Formulations of roxithromycin and methods for their preparation

Abstract

The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a roxithromycin preparation and a preparation method thereof. The roxithromycin preparation is prepared from the following raw materials: roxithromycin, a stabilizer, a glidant, a filler, a binder and a lubricant. The stabilizer is a mixture of hydroxypropyl methyl cellulose and povidone. The glidant is talc. The stabilizer system used in the traditional high-pressure homogenization technology (HPH) is optimized according to the particularity of the roxithromycin raw material. The hydroxypropyl methyl cellulose and the povidone are used together, and the talc is introduced to improve the powder properties of the prepared nanocrystals, so that the subsequent production and manufacturing are facilitated. The preparation prepared according to the method has stable drug quality and accurate dosage.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparation, and particularly relates to a roxithromycin preparation and a preparation method thereof. BACKGROUND

[0002] Roxithromycin is used for treating infections caused by roxithromycin-sensitive pathogens, ear, nose and throat infections; tonsillitis, pharyngitis, sinusitis, respiratory tract infections; acute bronchitis, pneumonia, skin and soft tissue infections; impetigo, urogenital tract infections; non-gonococcal urethritis, roxithromycin is a semi-synthetic macrolide antibiotic, which is stable to acid and can be rapidly absorbed by the gastrointestinal tract, has a high blood drug concentration, and has a long drug action time in the body, and has good pharmacokinetic characteristics; the antibacterial spectrum and antibacterial activity of roxithromycin in vitro are similar to those of erythromycin, the effect on gram-positive bacteria is slightly worse than that of erythromycin, the effect on Legionella pneumophila is stronger than that of erythromycin, the effect on penicillin-resistant Neisseria gonorrhoeae is very sensitive or moderately sensitive, the effect on Streptococcus meningitidis is moderately antibacterial, and the effect on Bordetella pertussis and 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 overall health status of the patient, and the general treatment course is 5-10 days.

[0004] Patent CN112137974A discloses a roxythromycin dispersible tablet and its preparation method, which contains 8-12% carboxymethyl starch sodium and other pharmaceutical excipients, and is prepared into a transparent semi-solid gel of 8-12% carboxymethyl starch sodium by mass percentage. Roxythromycin is prepared into a roxythromycin ethanol solution of 50-80% by mass percentage with 95% ethanol, and then the two are mixed uniformly and mixed with other excipients, granulated and compressed into tablets. This method effectively increases the solubility of roxythromycin in water, improves the dissolution rate of the preparation in water, and improves the taste. For example, patent CN105919960A also discloses a roxythromycin dispersible tablet and its preparation method, which comprises: a, first sieve roxythromycin, mannitol, lactose monohydrate and cross-linked polyvinylpyrrolidone for use, and then prepare 5% polyvinylpyrrolidone aqueous solution for use; b, weigh the added roxythromycin, mannitol, lactose monohydrate and cross-linked polyvinylpyrrolidone, mix uniformly, and prepare soft material with 5% polyvinylpyrrolidone aqueous solution; c, granulate with 18 mesh sieve, dry the wet granules in the drying oven, and sieve the dry granules with 32 mesh sieve; d, weigh the added excipients cross-linked polyvinylpyrrolidone, lactose monohydrate and magnesium stearate, mix uniformly with the dry granules, compress into tablets and package. However, in these preparation methods, roxythromycin needs to be prepared into a solution or soft material, which requires high requirements for the tank body in actual industrial production, and roxythromycin is a poorly soluble substance. The dissolution rate of the prepared dispersible tablet may be affected by the preparation of soft material, drying and tabletting, thereby affecting the taste and bioavailability. In the conventional tablet preparation method, the sieving and mixing process has high labor intensity, dust flying, and is not conducive to labor protection of employees; it is also difficult to ensure uniformity of mixing, and the product has problems of uneven content and low dissolution rate. In addition, the labor intensity of the slot type mixing granulation and oven drying process is high, the material is exposed for a long time, and the pollution risk is high. In addition, the uneven heat distribution and low drying efficiency of the oven drying prolong the wet heat time of the material and make it difficult to ensure the uniformity of the granule moisture.

[0005] As a typical poorly soluble drug, the development of roxythromycin preparations is often limited by the problems of insufficient solubility and bioavailability. Traditional methods often rely on poloxamer 188 as a surfactant to improve performance, but in the production of roxythromycin preparations, the use of this excipient has a double dilemma: first, enterprises usually use ordinary particle size poloxamer 188 treated twice through a 40-mesh sieve, which has high cost and low efficiency; second, directly purchasing low-particle-size products that meet the particle size requirements is difficult to meet the demand of large-scale production due to high price.

[0006] At the same time, the traditional wet granulation process is complicated, involving multiple processes such as granulation, drying, granulation, mixing, etc. Not only is the production cycle long, but it also faces challenges such as difficulty in controlling process parameters and complexity of equipment cleaning.

[0007] The roxythromycin preparation is limited by the characteristics of the raw material itself, and the proportion in the preparation formula is usually high. A high proportion of raw materials will directly lead to a decrease in the compressibility of the preparation, thereby causing key quality problems such as unqualified friability, tablet cracking and cap falling, and seriously affecting the product quality.

[0008] Therefore, it is of great industrial significance and clinical application value to develop a roxythromycin preparation to overcome the shortcomings of the prior art. SUMMARY

[0009] In view of the shortcomings of the prior art, the purpose of the present application is to provide a roxythromycin preparation to eliminate the problem of high labor intensity and dust flying caused by screening of raw and auxiliary materials, and to use a closed equipment for rapid treatment of raw and auxiliary materials.

[0010] The present application also provides a preparation method, which is simple, has good production continuity, high degree of mechanization and is suitable for industrial production.

[0011] The present application optimizes the stabilizer system used in the traditional high-pressure homogenization technology (HPH) according to the particularity of roxythromycin raw material, innovatively combines hydroxypropyl methyl cellulose with povidone, and introduces talc to improve the powder properties of the prepared nanocrystals, thereby facilitating subsequent production and manufacturing. The preparation prepared according to this method has stable drug quality, accurate dosage, and consistent quality with the original preparation.

[0012] The roxythromycin preparation described in the present application is prepared from roxythromycin raw material, stabilizer, glidant, filler, binder and lubricant;

[0013] The stabilizer is a mixture of hydroxypropyl methyl cellulose and povidone;

[0014] The glidant is talc.

[0015] The roxythromycin preparation is prepared from the following mass fractions of raw materials:

[0016] The proportion of roxythromycin raw material is 67.57%;

[0017] The stabilizer is 5.00%~6.00%;

[0018] The glidant is 0.30%~0.70%;

[0019] The filler is 18.73%~22.63%;

[0020] The binder is 3.50%~5.50%;

[0021] The lubricant is 1.00%~1.50%.

[0022] The stabilizer is a mixture of hydroxypropyl methyl cellulose E5 and povidone K30 in a mass ratio of 1:2.5~3.5.

[0023] The filler comprises one or more of microcrystalline cellulose, lactose monohydrate, and corn starch.

[0024] The particle size of the filler is D90=30-75 μm.

[0025] The binder is one or both of low-substituted hydroxypropyl cellulose and pregelatinized starch.

[0026] The lubricant is one or both of magnesium stearate and sodium stearate.

[0027] The preparation method of the roxithromycin preparation of the present application is prepared by the following steps:

[0028] A. dispersing roxithromycin raw material in a solvent to obtain a roxithromycin suspension; mixing hydroxypropyl methyl cellulose and povidone in water to prepare an aqueous solution, adding the aqueous solution to the roxithromycin suspension, adding talc powder at the same time, and then using high-pressure homogenization (HPH) to prepare a roxithromycin nanocrystal suspension, and drying at low temperature to obtain roxithromycin nanocrystal powder;

[0029] B. mixing the filler and the binder to obtain a premix, transferring the premix, roxithromycin nanocrystal powder, and lubricant to a lifting granulator for pretreatment of the materials before mixing, and adding the pretreated materials to a total mixing tank for mixing to obtain roxithromycin total mixed powder;

[0030] C. placing the roxithromycin total mixed powder in a tablet press for tabletting to obtain roxithromycin dispersible tablets.

[0031] The high-pressure homogenization (HPH) for preparing the roxithromycin nanocrystal suspension of step A is specifically:

[0032] The shear speed of the homogenizer is 8000-30000 rpm, and the shear time is 1-3 min; the pressure of the high-pressure homogenizer is 500 bar-1200 bar, and the homogenization frequency is 5-20 times.

[0033] The low-temperature drying of step A is specifically:

[0034] The suspension prepared by high pressure homogenization (HPH) is pretreated, the fine agglomerated particles are removed by vacuum filtration using a 0.22 mu m sterile filter membrane, the solid content is adjusted to 5%-10% w / v, then the suspension is divided into stainless steel freeze-drying trays, the liquid loading thickness is controlled to be 5-10 mm, and the suspension is evenly spread by gently shaking; low temperature drying is carried out by using an in-situ freeze-drying machine, the suspension is pre-frozen to below -40 DEG C to a hard solid state by stepwise rapid freezing (5 DEG C / min to -20 DEG C for 30 min, and then 10 DEG C / min to -60 DEG C for 2-4 h), then primary drying is carried out at a vacuum degree of 10-30 Pa, a shelf temperature of -25 DEG C to -20 DEG C for 8-12 h, then the shelf temperature is raised to 20-30 DEG C at a rate of <=5 DEG C / h under a vacuum degree of 5-15 Pa, and secondary drying is carried out for 4-6 h until the moisture content of the powder is <=2%; after drying, nitrogen gas with a purity of >=99.99% and a dew point of <=-40 DEG C is slowly introduced into the freeze-drying box to break the vacuum (the pressure recovery rate is <=0.02 MPa / min), the tray is taken out, and the loose block material is scraped off with a stainless steel shovel, and roxythromycin nanocrystal powder is obtained.

[0035] The solvent in step A is one or both of water or ethanol, and the mass ratio of the solvent to roxythromycin raw material is 18.00-20.00:1.

[0036] The screen of the lifting whole granulator in step B is a 1.2 mm screen.

[0037] The mixing process in the total mixing tank in step B is as follows: the rotation speed is 10 r / min, and the mixing time is 20 min.

[0038] The parameters of the tablet press in step C are set as follows: the tabletting speed is 10.0-20.0 million tablets / hour, the main pressure is 3.0-8.0 kN, and the pre-pressing pressure is 1.0-5.0 kN.

[0039] The present application proposes a formula scheme in which hydroxypropyl methyl cellulose, povidone and talc are used synergistically, and the performance of the preparation is significantly improved through multi-component functional complementation.

[0040] Although the traditional single stabilizer can realize the preparation of roxithromycin nanocrystals, it cannot solve the problem of poor powder properties of nanocrystals, and ultimately still faces the difficulties of poor flowability and difficult control of tabletting process. If povidone is used alone as a stabilizer, although a wrapping film can be formed on the surface of roxithromycin raw materials to initially improve the flowability, the wrapping film is prone to cracking due to stress shrinkage during low-temperature drying of nanocrystal powder, resulting in exposure of nanocrystals and loss of the effect of improving powder properties. If hydroxypropyl methylcellulose is used alone, its advantage lies in excellent film forming property, and the wrapping film formed can withstand temperature changes to avoid cracking during drying, so that the powder properties of nanocrystals are improved to a certain extent. However, due to the weak adhesion of hydroxypropyl methylcellulose, it cannot realize the full combination of materials, and problems such as low friability and cap falling still occur in the subsequent tabletting process.

[0041] When hydroxypropyl methylcellulose and povidone are used together, a synergistic effect can be formed: the molecular chain of hydroxypropyl methylcellulose has good flexibility and can be embedded in the interstitial gap of the high molecular chain of povidone, effectively reducing the interchain force, so that the complex wrapping film formed is softer and has significantly improved tensile resistance, fundamentally reducing the risk of cracking during low-temperature drying. At the same time, the strong adhesion of povidone can make up for the adhesion defects of hydroxypropyl methylcellulose, ensuring the close combination of materials in the preparation, and completely solving the problems of friability and cap falling in the tabletting stage.

[0042] In addition, in order to further strengthen the powder properties of nanocrystal powder, the stabilizer system is additionally introduced into talc in the present scheme. The layered particles of talc can be uniformly dispersed in the nanocrystal suspension, and after low-temperature drying, a dense "physical isolation layer" will be formed on the surface of the nanocrystal powder. Its low surface energy can effectively reduce the molecular attraction between solid powders, and the layered structure has good sliding property, which can reduce the frictional resistance between powder particles, so that the flowability of nanocrystal powder is fundamentally improved through the synergistic effect of the two effects, providing protection for the stable development of the subsequent tabletting process.

[0043] Compared with the prior art, the present application has the following advantages:

[0044] 1) The present application uses high-pressure homogenization technology (HPH) 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 nanocrystallizing the drug, the specific surface area is increased, the dissolution rate is improved, and the drugability of poorly soluble roxithromycin is greatly improved.

[0045] 2) The present application can significantly improve the solubility and bioavailability of roxithromycin by preparing it into nanocrystals without relying on poloxamer 188. This breakthrough not only effectively avoids the cost and process problems of traditional excipients, but also meets the special needs of roxithromycin formulations, significantly reducing production costs while ensuring product quality stability, and showing high commercial value and competitive advantage in the pharmaceutical market.

[0046] 3) The present application proposes a formula scheme for the synergistic use of hypromellose, povidone and talc, which significantly improves the performance of the preparation through multi-component functional complementation. The combination of hypromellose and povidone is the core design that breaks through the limitations of traditional single stabilizer.

[0047] 4) Compared with the traditional wet granulation process, the present application uses nanocrystal technology to completely revolutionize the production path. Nanocrystal technology has significant advantages in industrialized continuous production, with a simple and efficient preparation process that is easy to standardize, greatly reducing the dependence on the professional skills of operators. The subsequent powder direct compression technology further simplifies the production process and reduces intermediate link losses. From raw material input to finished product output, the entire production cycle only takes 3 days, significantly reducing time costs compared to traditional processes, and enabling a quick response to market dynamics, creating considerable economic benefits with lower production costs and higher production efficiency. DETAILED DESCRIPTION

[0048] The present application is further described below in conjunction with examples.

[0049] All raw materials used in the examples are commercially available unless otherwise specified.

[0050] Roxithromycin was purchased from Zhejiang Guobang Pharmaceutical Co., Ltd.;

[0051] Povidone K30 was purchased from BASF (China) Co., Ltd.;

[0052] Hypromellose E5 was purchased from Ashland Chemical (Nanjing) Co., Ltd.;

[0053] Low-substituted hydroxypropyl cellulose LH-22 was purchased from Anhui Shanhe Pharmaceutical Auxiliary Material Co., Ltd.;

[0054] Pre-gelatinized starch was purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd.;

[0055] Colloidal silicon dioxide was purchased from Cabot Corporation;

[0056] Magnesium stearate was purchased from Liao Cheng Ahua Pharmaceutical Auxiliary Material Co., Ltd.;

[0057] Talc was purchased from Laizhou Fengyu Talc Co., Ltd.;

[0058] Lactose monohydrate was purchased from Jiangsu Daoning Pharmaceutical Co., Ltd.

[0059] Microcrystalline cellulose was purchased from Jiangsu Xidian Pharmaceutical Auxiliary Material Co., Ltd.

[0060] Corn starch was purchased from Anhui Shanhe Pharmaceutical Auxiliary Material Co., Ltd.

[0061] Ethanol was purchased from Shandong Longyuquan Pharmaceutical Auxiliary Material Co., Ltd.

[0062] Sodium stearate was purchased from Huzhou Linghu Xiwang Chemical Co., Ltd.

[0063] Example 1

[0064] The preparation method of the roxithromycin preparation is prepared from the following steps:

[0065] A. 150.0 g of roxithromycin raw material was dispersed in 2850.0 g of purified water to obtain a roxithromycin suspension; 3.0 g of hydroxypropyl methyl cellulose E5 was mixed with 9.0 g of povidone K30 to prepare an aqueous solution by adding 108.0 g of purified water, and the aqueous solution was added to the roxithromycin suspension while adding 1.2 g of talc powder, and then a roxithromycin nanocrystal suspension was prepared using a high pressure homogenization method (HPH), the shear speed of the homogenizer was 19000 rpm, and the shear time was 2 min; the pressure of the high pressure homogenizer was 850 bar, and the homogenization times was 15 times, namely the roxithromycin nanocrystal suspension was obtained;

[0066] The suspension prepared by high pressure homogenization method (HPH) was pretreated first, and the small agglomerated particles were removed by vacuum filtration using a 0.22 μm sterile filter membrane, and then the solid content was adjusted to 7.5±2.5% w / v, and then it was divided into stainless steel freeze-drying trays, the liquid loading thickness was controlled to be 7.5±2.5 mm and the suspension was evenly spread by gently shaking; low temperature drying was carried out using an in-situ freeze-drying machine, first the suspension was pre-frozen to below -40℃ in a hard solid state by stepwise rapid freezing (5℃ / min to -20℃ for 30 min, then 10℃ / min to -60℃ for 3 h), then primary drying was carried out at a vacuum degree of 20±10 Pa, a shelf temperature of -25℃ to -20℃ for 10 h, then the shelf temperature was raised to 25±5℃ at a rate of ≤5℃ / h under a vacuum degree of 10 Pa, and secondary drying was carried out for 5 h until the moisture content of the powder was ≤2%; after drying, nitrogen gas with a purity of ≥99.99% and a dew point of ≤-40℃ was introduced into the freeze-drying box to slowly break the vacuum (the pressure recovery rate was ≤0.02 MPa / min), the loose blocky material was scraped off with a stainless steel shovel, and the roxithromycin nanocrystal powder was obtained;

[0067] B. 45.8 g of microcrystalline cellulose is premixed with 10.0 g of low-substituted hydroxypropyl cellulose to obtain a premixture, the premixture, roxithromycin nanocrystal powder and 3.0 g of magnesium stearate are transferred into a lifting granulator (1.2 mm screen) for pretreatment of the materials before mixing, the pretreated materials are added into a total mixing tank for mixing at a speed of 10 r / min for 20 min to obtain roxithromycin total mixed powder;

[0068] C. The roxithromycin total mixed powder is placed in a tablet press for tabletting at a speed of 1.5 million tablets / hour, a main pressure of 5.0 kN and a pre-pressing pressure of 2.0 kN to obtain roxithromycin dispersible tablets.

[0069] The particle size of the filler is: microcrystalline cellulose D90 = 30 μm.

[0070] Example 2

[0071] The preparation method of the roxithromycin preparation is prepared from the following steps:

[0072] A. 150.0 g of roxithromycin raw material is dispersed in 2700.0 g of purified water to obtain a roxithromycin suspension; 2.78 g of hydroxypropyl methyl cellulose E5 is mixed with 8.33 g of povidone K30 to prepare an aqueous solution by adding 99.9 g of purified water, the aqueous solution is added to the roxithromycin suspension while adding 0.67 g of talc powder, then using high pressure homogenization (HPH) to prepare roxithromycin nanocrystal suspension, the shear speed of the homogenizer is 19000 rpm and the shear time is 2 min; the pressure of the high pressure homogenizer is 850 bar and the homogenization times is 15 times, thus obtaining the roxithromycin nanocrystal suspension;

[0073] The suspension prepared by high pressure homogenization (HPH) is pretreated first, and the small agglomerated particles are removed by vacuum filtration using a 0.22 μm sterile filter membrane, then the solid content is adjusted to 7.5±2.5% w / v, and then is divided into stainless steel freeze-drying trays, the liquid loading thickness is controlled to be 7.5±2.5 mm and the suspension is evenly spread by gently shaking; low temperature drying is carried out by using an in-situ freeze-drying machine, first the suspension is pre-frozen to below -40℃ in a stepwise rapid freezing mode (5℃ / min to -20℃ for 30 min, then 10℃ / min to -60℃ for 3 h), then primary drying is carried out at a vacuum degree of 20±10 Pa, a shelf temperature of -25℃ to -20℃ for 10 h, then the shelf temperature is raised to 25±5℃ at a rate of ≤5℃ / h under a vacuum degree of 10 Pa for secondary drying for 5 h until the powder moisture is ≤2%; after drying, nitrogen gas with a purity of ≥99.99% and a dew point of ≤-40℃ is introduced into the freeze-drying box to slowly break the vacuum (the pressure recovery rate is ≤0.02 MPa / min), the tray is taken out and the loose blocky material is scraped off with a stainless steel spatula, and the roxithromycin nanocrystal powder is obtained.

[0074] B, 50.24 g of microcrystalline cellulose is premixed with 7.77 g of low-substituted hydroxypropyl cellulose to obtain a premixture, the premixture, roxithromycin nanocrystal powder and 2.22 g of magnesium stearate are transferred into a lifting granulator (1.2 mm screen) for pretreatment of material mixing, and the pretreated material is added into a total mixing tank for mixing at a speed of 10 r / min for 20 min to obtain roxithromycin total mixed powder;

[0075] C, the roxithromycin total mixed powder is placed in a tablet press for tabletting at a speed of 1.5 million tablets / hour, a main pressure of 5.0 kN and a pre-pressing pressure of 2.0 kN to obtain roxithromycin dispersible tablets.

[0076] The particle size of the filler is: microcrystalline cellulose D90=30 μm.

[0077] Example 3

[0078] The preparation method of the roxithromycin preparation is prepared by the following steps:

[0079] A, 150.0 g of roxithromycin raw material is dispersed in 3000.0 g of purified water to obtain a roxithromycin suspension; 3.33 g of hypromellose E5 is mixed with 9.99 g of povidone K30 to prepare an aqueous solution by adding 119.88 g of purified water, and the aqueous solution is added to the roxithromycin suspension while adding 1.554 g of talc powder, and then a roxithromycin nanocrystal suspension is prepared using a high-pressure homogenization method (HPH), the shear speed of the homogenizer is 19000 rpm, and the shear time is 2 min; the pressure of the high-pressure homogenizer is 850 bar, and the homogenization times is 15 times, thereby obtaining a roxithromycin nanocrystal suspension;

[0080] The suspension prepared by high pressure homogenization (HPH) was pretreated, and the fine agglomerated particles were removed by vacuum filtration using a 0.22 μm sterile filter membrane. Then, the solid content was adjusted to 7.5 ± 2.5% w / v. After that, the suspension was evenly spread by gently shaking and then was divided into stainless steel freeze-drying trays. The thickness of the liquid in the tray was controlled to be 7.5 ± 2.5 mm. The low-temperature drying was performed by using an in-situ freeze-drying machine. The suspension was pre-frozen to below -40°C to a hard solid state by using a stepwise rapid freezing (5°C / min to -20°C for 30 min, and then 10°C / min to -60°C for 3 h). Then, the primary drying was performed at a vacuum degree of 20 ± 10 Pa and a shelf temperature of -25°C to -20°C for 10 h. Subsequently, the shelf temperature was increased to 25 ± 5°C at a rate of ≤5°C / h under a vacuum degree of 10 Pa, and the secondary drying was performed for 5 h until the water content of the powder was ≤2%. After the drying, the nitrogen gas with a purity of ≥99.99% and a dew point of ≤-40°C was slowly introduced into the freeze-drying box to break the vacuum (the pressure recovery rate was ≤0.02 MPa / min). The loose block-shaped material was scraped off from the tray by using a stainless steel shovel, and the roxythromycin nanocrystal powder was obtained.

[0081] B. 41.58 g of microcrystalline cellulose was premixed with 12.21 g of low-substituted hydroxypropyl cellulose to obtain a premix. The premix, the roxythromycin nanocrystal powder, and 3.33 g of magnesium stearate were transferred into a lifting granulator (1.2 mm screen) for pretreatment before mixing of the materials. The pretreated materials were added to a total mixing tank for mixing at a rotation speed of 10 r / min for 20 min to obtain a roxythromycin total mixed powder.

[0082] C. The roxythromycin total mixed powder was placed in a tablet press for tabletting at a tabletting speed of 1.5 million tablets / hour, a main pressure of 5.0 kN, and a pre-pressing pressure of 2.0 kN to obtain roxythromycin dispersible tablets.

[0083] In the embodiment 1, the particle size of the filler was: microcrystalline cellulose D90 = 30 μm.

[0084] Embodiment 4

[0085] In the embodiment 4, the particle size of the filler was: microcrystalline cellulose D90 = 75 μm.

[0086] Embodiment 5

[0087] In the embodiment 5, the stabilizer was a mixture of hydroxypropyl methyl cellulose E5 and povidone K30 at a mass ratio of 1:2.5.

[0088] Embodiment 6

[0089] In the embodiment 6, the stabilizer was a mixture of hydroxypropyl methyl cellulose E5 and povidone K30 at a mass ratio of 1:3.5.

[0090] Example 7

[0091] The difference between this Example 7 and Example 1 is that the lubricant is changed from magnesium stearate to sodium stearate in the same mass fraction.

[0092] Example 8

[0093] The difference between this Example 8 and Example 1 is that the filler is changed from microcrystalline cellulose to lactose monohydrate in the same mass fraction.

[0094] Example 9

[0095] The difference between this Example 9 and Example 1 is that the filler is changed from microcrystalline cellulose to corn starch in the same mass fraction.

[0096] Example 10

[0097] The difference between this Example 10 and Example 1 is that the solvent used in the preparation of roxithromycin nanocrystals is changed from purified water to ethanol.

[0098] Example 11

[0099] The difference between this Example 11 and Example 1 is that the binder used in the preparation of roxithromycin formulation is changed from low-substituted hydroxypropyl cellulose to pregelatinized starch.

[0100] Non-preferred Example 12

[0101] The difference between this Example 12 and Example 1 is that the particle size of the filler is: microcrystalline cellulose D90 = 15 μm.

[0102] Non-preferred Example 13

[0103] The difference between this Example 13 and Example 1 is that the particle size of the microcrystalline cellulose is D90 = 100 μm.

[0104] Non-preferred Example 14

[0105] The difference between this Example 14 and Example 1 is that the screen size is changed from 1.2 mm to 2.0 mm before the material mixing pretreatment.

[0106] Comparative Example 1

[0107] The preparation method of the roxithromycin formulation comprises the following steps:

[0108] (1) 4.0 g colloidal silicon dioxide was mixed with half of the formulation amount (22.5 g) of microcrystalline cellulose, 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 further mixed for 10 min to obtain roxithromycin total mixed powder;

[0109] (2) The roxithromycin total mixed powder was placed in a tablet press to obtain roxithromycin dispersible tablets at a tabletting speed of 10.0 million tablets / hour, a main compression pressure of 4.0 kN, and a pre-compression pressure of 1.0 kN.

[0110] The particle size of the filler was: microcrystalline cellulose D90 = 30 μm.

[0111] Comparative Example 2

[0112] Comparative Example 2 differs from Example 1 in that the types of stabilizers were changed from hydroxypropyl methyl cellulose E5 and povidone K30 to the same mass fraction of poloxamer 188.

[0113] Comparative Example 3

[0114] Comparative Example 3 differs from Example 1 in that the types of stabilizers were changed from hydroxypropyl methyl cellulose E5 and povidone K30 to the same mass fraction of hydroxypropyl methyl cellulose E5.

[0115] Comparative Example 4

[0116] Comparative Example 4 differs from Example 1 in that the types of stabilizers were changed from hydroxypropyl methyl cellulose E5 and povidone K30 to the same mass fraction of povidone K30.

[0117] Comparative Example 5

[0118] Comparative Example 5 differs from Example 1 in that no flow aid talc was added when preparing the roxithromycin nanocrystal suspension.

[0119] Comparative Example 6

[0120] Commercially available roxithromycin tablet original research preparation-Sanofi Aventis France, trade name Rulide ® , batch number: 2PR7A.

[0121] Performance test

[0122] Content uniformity investigation: according to the content uniformity test method of the Chinese Pharmacopoeia, the content uniformity of the roxithromycin total mixed powder of Examples 1-14 and Comparative Example 6 (the reference preparation of Comparative Example 6 was tested for roxithromycin content in the tablet) was investigated, and the test results are shown in Tables 1 and 2.

[0123] Table 1 Content uniformity test table of roxithromycin total mixed powder

[0124]

[0125] Table 2 Content uniformity test table of roxithromycin total mixed powder

[0126]

[0127] The roxithromycin preparation prepared by the present application is detected according to the content uniformity test method of Chinese Pharmacopoeia 0941. The detection data of 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 with the reference preparation, the roxithromycin is prepared into nanocrystals and mixed, which can effectively prepare roxithromycin preparation with uniform quality.

[0128] On the contrary, the test results of non-optimal Examples 12-14 show A+2.2S≥15, which fails to meet the standard of the Pharmacopoeia, and the content uniformity is unqualified. The specific analysis of the reasons is as follows: the particle size of the filler selected in Examples 12-13 exceeds the appropriate range. Whether it is an extremely fine particle or a coarse particle, it will significantly change the specific surface area of the material during the mixing process. Under the condition that the amount of lubricant is fixed, it is difficult to fully wrap the surface of the material, resulting in uneven dispersion of the material during the mixing process, and ultimately leading to unsatisfactory content uniformity results. The unqualified situation of Example 14 is due to the use of a screen mesh with too large a mesh size during the pretreatment of the raw and auxiliary materials before mixing, which cannot effectively disperse the small lumps in the auxiliary materials, making it difficult for the material to be uniformly dispersed during the mixing process, and thus causing the content uniformity to be unqualified.

[0129] From the above data, it can be concluded that the roxithromycin preparation prepared by the present application has accurate dosage, and compared with the reference preparation, it can obtain a preparation with accurate dosage and uniform mixing, and the advantage of accurate dosage is obvious.

[0130] Dissolution curve test: the dissolution curves of roxithromycin preparations of Examples 1, 2, 3, 4, 5, and 6 and Comparative Examples 1 and 6 were investigated, and the test results are shown in Table 3.

[0131] Table 3 Dissolution curve test table of Examples 1, 2, 3, 4, 5, and 6 and Comparative Examples 1 and 6

[0132]

[0133] By analyzing the dissolution curves of the roxithromycin preparations, it was found that the dissolution curves of Examples 1, 2, 3, 4, 5, and 6 were highly fitted with Comparative Example 6 (reference preparation), exhibiting extremely similar dissolution characteristics. This result fully confirmed that preparing roxithromycin into nanocrystals and achieving extremely fine processing of the raw material could significantly improve its solubility in the medium. Through this process optimization, roxithromycin preparations were freed from the dependence on surfactants, and complete drug release could be achieved, effectively ensuring the dissolution efficiency and bioavailability of the preparation.

[0134] Comparative Example 1, due to its preparation process not having any treatment on the roxithromycin raw material and no surfactant added in the prescription, resulted in the drug being unable to be effectively released. This result further highlighted the key role of nanocrystallization processing of the raw material and reasonable addition of excipients in improving the dissolution performance of roxithromycin preparations.

[0135] Roxithromycin preparation shape, appearance, hardness, friability test: according to the Chinese Pharmacopoeia for detection, the shape, appearance, hardness, friability of roxithromycin preparations of Examples 1, 2, 3, 4, 5, and 6 and Comparative Examples 2, 3, 4, 5, and 6 were tested as shown in Table 4.

[0136] Table 4 Shape, appearance, hardness, friability of roxithromycin preparations

[0137]

[0138] The roxithromycin preparation prepared by the present application, according to the Chinese Pharmacopoeia, the shape, appearance, hardness, friability are detected. Example 1, 2, 3, 4, 5, 6 and comparative example 6 (reference preparation) can obtain complete, smooth and uniform white tablets, and the hardness is uniform, and the friability meets the requirements. This is because compared with the reference preparation, the roxithromycin is prepared into nanocrystals, and the stabilizer with adhesive properties is used, and the talc powder is added at the same time, which can cover the surface of the roxithromycin raw material more uniformly. The subsequent process can avoid the problems of traditional roxithromycin preparation such as sticking, cover falling off, cracking, unqualified friability and the like. Comparative examples 2, 3, 4 and 5 are unqualified tablets, the main reason is that comparative example 2 prepares roxithromycin into nanocrystals but does not use stabilizer with adhesive properties, only uses surfactant as stabilizer. Although roxithromycin nanocrystals can be prepared, the subsequent process cannot be guaranteed. Comparative examples 3 and 4 use hydroxypropyl methylcellulose E5 or povidone K30 as stabilizer, which cannot avoid the defects of single stabilizer in the preparation process and cannot be tabletted. Comparative example 5 is an unqualified tablet, and the tablet surface appears a concave indentation due to sticking. The main reason is that talc powder is not added in the preparation of roxithromycin nanocrystal powder, which causes poor flowability and causes sticking. From the characteristics of roxithromycin nanocrystal powder itself, the nanoscale particle size greatly increases the specific surface area, and the van der Waals force and hydrogen bond force between particles are significantly enhanced, which naturally has strong agglomeration tendency. As an anti-adhesive and flow aid commonly used in solid preparations, talc powder has a unique layered crystal structure and low surface energy characteristics, which can play a key role in this process: the small particles of talc powder can uniformly disperse on the surface of roxithromycin nanocrystal particles, like a "physical isolation layer", which can weaken the adsorption force between particles, reduce the agglomeration probability, and significantly improve the overall flowability of the material, ensuring that each mold hole can be accurately filled with the quantitative powder during tabletting; on the other hand, talc powder can coordinate with magnesium stearate in the auxiliary material to play a lubricating role, avoiding the influence of single use of magnesium stearate on the dissolution rate of roxithromycin nanocrystals.

[0139] Roxithromycin total mixed powder powder property test: according to the Chinese Pharmacopoeia, roxithromycin total mixed powder powder property test of example 1-6 and comparative examples 3, 4 and 5 is shown in table 5.

[0140] Table 5 roxithromycin total mixed powder powder property

[0141]

[0142] From the powder property data, it can be seen that the roxithromycin nanocrystal powder prepared by using the stabilizers in combination and adding talc powder simultaneously in Examples 1, 2, 3, 4, 5 and 6 has excellent powder property and good flowability. However, the flowability of the roxithromycin nanocrystal powder prepared by using single stabilizer and without adding talc powder in Comparative Examples 3, 4 and 5 is poor. The reason is that talc powder is not added: on the one hand, the physical isolation and flow-aiding effect between particles are lost, leading to direct contact between particles; on the other hand, the single hydroxypropyl methyl cellulose E5 film is prone to self-agglomeration due to the strong hydrogen bond between molecules, and the polyvidone K30 film is prone to show significant stickiness due to chain entanglement. The two factors act together, which can sharply increase the internal frictional resistance of the nanocrystal particles and significantly enhance the agglomeration tendency of the nanocrystal particles; finally, the drug particle rest angle is increased, the bulk density is decreased, and the flowability is poor.

[0143] As can be seen from the above, the roxithromycin preparation prepared by the present application has obvious advantages over the original preparation.

Claims

1. A roxithromycin formulation, characterized in that, Prepared from roxithromycin raw material, stabilizer, glidant, filler, binder, lubricant; The stabilizer is a mixture of hydroxypropyl methyl cellulose and povidone; The glidant is talc; The preparation method of the roxithromycin preparation is prepared from the following steps: A. Disperse roxithromycin raw material in solvent to obtain roxithromycin suspension; mix hydroxypropyl methyl cellulose and povidone into water to prepare an aqueous solution, add the aqueous solution to the roxithromycin suspension and add talc at the same time, then use high-pressure homogenization method to prepare roxithromycin nanocrystal suspension, dry to obtain roxithromycin nanocrystal powder; B. Premix the filler and the binder to obtain a premix, transfer the premix, roxithromycin nanocrystal powder and lubricant to the lifting granulator for pretreatment before material mixing, add the pretreated material to the total mixing tank for mixing to obtain roxithromycin total mixed powder; C. Place the roxithromycin total mixed powder in the tablet press for tabletting to obtain roxithromycin dispersible tablets.

2. The roxithromycin formulation according to claim 1, characterized in that, Prepared from the following mass fractions of raw materials: Roxithromycin raw material accounts for 67.57%; Stabilizer 5.00%~6.00%; Glidant 0.30%~0.70%; Filler 18.73%~22.63%; Binder 3.50%~5.50%; Lubricant 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, Prepared from the following steps: A. Disperse roxithromycin raw material in solvent to obtain roxithromycin suspension; mix hydroxypropyl methyl cellulose and povidone into water to prepare an aqueous solution, add the aqueous solution to the roxithromycin suspension and add talc at the same time, then use high-pressure homogenization method to prepare roxithromycin nanocrystal suspension, dry to obtain roxithromycin nanocrystal powder; B. Premix the filler and the binder to obtain a premix, transfer the premix, roxithromycin nanocrystal powder and lubricant to the lifting granulator for pretreatment before material mixing, add the pretreated material to the total mixing tank for mixing to obtain roxithromycin total mixed powder; C. Place the roxithromycin total mixed powder in the 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 or 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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