Roxithromycin preparation and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a roxithromycin preparation and a preparation method thereof. The roxithromycin tablet is prepared from the following raw materials: a roxithromycin raw material, a stabilizer, a flow aid, a filler, an adhesive and a lubricant. The stabilizer is a mixture of hydroxypropyl methylcellulose and povidone; the flow aid is talcum powder. Aiming at the particularity of a roxithromycin raw material, a stabilizer system used in a traditional high pressure homogenization (HPH) technology is optimized, hydroxypropyl methylcellulose and povidone are innovatively combined, and talcum powder is introduced to improve the powder chemical property of the prepared nanocrystal, so that subsequent production and manufacturing are facilitated. The preparation medicine prepared by the method is stable in quality and accurate in dosage.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to roxithromycin preparations and their preparation methods. Background Technology

[0002] Roxithromycin is used to treat infections caused by pathogens susceptible to roxithromycin, including ear, nose, and throat infections; tonsillitis, pharyngitis, sinusitis, respiratory tract infections; acute bronchitis, pneumonia, skin and soft tissue infections; impetigo; genitourinary tract infections; and non-gonococcal urethritis. Roxithromycin is a semi-synthetic macrolide antibiotic characterized by acid stability, rapid gastrointestinal absorption, high blood concentrations, long duration of action in vivo, and good pharmacokinetic characteristics. In vitro, roxithromycin exhibits a similar antibacterial spectrum and activity to erythromycin, but its activity against Gram-positive bacteria is slightly weaker than erythromycin. It is more effective against Legionella pneumophila than erythromycin, highly or moderately sensitive to penicillin-resistant gonococci, and has moderate antibacterial activity against meningococci. Its activity against Bordetella pertussis and Bordetella parapertussis is weaker than that of erythromycin.

[0003] The dosage and administration method of roxithromycin depend on the severity of the infection, the sensitivity of the pathogen to the drug, and the patient's overall health status. The course of treatment is generally 5-10 days.

[0004] Patent CN112137974A discloses a roxithromycin dispersible tablet and its preparation method. The tablet contains 8-12% sodium carboxymethyl starch and other pharmaceutical excipients, prepared as a transparent semi-solid colloid with a mass percentage of 8-12% sodium carboxymethyl starch. Roxithromycin is then mixed with 95% ethanol to prepare a roxithromycin ethanol solution with a mass percentage of 50-80%. The two solutions are then mixed evenly, followed by mixing with other excipients, granulation, and tableting. This method effectively increases the solubility of roxithromycin in water, improves the dissolution rate of its formulation in water, and enhances the palatability. For example, patent CN105919960A also discloses a roxithromycin dispersible tablet and its preparation method. The method includes: a) sieving roxithromycin, mannitol, lactose monohydrate, and crospovidone separately for later use, and then preparing a 5% polyvinylpyrrolidone aqueous solution for later use; b) weighing the added raw materials roxithromycin, mannitol, lactose monohydrate, and crospovidone, mixing them evenly, and preparing a soft mass with a 5% polyvinylpyrrolidone aqueous solution; c) granulating the tablets using an 18-mesh sieve, drying the wet tablets in a drying oven, and sizing the dry tablets by passing them through a 32-mesh sieve; d) weighing the added excipients crospovidone, lactose monohydrate, and magnesium stearate, mixing them evenly with the dry tablets, compressing them into tablets, and packaging them. However, these preparation methods require roxithromycin to be made into a solution or soft mass. In actual industrial production, the requirements for the container are relatively high. Furthermore, roxithromycin is a poorly soluble substance. Preparing a soft mass, then drying and compressing it may affect the dissolution rate of the resulting dispersible tablets, thus affecting the taste and bioavailability. In conventional tablet preparation methods, the sieving and mixing process is labor-intensive, generates a lot of dust, and is detrimental to employee health. It is also difficult to ensure uniform mixing, resulting in uneven content and low dissolution in the product. In contrast, the trough mixing granulation and oven drying processes are labor-intensive, have long material exposure time, and pose a high risk of contamination. Furthermore, the uneven heat distribution and low drying efficiency of oven drying not only prolong the wet heat time of the material but also make it difficult to ensure the uniformity of particle moisture.

[0005] Roxithromycin, as a typical poorly soluble drug, is often limited in formulation development by the challenges of insufficient solubility and bioavailability. Traditional methods often rely on poloxamer 188 as a surfactant to improve performance, but the use of this excipient in roxithromycin formulation production faces a double dilemma: firstly, companies routinely use ordinary-sized poloxamer 188 through a 40-mesh sieve for secondary processing, which is costly and inefficient due to manual screening; secondly, directly purchasing low-particle-size products that meet the particle size requirements is too expensive to meet the needs of large-scale production.

[0006] Meanwhile, the traditional wet granulation process is complicated, involving multiple steps such as granulation, drying, sizing, and mixing. It not only has a long production cycle, but also faces challenges such as difficulty in controlling process parameters and complex equipment cleaning.

[0007] Due to the inherent characteristics of the raw materials, roxithromycin formulations typically have a high proportion of these raw materials in their formulations. A high proportion of these raw materials directly leads to decreased compressibility of the formulation, resulting in critical quality issues such as substandard brittleness, tablet cracking, and cap loss, severely impacting product quality. Therefore, developing a roxithromycin formulation to overcome the shortcomings of existing technologies has significant industrial and clinical application value. Summary of the Invention

[0008] To address the shortcomings of existing technologies, the purpose of this invention is to provide a roxithromycin preparation that eliminates the problems of high labor intensity and dust caused by sieving raw and auxiliary materials, and uses a closed system to rapidly process the raw and auxiliary materials.

[0009] The present invention also provides a preparation method, which is simple, has good production continuity, high degree of mechanization, and is suitable for industrial production.

[0010] This invention addresses the unique characteristics of roxithromycin raw materials by optimizing the stabilizer system used in traditional high-pressure homogenization (HPH) technology. It innovatively combines hydroxypropyl methylcellulose with povidone and introduces talc to improve the powder properties of the resulting nanocrystals, thus facilitating subsequent manufacturing. The formulation prepared using this method exhibits stable drug quality, accurate dosage, and consistency with the original formulation.

[0011] The roxithromycin preparation of the present invention is made from roxithromycin raw material, stabilizer, flow aid, filler, binder and lubricant; The stabilizer is a mixture of hydroxypropyl methylcellulose and povidone; The gliding agent is talc.

[0012] The roxithromycin preparation is made from the following raw materials in parts by weight: Roxithromycin raw materials account for 67.57%; Stabilizer 5.00%~6.00%; Flow aid 0.30%~0.70%; Filler content: 18.73%~22.63%; Adhesive 3.50%~5.50%; Lubricant 1.00%~1.50%.

[0013] The stabilizer is a mixture of hydroxypropyl methylcellulose E5 and povidone K30 in a mass ratio of 1:2.5~3.5.

[0014] The filler includes one or more of microcrystalline cellulose, lactose monohydrate, and corn starch.

[0015] The particle size of the filler is D90 = 30-75 μm.

[0016] The adhesive is one or both of low-substituted hydroxypropyl cellulose and pregelatinized starch.

[0017] The lubricant is one or both of magnesium stearate and sodium stearate.

[0018] The method for preparing the roxithromycin preparation of the present invention comprises the following steps: A. Disperse roxithromycin raw material in a solvent to obtain roxithromycin suspension; mix hydroxypropyl methylcellulose and povidone and add water to prepare an aqueous solution, add the aqueous solution to the roxithromycin suspension and add talc powder at the same time, and then use high pressure homogenization (HPH) to obtain roxithromycin nanocrystal suspension, and then dry at low temperature to obtain roxithromycin nanocrystal powder. B. The filler and binder are premixed to obtain a premix. The premix, roxithromycin nanocrystal powder and lubricant are transferred to an elevator granulator for pretreatment before material mixing. The pretreated material is added to the total mixing tank for mixing to obtain roxithromycin total mixed powder. C. Place the total powder of roxithromycin into a tablet press and compress it to obtain roxithromycin dispersible tablets.

[0019] The preparation of roxithromycin nanocrystal suspension by the high-pressure homogenization (HPH) method in step A specifically involves: The homogenizer has a shearing speed of 8000-30000 rpm and a shearing time of 1-3 min; the high-pressure homogenizer has a pressure of 500 bar-1200 bar and a homogenization cycle of 5-20 times.

[0020] The low-temperature drying described in step A specifically involves: The suspension obtained by high-pressure homogenization (HPH) was pretreated by vacuum filtration through a 0.22 μm sterile filter membrane to remove fine agglomerates. The solid content was then adjusted to 5%-10% w / v. The suspension was then dispensed into stainless steel freeze-drying trays, with the thickness controlled at 5-10 mm and gently agitated to ensure even spreading. Low-temperature drying was performed using an in-situ freeze dryer, first pre-freezing the suspension to below -40°C using a stepped rapid freezing method (lowering the temperature at 5°C / min to -20°C and holding for 30 min, then lowering it at 10°C / min to -60°C and holding for 2-4 h). It is in a hard solid state. Then, it is subjected to primary drying at a vacuum degree of 10-30 Pa and a shelf temperature of -25℃ to -20℃ for 8-12 hours. Subsequently, the shelf temperature is raised to 20-30℃ at a vacuum degree of 5-15 Pa and a rate of ≤5℃ / h for 4-6 hours for secondary drying until the powder moisture content is ≤2%. After drying, nitrogen gas with a purity of ≥99.99% and a dew point of ≤-40℃ is introduced into the freeze-drying chamber to slowly break the vacuum (pressure recovery rate ≤0.02MPa / min). The tray is removed and the loose lumps are scraped off with a stainless steel spatula. After processing, roxithromycin nanocrystalline powder is obtained.

[0021] The solvent mentioned in step A is one or both of water and ethanol, and the mass ratio of solvent to roxithromycin raw material is 18.00~20.00:1.

[0022] The screen of the lifting granulator described in step B is a 1.2mm screen.

[0023] The mixing process in the mixing tank described in step B is as follows: the rotation speed is 10 r / min, and the mixing time is 20 min; The parameters of the tablet press in step C are set as follows: tableting speed of 100,000-200,000 tablets / hour, main pressure of 3.0-8.0 kN, and pre-compression pressure of 1.0-5.0 kN.

[0024] This invention proposes a formulation that uses hydroxypropyl methylcellulose, povidone, and talc in a synergistic manner, achieving a significant improvement in formulation performance through the complementary functions of multiple components. The combined application of hydroxypropyl methylcellulose and povidone is a core design that overcomes the limitations of traditional single stabilizers.

[0025] While traditional single stabilizers can achieve the preparation of roxithromycin nanocrystals, they cannot solve the problem of poor nanocrystalline powder properties, ultimately leading to difficulties in poor flowability and uncontrollable tableting processes. If povidone is used alone as a stabilizer, it can form a coating on the surface of the roxithromycin raw material to initially improve flowability. However, during the low-temperature drying process of the nanocrystalline powder, this coating is prone to cracking due to stress shrinkage, resulting in the exposure of the nanocrystals and negating its effect on improving powder properties. If hydroxypropyl methylcellulose is used alone, its advantage lies in its excellent film-forming properties; the formed coating can withstand temperature changes and avoid cracking during drying, thus improving the nanocrystalline powder properties to some extent. However, due to the weak viscosity of hydroxypropyl methylcellulose, it cannot achieve sufficient binding between materials, and problems such as low brittleness and cap loss still occur during subsequent tableting.

[0026] When hydroxypropyl methylcellulose (HMC) and povidone are used together, they can form a synergistic effect: the HMC molecular chain has good flexibility and can be embedded in the gaps between the polymer chains of povidone, effectively reducing the inter-chain forces, making the resulting composite coating film softer and significantly improving its tensile strength, thus fundamentally reducing the risk of cracking during the low-temperature drying process; at the same time, the strong viscosity of povidone can compensate for the viscosity defects of HMC, ensuring that the materials in the formulation are tightly bound, and completely solving the problems of brittleness and cap loss during the tableting stage. Furthermore, to further enhance the powder properties of the nanocrystalline powder, this scheme introduces talc powder in addition to the stabilizer system. The layered particles of talc powder can be uniformly dispersed in the nanocrystalline suspension. After low-temperature drying, a dense "physical isolation layer" forms on the surface of the nanocrystalline powder. Its low surface energy effectively reduces the molecular attraction between solid powders, while the layered structure provides good sliding properties, reducing the frictional resistance between powder particles. This dual effect synergistically achieves a fundamental improvement in the flowability of the nanocrystalline powder, ensuring the stable operation of the subsequent tableting process.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows: 1) This invention uses high pressure homogenization (HPH) technology to prepare roxithromycin nanocrystals, which greatly reduces the particle size of roxithromycin raw materials. The smaller the particle size, the larger the specific surface area. By increasing the specific surface area through drug nano-sizing, the dissolution rate is improved, and the drug-like properties of poorly soluble roxithromycin are significantly improved.

[0028] 2) This invention significantly improves drug solubility and bioavailability by preparing roxithromycin into nanocrystals without relying on poloxamer 188. This breakthrough not only effectively avoids the cost and process challenges of traditional excipients, but also meets the special requirements of roxithromycin formulations, greatly reducing production costs for enterprises while ensuring product quality stability, demonstrating extremely high commercial application value and competitive advantage in the pharmaceutical market.

[0029] 3) This invention proposes a formulation scheme that uses hydroxypropyl methylcellulose, povidone, and talc in a synergistic manner, achieving a significant improvement in formulation performance through the complementary functions of multiple components. The combined application of hydroxypropyl methylcellulose and povidone is a core design that breaks through the limitations of traditional single stabilizers.

[0030] 4) Compared to traditional wet granulation processes, this invention innovatively utilizes nanocrystal technology, completely revolutionizing the production process. Nanocrystal technology offers significant advantages for continuous industrial production; its preparation process is simple and efficient, core operations are easily standardized, and it greatly reduces reliance on operators' professional skills. The subsequent use of direct powder pressing technology further simplifies the production process and reduces losses in intermediate stages. From raw material input to finished product output, the entire production cycle takes only 3 days, significantly reducing time costs compared to traditional processes. This allows for rapid response to market dynamics, creating considerable economic benefits with lower production costs and higher production efficiency. Detailed Implementation

[0031] The present invention will be further described below with reference to the embodiments.

[0032] Unless otherwise specified, all raw materials used in the examples were commercially available.

[0033] Roxithromycin was purchased from Zhejiang Guobang Pharmaceutical Co., Ltd. Povidone K30 was purchased from BASF (China) Co., Ltd. Hydroxypropyl methylcellulose E5 was purchased from Ashland Chemical (Nanjing) Co., Ltd.; Low-substituted hydroxypropyl cellulose LH-22 was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd. The pregelatinized starch was purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd. The colloidal silica was purchased from Cabot Corporation; Magnesium stearate was purchased from Liaocheng Ahua Pharmaceutical Excipients Co., Ltd. The talc powder was purchased from Laizhou Fengyu Talc Powder Co., Ltd. Lactose monohydrate was purchased from Jiangsu Daoning Pharmaceutical Co., Ltd. Microcrystalline cellulose was purchased from Jiangsu Xidian Pharmaceutical Excipients Co., Ltd. The corn starch was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd. Ethanol was purchased from Shandong Longyuquan Pharmaceutical Excipients Co., Ltd. Sodium stearate was purchased from Huzhou Linghu Xinwang Chemical Co., Ltd.

[0034] Example 1 The roxithromycin preparation is obtained by the following steps: A. 150.0g of roxithromycin raw material was dispersed in 2850.0g of purified water to obtain a roxithromycin suspension; 3.0g of hydroxypropyl methylcellulose E5 and 9.0g of povidone K30 were mixed and added to 108.0g of purified water to prepare an aqueous solution. The aqueous solution was added to the roxithromycin suspension along with 1.2g of talc powder. Then, a high-pressure homogenization (HPH) method was used to obtain a roxithromycin nanocrystal suspension. The shearing speed of the homogenizer was 19000rpm and the shearing time was 2min. The pressure of the high-pressure homogenizer was 850bar and the homogenization was performed 15 times to obtain the roxithromycin nanocrystal suspension. The suspension prepared by high-pressure homogenization (HPH) was pretreated by vacuum filtration through a 0.22 μm sterile filter membrane to remove fine agglomerates. The solid content was then adjusted to 7.5 ± 2.5% w / v. The suspension was then dispensed into stainless steel freeze-drying trays, with the thickness controlled at 7.5 ± 2.5 mm and gently agitated to ensure even spreading. Low-temperature drying was performed using an in-situ freeze dryer, first by rapid, stepped freezing (lowering to -20°C at 5°C / min and holding for 30 min, then lowering to -60°C at 10°C / min and holding for 3 h) to pre-freeze the suspension to - Below 40℃, it is in a hard solid state. Then, it is subjected to primary drying for 10 hours under a vacuum of 20±10Pa and a shelf temperature of -25℃ to -20℃. Subsequently, under a vacuum of 10Pa, the shelf temperature is raised to 25±5℃ at a rate of ≤5℃ / h and continued for 5 hours for secondary drying until the powder moisture content is ≤2%. After drying, nitrogen gas with a purity of ≥99.99% and a dew point of ≤-40℃ is introduced into the freeze-drying chamber to slowly break the vacuum (pressure recovery rate ≤0.02MPa / min). The tray is removed and the loose lumps are scraped off with a stainless steel spatula. After processing, roxithromycin nanocrystalline powder is obtained. B. 45.8g of microcrystalline cellulose and 10.0g of low-substituted hydroxypropyl cellulose were premixed to obtain a premix. The premix, roxithromycin nanocrystalline powder and 3.0g of magnesium stearate were transferred to an elevator granulator (1.2mm screen) for material pretreatment before mixing. The pretreated material was added to the total mixing tank for mixing at a speed of 10r / min for 20min to obtain roxithromycin total mixed powder. C. Place the total mixed powder of roxithromycin into a tablet press and compress it into tablets at a speed of 150,000 tablets / hour, a main pressure of 5.0 kN, and a pre-compression pressure of 2.0 kN to obtain roxithromycin dispersible tablets.

[0035] The particle size of the filler is: microcrystalline cellulose D90 = 30 μm.

[0036] Example 2 The roxithromycin preparation is obtained by the following steps: A. 150.0g of roxithromycin raw material was dispersed in 2700.0g of purified water to obtain a roxithromycin suspension; 2.78g of hydroxypropyl methylcellulose E5 and 8.33g of povidone K30 were mixed and added to 99.9g of purified water to prepare an aqueous solution. The aqueous solution was added to the roxithromycin suspension along with 0.67g of talc powder. Then, a high-pressure homogenization (HPH) method was used to obtain a roxithromycin nanocrystal suspension. The shearing speed of the homogenizer was 19000rpm and the shearing time was 2min. The pressure of the high-pressure homogenizer was 850bar and the homogenization was performed 15 times to obtain the roxithromycin nanocrystal suspension. The suspension prepared by high-pressure homogenization (HPH) was pretreated by vacuum filtration through a 0.22 μm sterile filter membrane to remove fine agglomerates. The solid content was then adjusted to 7.5 ± 2.5% w / v. The suspension was then dispensed into stainless steel freeze-drying trays, with the thickness controlled at 7.5 ± 2.5 mm and gently agitated to ensure even spreading. Low-temperature drying was performed using an in-situ freeze dryer, first by rapid, stepped freezing (lowering to -20°C at 5°C / min and holding for 30 min, then lowering to -60°C at 10°C / min and holding for 3 h) to pre-freeze the suspension to - Below 40℃, it is in a hard solid state. Then, it is subjected to primary drying for 10 hours under a vacuum of 20±10Pa and a shelf temperature of -25℃ to -20℃. Subsequently, under a vacuum of 10Pa, the shelf temperature is raised to 25±5℃ at a rate of ≤5℃ / h and continued for 5 hours for secondary drying until the powder moisture content is ≤2%. After drying, nitrogen gas with a purity of ≥99.99% and a dew point of ≤-40℃ is introduced into the freeze-drying chamber to slowly break the vacuum (pressure recovery rate ≤0.02MPa / min). The tray is removed and the loose lumps are scraped off with a stainless steel spatula. After processing, roxithromycin nanocrystalline powder is obtained. B. 50.24g of microcrystalline cellulose and 7.77g of low-substituted hydroxypropyl cellulose were premixed to obtain a premix. The premix, roxithromycin nanocrystalline powder and 2.22g of magnesium stearate were transferred to an elevator granulator (1.2mm screen) for pretreatment before material mixing. The pretreated material was added to the total mixing tank for mixing at a speed of 10r / min for 20min to obtain roxithromycin total mixed powder. C. Place the total mixed powder of roxithromycin into a tablet press and compress it into tablets at a speed of 150,000 tablets / hour, a main pressure of 5.0 kN, and a pre-compression pressure of 2.0 kN to obtain roxithromycin dispersible tablets.

[0037] The particle size of the filler is: microcrystalline cellulose D90 = 30 μm.

[0038] Example 3 The roxithromycin preparation is obtained by the following steps: A. 150.0g of roxithromycin raw material was dispersed in 3000.0g of purified water to obtain a roxithromycin suspension; 3.33g of hydroxypropyl methylcellulose E5 and 9.99g of povidone K30 were mixed and added to 119.88g of purified water to prepare an aqueous solution. The aqueous solution was added to the roxithromycin suspension along with 1.554g of talc powder. Then, a high-pressure homogenization (HPH) method was used to obtain a roxithromycin nanocrystal suspension. The homogenizer shearing speed was 19000rpm and the shearing time was 2min. The pressure of the high-pressure homogenizer was 850bar and the homogenization was performed 15 times to obtain the roxithromycin nanocrystal suspension. The suspension prepared by high-pressure homogenization (HPH) was pretreated by vacuum filtration through a 0.22 μm sterile filter membrane to remove fine agglomerates. The solid content was then adjusted to 7.5 ± 2.5% w / v. The suspension was then dispensed into stainless steel freeze-drying trays, with the thickness controlled at 7.5 ± 2.5 mm and gently agitated to ensure even spreading. Low-temperature drying was performed using an in-situ freeze dryer, first by rapid, stepped freezing (lowering to -20°C at 5°C / min and holding for 30 min, then lowering to -60°C at 10°C / min and holding for 3 h) to pre-freeze the suspension to - Below 40℃, it is in a hard solid state. Then, it is subjected to primary drying for 10 hours under a vacuum of 20±10Pa and a shelf temperature of -25℃ to -20℃. Subsequently, under a vacuum of 10Pa, the shelf temperature is raised to 25±5℃ at a rate of ≤5℃ / h and continued for 5 hours for secondary drying until the powder moisture content is ≤2%. After drying, nitrogen gas with a purity of ≥99.99% and a dew point of ≤-40℃ is introduced into the freeze-drying chamber to slowly break the vacuum (pressure recovery rate ≤0.02MPa / min). The tray is removed and the loose lumps are scraped off with a stainless steel spatula. After processing, roxithromycin nanocrystalline powder is obtained. B. 41.58g of microcrystalline cellulose and 12.21g of low-substituted hydroxypropyl cellulose were premixed to obtain a premix. The premix, roxithromycin nanocrystalline powder and 3.33g of magnesium stearate were transferred to an elevator granulator (1.2mm screen) for pretreatment before material mixing. The pretreated material was added to the total mixing tank for mixing at a speed of 10r / min for 20min to obtain roxithromycin total mixed powder. C. Place the total mixed powder of roxithromycin into a tablet press and compress it into tablets at a speed of 150,000 tablets / hour, a main pressure of 5.0 kN, and a pre-compression pressure of 2.0 kN to obtain roxithromycin dispersible tablets.

[0039] The particle size of the filler is: microcrystalline cellulose D90 = 30 μm.

[0040] Example 4 The difference between Example 4 and Example 1 is that the particle size of the filler is: microcrystalline cellulose D90 = 75 μm.

[0041] Example 5 The difference between Example 5 and Example 1 is that the stabilizer is a mixture of hydroxypropyl methylcellulose E5 and povidone K30 in a mass ratio of 1:2.5.

[0042] Example 6 The difference between Example 6 and Example 1 is that the stabilizer is a mixture of hydroxypropyl methylcellulose E5 and povidone K30 in a mass ratio of 1:3.5.

[0043] Example 7 The difference between Example 7 and Example 1 is that the type of lubricant is changed from magnesium stearate to sodium stearate in equal parts by mass.

[0044] Example 8 The difference between Example 8 and Example 1 is that the filler is changed from microcrystalline cellulose to an equal mass fraction of lactose monohydrate.

[0045] Example 9 The difference between Example 9 and Example 1 is that the filler is changed from microcrystalline cellulose to corn starch of equal mass.

[0046] Example 10 The difference between Example 10 and Example 1 is that the solvent used in preparing roxithromycin nanocrystals is changed from purified water to ethanol.

[0047] Example 11 The difference between Example 11 and Example 1 is that the binder used in preparing the roxithromycin formulation was changed from low-substituted hydroxypropyl cellulose to pregelatinized starch.

[0048] Non-preferred embodiment 12 The difference between Example 12 and Example 1 is that the particle size of the filler is: microcrystalline cellulose D90 = 15 μm.

[0049] Non-preferred embodiment 13 The difference between Example 13 and Example 1 is that the microcrystalline cellulose particle size is D90=100μm.

[0050] Non-preferred embodiment 14 The difference between Example 14 and Example 1 is that the 1.2mm screen is replaced with a 2.0mm screen during the pretreatment of material mixing.

[0051] Comparative Example 1 The preparation method of the roxithromycin preparation includes the following steps: (1) 4.0 g of colloidal silica was mixed with half of the formulation amount (22.5 g) of microcrystalline cellulose and half of the formulation amount (75.0 g) of roxithromycin raw material to obtain a premix. The premix, the remaining microcrystalline cellulose (22.5 g), roxithromycin raw material (75.0 g), low-substituted hydroxypropyl cellulose (5.0 g) and magnesium stearate (3.0 g) were mixed for 10 min to obtain roxithromycin total mixed powder; (2) Place the total mixed powder of roxithromycin into a tablet press and compress it into tablets. The tableting speed is 100,000 tablets / hour, the main pressure is 4.0kN, and the pre-compression pressure is 1.0kN to obtain roxithromycin dispersible tablets.

[0052] The particle size of the filler is: microcrystalline cellulose D90 = 30 μm.

[0053] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that the stabilizer was replaced by an equal amount of poloxamer 188 instead of hydroxypropyl methylcellulose E5 and povidone K30.

[0054] Comparative Example 3 The difference between Comparative Example 3 and Example 1 is that the stabilizer was replaced by an equal mass fraction of hydroxypropyl methylcellulose E5 instead of hydroxypropyl methylcellulose E5 and povidone K30.

[0055] Comparative Example 4 The difference between Comparative Example 4 and Example 1 is that the stabilizer was replaced by an equal mass fraction of povidone K30 instead of hydroxypropyl methylcellulose E5 and povidone K30.

[0056] Comparative Example 5 The difference between Comparative Example 5 and Example 1 is that no talc powder, a flow aid, was added when preparing the roxithromycin nanocrystal suspension.

[0057] Comparative Example 6 Original formulation of commercially available roxithromycin tablets - Sanofi Aventis France, brand name Rulide ® Batch number: 2PR7A.

[0058] Performance testing Content uniformity test: The content uniformity of the total mixed powder of roxithromycin in Examples 1-14 and Comparative Example 6 was tested according to the content uniformity test method in the Chinese Pharmacopoeia. The test results are shown in Table 1 and Table 2.

[0059] Table 1. Evaluation of the uniformity of roxithromycin content in the total mixed powder.

[0060] Table 2. Evaluation of the uniformity of roxithromycin content in the total mixed powder.

[0061] In the roxithromycin preparation of this invention, the content uniformity was tested according to the Chinese Pharmacopoeia 0941 "Method for Testing Content Uniformity". The test data from Examples 1-11 and Comparative Example 6 show that the test results meet the standard of A+2.2S≤15, and the content uniformity meets the requirements. Therefore, compared to the reference preparation, preparing roxithromycin into nanocrystals and mixing them can effectively produce a roxithromycin preparation with uniform quality. In contrast, the non-preferred examples 12-14 showed an A+2.2S≥15, failing to meet the pharmacopoeia standard and resulting in unsatisfactory content uniformity. The specific reasons are as follows: The filler particle size used in examples 12-13 exceeded the suitable range. Whether extremely fine or coarse, both significantly altered the specific surface area of ​​the material during mixing. With a fixed amount of lubricant, it was difficult to fully coat the material surface, leading to uneven dispersion and ultimately unsatisfactory content uniformity. The failure in example 14 was due to an excessively large mesh size used during the pretreatment of raw materials before mixing. This prevented effective dispersion of small clumps in the excipients, hindering uniform dispersion during mixing and resulting in substandard content uniformity.

[0062] The data above show that the roxithromycin preparation obtained by this invention has accurate dosage. Compared with the reference preparation, it can also produce a preparation with accurate dosage and uniform mixing, demonstrating a significant advantage in dosage accuracy.

[0063] Dissolution curve analysis: Dissolution curves of roxithromycin preparations from Examples 1, 2, 3, 4, 5, and 6 and Comparative Examples 1 and 6 were analyzed. The results are shown in Table 3 below.

[0064] Table 3. Dissolution curves of Examples 1, 2, 3, 4, 5, and 6 and Comparative Examples 1 and 6

[0065] Analysis of the dissolution curves of roxithromycin formulations revealed a high degree of fit between the dissolution curves of Examples 1, 2, 3, 4, 5, and 6 and Comparative Example 6 (reference formulation), exhibiting remarkably similar dissolution characteristics. This result fully demonstrates that preparing roxithromycin into nanocrystals and achieving extremely fine processing of the raw material can significantly improve its solubility in the medium. Through this process optimization, roxithromycin formulations are freed from dependence on surfactants, enabling complete drug release and effectively ensuring the dissolution efficiency and bioavailability of the formulation. In contrast, Example 1, due to the lack of any treatment of the roxithromycin raw material in its formulation process and the absence of surfactants in the formulation, resulted in ineffective drug release. This result further highlights the crucial role of raw material nanocrystallization and the appropriate addition of excipients in improving the dissolution performance of roxithromycin formulations.

[0066] Roxithromycin preparation shape, appearance, hardness, and friability test: The tests were conducted according to the Chinese Pharmacopoeia. The shape, appearance, hardness, and friability of the roxithromycin preparations of Examples 1, 2, 3, 4, 5, and 6 and Comparative Examples 2, 3, 4, 5, and 6 are shown in Table 4.

[0067] Table 4. Shape, appearance, hardness, and friability of roxithromycin preparations

[0068] In the roxithromycin formulation prepared by this invention, the shape, appearance, hardness, and friability were tested according to the Chinese Pharmacopoeia. Examples 1, 2, 3, 4, 5, 6, and Comparative Example 6 (reference formulation) all yielded complete, smooth, and uniform white tablets with uniform hardness and meeting the friability requirements. This is because, compared to the reference formulation, preparing roxithromycin into nanocrystals and using a stabilizer with adhesive properties, along with the simultaneous addition of talc, allows for a more uniform coating of the roxithromycin raw material surface. This avoids problems such as sticking, cap loss, tablet cracking, and unacceptable friability in the subsequent tableting process, which are common with traditional roxithromycin formulations. Comparative Examples 2, 3, 4, and 5 were substandard tablets, mainly because Comparative Example 2, although preparing roxithromycin into nanocrystals, did not use a stabilizer with adhesive properties, only a surfactant as a stabilizer. While this allows for the preparation of roxithromycin nanocrystals, it cannot guarantee the smooth progress of subsequent processes. Comparative Examples 3 and 4 failed to form tablets because the use of only hydroxypropyl methylcellulose E5 or povidone K30 as stabilizers could not avoid the defects of a single stabilizer in the formulation process. Comparative Example 5 was a substandard tablet with dents on the surface. The main reason was the absence of talc in the preparation of roxithromycin nanocrystalline powder, resulting in poor flowability and dents. From the perspective of the characteristics of roxithromycin nanocrystalline powder itself, the nanoscale particle size significantly increases its specific surface area, and the van der Waals forces and hydrogen bonds between particles are significantly enhanced, naturally giving it a strong tendency to agglomerate. Talc, a commonly used anti-blocking and flow aid in solid dosage forms, plays a crucial role in this process due to its unique layered crystal structure and low surface energy. The tiny talc particles can be uniformly dispersed on the surface of roxithromycin nanocrystal particles, acting as a "physical isolation layer" to weaken the adsorption force between particles, reduce the probability of agglomeration, and significantly improve the overall flowability of the material, ensuring that each die cavity is accurately filled with a quantitative amount of powder during tableting. On the other hand, talc can coordinate with magnesium stearate in the excipients to play a lubricating role, avoiding the impact of using magnesium stearate alone on the dissolution rate of roxithromycin nanocrystals.

[0069] Roxithromycin total mixed powder powder test: The test was conducted in accordance with the Chinese Pharmacopoeia. The roxithromycin total mixed powder powder test results for Examples 1-6 and Comparative Examples 3, 4, and 5 are shown in Table 5.

[0070] Table 5. Powder properties of roxithromycin total mixed powder

[0071] The powder properties data show that the roxithromycin nanocrystalline powder prepared by combining stabilizers and simultaneously adding talc in Examples 1, 2, 3, 4, 5, and 6 exhibits superior powder properties and good flowability when used for material mixing. However, comparative examples 3, 4, and 5, which use a single stabilizer and do not add talc, show poor flowability. This is because without talc, on the one hand, the particles lose their physical isolation and flow-aiding effect, leading to direct particle contact; on the other hand, the single hydroxypropyl methylcellulose E5 membrane is prone to self-aggregation due to strong intermolecular hydrogen bonding, while the povidone K30 membrane exhibits significant viscosity due to chain segment entanglement. These two factors combined cause a sharp increase in the internal frictional resistance of the nanocrystalline particles and significantly enhance their aggregation tendency; ultimately leading to an increase in the angle of repose of the drug particles, a decrease in bulk density, and thus exhibiting poor flowability.

[0072] In summary, the roxithromycin formulation prepared by this invention has significant advantages over the original formulation.

Claims

1. A roxithromycin formulation, characterized in that, The roxithromycin is prepared from roxithromycin raw material, stabilizer, flow aid, filler, binder, lubricant; The stabilizer is a mixture of hydroxypropyl methyl cellulose and povidone; The flow aid is talc.

2. The roxithromycin formulation according to claim 1, characterized in that, The following raw materials are prepared in the following mass fractions: The roxithromycin raw material accounts for 67.57%; The stabilizer accounts for 5.00%~6.00%; The flow aid accounts for 0.30%~0.70%; The filler accounts for 18.73%~22.63%; The binder accounts for 3.50%~5.50%; The lubricant accounts for 1.00%~1.50%.

3. The roxithromycin formulation according to claim 1, characterized in that, The stabilizer is a mixture of hydroxypropyl methyl cellulose and povidone in a mass ratio of 1:2.5~3.

5.

4. The roxithromycin formulation according to claim 1, characterized in that, The filler includes one or more of microcrystalline cellulose, lactose monohydrate, and corn starch.

5. The roxithromycin formulation according to claim 1, characterized in that, The particle size of the filler is D90=30-75μm.

6. The roxithromycin formulation according to claim 1, characterized in that, The binder is one or both of low-substituted hydroxypropyl cellulose and pregelatinized starch.

7. The roxithromycin formulation according to claim 1, characterized in that, The lubricant is one or both of magnesium stearate and sodium stearate.

8. A process for the preparation of a roxithromycin formulation according to any one of claims 1 to 7, characterized in that, The following steps are used to prepare the roxithromycin dispersible tablets: A. Disperse the roxithromycin raw material in a solvent to obtain a roxithromycin suspension; mix hydroxypropyl methyl cellulose and povidone in water to prepare an aqueous solution, and add the aqueous solution to the roxithromycin suspension while adding talc powder, then use high-pressure homogenization to obtain a roxithromycin nanocrystal suspension, and dry to obtain roxithromycin nanocrystal powder; B. Mix the filler and the binder to obtain a premix, transfer the premix, roxithromycin nanocrystal powder, and lubricant to a lifting granulator for pretreatment of the materials before mixing, and add the pretreated materials to a total mixing tank for mixing to obtain roxithromycin total mixed powder; C. Place the roxithromycin total mixed powder in a tablet press for tabletting to obtain roxithromycin dispersible tablets.

9. The method of preparing a roxithromycin formulation according to claim 8, characterized in that, The solvent in step A is one or both of water and ethanol, and the mass ratio of solvent to roxithromycin raw material is 18.00~20.00:

1.

10. The method of preparing a roxithromycin formulation according to claim 8, characterized in that, The screen of the lifting granulator in step B is a 1.2mm screen.

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