Compound roxithromycin composition and preparation method thereof

Abstract

The invention relates to the technical field of pharmacy, in particular to a compound roxithromycin composition and a preparation method thereof. The compound roxithromycin composition is prepared from the following raw material components: a roxithromycin compound and an ambroxol hydrochloride compound, wherein the roxithromycin compound is obtained by treating roxithromycin with a coating material; the ambroxol hydrochloride compound is obtained by treating ambroxol hydrochloride with a coating material; according to the compound roxithromycin composition and the preparation method thereof, fluidized bed equipment is adopted for treating raw materials, a film coating material is prepared into suspension liquid, ambroxol hydrochloride is wrapped by a compact film formed in a fluidized state, and bitter taste is well covered; and meanwhile, the problem of bitter taste diffusion caused in production is solved, and industrial production is favorably realized.

Description

Technical Field

[0001] This application relates to the technical field of pharmaceuticals, and in particular to a compound roxithromycin composition and a preparation method thereof. Background Art

[0002] Pulmonary infections are usually caused by bacteria, viruses or fungi, and are common and frequently-occurring diseases in the respiratory system. The main clinical manifestations are mainly cough and expectoration, and generally antibiotics are used for treatment; when the lungs are infected, the immune system will release a large number of white blood cells and other inflammatory factors to resist pathogens, resulting in increased sputum. As the infection worsens, the sputum may become thick and sticky, and the sputum will adhere to the tracheal wall and is not easy to cough out; infants with weak cough, the elderly and the infirm need to be combined with expectorant drugs to dilute the sputum and promote the discharge of sputum. Therefore, the effective treatment of pulmonary infections should include reasonable antibacterial treatment and effective drug expectoration.

[0003] Roxithromycin belongs to macrolide antibiotics, has poor water solubility and extremely bitter taste. The characteristic of roxithromycin is that it can quickly enter macrophages, lung cells, alveoli and polymorphonuclear leukocytes. It mainly binds to the 50S ribosomal subunit of bacteria and inhibits the synthesis of bacterial proteins by blocking the transpeptidation and mRNA translocation, thereby playing an antibacterial role.

[0004] Ambroxol hydrochloride, the 8th metabolite of bromhexine, in addition to having a powerful mucus-dissolving effect, its greatest feature is that it can stimulate type II alveolar cells, promote the synthesis and secretion of pulmonary surfactant, regulate the secretion of serous and mucinous substances, increase the secretion of neutral mucopolysaccharides, reduce the synthesis of acidic mucopolysaccharides and promote metabolism, making the physical and chemical properties of respiratory mucus tend to be normal, thereby reducing airway resistance, reducing the adhesion of mucus, activating the mucus cilia function, promoting mucus cilia transport, and enhancing the elimination effect of the respiratory tract. The combination of roxithromycin and ambroxol hydrochloride has a synergistic effect and can effectively treat acute bronchitis (bacterial), acute exacerbation of chronic bronchitis, bronchopneumonia, pneumonia due to typical pathogens, bacterial infection combined with bronchial asthma or bronchiectasis. A compound roxithromycin dispersible tablet and a preparation method thereof are disclosed in the related art, which ensure good forming effect of the tablets and enable them to disintegrate rapidly and exert curative effects; however, for infants, children and other patients with difficulty in swallowing, although the compound preparation reduces the number of medication times and the dispersible dosage form helps to improve the compliance of patients, because this product has an extremely bitter taste, it seriously affects the medication experience of patients.

[0005] Therefore, how to prepare a compound roxithromycin composition without bitterness has become an urgent problem to be solved at present. Summary of the Invention

[0006] In view of the deficiencies of the prior art, this application provides a compound roxithromycin composition and a preparation method thereof.

[0007] The existing Roxithromycin and Ambroxol Hydrochloride Dispersible Tablets have extremely bitter taste. This application provides a taste masking technology for Roxithromycin and Ambroxol Hydrochloride. By using a fluidized bed to add a film coating material, the dense film formed by the film coating material in the fluidized state wraps Roxithromycin and Ambroxol Hydrochloride. After making Roxithromycin and Ambroxol Hydrochloride into dry powder granules, a compound Roxithromycin composition is prepared. By mixing the prepared compound Roxithromycin composition with pharmaceutically acceptable carriers and excipients, pharmaceutical preparations of different dosage forms can be made.

[0008] In the first aspect, this application provides a pharmaceutical composition, adopting the following technical scheme: A compound Roxithromycin composition, comprising the following raw material components: Roxithromycin complex and Ambroxol Hydrochloride complex; wherein, the Roxithromycin complex is obtained by treating Roxithromycin with a film coating material; The Ambroxol Hydrochloride complex is obtained by treating Ambroxol Hydrochloride with a film coating material.

[0009] Preferably, the mass ratio of Roxithromycin to the film coating material in the Roxithromycin complex is (3.3 - 20):1. More preferably, the mass ratio of Roxithromycin to the film coating material in the Roxithromycin complex is (4 - 10):1.

[0010] Preferably, the mass ratio of Ambroxol Hydrochloride to the film coating material in the Ambroxol Hydrochloride complex is (3.3 - 20):1. More preferably, the mass ratio of Ambroxol Hydrochloride to the film coating material in the Ambroxol Hydrochloride complex is (4 - 10):1.

[0011] Preferably, the mass ratio of Roxithromycin in the Roxithromycin complex to Ambroxol Hydrochloride in the Ambroxol Hydrochloride complex is (4 - 5):1.

[0012] Preferably, the preparation steps of the Roxithromycin complex are as follows: Using a fluidized bed to mix the film coating material with Roxithromycin to obtain the Roxithromycin complex.

[0013] Preferably, the preparation steps of the Ambroxol Hydrochloride complex are as follows: Using a fluidized bed to mix the film coating material with Ambroxol Hydrochloride to obtain the Ambroxol Hydrochloride complex.

[0014] By adopting the above technical scheme, this application uses a fluidized bed device to process the raw materials, prepares the film coating material into a suspension, and the dense film formed in the fluidized state wraps Roxithromycin and Ambroxol Hydrochloride, which can well mask the bitter taste.

[0015] In this application, a fluidized bed device is used to process raw materials, which can make the coating material evenly wrap Roxithromycin and Ambroxol Hydrochloride respectively, block the contact between the bitter taste and the taste buds in the mouth, and effectively isolate the bitter taste.

[0016] Preferably, the parameters of the fluidized bed are: top spray, inlet air temperature: 50 - 70 °C, inlet air volume: 40 - 75 CFM, material temperature: 30 - 45 °C, fan frequency: 10 - 40 Hz, liquid supply speed: 10 - 20 g / min, atomization pressure: 1.5 - 2.5 bar.

[0017] Preferably, the coating material is a water-insoluble polymer substance.

[0018] Preferably, the water-insoluble polymer substance includes at least one of ethyl cellulose, cellulose acetate phthalate, and dibutyl sebacate.

[0019] By adopting the above technical solution, this application selects a water-insoluble polymer substance as the coating material. The water-insoluble polymer substance is a dense polymer material, which can not only coat bitter drugs, but also the water-insoluble polymer substance will not quickly break the film in the mouth, thus effectively isolating the bitter taste.

[0020] Preferably, the particle size of the Roxithromycin complex is 100 μm - 300 μm.

[0021] Preferably, the particle size of the Ambroxol Hydrochloride complex is 100 μm - 300 μm.

[0022] By adopting the above technical solution, the particle size of the main drug component particles will increase after fluidization. If the particle size is too large, there will be a gritty feeling in the taste. Therefore, this application controls the particle size of the material after fluidization to effectively reduce the foreign body sensation.

[0023] Preferably, the Roxithromycin complex weighs 5% - 30% more than Roxithromycin; more preferably, the Roxithromycin complex weighs 10% - 25% more than Roxithromycin.

[0024] Preferably, the Ambroxol Hydrochloride complex weighs 5% - 30% more than Ambroxol Hydrochloride; more preferably, the Ambroxol Hydrochloride complex weighs 10% - 25% more than Ambroxol Hydrochloride.

[0025] Among them, the calculation formula for weight gain is as follows: Roxithromycin weight gain (%) = (Roxithromycin complex mass m2 - Roxithromycin mass m1) / Roxithromycin mass m1.

[0026] Ambroxol Hydrochloride weight gain (%) = (Ambroxol Hydrochloride complex mass M2 - Ambroxol Hydrochloride mass M1) / Ambroxol Hydrochloride mass M1.

[0027] Preferably, the compound roxithromycin composition further comprises a pharmaceutically acceptable carrier and an excipient.

[0028] Among them, the pharmaceutically acceptable carrier includes at least one of a disintegrant, a water-soluble substance, a lubricant, a binder, a film-forming agent, and a plasticizer.

[0029] Preferably, the excipient includes at least one of pregelatinized starch, cellulose silicate, and lactose.

[0030] Preferably, the disintegrant includes at least one of crospovidone and croscarmellose sodium.

[0031] Preferably, the water-soluble substance includes at least one of lactose, mannitol, and sorbitol.

[0032] Preferably, the lubricant includes at least one of colloidal silicon dioxide and magnesium stearate.

[0033] Preferably, the binder is povidone.

[0034] Preferably, the film-forming agent includes at least one of ethyl cellulose and cellulose acetate phthalate.

[0035] Preferably, the plasticizer is dibutyl sebacate.

[0036] Preferably, the dosage form of the compound roxithromycin composition is tablets, capsules, granules, powders, or pills.

[0037] In a second aspect, the present application provides a preparation method of a compound roxithromycin composition, adopting the following technical solution: A preparation method of a compound roxithromycin composition, the steps of the preparation method are as follows: (1) Weigh each raw material according to the prescription amount; (2) Preparation of roxithromycin complex: Mix the film coating material and water to obtain a suspension with a mass concentration of 5%-30%; Use a fluidized bed to mix the suspension with roxithromycin to obtain a roxithromycin complex; (3) Preparation of ambroxol hydrochloride complex: Mix the film coating material and water to obtain a suspension with a mass concentration of 5%-30%; Use a fluidized bed to mix the suspension with ambroxol hydrochloride to obtain an ambroxol hydrochloride complex; (4) After mixing the roxithromycin complex, the ambroxol hydrochloride complex with a pharmaceutically acceptable carrier and an excipient, a compound roxithromycin composition is obtained.

[0038] Preferably, the dosage form of the compound roxithromycin composition is tablets, capsules, granules, powders or pills.

[0039] By adopting the above technical solution, the existing roxithromycin ambroxol dispersible tablets have extremely bitter taste. In this application, a fluidized bed device is used to process the raw materials, which can well cover up the bitter taste; the solvent of the film coating material is water, reducing the explosion-proof risk brought by organic solvents during production and the solvent residues in the drug, avoiding the damage of organic solvents to operators, being beneficial to cost reduction, safety improvement and environmental protection; at the same time, it solves the problem of bitter taste diffusion caused by roxithromycin and ambroxol hydrochloride during the production process, being conducive to realizing industrial production.

[0040] The compound roxithromycin composition prepared in this application can be prepared into pharmaceutical preparations of different dosage forms, such as: tablets (ordinary tablets, dispersible tablets, sustained-release tablets, controlled-release tablets), capsules (hard capsules, soft capsules), granules, powders, pills, etc.

[0041] A preparation method of a compound roxithromycin composition disclosed in this application has a simple preparation process. A polymer suspension polymerization dispersant (i.e., suspension) prepared from a water-insoluble polymer substance is used to process roxithromycin and ambroxol hydrochloride respectively by a fluidized bed, and then the obtained materials are mixed with some pharmaceutically acceptable medicinal excipients and shaping agents, and can be prepared into pharmaceutical preparations of different dosage forms; during the production process, the polymer suspension polymerization dispersant (i.e., suspension) prepared from a water-insoluble polymer substance forms a dense film in the fluidized state to wrap roxithromycin and ambroxol hydrochloride, which has a good covering effect on the bitter taste; at the same time, it also solves the problem of bitter taste diffusion caused by roxithromycin and ambroxol hydrochloride during production, being conducive to realizing industrial production.

[0042] In summary, this application includes at least one of the following beneficial technical effects: This application discloses a compound roxithromycin composition and its preparation method. In this application, a fluidized bed is used to process roxithromycin and ambroxol hydrochloride. In the fluidized state, a dense film formed by the film coating material wraps roxithromycin and ambroxol hydrochloride, which has a good covering effect on the bitter taste; This application discloses a compound roxithromycin composition and its preparation method. The solvent of the film coating material is water, reducing the explosion-proof risk brought by organic solvents during production and the solvent residues in the drug, avoiding the damage of organic solvents to operators, being beneficial to cost reduction, safety improvement and environmental protection. Detailed implementation manners

[0043] The technical solutions of this application are further described below through specific examples. The specific examples do not represent limitations on the protection scope of this application; some non-essential modifications and adjustments made by others based on the concept of this application still fall within the protection scope of this application.

[0044] All raw materials involved in this application are commercially available products, among which: Ethyl cellulose, purchased from Ashland, pharmaceutical grade, specification model N50 - N100, viscosity 40 - 105 cps; Cellulose acetate phthalate, purchased from DU PONT, formulated into a suspension of about 8% - 15%; Roxithromycin, purchased from Yichang Dongyangguang Biochemical Pharmaceutical Co., Ltd., particle size about 80 - 110 mesh; Ambroxol hydrochloride, purchased from Yangzhou Sanyao Pharmaceutical Co., Ltd., particle size about 80 - 110 mesh; Pregelatinized starch, purchased from Roquette, model Lycatab C; Polyvinylpyrrolidone, purchased from BASF SE, model K29 - K31 are all acceptable; Crosslinked polyvinylpyrrolidone, purchased from Ashland, model XL type, XXL type are all acceptable; Microcrystalline silica (also called colloidal silica), purchased from Evonik Specialty Chemicals (Shanghai) Co., Ltd.; Silicified microcrystalline cellulose (cellulose silicate), purchased from Jiangsu Xidian Pharmaceutical Excipients Co., Ltd., model SMCC 90; Sorbitol, purchased from Shijiazhuang Ruixue Pharmaceutical Co., Ltd., pharmaceutical grade; Mannitol, purchased from Roquette Management (Shanghai) Co., Ltd., model 100SD, 200SD.

[0045] Croscarmellose sodium, purchased from JRS, model VIVASOL.

[0046] The present application will be further described in detail below in combination with examples and comparative examples.

[0047] The compound roxithromycin composition prepared in the present application can be prepared into pharmaceutical preparations of different dosage forms, such as: tablets (ordinary tablets, dispersible tablets, sustained - release tablets, controlled - release tablets), capsules (hard capsules, soft capsules), granules, powders, pills, etc.

[0048] In the following examples, tablets are taken as an example for illustration.

[0049] Example 1: Preparation of compound roxithromycin tablets A compound roxithromycin tablet, the prescription composition is as follows: Table 1 Raw material components of compound roxithromycin tablets Raw and auxiliary materials Weight (g / 1000 tablets) Roxithromycin complex (calculated as roxithromycin) 150 Ambroxol hydrochloride complex (calculated as ambroxol hydrochloride) 30 Lactose 200 Pregelatinized starch 45 Povidone 5 Crospovidone 15 Aerosil 2 1. Preparation of roxithromycin complex and ambroxol hydrochloride complex, the steps are as follows: (1) Add water to 90 g of ethylcellulose and mix to prepare an ethylcellulose suspension with a mass concentration of 30%. (2) Place 150 g of roxithromycin in a fluidized bed, turn on the blower for heating, and set the parameters as follows: inlet air temperature: 60 °C, inlet air volume: 40 CFM, material temperature 35 °C, blower frequency: 20 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 30% mass concentration ethylcellulose suspension onto roxithromycin, with a liquid supply speed of 10 g / min and an atomization pressure of 1.5 bar for fluidization until the material weight increases by 20% to obtain roxithromycin-ethylcellulose complex (150 mesh, particle size about 104 μm, and the mass ratio of roxithromycin to ethylcellulose in the complex is 5:1).

[0050] (3) Place 30 g of ambroxol hydrochloride in a fluidized bed, turn on the blower for heating, and set the parameters as follows: inlet air temperature: 50 °C, inlet air volume: 50 CFM, material temperature 40 °C, blower frequency: 30 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 30% mass concentration ethylcellulose suspension onto ambroxol hydrochloride, with a liquid supply speed of 15 g / min and an atomization pressure of 2.0 bar for fluidization until the material weight increases by 20% to obtain ambroxol hydrochloride-ethylcellulose complex (150 mesh, particle size about 108 μm, and the mass ratio of ambroxol hydrochloride to ethylcellulose in the complex is 5:1).

[0051] 2. Preparation method of compound roxithromycin tablets, the steps are as follows: Take roxithromycin complex (i.e., roxithromycin-ethylcellulose complex, 150 mesh, particle size about 104 μm), ambroxol hydrochloride complex (i.e., ambroxol hydrochloride-ethylcellulose complex, 150 mesh, particle size about 108 μm), lactose, pregelatinized starch, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, and microcrystalline silica, mix them evenly, and then press tablets with a diamond punch to obtain compound roxithromycin tablets.

[0052] Example 2: Preparation of compound roxithromycin tablets A compound roxithromycin tablet, the prescription composition is as follows: Table 2 Raw material components of compound roxithromycin tablets Raw and auxiliary materials Weight (g / 1000 tablets) Roxithromycin complex (calculated as roxithromycin) 150 Ambroxol hydrochloride complex (calculated as ambroxol hydrochloride) 30 Mannitol 150 Silicified microcrystalline cellulose 21 Sodium carboxymethyl starch 10 Magnesium stearate 5 1. Preparation of roxithromycin complex and ambroxol hydrochloride complex, the steps are as follows: (1) Add water to 115 g of cellulose acetate phthalate and mix to prepare a cellulose acetate phthalate suspension with a mass concentration of 10%. (2) Place 150 g of roxithromycin in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 65 °C, inlet air volume: 55 CFM, material temperature: 45 °C, fan frequency: 30 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 10% (mass concentration) cellulose acetate phthalate suspension onto the roxithromycin, with a liquid supply rate of 20 g / min and an atomization pressure of 2.5 bar for fluidization until the material weight increases by 25%, obtaining the roxithromycin-cellulose acetate phthalate complex (80 mesh, particle size about 180 μm, and the mass ratio of roxithromycin to cellulose acetate phthalate in the complex is 4:1).

[0053] (3) Place 30 g of ambroxol hydrochloride in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 65 °C, inlet air volume: 45 CFM, material temperature: 35 °C, fan frequency: 25 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 10% (mass concentration) cellulose acetate phthalate suspension onto the ambroxol hydrochloride, with a liquid supply rate of 18 g / min and an atomization pressure of 2.3 bar for fluidization until the material weight increases by 15%; obtaining the ambroxol hydrochloride-cellulose acetate phthalate complex (80 mesh, particle size about 180 μm, and the mass ratio of ambroxol hydrochloride to cellulose acetate phthalate in the complex is 20:3).

[0054] 2. Preparation method of compound roxithromycin tablets, the steps are as follows: Take the roxithromycin complex (i.e., roxithromycin-cellulose acetate phthalate complex, 80 mesh, particle size about 180 μm), ambroxol hydrochloride complex (i.e., ambroxol hydrochloride-cellulose acetate phthalate complex, 80 mesh, particle size about 180 μm), mannitol, silicified microcrystalline cellulose, croscarmellose sodium, and magnesium stearate, mix them evenly, and then press tablets with a diamond-shaped punch to obtain compound roxithromycin tablets.

[0055] Example 3: Preparation of compound roxithromycin tablets A kind of compound roxithromycin tablets, the prescription composition is as follows: Table 3 Raw material components of compound roxithromycin tablets Raw and auxiliary materials Weight (g / 1000 tablets) Roxithromycin complex (calculated as roxithromycin) 300 Ambroxol hydrochloride complex (calculated as ambroxol hydrochloride) 75 Lactose 90 Silicified microcrystalline cellulose 25 Crospovidone 5 Magnesium stearate 5 1. Preparation of roxithromycin complex and ambroxol hydrochloride complex, the steps are as follows: (1) Add water to 250 g of dibutyl sebacate for mixing to prepare a 25% (mass concentration) dibutyl sebacate suspension.

[0056] (2) Place 300 g of roxithromycin in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 60 °C, inlet air volume: 40 CFM, material temperature 35 °C, fan frequency: 20 Hz. When the material temperature reaches the set value, turn on the top spray, spray the dibutyl sebacate suspension with a mass concentration of 25% onto roxithromycin, with a liquid supply speed of 15 g / min and an atomization pressure of 2.0 bar for fluidization until the material weight increases by 20%, obtaining a roxithromycin-dibutyl sebacate complex (50 mesh, particle size about 297 μm, and the mass ratio of roxithromycin to dibutyl sebacate in the complex is 5:1).

[0057] (3) Place 75 g of ambroxol hydrochloride in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 50 °C, inlet air volume: 50 CFM, material temperature 40 °C, fan frequency: 30 Hz. When the material temperature reaches the set value, turn on the top spray, spray the dibutyl sebacate suspension with a mass concentration of 25% onto ambroxol hydrochloride, with a liquid supply speed of 13 g / min and an atomization pressure of 1.8 bar for fluidization until the material weight increases by 25%, obtaining an ambroxol hydrochloride-dibutyl sebacate complex (50 mesh, particle size about 300 μm, and the mass ratio of ambroxol hydrochloride to dibutyl sebacate in the complex is 4:1).

[0058] 2. Preparation method of compound roxithromycin tablets, the steps are as follows: Take the roxithromycin complex (i.e., roxithromycin-dibutyl sebacate complex, 50 mesh, particle size about 297 μm), ambroxol hydrochloride complex (i.e., ambroxol hydrochloride-dibutyl sebacate complex, 50 mesh, particle size about 300 μm), lactose, silicified microcrystalline cellulose, crospovidone, and magnesium stearate, mix them evenly, and then press tablets with a diamond-shaped punch die to obtain compound roxithromycin tablets.

[0059] Example 4: Preparation of compound roxithromycin tablets A kind of compound roxithromycin tablets, the prescription composition is as follows: Table 4 Raw material components of compound roxithromycin tablets Raw and auxiliary materials Weight (g / 1000 tablets) Roxithromycin complex (calculated as roxithromycin) 100 Ambroxol hydrochloride complex (calculated as ambroxol hydrochloride) 20 Sorbitol 200 Pregelatinized starch 45 Povidone 5 Crospovidone 15 Aerosil 2 1. Preparation of roxithromycin complex and ambroxol hydrochloride complex, the steps are as follows: (1) Add water to 40 g of ethylcellulose for mixing to prepare an ethylcellulose suspension with a mass concentration of 5%. (2) Place 100 g of roxithromycin in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 60 °C, inlet air volume: 40 CFM, material temperature 35 °C, fan frequency: 20 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 5% (mass concentration) ethylcellulose suspension onto the roxithromycin, with a liquid supply rate of 10 g / min and an atomization pressure of 1.5 bar for fluidization until the material weight increases by 20%, to obtain a roxithromycin-ethylcellulose complex (100 mesh, particle size about 165 μm, and the mass ratio of roxithromycin to ethylcellulose in the complex is 5:1).

[0060] (3) Place 20 g of ambroxol hydrochloride in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 50 °C, inlet air volume: 50 CFM, material temperature 40 °C, fan frequency: 30 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 5% (mass concentration) ethylcellulose suspension onto the ambroxol hydrochloride, with a liquid supply rate of 15 g / min and an atomization pressure of 2.0 bar for fluidization until the material weight increases by 10%, to obtain an ambroxol hydrochloride-ethylcellulose complex (100 mesh, particle size about 150 μm, and the mass ratio of ambroxol hydrochloride to ethylcellulose in the complex is 10:1).

[0061] 2. Preparation method of compound roxithromycin tablets, the steps are as follows: Take the roxithromycin complex (i.e., roxithromycin-ethylcellulose complex, 100 mesh, particle size about 165 μm), ambroxol hydrochloride complex (i.e., ambroxol hydrochloride-ethylcellulose complex, 100 mesh, particle size about 150 μm), sorbitol, pregelatinized starch, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, and microcrystalline silica, mix them evenly, and then press tablets with a diamond-shaped punch die to obtain compound roxithromycin tablets.

[0062] Example 5: Preparation of compound roxithromycin tablets A kind of compound roxithromycin tablets, the prescription composition is as follows: Table 5 Raw material components of compound roxithromycin tablets Raw and auxiliary materials Weight (g / 1000 tablets) Roxithromycin complex (calculated as roxithromycin) 150 Ambroxol hydrochloride complex (calculated as ambroxol hydrochloride) 30 Lactose 200 Pregelatinized starch 45 Povidone 5 Crospovidone 15 Aerosil 2 1. Preparation of roxithromycin complex and ambroxol hydrochloride complex, the steps are as follows: (1) Add water to 90 g of ethylcellulose for mixing to prepare an ethylcellulose suspension with a mass concentration of 30%. (2) Place 150 g of roxithromycin in a fluidized bed, turn on the blower for heating, and set the parameters as follows: inlet air temperature: 60 °C, inlet air volume: 40 CFM, material temperature 35 °C, blower frequency: 20 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 30% (mass concentration) ethylcellulose suspension onto roxithromycin, with a liquid supply rate of 10 g / min and an atomization pressure of 1.5 bar for fluidization until the material weight increases by 10%, to obtain a roxithromycin-ethylcellulose complex (150 mesh, particle size about 100 μm, and the mass ratio of roxithromycin to ethylcellulose in the complex is 10:1).

[0063] (3) Place 30 g of ambroxol hydrochloride in a fluidized bed, turn on the blower for heating, and set the parameters as follows: inlet air temperature: 50 °C, inlet air volume: 50 CFM, material temperature 40 °C, blower frequency: 30 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 30% (mass concentration) ethylcellulose suspension onto ambroxol hydrochloride, with a liquid supply rate of 15 g / min and an atomization pressure of 2.0 bar for fluidization until the material weight increases by 10%, to obtain an ambroxol hydrochloride-ethylcellulose complex (150 mesh, particle size about 103 μm, and the mass ratio of ambroxol hydrochloride to ethylcellulose in the complex is 10:1).

[0064] 2. Preparation method of compound roxithromycin tablets, the steps are as follows: Take the roxithromycin complex (i.e., roxithromycin-ethylcellulose complex, 150 mesh, particle size about 100 μm), ambroxol hydrochloride complex (i.e., ambroxol hydrochloride-ethylcellulose complex, 150 mesh, particle size about 103 μm), lactose, pregelatinized starch, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, and microcrystalline silica, mix them evenly, and then press tablets with a diamond-shaped punch die to obtain compound roxithromycin tablets.

[0065] Example 6: Preparation of compound roxithromycin tablets A kind of compound roxithromycin tablet, the prescription composition is as follows: Table 6 Raw material components of compound roxithromycin tablets Raw and auxiliary materials Weight (g / 1000 tablets) Roxithromycin complex (calculated as roxithromycin) 150 Ambroxol hydrochloride complex (calculated as ambroxol hydrochloride) 30 Lactose 200 Pregelatinized starch 45 Povidone 5 Crospovidone 15 Aerosil 2 1. Preparation of roxithromycin complex and ambroxol hydrochloride complex, the steps are as follows: (1) Add water to 90 g of ethylcellulose for mixing to prepare a 30% (mass concentration) ethylcellulose suspension; (2) Place 150 g of roxithromycin in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 60 °C, inlet air volume: 40 CFM, material temperature 35 °C, fan frequency: 20 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 30% (mass concentration) ethylcellulose suspension onto the roxithromycin, with a liquid supply rate of 10 g / min and an atomization pressure of 1.5 bar for fluidization until the material weight gain reaches 25%, obtaining a roxithromycin-ethylcellulose complex (150 mesh, particle size about 105 μm, and the mass ratio of roxithromycin to ethylcellulose in the complex is 4:1).

[0066] (3) Place 30 g of ambroxol hydrochloride in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 50 °C, inlet air volume: 50 CFM, material temperature 40 °C, fan frequency: 30 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 30% (mass concentration) ethylcellulose suspension onto the ambroxol hydrochloride, with a liquid supply rate of 15 g / min and an atomization pressure of 2.0 bar for fluidization until the material weight gain reaches 25%, obtaining an ambroxol hydrochloride-ethylcellulose complex (150 mesh, particle size about 102 μm, and the mass ratio of ambroxol hydrochloride to ethylcellulose in the complex is 4:1).

[0067] 2. Preparation method of compound roxithromycin tablets, the steps are as follows: Take the roxithromycin complex (i.e., roxithromycin-ethylcellulose complex, 150 mesh, particle size about 105 μm), ambroxol hydrochloride complex (i.e., ambroxol hydrochloride-ethylcellulose complex, 150 mesh, particle size about 102 μm), lactose, pregelatinized starch, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, and microcrystalline silica, mix them evenly, and then press tablets with a diamond-shaped punch die to obtain compound roxithromycin tablets.

[0068] Example 7: Preparation of compound roxithromycin tablets A kind of compound roxithromycin tablets, the prescription composition is as follows: Table 7 Raw material components of compound roxithromycin tablets Raw and auxiliary materials Weight (g / 1000 tablets) Roxithromycin complex (calculated as roxithromycin) 150 Ambroxol hydrochloride complex (calculated as ambroxol hydrochloride) 30 Lactose 200 Pregelatinized starch 45 Povidone 5 Crospovidone 15 Aerosil 2 1. Preparation of roxithromycin complex and ambroxol hydrochloride complex, the steps are as follows: (1) Add water to 90 g of ethylcellulose for mixing to prepare a 30% (mass concentration) ethylcellulose suspension; (2) Place 150 g of roxithromycin in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 60 °C, inlet air volume: 40 CFM, material temperature 35 °C, fan frequency: 20 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 30% (mass concentration) ethylcellulose suspension onto the roxithromycin, with a liquid supply rate of 10 g / min and an atomization pressure of 1.5 bar for fluidization until the material weight increases by 30%, obtaining a roxithromycin-ethylcellulose complex (150 mesh, particle size about 103 μm, and the mass ratio of roxithromycin to ethylcellulose in the complex is 10:3).

[0069] (3) Place 30 g of ambroxol hydrochloride in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 50 °C, inlet air volume: 50 CFM, material temperature 40 °C, fan frequency: 30 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 30% (mass concentration) ethylcellulose suspension onto the ambroxol hydrochloride, with a liquid supply rate of 15 g / min and an atomization pressure of 2.0 bar for fluidization until the material weight increases by 30%, obtaining an ambroxol hydrochloride-ethylcellulose complex (150 mesh, particle size about 105 μm, and the mass ratio of ambroxol hydrochloride to ethylcellulose in the complex is 10:3).

[0070] 2. Preparation method of compound roxithromycin tablets, the steps are as follows: Take the roxithromycin complex (i.e., roxithromycin-ethylcellulose complex, 150 mesh, particle size about 103 μm), ambroxol hydrochloride complex (i.e., ambroxol hydrochloride-ethylcellulose complex, 150 mesh, particle size about 105 μm), lactose, pregelatinized starch, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, and microcrystalline silica, mix them evenly, and then press tablets with a diamond-shaped punch die to obtain compound roxithromycin tablets.

[0071] Example 8: Preparation of compound roxithromycin tablets A kind of compound roxithromycin tablet, the prescription composition is as follows: Table 8 Raw material components of compound roxithromycin tablets Raw and auxiliary materials Weight (g / 1000 tablets) Roxithromycin complex (calculated as roxithromycin) 150 Ambroxol hydrochloride complex (calculated as ambroxol hydrochloride) 30 Lactose 200 Pregelatinized starch 45 Povidone 5 Crospovidone 15 Aerosil 2 1. Preparation of roxithromycin complex and ambroxol hydrochloride complex, the steps are as follows: (1) Add water to 90 g of ethylcellulose for mixing to prepare a 30% (mass concentration) ethylcellulose suspension; (2) Place 150 g of roxithromycin in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 60 °C, inlet air volume: 40 CFM, material temperature 35 °C, fan frequency: 20 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 30% (mass concentration) ethylcellulose suspension onto the roxithromycin, with a liquid supply rate of 10 g / min and an atomization pressure of 1.5 bar for fluidization until the material weight increases by 5%, obtaining a roxithromycin-ethylcellulose complex (150 mesh, particle size about 100 μm, and the mass ratio of roxithromycin to ethylcellulose in the complex is 20:1).

[0072] (3) Place 30 g of ambroxol hydrochloride in a fluidized bed, turn on the fan for heating, and set the parameters as follows: inlet air temperature: 50 °C, inlet air volume: 50 CFM, material temperature 40 °C, fan frequency: 30 Hz. When the material temperature reaches the set value, turn on the top spray, spray the 30% (mass concentration) ethylcellulose suspension onto the ambroxol hydrochloride, with a liquid supply rate of 15 g / min and an atomization pressure of 2.0 bar for fluidization until the material weight increases by 5%, obtaining an ambroxol hydrochloride-ethylcellulose complex (150 mesh, particle size about 108 μm, and the mass ratio of ambroxol hydrochloride to ethylcellulose in the complex is 20:1).

[0073] 2. Preparation method of compound roxithromycin tablets, the steps are as follows: Take the roxithromycin complex (i.e., roxithromycin-ethylcellulose complex, 150 mesh, particle size about 100 μm), ambroxol hydrochloride complex (i.e., ambroxol hydrochloride-ethylcellulose complex, 150 mesh, particle size about 108 μm), lactose, pregelatinized starch, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, and microcrystalline silica, mix them evenly, and then press tablets with a diamond-shaped punch die to obtain compound roxithromycin tablets.

[0074] Comparative Example 1: Compound roxithromycin dispersible tablets prepared by the conventional process A kind of compound roxithromycin tablets, the prescription composition is as follows: Table 9 Raw material components of compound roxithromycin dispersible tablets Raw and auxiliary materials Weight (g / 1000 tablets) Roxithromycin 150 Ambroxol hydrochloride 30 Starch 280 Low-substituted hydroxypropyl cellulose 20 Tween-80 5 1% Hydroxypropyl methylcellulose ethanol solution Appropriate amount Crospovidone 15 Magnesium stearate 5 Preparation method of compound roxithromycin dispersible tablets, the steps are as follows: 1) Respectively crush roxithromycin, ambroxol hydrochloride, starch, and low-substituted hydroxypropyl cellulose through a 120-mesh sieve, and mix them evenly.

[0075] 2) Preparation of the binder: Take the total amount of ethanol solution, add hydroxypropyl methylcellulose and Tween-80 while stirring, and stir until completely dissolved.

[0076] 3) Make the powder in 1) into a soft material with the binder in 2), granulate through an 18-mesh sieve, dry at 40 °C, screen and size through an 18-mesh sieve, add crosslinked polyvinylpyrrolidone and magnesium stearate, mix them evenly, and press tablets to obtain.

[0077] Comparative Example 2: Compound Roxithromycin Sustained Release Tablets Prepared by Conventional Process A compound roxithromycin tablet has the following prescription composition: Table 10 Raw Material Components of Compound Roxithromycin Sustained Release Tablets Raw and auxiliary materials Weight (g / 1000 tablets) Roxithromycin 150 Ambroxol hydrochloride 30 Hydroxypropyl methylcellulose 30 Calcium hydrogen phosphate 85 Stearic acid 12 Silicon dioxide 20 75% Ethanol solution Appropriate amount Magnesium stearate 5 The preparation method of the compound roxithromycin sustained release tablets is as follows: 1) Respectively pass roxithromycin, ambroxol hydrochloride, hydroxypropyl methylcellulose, calcium hydrogen phosphate, stearic acid, and silicon dioxide through a 80-mesh sieve, and mix evenly.

[0078] 2) Add 75% ethanol solution to the above materials, stir while adding to make a suitable soft material, pass through a sieve to make granules, dry at 60°C, size the granules, add magnesium stearate, mix evenly, and press into tablets to obtain the product.

[0079] Performance detection: 1. Detection of dispersion uniformity: According to General Chapter 0100 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition, check according to General Chapter 0921. The inner diameter of the sieve holes of the stainless steel wire mesh is 710 μm, and the water temperature is 15 - 25°C; take 6 tablets of the test sample, and all should disintegrate and pass through the sieve within 3 minutes. If a small amount cannot pass through the sieve, but has softened into a light floating mass without a hard core, it meets the requirements.

[0080] Table 11 Detection Results of Dispersion Uniformity Example Dispersion uniformity Example 1 Complies with regulations Example 2 Complies with regulations Example 3 Complies with regulations Example 4 Complies with regulations Example 5 Complies with regulations Example 6 Complies with regulations Example 7 Complies with regulations Example 8 Complies with regulations Control Example 1 Complies with regulations Control Example 2 Does not comply with regulations (non-dispersed type) Examples 1 - 8 and Comparative Example 1 are qualified in terms of dispersion uniformity in water; Comparative Example 2 is a non-dispersible tablet and shows a softened viscous mass in water. Therefore, Comparative Example 2 is not conducive to swallowing by patients with swallowing difficulties.

[0081] 2. Detection of dissolution in water: Take this product, according to the dissolution test method (Second Method in Appendix XC of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition), use 900 mL of water as the dissolution medium, rotate at 100 revolutions per minute, operate according to the law, take 5 mL of samples at 5 min and 15 min, filter with a filter membrane (pore size not greater than 0.45 μm), and take the subsequent filtrate as the test solution. Separately take 15 mg of ambroxol hydrochloride reference substance, accurately weigh it, place it in a 50 mL volumetric flask, add an appropriate amount of anhydrous ethanol to dissolve it and dilute it to the mark with phosphate buffer solution (pH 5.8), and shake well to obtain the ambroxol hydrochloride reference solution; separately take 15 mg of roxithromycin reference substance, accurately weigh it, place it in a 100 mL volumetric flask, add an appropriate amount of anhydrous ethanol to dissolve it, accurately add 10 mL of the above ambroxol hydrochloride reference solution, and dilute it to the mark with phosphate buffer solution (pH 5.8), and shake well to obtain the reference solution. Use HPLC method to detect the dissolution of roxithromycin and ambroxol hydrochloride in each tablet.

[0082] Table 12 Water dissolution test results Combined with the dissolution test results of Example 1 to Example 7, it can be seen that after 5 minutes of dispersion in water, Example 1 to Example 7 are almost not dissolved, and there is basically no bitterness after oral administration, which shows that the method of the present application has a good masking effect on the bitterness of the main drug.

[0083] Combining the dissolution test results of Example 1 and Example 8, it can be seen that the dissolution amount of Example 8 is large and has a slight bitter taste, indicating that when the mass ratio of the main drug (i.e., roxithromycin or ambroxol hydrochloride) to the coating material is 20:1, the amount of coating material added is too small, so that the coating material is not dense enough to wrap roxithromycin and ethyl cellulose, so there is a slight bitter taste.

[0084] Combining the dissolution test results of Comparative Example 1 and Comparative Example 2, it can be seen that the dissolution amounts of Comparative Example 1 and Comparative Example 2 are relatively large, indicating that the bitterness of the samples prepared in Comparative Example 1 and Comparative Example 2 is not masked.

[0085] 3. Release degree detection: Take this product and follow the dissolution method (Appendix XC Method 2 of Part IV of the 2020 edition of the Chinese Pharmacopoeia), use 900mL of phosphate buffer (pH 5.8, take 8.34g of potassium dihydrogen phosphate and 0.87g of potassium dihydrogen phosphate, add water to dissolve to make 1000ml) as the dissolution medium, the speed is 100 revolutions per minute, operate according to the law, sample 5mL at different times, filter with a filter membrane (pore size not greater than 0.45μm), and take the filtrate as the test solution. Separately take 15 mg of ambroxol hydrochloride reference substance, accurately weigh it, place it in a 50 ml volumetric flask, add an appropriate amount of anhydrous ethanol to dissolve it, add phosphate buffer (pH 5.8) to dilute it to the scale, shake it well, and use it as the ambroxol hydrochloride reference substance solution; separately take 15 mg of roxithromycin reference substance, accurately weigh it, place it in a 100 ml volumetric flask, add an appropriate amount of anhydrous ethanol to dissolve it, accurately add 10 ml of the above-mentioned ambroxol hydrochloride reference substance solution, and dilute it to the scale with phosphate buffer (pH 5.8), shake it well, and use it as the reference substance solution. Take the test sample and reference substance solutions, detect them by HPLC, and calculate the dissolution amount of each roxithromycin and ambroxol hydrochloride tablet. Table 13 Release test results The results showed that the samples prepared in Examples 1 to 6 had stable dissolution rates of roxithromycin and ambroxol hydrochloride, and the drug efficacy could be maintained for 8-12 hours.

[0086] Combining the test results of Example 1 and Example 7, it can be seen that for the sample prepared in Example 7, the dissolution rates of roxithromycin and ambroxol hydrochloride are slightly slow. This indicates that when the mass ratio of the main drug (i.e., roxithromycin or ambroxol hydrochloride) to the film coating material is 10:3, due to the relatively thick insoluble material on the surface and strong barrier properties, the main drug components are not easily dissolved and dispersed. Therefore, the release rate of the sample is slightly slow, which is not conducive to the increase of blood drug concentration in the body, thus achieving the bactericidal effect.

[0087] Combining the test results of Example 1 and Example 8, it can be seen that for the sample prepared in Example 8, the dissolution rates of roxithromycin and ambroxol hydrochloride are completely dissolved in about 2 - 4 hours, and the daily dosing frequency increases; and combining Table 12, it can be seen that Example 8 has a slight bitter taste, indicating that when the mass ratio of the main drug (i.e., roxithromycin or ambroxol hydrochloride) to the film coating material is 20:1, the taste masking effect is not good.

[0088] Combining Table 12 and Table 13, and based on the test results of Example 1 and Examples 5 - 8, it can be seen that the mass ratio of the main drug (i.e., roxithromycin or ambroxol hydrochloride) to the film coating material affects the dissolution amount and dissolution rate of the sample. And when the mass ratio of the main drug (i.e., roxithromycin or ambroxol hydrochloride) to the film coating material is (4 - 10):1, it can ensure the taste while maintaining the stability of the drug effect in the body.

[0089] Existing roxithromycin sustained-release tablets and ambroxol hydrochloride sustained-release tablets are mostly matrix tablets, which cannot be taken in a divided form or dispersed before taking, and are not suitable for infants or patients with difficulty swallowing. The compound roxithromycin tablets prepared in this application can be taken after being dispersed in water, which can ensure the taste while maintaining the stability of the drug effect in the body.

[0090] When the compound roxithromycin composition prepared in this application is prepared into dispersible tablets, it is found that its dispersion uniformity is good and the taste is greatly improved; at the same time, roxithromycin in the compound roxithromycin tablet composition prepared in this application can stably maintain the effective blood drug concentration; the prepared dispersible tablets have a good masking effect on bitterness; at the same time, the dispersibility and sustained-release performance of the compound roxithromycin tablet composition are effectively improved.

Claims

1. A compound roxithromycin composition, characterized in that: The invention comprises the following raw material components: roxithromycin complex and ambroxol hydrochloride complex; Wherein, the roxithromycin complex is obtained by treating roxithromycin with a coating material; The ambroxol hydrochloride complex is obtained by treating the ambroxol hydrochloride with a coating material.

2. A compound roxithromycin composition according to claim 1, characterized in that: The mass ratio of roxithromycin to the coating material in the roxithromycin complex is (3.3-20):1; The mass ratio of ambroxol hydrochloride to the coating material in the ambroxol hydrochloride complex is (3.3-20):1; The ratio of the mass of roxithromycin in the roxithromycin complex to the mass of ambroxol hydrochloride in the ambroxol hydrochloride complex is (4-5):

1.

3. A compound roxithromycin composition according to claim 2, characterized in that: The mass ratio of roxithromycin to the coating material in the roxithromycin complex is (4-10):1; The mass ratio of ambroxol hydrochloride to the coating material in the ambroxol hydrochloride complex is (4-10):

1.

4. A compound roxithromycin composition according to claim 1, characterized in that: The preparation steps of the roxithromycin complex are as follows: using a fluidized bed to mix the coating material with the roxithromycin complex to obtain the roxithromycin complex; The preparation steps of the ambroxol hydrochloride complex are as follows: a coating material and ambroxol hydrochloride are mixed by a fluidized bed to obtain the ambroxol hydrochloride complex.

5. A compound roxithromycin composition according to claim 4, characterized in that: The parameters of the fluidized bed are: top spray, air inlet temperature: 50-70°C, air inlet volume: 40-75CFM, material temperature: 30-45°C, fan frequency: 10-40Hz, liquid supply speed: 10-20g / min, atomization pressure: 1.5-2.5bar.

6. The compound roxithromycin composition according to any one of claims 1 to 4, characterized in that: The coating material is a water-insoluble polymer substance.

7. A compound roxithromycin composition according to claim 6, characterized in that: The water-insoluble polymer substance includes at least one of ethyl cellulose, cellulose acetate phthalate, and dibutyl sebacate.

8. A compound roxithromycin composition according to claim 1, characterized in that: The particle size of the roxithromycin complex is 100 μm-300 μm; the particle size of the ambroxol hydrochloride complex is 100 μm-300 μm; The roxithromycin complex is 5% to 30% heavier than roxithromycin; The ambroxol hydrochloride complex is 5%-30% heavier than ambroxol hydrochloride.

9. A compound roxithromycin composition according to claim 1, characterized in that: The compound roxithromycin composition also includes a pharmaceutically acceptable carrier and an excipient; Wherein, the pharmaceutically acceptable carrier includes at least one of a disintegration promoter, a water-soluble substance, a lubricant, a binder, a film-forming agent, and a plasticizer.

10. A method for preparing a compound roxithromycin composition, characterized in that: The preparation method steps are as follows: (1) Weigh each raw material according to the prescription amount; (2) Preparation of roxithromycin complex: Mix the coating material and water to obtain a suspension with a mass concentration of 5%-30%; The suspension is mixed with the mixture by using a fluidized bed to obtain a roxithromycin complex; (3) Preparation of Ambroxol Hydrochloride Complex: Mix the coating material and water to obtain a suspension with a mass concentration of 5%-30%; The suspension is mixed with ambroxol hydrochloride by using a fluidized bed to obtain an ambroxol hydrochloride complex; (4) mixing the roxithromycin complex and the ambroxol hydrochloride complex with a pharmaceutically acceptable carrier and an excipient to obtain a compound roxithromycin composition; The dosage form of the compound roxithromycin composition is tablet, capsule, granule, powder or pill.

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