Cefcapene pivoxil composition and preparation process thereof

Abstract

The invention provides a cefcapene pivoxil composition and a preparation process thereof, and relates to the field of pharmaceutical preparations. The cefcapene pivoxil composition disclosed by the invention comprises cefcapene pivoxil particles, and the cefcapene pivoxil particles are prepared by the following process: preparing medicine carrying particles containing the cefcapene pivoxil by using the cefcapene pivoxil and pharmaceutically acceptable auxiliary materials; and heating and melting the hydrophobic coating material into a liquid state to obtain a coating solution, and coating the drug-loaded particles with the coating solution to obtain coated particles. The hydrophobic coating material is heated and melted into a liquid state to coat the drug-loaded particles, and compared with a method for coating by using solid powder, the liquid coating material has lower requirements on equipment and can more conveniently realize control on the coating speed so as to form a more uniform coating layer. And the temperature in the coating process is lower, so that the stability of the cefcapene pivoxil is ensured. In addition, no organic solvent is used in the coating process, so that the preparation is environment-friendly, organic solvent residues in the preparation are avoided, and the safety of the preparation is improved. The preparation process provided by the invention perfectly solves the problems of taste, stability and safety of the cefcapene pivoxil, reduces the requirements on production equipment, is environment-friendly, and powerfully promotes the further development and clinical application of the cefcapene pivoxil preparation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and more specifically, to a cefoperazone composition and its preparation process. Background Technology

[0002] Cefcapene pivoxil hydrochloride, chemically named (6R,7R)-7-[(Z)-2-(2-aminothiazo-4-yl)-2-pentenylamino]-3-[(aminocarbonyl)oxy]methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (2,2-dimethyloxypropoxymethyl) ester, is a third-generation cephalosporin manufactured by Shionogi & Co., Ltd. of Japan. Currently, it is available in tablet and granule formulations. In children, cefcapene pivoxil is clinically used to treat superficial skin infections, deep skin infections, lymphadenitis and lymphadenitis, chronic pyoderma pharyngitis, tonsillitis (including peritonitis and peritonsillar abscess), acute bronchitis, pneumonia, cystitis, pyelonephritis, otitis media, sinusitis, and scarlet fever. In adults, it is mainly used clinically for superficial skin infections, deep skin infections, lymphadenitis and lymphadenitis, chronic pyoderma, secondary infections such as traumatic, burn and surgical wounds, mastitis, perianal abscess, pharyngitis, tonsillitis (including peritonitis, peritonsillar abscess), acute bronchitis, pneumonia, chronic, secondary respiratory tract infections, cystitis, pyelonephritis, urethritis, cervicitis, cholecystitis, cholangitis, batalin gland inflammation, intrauterine infection, pelvic inflammatory disease, dacryoadenitis, oat grain tumors, scapular gland inflammation, otitis externa, otitis media, sinusitis, periodontitis, pericoronary artery inflammation, and mandibular diseases.

[0003] Cefcarpine ester has the following characteristics, which restrict its further development and clinical use: (1) Cefcarpine ester has poor stability. Degradation reactions may occur at multiple sites, including the amide side chain at position 7, the carbamoyl group at position 3, the 4-pentanoyloxymethyl ester and the β-lactam ring, and the primary amine group on the thiazole ring. Therefore, cefcarpine ester will degrade to varying degrees under high temperature, excessive acidity, and excessive alkalinity conditions. (2) Cefcarpine ester has a very bitter taste that is difficult to mask. In order to improve the taste of cefcarpine ester granules, Shionogi Pharmaceutical Co., Ltd. has disclosed a coating preparation method that eliminates unpleasant taste in its patent WO2005039538. This method adds a hydrophobic substance in powder form to a fluidized bed and coats the surface of the granules with hot melt coating to eliminate unpleasant taste. This method requires, on the one hand, the powdered material to be added to the fluidized bed at a controllable rate, which places very strict requirements on the equipment, and is generally difficult to meet the requirements of a fluidized bed; on the other hand, the preparation needs to be heated to above 80°C and the duration is usually more than 10 minutes, so that the coating material of the powdered material can be fully melted and reach a certain amount on the particle surface. Cefaclor is unstable at high temperatures and is prone to degradation and impurities. Summary of the Invention

[0004] One of the objectives of this invention is to provide a preparation process for cefoperazone granules. This process perfectly solves the stability and bitterness problems of cefoperazone through low-temperature coating. The resulting composition has high stability, good taste, and high safety. It also has low equipment requirements, is environmentally friendly, and is suitable for large-scale industrial production.

[0005] Another object of the present invention is to provide a cefoperazone composition prepared by the above-described preparation process.

[0006] The technical solution adopted in this invention is as follows:

[0007] A process for preparing cefoperazone granules includes the following steps:

[0008] Cefoperazone-containing drug-loaded particles were prepared using cefoperazone and pharmaceutically acceptable excipients.

[0009] The hydrophobic coating material is heated and melted into a liquid to obtain a coating solution. The drug-loaded particles are coated with the coating solution to obtain coated particles.

[0010] In a preferred embodiment of the present invention, the coating material accounts for 2%-60% of the weight of the drug-loaded particles.

[0011] In a preferred embodiment of the present invention, the material temperature is controlled at 30-70°C, or 30-65°C, or 30-50°C, or 25-55°C, or 25-45°C during the coating process.

[0012] In a preferred embodiment of the present invention, the material temperature is controlled at 30-60°C, 40-60°C, or 30-45°C during the coating process.

[0013] In a preferred embodiment of the present invention, the drug-loaded particles are prepared by dry granulation.

[0014] In a preferred embodiment of the present invention, a fluidized bed coating method is used to spray the coating liquid onto the drug-loaded particles for coating. The spraying methods include top spraying, bottom spraying, side spraying, and tangential spraying.

[0015] In a preferred embodiment of the present invention, the atomization pressure is 0.05-0.8 MPa and the coating flow rate is 5-2000 g / min.

[0016] In a preferred embodiment of the present invention, the hydrophobic coating material is selected from any one or more of stearyl alcohol, stearic acid, palmitic acid, carnauba wax, hydrogenated castor oil, hydrogenated soybean oil, hydrogenated palm oil, or PEG6000.

[0017] A cefcarpine ester composition comprising cefcarpine ester particles, said cefcarpine ester particles being prepared by any one of the preceding cefcarpine ester particle preparation processes.

[0018] In a preferred embodiment of the present invention, the cefoperazone granules further include any one or more of a diluent, a binder, a disintegrant, a sweetener, and a lubricant.

[0019] In a preferred embodiment of the invention, it further includes sweetening particles, which include sweeteners, binders, and / or disintegrants.

[0020] In a preferred embodiment of the present invention, it further includes a suspending agent, which includes a surfactant and silica.

[0021] In a preferred embodiment of the present invention, the surfactant is selected from any one or more of sodium dodecyl sulfate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene (40) monostearate, polyoxyethylene hydrogenated castor oil 60, and poloxamer.

[0022] In a preferred embodiment of the present invention, the silicon dioxide is hydrophilic silicon dioxide.

[0023] The beneficial effects of this invention are as follows:

[0024] The preparation process of cefoperazone ester granules provided by this invention involves heating and melting a hydrophobic coating material into a liquid state to coat the drug-loaded granules. Compared with coating using solid powder, the liquid coating material has lower equipment requirements, allows for easier control of the coating speed, and results in a more uniform coating layer. Furthermore, the lower temperature during the coating process helps ensure the stability of cefoperazone ester. Additionally, since no organic solvents are used in the coating process, it is environmentally friendly and avoids residual organic solvents in the formulation, thus improving formulation safety. In short, the preparation process of this invention perfectly solves the problems of taste, stability, and safety of cefoperazone ester, while reducing the requirements for production equipment and being environmentally friendly, effectively promoting the further development and clinical application of cefoperazone ester formulations. Detailed Implementation

[0025] In this invention, unless otherwise specified, cefoperazone refers to free cefoperazone or its pharmaceutically acceptable salts or solvates, such as hydrochloride, hydrochloride monohydrate, etc.

[0026] To mask the bitterness of oral formulations, they are typically coated, commonly using sugar coatings and hydrophobic polymer coatings. Hydrophobic polymer coatings usually involve dissolving the coating material in an organic solvent before spraying. This method requires finding a suitable organic solvent to dissolve the coating material, and the use of organic solvents can cause environmental pollution, solvent residue, and other problems. During their research, the inventors discovered that the coating materials suitable for use in this invention have very limited solubility in common organic solvents, making them difficult to dissolve quickly or easily. This hinders the coating process and also presents problems of environmental pollution and solvent residue in the formulation.

[0027] This invention provides a process for preparing cefoperazone ester particles. The process involves melting a hydrophobic coating material into a liquid state and then using this liquid coating material to coat cefoperazone ester-containing drug-loaded particles at a relatively low temperature. This forms a uniform and dense coating layer, masking the bitter taste of cefoperazone ester. Because the coating is performed at a lower temperature, the stability of cefoperazone ester is ensured. Simultaneously, the use of organic solvents is avoided, making the process environmentally friendly and preventing residual organic solvents in the formulation, thus improving formulation safety. The hydrophobic coating material used in this invention can be a waxy substance permitted in the pharmaceutical formulation field, possessing a suitable melting point so that it can be converted into a liquid state by common heating methods and / or temperatures. A suitable melting point can be 40℃-100℃, preferably 50℃-100℃. Therefore, suitable coating materials can be selected from stearyl alcohol (approximately 59°C, melting point, the same below), stearic acid (approximately 71°C), palmitic acid (approximately 63°C), carnauba wax (approximately 74°C-84°C), hydrogenated castor oil (approximately 85°C-88°C), hydrogenated soybean oil (approximately 69°C-71°C), hydrogenated palm oil (approximately 56°C-58°C), and PEG6000 (approximately 58°C-65°C).

[0028] In specific implementation schemes, the weight of the coating material accounts for 2%-60% of the weight of the drug-loaded particles, which can be understood as an increase in the weight of the drug-loaded particles due to coating of approximately 2%-60%. Preferably, the increase in the weight of the drug-loaded particles due to coating is approximately 4%-56%. If the increase in coating weight is too low, such as incomplete coating of the drug-loaded particles, cefoperazone may easily leak out, resulting in a bitter taste. If the increase in coating weight is too high, it may affect disintegration in vivo.

[0029] The present invention provides a cefoperazone composition comprising cefoperazone particles, which are prepared by the preparation process of the present invention.

[0030] In one specific embodiment, the cefoperazone composition of the present invention comprises the aforementioned cefoperazone drug-loaded particles, wherein the drug-loaded particles further comprise one or more pharmaceutically acceptable excipients, including but not limited to diluents, disintegrants, lubricants, binders, sweeteners, or flavorings. As specific examples, the diluent may be selected from any one or more of sucrose, lactose, starch, mannitol, maltitol, sorbitol, xylitol, and microcrystalline cellulose. The disintegrant may be selected from any one or more of croscarmellose sodium, croscarmellose calcium, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch. The lubricant may be selected from any one or more of magnesium stearate, talc, and sodium stearate fumarate. The binder may be selected from any one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, or the aforementioned waxy substances. The sweetener may be selected from any one or more of lactose, sucrose, glucose, xylitol, mannitol, sorbitol, maltose, erythritol, aspartame, saccharin, sodium saccharin, potassium butyrate, or dipotassium glycyrrhizate. The flavoring agent includes, but is not limited to, fruit flavorings, such as orange flavoring and strawberry flavoring. In one specific embodiment, the pharmaceutically acceptable excipients in the drug-loaded particles of the present invention include diluents, disintegrants, binders, and lubricants.

[0031] In one specific embodiment, the cefcapine ester composition further includes a suspending agent. In this specific embodiment, the suspending agent comprises a surfactant and silica. The surfactant is selected from any one or more of sodium dodecyl sulfate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene (40) monostearate, polyoxyethylene hydrogenated castor oil 60, and poloxamer. Preferably, the silica is hydrophilic silica. In this specific embodiment, the surfactant and silica are prepared into suspending particles. The amount of surfactant used is approximately 1%-30% of the mass of cefcapine ester, preferably 5%-25%, more preferably 10%-25%. The amount of silica used is approximately 0.1%-20% of the mass of cefcapine ester, preferably 0.5%-10%, more preferably 1%-10%.

[0032] To further improve the palatability, the cefoperazone composition also includes a sweetener. In one specific embodiment, the sweetener is prepared into sweetened granules together with other acceptable excipients such as binders and / or disintegrants. The mass ratio of sweetened granules to drug-loaded granules is 0.2-1:1, preferably 0.4-1:1, more preferably 0.5-1:1. The particle size of both the sweetened granules and the drug-loaded granules is 20-120 mesh, preferably 30-100 mesh.

[0033] The cefoperazone composition of this invention can be manufactured using any particle manufacturing method commonly used in the art, including wet granulation and dry granulation. Wet granulation refers to the method of adding water and / or an organic solvent and using a binder to form granules. Dry granulation refers to the method of compressing powder to form granules without using water or organic solvents. Preferably, the cefoperazone drug-loaded particles of this invention are produced using dry granulation. The drying, granulation, and grading of the granules can be performed according to conventional methods in the art.

[0034] The coating method for drug-loaded particles in this invention can be any conventional coating method in the art, including but not limited to the rolling coating method, fluidized bed coating method, tube-embedded coating method, and compression coating method. Preferably, the fluidized bed coating method in this invention uses a liquid hydrophobic coating material to coat the drug-loaded particles, that is, the coating material is sprayed onto the drug-loaded particles in a fluidized bed to complete the coating.

[0035] In a specific embodiment, the preparation process of the cefoperazone granules of the present invention includes the following steps:

[0036] Preparation of drug-loaded granules: Raw materials and excipients, excluding lubricant, are prepared according to the prescription and added to a mixer for mixing. Lubricant is then added and mixed again. The resulting mixture is granulated using a dry granulator. Preferably, the dry granulator is configured with a roller gap of 0.5-2.5 mm, a screw feed rate of 40-100 rpm, a hydraulic pressure of 30-100 bar, a granulation rate of 100-150 rpm, and a granulation screen aperture of 0.6-1.0 mm. The prepared dry granules are sieved using a screen to collect the drug-loaded granules. Preferably, the particle size of the drug-loaded granules is 20-120 mesh, more preferably 30-100 mesh.

[0037] Coated granules: After heating the coating material to melt it into a liquid, it is kept at a constant temperature for later use. Drug-loaded granules are added to a fluidized bed, the fan and heater are turned on, and once the material temperature reaches the required value, the molten coating material is sprayed onto the drug-loaded granules in liquid form to coat them, resulting in coated granules. After all the prescribed amount of coating has been sprayed, the heating is turned off, and the material is allowed to cool before the machine is stopped and the granules are discharged. Spraying methods for the coating material include top spraying, bottom spraying, side spraying, and tangential spraying. The material temperature is controlled at 25-70℃ during the coating process. Depending on the spraying method, the atomization pressure during the coating process is 0.05-0.8MPa, and the coating flow rate is 5-2000g / min.

[0038] The inventors discovered during their research that the material temperature has a significant impact on the coating process. If the material temperature is too low, the liquid coating material solution solidifies at the spray nozzle, causing blockage. If the material temperature is too high, the liquid coating material, after being sprayed onto the drug-loaded particles, easily clumps together, making it difficult to ensure uniform coating. Research found that the suitable coating temperature range is not entirely consistent for different coating materials. For example, when using hydrogenated castor oil, a material temperature of 30-70℃ can largely avoid the above two problems; preferably, the material temperature is controlled at 30-60℃. More preferably, the material temperature is controlled at 40-60℃. When the coating material is stearic acid, the suitable material temperature is 30-50℃. When the coating material is carnauba wax, the suitable material temperature is 30-65℃. When the coating material is hydrogenated soybean oil, the suitable material temperature is 25-55℃. When the coating material is PEG6000, the suitable material temperature is 25-45℃. When the material temperature is maintained at 30-45℃, most coating materials can be successfully coated.

[0039] In a specific embodiment, the cefcarpine ester composition is in the form of granules, and the preparation process of the cefcarpine ester granules of the present invention further includes the following steps:

[0040] Preparation of sweet granules: Prepare the binder solution. Mix the remaining excipients using a wet granulator. Add the binder solution to the wet granulator for granulation, dry in a fluidized bed, granulate, and then sieve using a vibrating screen to obtain sweet granules.

[0041] Total mixture: Add the medicated coated granules, sweet granules and added excipients into a mixer and mix.

[0042] The cefoperazone-loaded particles, coated particles, and / or compositions prepared in this invention can be further prepared with one or more of the aforementioned pharmaceutically acceptable excipients to prepare common pharmaceutical formulations in the art, such as tablets, capsules, microcapsules, etc.

[0043] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0044] Example 1

[0045] Different specific formulations were developed in this embodiment to verify the advantages of the preparation process in this invention, as shown in Table 1.

[0046] Table 1 Prescription List

[0047]

[0048] It should be noted that the prescription in this embodiment is only an exemplary prescription composition used to verify the advantages of the preparation process of the present invention, but should not be construed as a limitation of the present invention, that is, the technical effects of the present invention can not be achieved only by the above prescription.

[0049] Example 2

[0050] A cefoperazone granule was prepared according to Formulation 1 in Table 1 of Example 1, specifically including the following steps:

[0051] ① Preparation of drug-loaded granules: All raw and auxiliary materials (excluding lubricant) are prepared according to the prescription and added to a mixer. The mixture is mixed for 10 minutes, followed by adding the lubricant and mixing for another 5 minutes. The mixed material is then granulated using a dry granulator. The roller gap is controlled at 0.7-1.5 mm, the screw feed rate at 60-80 rpm, the hydraulic pressure at 30-70 bar, the granulation rate at 100-150 rpm, and the granulation screen aperture at 0.6-1.0 mm. The prepared dry granules are then sieved, and particles within the 30-100 mesh range are collected to obtain drug-loaded granules.

[0052] ② Low-temperature coating of drug-loaded granules: Hydrogenated castor oil is heated to melt into a liquid and kept at that temperature for later use. The drug-loaded granules are then placed in a fluidized bed, and the fan and heater are turned on. Once the material temperature reaches the required value, the molten hydrogenated castor oil is sprayed onto the drug-loaded granules using a top-spray method for coating. During the coating process, the material temperature is controlled at 30-60℃, the atomization pressure at 0.05-0.3MPa, and the coating flow rate at 5-100g / min. After all the prescribed amount of hydrogenated castor oil has been sprayed, the heating is turned off, and the material is allowed to cool before the machine is stopped and the coated granules are discharged.

[0053] ③ Preparation of sweet granules: A binder is prepared by dispersing / dissolving a portion of aspartame and a portion of hydroxypropyl cellulose in an appropriate amount of water. The remaining aspartame, mannitol, xylitol, hydroxypropyl cellulose, and pregelatinized starch are mixed using a wet granulator. The binder is added to the wet granulator for granulation, dried in a fluidized bed, sized, and then sieved using a vibrating screen to obtain 30-100 mesh granules.

[0054] ④ Total Mixing: Add the drug-coated granules, sweetened granules, and excipients to a mixer and mix for 5 minutes to obtain total mixed granules. The total mixed granules are packaged in 0.5g bags, each containing 50mg of active ingredient (calculated as cefoperazone).

[0055] Example 3

[0056] The preparation of cefoperazone granules according to prescription 2 in Table 1 includes the following steps:

[0057] ① Preparation of drug-loaded particles: Same as in Example 2.

[0058] ② Low-temperature coating of drug-loaded particles: Hydrogenated castor oil is heated to melt it into a liquid and kept at that temperature for later use. The drug-loaded particles are then placed in a fluidized bed, and the fan and heater are turned on. Once the material temperature reaches the required value, the molten hydrogenated castor oil is sprayed onto the drug-loaded particles using a side-spraying method for coating. During the coating process, the material temperature is controlled at 30-60℃, the atomization pressure at 0.1-0.4MPa, and the coating flow rate at 50-500g / min. After all the prescribed amount of hydrogenated castor oil has been sprayed, the heating is turned off, and the material is stopped and discharged after cooling.

[0059] ③ Preparation of sweet granules: Same as in Example 2.

[0060] ④ Total mixing: Same as in Example 2.

[0061] Example 4

[0062] The preparation of cefoperazone granules according to prescription 3 in Table 1 includes the following steps:

[0063] ① Preparation of drug-loaded particles: Same as in Example 2.

[0064] ② Low-temperature coating of drug-loaded particles: Hydrogenated castor oil is heated to melt into a liquid and kept at that temperature for later use. 30-100 mesh drug-loaded particles are added to a fluidized bed. The fan and heater are turned on. Once the material temperature reaches the required value, the molten hydrogenated castor oil is sprayed onto the drug-loaded particles using a bottom spray method for coating. During the coating process, the material temperature is controlled at 30-60℃, the atomization pressure at 0.15-0.7MPa, and the coating flow rate at 100-1000g / min. After all the prescribed amount of hydrogenated castor oil has been sprayed, the heating is turned off, and the material is stopped and discharged after cooling.

[0065] ③ Preparation of sweet granules: Same as in Example 2.

[0066] ④ Total mixing: Same as in Example 2.

[0067] Example 5

[0068] The preparation of cefoperazone granules according to prescription 4 in Table 1 includes the following steps:

[0069] ① Preparation of drug-loaded granules: All raw and excipient materials, except magnesium stearate, are prepared according to the prescription and added to a mixer. The mixture is mixed for 10 minutes, then magnesium stearate is added and mixed for another 5 minutes. The mixed material is then granulated using a dry granulator. The roller gap is controlled at 0.5-2.5 mm, the screw feed rate at 40-100 rpm, the hydraulic pressure at 30-100 bar, the secondary granulation rate at 100-150 rpm, and the granulation screen aperture at 0.8 mm. The prepared dry granules are sieved using 30-mesh and 100-mesh screens, and granules within the 30-100 mesh range are collected to obtain drug-loaded granules.

[0070] ② Low-temperature coating of drug-loaded particles: Hydrogenated castor oil is heated to melt into a liquid and kept at that temperature for later use. Drug-loaded particles in the 30-100 mesh range are added to a fluidized bed, the fan and heater are turned on, and when the material temperature reaches the required value, the molten hydrogenated castor oil is sprayed onto the drug-loaded particles using a rotating tangential spraying method for coating. During the coating process, the material temperature is controlled at 30-60℃, the atomization pressure at 0.2-0.7MPa, and the coating flow rate at 200-2000g / min. After all the prescribed amount of hydrogenated castor oil has been sprayed, the heating is turned off, and the material is stopped and discharged after cooling.

[0071] ③ Preparation of sweet granules: Same as in Example 2.

[0072] ④ Total mixing: Same as in Example 2.

[0073] Example 6

[0074] The preparation of cefoperazone granules according to prescription 5 in Table 1 includes the following steps:

[0075] ① Preparation of drug-loaded particles: Same as in Example 5.

[0076] ② Low-temperature coating of drug-loaded particles: Stearic acid is heated to melt it into a liquid and kept at that temperature for later use. Drug-loaded particles in the range of 30-100 mesh are added to a fluidized bed, the fan and heater are turned on, and when the material temperature reaches the required value, the molten stearic acid is sprayed onto the drug-loaded particles using a rotating tangential spraying method for coating. During the coating process, the material temperature is controlled at 30-50℃, the atomization pressure is 0.2-0.6MPa, and the coating flow rate is 300-1500g / min. After all the prescribed amount of stearic acid has been sprayed, the heating is turned off, and the machine is stopped and the material is discharged after cooling.

[0077] ③ Preparation of sweet granules: Same as in Example 2.

[0078] ④ Total mixing: Same as in Example 2.

[0079] Example 7

[0080] The preparation of cefoperazone granules according to prescription 6 in Table 1 includes the following steps:

[0081] ① Preparation of drug-loaded particles: Same as in Example 2.

[0082] ② Low-temperature coating of drug-loaded particles: Carnauba wax is heated to melt it into a liquid and kept at that temperature for later use. 30-100 mesh drug-loaded particles are added to a fluidized bed. The fan and heater are turned on. Once the material temperature reaches the required value, the molten carnauba wax is sprayed onto the drug-loaded particles using a top-spray method for coating. During the coating process, the material temperature is controlled at 30-65℃, the atomization pressure at 0.1-0.7MPa, and the coating flow rate at 100-1000g / min. After all the prescribed amount of carnauba wax has been sprayed, the heating is turned off, and the material is stopped and discharged after cooling.

[0083] ③ Preparation of sweet granules: Same as in Example 2.

[0084] ④ Total mixing: Same as in Example 2.

[0085] Example 8

[0086] The preparation of cefoperazone granules according to prescription 7 in Table 1 includes the following steps:

[0087] ① Preparation of drug-loaded particles: Same as in Example 2.

[0088] ② Low-temperature coating of drug-loaded particles: Hydrogenated soybean oil is heated to melt into a liquid and kept at a constant temperature. 30-100 mesh drug-loaded particles are added to a fluidized bed. The fan and heater are turned on. Once the material temperature reaches the required value, the melted hydrogenated soybean oil is sprayed onto the drug-loaded particles using a side-spraying method for coating. During the coating process, the material temperature is controlled at 25-55℃, the atomization pressure at 0.05-0.3MPa, and the coating flow rate at 5-100g / min. After all the prescribed amount of hydrogenated soybean oil has been sprayed, the heating is turned off, and the material is stopped and discharged after cooling.

[0089] ③ Preparation of sweet granules: Same as in Example 2.

[0090] ④ Total mixing: Same as in Example 2.

[0091] Example 9

[0092] The preparation of cefoperazone granules according to prescription 8 in Table 1 includes the following steps:

[0093] ① Preparation of drug-loaded particles: Same as in Example 5.

[0094] ② Low-temperature coating of drug-loaded particles: After heating PEG6000 to melt it into a liquid, keep it at that temperature for later use. Add drug-loaded particles in the range of 30-100 mesh into a fluidized bed, turn on the fan and heater, and wait for the material temperature to reach the required value. Then, use a bottom spraying method to spray the melted PEG6000 onto the drug-loaded particles for coating. During the coating process, control the material temperature at 25-45℃, the atomization pressure at 0.1-0.4MPa, and the coating flow rate at 50-500g / min. After all the prescribed amount of PEG6000 has been sprayed, turn off the heater, and after the material cools down, stop the machine and discharge the material.

[0095] ③ Preparation of sweet granules: Same as in Example 2.

[0096] ④ Total mixing: Same as in Example 2.

[0097] Comparative Example 1

[0098] The preparation of cefoperazone granules according to prescription 4 in Table 1 includes the following steps:

[0099] ① Preparation of drug-loaded particles: Same as in Example 5.

[0100] ② High-temperature coating of drug-loaded particles: The drug-loaded particles are placed in a fluidized bed, and the blower and heater are turned on. Once the material temperature reaches 80℃, solid powdered hydrogenated castor oil is added to the fluidized bed, maintaining the material temperature at 80-85℃ during the addition process. After the hydrogenated castor oil is added, the material temperature is maintained at 80-85℃ for 10 minutes for hot-melting. After hot-melting is complete, the heating is turned off, and the material is stopped and discharged after cooling.

[0101] ③ Preparation of sweet granules: Same as in Example 5.

[0102] ④ Total mixing: Same as in Example 5.

[0103] Comparative Example 2

[0104] The preparation of cefoperazone granules according to prescription 4 in Table 1 includes the following steps:

[0105] ① Preparation of drug-loaded particles: Same as in Example 5.

[0106] ② High-temperature coating of drug-loaded particles: The drug-loaded particles are placed in a fluidized bed, and the blower and heater are turned on. Once the material temperature reaches 80℃, solid powdered hydrogenated castor oil is added to the fluidized bed, maintaining the material temperature at 80-85℃ during the addition process. After the hydrogenated castor oil is added, the material temperature is maintained at 80-85℃ for 20 minutes for hot-melting. After hot-melting is complete, the heating is turned off, and the material is stopped and discharged after cooling.

[0107] ③ Preparation of sweet granules: Same as in Example 5.

[0108] ④ Total mixing: Same as in Example 5.

[0109] Comparing the preparation processes of each embodiment and comparative example, the following phenomena were observed: During the implementation of Comparative Example 1 and Comparative Example 2, it was found that when adding solid powdered hydrogenated castor oil to the fluidized bed, it was difficult to control the addition rate of the hydrogenated castor oil. If the addition rate was too fast, the particles in the fluidized bed were prone to agglomeration, resulting in coating failure. However, if the addition rate was too slow, the heating time of the material would be prolonged, leading to excessive growth of impurities. In contrast, in Examples 2-5, the coating process was carried out by spraying liquid coating material with a spray gun, which made it easier to control the coating speed, resulting in a smoother production process and a more uniform coating layer.

[0110] Experimental Example

[0111] 1. Related substances testing

[0112] Referring to the method under the section "Purity(1) Related substances I" in the Japanese Pharmacopoeia JP18 for cefcapene pivoxil hydrochloride fine granules, the related substances in the samples of each example and comparative example were tested and compared with commercially available granules. (Compare with cefcapine hydrochloride granules, manufactured by Shionogi Pharma Co., Ltd. Kanegasaki Plant, batch number: 0012).

[0113] Table 2 shows the results of related substances in the samples of each embodiment and comparative example. The results indicate that the trans isomer content and total impurity content of the samples prepared by the low-temperature coating process are significantly lower than those of the high-temperature hot-melt coating and the granules available in China. (Flomox).

[0114] Table 2 Results related to substances

[0115]

[0116]

[0117] Note: The structural formulas of the trans isomers (related substances) in Table 2 are shown in the figure:

[0118]

[0119] 2. Odor masking effect

[0120] Granules are generally taken by adding a certain amount of water and stirring. If the granules are not completely coated, the raw materials can easily leak out, causing a bitter taste when dissolved in water. Because it is difficult to standardize the stirring intensity and frequency, to ensure consistent testing conditions, the samples were soaked in water for 30 minutes, then filtered, and the amount of cefoperazone dissolved in the water was measured. A high dissolution rate indicates easy leakage of the raw materials. Simultaneously, the taste of each sample was directly evaluated by tasting. The results are shown in Table 3.

[0121] Table 3 Comparison results of odor masking effect

[0122]

[0123]

[0124] Table 3 shows that the uncoated drug-loaded particles had the highest dissolution rate and the strongest bitterness. Examples 2-9, which were coated at low temperatures, showed significantly lower cefoperazone leakage and a marked reduction in bitterness compared to the uncoated drug-loaded particles. Due to the addition of a sweetener to the formulation, Comparative Example 1... The (Flomox) granules also showed good bitterness suppression, but the amount of cefoperazone leakage was higher than in Examples 2-9.

[0125] 3. Dissolution effect

[0126] The dissolution curves of the samples from each embodiment are shown in Table 4. The values ​​of each embodiment and commercially available granules were calculated. The similarity factor (f2) for Flomox is used to determine that the dissolution behavior of two samples is similar if the similarity factor f2 > 50. The results show that all examples are similar to commercially available granules. (Flomox) exhibits similar in vitro dissolution behavior.

[0127] Table 4 Dissolution curve results

[0128]

[0129] Note: The dissolution curves in Table 4 were tested using a paddle method at 50 rpm, a temperature of 37°C, a medium volume of 900 ml, and a pH 5.0 phosphate buffer solution as the dissolution medium.

[0130] In summary, compared with cefoperazone granules prepared by existing coating processes, the cefoperazone granules prepared by the low-temperature liquid coating process provided by this invention exhibit higher stability and significantly reduced formation of related substances. Furthermore, they demonstrate better taste masking and exhibit in vitro dissolution behavior highly similar to the original formulation. Moreover, the low-temperature liquid coating process provided by this invention is easier to operate and control, environmentally friendly, and suitable for large-scale industrial production.

Claims

1. A preparation process for cefoperazone granules, characterized in that, It includes the following steps: Cefoperazone-containing drug-loaded particles were prepared using cefoperazone and pharmaceutically acceptable excipients. The hydrophobic coating material is heated and melted into a liquid to obtain a coating solution. The drug-loaded particles are coated with the coating solution to obtain coated particles.

2. The preparation process of cefoperazone granules according to claim 1, characterized in that, The coating material accounts for 2%-60% of the weight of the drug-loaded particles.

3. The preparation process of cefoperazone granules according to claim 1 or 2, characterized in that, The material temperature is controlled at 30-70℃, 30-65℃, 30-50℃, 25-55℃, or 25-45℃ during the coating process.

4. The preparation process of cefoperazone granules according to claim 3, characterized in that, The material temperature is controlled at 30-60℃, 40-60℃, or 30-45℃ during the coating process.

5. The preparation process of cefoperazone granules according to claim 3, characterized in that, Drug-loaded particles are prepared by dry granulation.

6. The preparation process of cefoperazone granules according to claim 1, characterized in that, The fluidized bed coating method is used to spray the coating liquid onto the drug-loaded particles for coating. The spraying methods include top spraying, bottom spraying, side spraying, and tangential spraying.

7. The preparation process of cefoperazone granules according to claim 6, characterized in that, Atomization pressure 0.05-0.8MPa, coating flow rate 5-2000g / min.

8. The preparation process of cefoperazone granules according to any one of claims 1-7, characterized in that, The hydrophobic coating material is selected from any one or more of stearyl alcohol, stearic acid, palmitic acid, carnauba wax, hydrogenated castor oil, hydrogenated soybean oil, hydrogenated palm oil, or PEG6000.

9. A cefoperazone composition, characterized in that, It includes cefoperazone ester particles, which are prepared by the cefoperazone ester particle preparation process according to any one of claims 1-8.

10. The cefoperazone composition according to claim 9, characterized in that, The cefoperazone granules also include any one or more of the following: diluent, binder, disintegrant, sweetener, and lubricant.

11. The cefoperazone composition according to claim 9, characterized in that, It also includes sweetened particles, which include sweeteners, as well as binders and / or disintegrants.

12. The cefoperazone composition according to any one of claims 9-11, characterized in that, It also includes suspending agents, which include surfactants and silica.

13. The cefoperazone composition according to claim 12, characterized in that, The surfactant is selected from any one or more of sodium dodecyl sulfate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene (40) monostearate, polyoxyethylene hydrogenated castor oil 60, and poloxamer.

14. The cefoperazone composition according to claim 12, characterized in that, The silica is hydrophilic silica.

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