing technology 2: sustained-release tablet formulation, but with different active ingredients.

[0038] Referring to the sustained-release tablet formulation of Example 1 in prior art 2 (CN110227067A) (pramiplexoline hydrochloride 0.375mg, microcrystalline cellulose 102 88.383mg, anhydrous calcium hydrogen phosphate 58.00mg, Eudragit RD 45.25mg, HPMC K100M3 0.00mg, HPMC K4M 26.25mg, sodium stearate fumarate 1.00mg, magnesium stearate 0.75mg), the active ingredient was replaced with bromhexine hydrochloride in equal amounts (the amount was adjusted while maintaining the molar ratio), and sustained-release tablets (8mm in diameter) were prepared using a direct powder compression process. The preparation steps are as described in Comparative Document 2: Bromhexine hydrochloride is mixed with 30% microcrystalline cellulose and sodium stearate fumarate for 5 min; Eudragit RD and HPMC K100M are added and mixed for 5 min; HPMC K4M and the remaining microcrystalline cellulose are added and mixed for 10 min; anhydrous calcium hydrogen phosphate is added and mixed for 5 min; magnesium stearate is added and mixed for 3 min; tablets are then compressed.

[0039] Comparative Example 3 It lacks ethyl cellulose and has a binary skeleton.

[0040] The formulation is basically the same as in Example 1, but ethyl cellulose is removed, and the amount of microcrystalline cellulose is increased to 33 parts. The preparation process is the same as in Example 1.

[0041] Comparative Example 4 Lacking carbomer, binary skeleton.

[0042] The formulation is basically the same as in Example 1, but carbomer is removed, and the amount of hydroxypropyl methylcellulose is increased to 33 parts. The preparation process is the same as in Example 1.

[0043] Comparative Example 5 Povidone is added via a wet process.

[0044] The formula is the same as in Example 1, but the preparation process is changed to wet granulation: bromhexine hydrochloride, hydroxypropyl methylcellulose, carbomer, ethylcellulose and microcrystalline cellulose are mixed evenly, and an aqueous solution of povidone K30 (prepared to a concentration of 5%) is added to make a soft mass, which is granulated through a 20-mesh sieve, dried at 50°C, granulated, magnesium stearate and micronized silica gel are added and mixed, and pressed into micro flakes (3 mm in diameter).

[0045] Comparative Example 6 Eudragit RD was used instead of ethyl cellulose.

[0046] The formulation is basically the same as in Example 1, except that ethyl cellulose is replaced with an equal amount of Eudragit RD (acrylic resin), while the rest remains unchanged. The preparation process is the same as in Example 1.

[0047] Test Example 1 Content uniformity determination Test method: The content uniformity test was conducted according to the "Content Uniformity Test Method" in General Chapter 0941 of the 2020 edition of the Chinese Pharmacopoeia, Part IV. Ten tablets were randomly selected from each prescription, and the content of each tablet was measured. The average content, standard deviation S, and A+2.2S value were calculated. The standard stipulates that A+2.2S ≤ 15.0.

[0048] Test results: See Table 2.

[0049] Results Analysis: The A+2.2S values ​​of Examples 1-4 of this invention are all less than 6, far exceeding the pharmacopoeia limit, indicating that the formulation of this invention and the direct powder compression process have good mixing uniformity. Comparative Example 2, because it directly adopted the formulation of Comparative Document 2 (but with different active ingredients), had the worst content uniformity (12.5), close to the limit, indicating that this formulation is not suitable for bromhexine hydrochloride. Comparative Example 5, which used wet granulation, also had poor uniformity (9.2), indicating that drug migration may occur during wet granulation. The embodiments of this invention, through dry powder mixing, effectively ensured the uniform distribution of low-dose drugs in the composite matrix.

[0050] Test Example 2 Hardness testing Test method: Using a YD-20 tablet hardness tester, 10 tablets were randomly selected from each prescription, and the hardness was measured. The average value and RSD value were calculated.

[0051] Test results: See Table 3.

[0052] Results Analysis: The hardness of the tablets in Examples 1-4 of this invention was controlled within the target range of 20-50 N, indicating sufficient mechanical strength and suitability for swallowing. Comparative Examples 1 and 2 were conventionally sized tablets (8 mm in diameter) with higher hardness. Comparative Example 5, due to the use of wet granulation, exhibited altered particle compressibility and a slightly higher hardness than the examples. The results demonstrate that the direct powder compression process of this invention, combined with the selected excipients, can produce microtablet formulations with suitable hardness and minimal batch-to-batch variation.

[0053] Test Example 3 In vitro release assay Test method: According to the Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II (Paddle Method), 900 mL of pH 6.8 phosphate buffer was used as the release medium, at a temperature of 37±0.5℃ and a rotation speed of 50 rpm. 10 mL samples were taken at 2, 4, 6, 8, 12, and 24 hours, with an equal volume of fresh medium added at the same time. The samples were filtered through a 0.45 μm filter membrane, and the filtrate was used to determine the content by high-performance liquid chromatography (HPLC), and the cumulative release percentage was calculated.

[0054] Test results: See Table 4 and Figure 1 .

[0055] Results analysis: from Figure 1 As can be seen from the release curves shown, Examples 1-3 of the present invention exhibit a stable sustained-release characteristic within 24 hours, while Comparative Example 1 (dispersible tablets) releases more than 85% within 2 hours, which is a typical immediate-release behavior and does not meet the requirements of sustained-release formulations.

[0056] Ternary skeleton integrity verification: comparison Figure 1 The release curves of Comparative Example 3 (without ethyl cellulose) and Comparative Example 4 (without carbomer) show that their release rates are significantly faster than those of Example 1. In particular, Comparative Example 3 achieved 93.5% release within 12 hours, nearly complete release, indicating that the absence of ethyl cellulose led to structural collapse in the later stages of the ternary framework, making sustained release impossible. Comparative Example 4 also released relatively quickly, but slightly slower than Comparative Example 3, demonstrating that carbomer's reinforcing effect on the framework is indispensable. Examples 1-4 of this invention maintained stable release within 24 hours, proving that the synergistic effect of the ternary framework effectively maintained the integrity of the framework.

[0057] The effect of the method of adding povidone: Figure 1 The release curve of Comparative Example 5 (wet granulation) was significantly faster than that of Example 1, with 90.2% release achieved in 12 hours and almost complete release in 24 hours. This indicates that wet granulation alters the distribution of povidone within the matrix, transforming it from a "uniformly dispersed auxiliary matrix material" into a "binder concentrated within the particles," thus weakening its function of filling matrix pores and enhancing gel layer density in its dry powder state. The method of adding povidone dry powder in this invention plays a crucial role in achieving stable sustained release.

[0058] Compared with the formulation in Comparative Document 2: Comparative Example 2 (using the Eudragit formulation from Comparative Document 2) showed slightly faster release than Example 1, reaching 89.3% within 12 hours. More importantly, Eudragit RD is a pH-dependent material (see Comparative Document 2). Figure 2 (And test example 5), the release behavior may vary under different pH conditions. This invention uses ethyl cellulose, a pH-independent material, to ensure stable release throughout the entire gastrointestinal tract.

[0059] Effect of different viscosities of HPMC: Figure 1 Example 3 (HPMC K100M) showed the slowest release, while Example 2 (HPMC K4M) showed the fastest release, indicating that the release rate can be adjusted by selecting HPMCs of different viscosities to meet different clinical needs.

[0060] Test Example 4 Accelerated stability test Test method: Samples from Examples 1-4 and Comparative Examples 2, 5, and 6 were placed in aluminum-plastic packaging and placed under accelerated conditions (40℃±2℃, 75%±5%RH) for 6 months. Samples were taken at 0, 1, 2, 3, and 6 months to examine changes in appearance, content, release rate, and related substances.

[0061] Test results: See Tables 5 and 6. Figure 2 .

[0062] from Figure 2 The content change trends shown are quite intuitive. In Examples 1-4 of this invention, after being placed under accelerated conditions for 6 months, the content decrease was less than 1.5%, and the curves were flat, indicating good formulation stability. Comparative Example 5 (wet granulation) showed the most significant content decrease (-6.5%), with a steep drop in the curve, suggesting that moisture and temperature during wet granulation may have induced drug degradation, or that residual moisture accelerated the degradation reaction. Comparative Examples 2 and 6 also showed significant content decreases (-4.9% and -4.1%, respectively), which may be related to the Eudragit material used.

[0063] Related substances: The total impurities in the embodiments of this invention increased slowly, remaining below 0.3% after 6 months. Comparative Example 5 showed the fastest increase in total impurities, reaching 1.05% after 6 months, further demonstrating the adverse effect of wet granulation on the stability of bromhexine hydrochloride. Comparative Examples 2 and 6 also showed significant increases in total impurities (0.78% and 0.71%, respectively), indicating that the Eudragit material may interact with the drug under accelerated conditions.

[0064] Release rate change: After 6 months, the release curve of the embodiment of the present invention showed no significant change compared with 0 months (release rate difference <5%). The release curve of Comparative Example 6 increased slightly after 6 months (24h release increased from 97.6% to 99.5%, and 2h release increased from 21.3% to 25.8%), possibly due to the aging of Eudragit material.

[0065] Conclusion: The direct powder compression process of this invention, combined with a ternary composite framework, effectively improves the stability of bromhexine hydrochloride sustained-release microtablets, which is superior to wet granulation process and formulations containing Eudragit.

[0066] Test Example 5 Release behavior in different pH media Test objective: To examine the differences in release behavior between the formulation of the present invention (represented by Example 1) and the formulation containing pH-dependent materials (Comparative Example 6) under different pH environments, and to verify the pH-independent advantage of the ternary framework of the present invention.

[0067] Test method: Using pH 1.2 hydrochloric acid solution, pH 4.5 acetate buffer, pH 6.8 phosphate buffer and water as release media, and other conditions as in Test Example 3, the cumulative release rates of Example 1 and Comparative Example 6 were determined at 2h, 8h and 24h.

[0068] Test results: See Table 7 and Figure 3 .

[0069] from Figure 3 The differences in release behavior between Example 1 of the present invention and the formulation containing pH-dependent materials (Comparative Example 6) under different pH environments can be directly compared.

[0070] pH independence of Example 1: as Figure 3 As shown, the release rate of Example 1 of the present invention is basically consistent in different pH media, and the difference in release rate at each time point is less than 3%, indicating that its release behavior is not affected by pH. This is because ethyl cellulose is a water-insoluble material, and its skeletal pore diffusion mechanism is not pH-dependent; although HPMC and carbomer have certain pH responsiveness, the overall release of the ternary skeleton is controlled by multiple mechanisms in a synergistic manner, which offsets the pH dependence of a single material.

[0071] pH dependence of Comparative Example 6: From Figure 3 It is evident that Comparative Example 6 (containing Eudragit RD) exhibited significant differences in release across different pH media. The fastest release was observed at pH 6.8 (97.6% at 24h), followed by slower release at pH 1.2 (86.3% at 24h), and the slowest release was found in water (75.8% at 24h). This is because Eudragit RD is a methacrylic acid copolymer, soluble at intestinal pH but insoluble in gastric acid, leading to pH-dependent release behavior. This pH dependence may contribute to individual differences in drug absorption and the influence of food.

[0072] Clinical Significance: The pH of the human gastrointestinal tract varies significantly from the strongly acidic environment of the stomach (pH 1-3) to the near-neutral environment of the intestines (pH 6-7). Sustained-release formulations using pH-dependent materials may exhibit fluctuating release behavior in vivo due to variations in the patient's physiological state and dietary intake, affecting the stability of therapeutic efficacy. This invention employs a pH-independent ternary framework, ensuring stable drug release throughout the entire gastrointestinal tract and improving the predictability of therapeutic effects.

[0073] Test Example 6 Comparison of swallowing compliance between micro-tablets and regular tablets Test objective: To evaluate the difference in swallowing difficulty between the microplates (2-4 mm in diameter) of the present invention and ordinary tablets (8 mm in diameter), and to verify the advantages of the present invention in improving patient compliance.

[0074] Methodology: Twenty healthy volunteers (10 men and 10 women, aged 25-65 years) were recruited. A double-blind method was used, with one volunteer receiving a placebo microparticle (3 mm in diameter) and the other a regular placebo tablet (8 mm in diameter). Volunteers were asked to swallow the tablet with a sip of water. The difficulty of swallowing was assessed using the Visual Analogue Scale (VAS, where 0 indicates very easy to swallow and 10 indicates very difficult to swallow). The number of swallows required for complete swallowing (if multiple swallows were required) was also recorded.

[0075] Test results: See Table 8.

[0076] Results analysis: The average VAS score of the microplate group (2.3) was significantly lower than that of the conventional tablet group (6.8), indicating that the microplate was much easier to swallow than the conventional tablet. Only 5% of volunteers needed to swallow the microplate in multiple portions, compared to 40% in the conventional tablet group. 85% of volunteers preferred the microplate form. The results show that the microplate form developed in this invention significantly improves swallowing compliance, and is especially suitable for children, the elderly, and patients with swallowing difficulties.

[0077] In summary, the following conclusions can be drawn from the above test cases: 1. Excellent content uniformity: The A+2.2S values ​​in the embodiments of this invention are all less than 6, which is far superior to the pharmacopoeia limit, proving that the direct compression process of powder combined with the composite matrix formulation of this invention can achieve uniform distribution of low-dose drugs.

[0078] 2. Stable and controllable release behavior: The ternary composite framework (HPMC + carbomer + ethyl cellulose) of this invention, combined with dry-powdered povidone, achieves a stable sustained release over 24 hours, and comparative studies have confirmed that each component is indispensable. Compared with formulations containing Eudragit, the release behavior of this invention is not affected by pH, and the in vivo release is more predictable.

[0079] 3. Good stability: After 6 months of accelerated testing, the content of the present invention decreased by less than 1.5%, the total impurities were less than 0.3%, and the release curve showed no significant change, which is significantly better than the wet granulation formulation and the formulation containing Eudragit.

[0080] 4. Strong process adaptability: The direct compression process of the powder in this invention avoids the influence of damp heat on drug stability, and is simple to operate, making it suitable for industrial production.

[0081] 5. High patient compliance: The microtablet form significantly reduces the difficulty of swallowing, which has been highly favored by volunteers and is especially suitable for special populations.

[0082] In summary, the bromhexine hydrochloride sustained-release microtablets provided by this invention exhibit significant advantages in terms of release controllability, formulation uniformity, stability, and patient compliance, solving many problems existing in the prior art and possessing outstanding substantive features and significant progress.

Claims

1. A sustained-release microtablet of bromhexine hydrochloride, characterized in that, It is made from the following raw materials by direct powder compression process in parts by weight: Raw material composition: 5-20 parts of bromhexine hydrochloride 15-35 parts of hydroxypropyl methylcellulose Carbomer 5-15 servings 5-15 parts of ethyl cellulose 10-40 parts of microcrystalline cellulose 2-8 parts of povidone Lubricant 0.5-5 parts; Preparation steps: (1) After passing bromhexine hydrochloride, hydroxypropyl methylcellulose, carbomer, ethyl cellulose, microcrystalline cellulose and povidone through an 80-100 mesh sieve, they are put into a mixer and mixed for 20-40 minutes to obtain a premixed powder; (2) Add lubricant to the premixed powder and continue mixing for 3-8 minutes to obtain the total powder mixture; (3) A rotary tablet press is used, equipped with a die with a diameter of 2-4 mm, and the tableting pressure is controlled at 5-15 kN to directly press the total powder mixture into micro tablets; The povidone is added in dry powder form as a dry powder binder; the hydroxypropyl methylcellulose, carbomer and ethylcellulose together constitute a composite sustained-release framework system, which synergistically controls the release rate of bromhexine hydrochloride.

2. The bromhexine hydrochloride sustained-release microplate according to claim 1, characterized in that, The weight ratio of hydroxypropyl methylcellulose, carbomer and ethylcellulose is 3-6:1:1-2.

3. The bromhexine hydrochloride sustained-release microplate according to claim 1, characterized in that, The povidone is povidone K30.

4. The bromhexine hydrochloride sustained-release microplate according to claim 1, characterized in that, The lubricant is a mixture of magnesium stearate and micronized silica gel, wherein the weight ratio of magnesium stearate to micronized silica gel is 2:1 to 5:

1.

5. The bromhexine hydrochloride sustained-release microplate according to claim 1, characterized in that, The hardness of the micro-sheets in step (3) is controlled at 20-50N, and the weight difference is less than ±5%.

6. A process for preparing bromhexine hydrochloride sustained-release microplates as described in any one of claims 1-5, characterized in that, Includes the following steps: (1) After passing bromhexine hydrochloride, hydroxypropyl methylcellulose, carbomer, ethyl cellulose, microcrystalline cellulose and povidone through an 80-100 mesh sieve, they are put into a mixer and mixed for 20-40 minutes to obtain a premixed powder; (2) Add lubricant to the premixed powder and continue mixing for 3-8 minutes to obtain the total powder mixture; (3) A rotary tablet press is used, with a die with a diameter of 2-4 mm. The tableting pressure is controlled at 5-15 kN to directly press the total powder into micro tablets.

7. The use of bromhexine hydrochloride sustained-release microtablets as described in any one of claims 1-5 in the preparation of a medicament for treating respiratory diseases requiring expectoration.

8. The application according to claim 7, characterized in that, The respiratory disease mentioned is chronic bronchitis, asthma, or bronchiectasis, which causes thick sputum or difficulty in coughing up phlegm.

9. The application according to claim 7, characterized in that, The microplates are administered orally, once or twice daily.

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