Composition of cefaclor sustained-release tablets and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a cefaclor sustained release tablet composition and a preparation method thereof, the composition comprises a tablet core, the tablet core comprises the following components: 70-80 parts of cefaclor, the particle size d (0.9) of the cefaclor is 40-130 [mu] m; 1-10 parts of a filling agent and / or a pore-foaming agent; 1-10 parts of an adhesive; 10-30 parts of a sustained release material; and 0.3-5 parts of a lubricant and / or a flow aid. The coating layer comprises the following components: 2-10 parts of film coating powder taking HPMC, HPC, PVA, talcum powder or titanium dioxide and the like as a film material, the preparation method comprises wet granulation or one-step granulation, no organic solvent or acrylic resin and other materials are needed, the residual risk caused by difficult-to-clean materials and the environmental pollution caused by the use of the organic solvent are avoided, and the preparation method is simple and convenient. The invention has the advantages of simple prescription, simple process, good product quality, low material cost and high production efficiency.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and particularly to a composition of cefaclor sustained-release tablets and a method for preparing the same. Background Technology

[0002] Cefaclor, as a second-generation cephalosporin antibiotic, is widely used in clinical treatment of various bacterial infections. With increasing demands for patient convenience and adherence in clinical practice, the development of sustained-release cefaclor formulations has attracted significant attention. Currently, several research reports on sustained-release cefaclor formulations have been published, such as Chinese patent CN101897678B, which discloses a sustained-release cefaclor composition using polyacrylic acid resin and magnesium stearate.

[0003] However, existing cefaclor sustained-release formulations suffer from the following drawbacks: First, the formulation is overly complex, typically requiring multiple excipients such as polyacrylates, magnesium stearate, stearic acid, hydroxypropyl cellulose, talc, lactose, mannitol, and hydroxypropyl methylcellulose. Stearic acid and acrylic resins are difficult to clean, posing a high risk of cleaning residues during industrial production and increasing production costs. Second, due to the poor flowability of the raw materials and excipients in cefaclor sustained-release formulations, direct tableting is not feasible. Therefore, existing processes often use organic solvents (such as isopropanol, propylene glycol, and ethanol) or organic solvent binders in aqueous solutions of a certain concentration for granulation, resulting in complex processes and safety hazards. Third, current processes are difficult to produce, involving numerous steps, high costs, and stringent process conditions, making continuous industrial-scale production challenging.

[0004] Therefore, there is an urgent need to develop a cefaclor sustained-release tablet composition and its preparation method that is simple to formulate, has efficient processing, low production cost, good stability, and can be continuously produced industrially. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide a composition for cefaclor sustained-release tablets and a method for preparing the same. This composition has a simple formulation, uses few excipients, and avoids the use of difficult-to-clean materials. It employs a simplified one-step granulation process, does not use organic solvents, and eliminates explosion hazards. The process involves fewer steps, has a high degree of continuous production, and ensures good product release and stability.

[0006] To achieve the above objectives, the present invention provides the following technical solution: The composition of cefaclor extended-release tablets includes: Chip core, the chip core comprising the following components: 70-80 parts of cefaclor, wherein the particle size d(0.9) of the cefaclor is 40-130 μm; 1 to 10 parts of filler and / or porogen; 1-10 parts adhesive; 10-30 portions of sustained-release material; 0.3 to 5 parts of lubricant and / or flow aid; The coating layer comprises 2 to 10 parts of film coating powder.

[0007] Preferably, the filler and / or pore-forming agent is selected from one or more of sucrose, mannitol, microcrystalline cellulose, povidone, starch, dextrin, and hydroxypropyl cellulose; the binder is selected from one or two of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone; the sustained-release material is selected from one or two of hydroxypropyl methylcellulose, sodium alginate, and chitosan; and the lubricant and / or flow aid is selected from one or more of magnesium stearate, stearic acid, sodium stearate fumarate, silica, and colloidal silica.

[0008] More preferably, the filler and / or pore-forming agent is sucrose; the binder is hydroxypropyl cellulose; the sustained-release material is hydroxypropyl methylcellulose; and the lubricant and / or flow aid is magnesium stearate.

[0009] Furthermore, when the sustained-release material includes hydroxypropyl methylcellulose, the standard viscosity of the hydroxypropyl methylcellulose is 2~200 mPa·s.

[0010] In a preferred embodiment of the present invention, the amount of the filler and / or pore-forming agent is 2 to 7 parts; the amount of the adhesive is 3 to 8 parts; the amount of the slow-release material is 15 to 25 parts; the amount of the lubricant and / or flow aid is 0.5 to 2 parts; and the film coating powder is a film coating powder with HPMC, HPC, PVA, talc or titanium dioxide as the film material, and the amount of the film coating powder is 3 to 5.5 parts.

[0011] The present invention also provides a method for preparing the above-mentioned cefaclor sustained-release tablet composition, the method comprising the following steps: (1) One-step granulation: Weigh the raw materials and excipients according to the prescription amount for the tablet core, and directly suck or pour the raw materials and excipients into a fluidized bed for one-step granulation with water or an aqueous solution of binder. During the one-step granulation process, the inlet air temperature is controlled between 40 and 90°C, the material temperature and / or exhaust air temperature is controlled between 25 and 65°C, the liquid spraying atomization pressure is 0.2 to 0.6 MPa, and the moisture content of the dried material is controlled to not exceed 6.5%. (2) Granulation and / or total blend: The material discharged from the fluidized bed is granulated or directly mixed with lubricant and / or flow aid to obtain an intermediate. (3) Tableting: The intermediate is added to a tablet press for tableting. The tablets are made according to the specification of 0.375g (calculated as cefaclor), and the weight of a single tablet is controlled at 480~600mg, and the hardness is controlled at 100~240N. (4) Coating: The pressed raw film is coated, and the weight gain of the coating is controlled to be 3-5.5%.

[0012] Preferably, in step (1), the adhesive is selected from one or two of hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone.

[0013] Preferably, in step (2), if granulation is performed, the granulation is performed using an 8-40 mesh sieve or a sieve or equipment with an aperture of 0.3-2.5 mm.

[0014] More preferably, in step (2), the mixing time is 5 to 10 minutes.

[0015] Furthermore, the lubricant and / or flow aid is preferably one or more of magnesium stearate, stearic acid, sodium stearate fumarate, silica, and colloidal silica, more preferably magnesium stearate or magnesium stearate combined with another lubricant or flow aid.

[0016] The beneficial effects of this invention include: 1. The cefaclor sustained-release tablet composition provided by this invention has a simple formulation, and the number of tablet core excipients can be controlled to ≤4. There is no need to add organic solvents and acrylic resins, thus avoiding the risk of residue from difficult-to-clean materials. The cefaclor sustained-release tablet composition and its preparation method provided by this invention have a simple formulation, a simple process, good product quality, low material cost, and high production efficiency.

[0017] 2. This invention adopts a one-step granulation process, which avoids the problems of material stickiness that easily occur when water or aqueous binder is added during the high-shear wet granulation process, as well as the problems of explosion prevention and environmental pollution faced when adding organic solvents. The production process is simple and highly continuous.

[0018] 3. The preparation method of the present invention can achieve a yield of over 99% after one-step granulation, which is much higher than the yield of traditional wet granulation (about 83%). At the same time, it solves the problem that the flowability of powder material is poor and cannot be compressed into tablets when pressed directly.

[0019] 4. The cefaclor sustained-release tablets prepared by this invention have good release rate, meet the requirements of sustained-release preparations, and have excellent stability. The changes in related substances and content after 30 days of accelerated testing are less than those in the comparative example.

[0020] 5. The process of this invention is simple, has a high degree of continuous production, requires fewer personnel and equipment, has less dust exposure, has a low risk of material contact with moisture absorption, and has lower production costs. It is particularly suitable for large-scale industrial continuous manufacturing in the current centralized procurement environment. Detailed Implementation

[0021] The present invention will be further described in detail below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0022] All raw and auxiliary materials used in this invention are pharmaceutical grade, as detailed below: Cefaclor: Pharmaceutical grade, particle size d(0.9) controlled at 40~130μm.

[0023] Hydroxypropyl methylcellulose (HPMC): Standard viscosity of 2~200 mPa·s can be selected, such as TC-5E (standard viscosity 4~6 mPa·s) produced by Shin-Etsu Chemical Co., Ltd. or Methocel E50 (standard viscosity 40~60 mPa·s) produced by Dow Chemical Company.

[0024] Sucrose: pharmaceutical grade.

[0025] Hydroxypropyl cellulose: Standard viscosity of 150~400 mPa·s can be selected.

[0026] Magnesium stearate: pharmaceutical grade.

[0027] Film coating powder: such as Kollicoat MAE 30 DP produced by BASF or Opadry II produced by Colorcon, specifically film coating powder with HPMC, HPC, PVA, talc or titanium dioxide as the film material.

[0028] Example 1 The composition of cefaclor sustained-release tablets comprises the following components in the tablet core: 75 parts of cefaclor with a particle size d (0.9) of 85 μm; 3 parts of sucrose; 5 parts of hydroxypropyl cellulose; 20.5 parts of hydroxypropyl methylcellulose (standard viscosity 5 mPa·s); 1.5 parts of magnesium stearate; and a coating layer comprising 5 parts of film coating powder.

[0029] The preparation method is as follows: (1) One-step granulation: First, weigh 75g of cefaclor (particle size d(0.9) = 85μm), 3g of sucrose, 5g of hydroxypropyl cellulose, and 20.5g of hydroxypropyl methylcellulose (standard viscosity 5mPa·s), and directly draw these materials into the fluidized bed. Then, use purified water as a binder solution for one-step granulation, wherein the inlet air temperature is controlled at 65℃, the material temperature is controlled at 40℃, the exhaust air temperature is controlled at 35℃, and the spray atomization pressure is 0.4MPa. After granulation, dry the material until the moisture content does not exceed 4.5%, and then remove it from the pot.

[0030] (2) Granulation and mixing: The material discharged from the fluidized bed is granulated through a 20-mesh sieve, and then 1.5g of magnesium stearate is added. The mixture is mixed in a V-type mixer for 8 minutes to obtain an intermediate.

[0031] (3) Tableting: The intermediate is added to a rotary tablet press for tableting. The tablets are made according to the specification of 0.375g (calculated as cefaclor) of cefaclor sustained-release tablets, with the weight of each tablet controlled at 500mg and the hardness controlled at 180N.

[0032] (4) Coating: The pressed sheets are coated in a high-efficiency coating machine using an aqueous dispersion of film coating powder, and the coating weight gain is controlled to be 5%.

[0033] After preparation, the product was placed at 40℃ / 75%RH for stability testing, and the release rate was determined according to the pharmacopoeia method. The test medium was hydrochloric acid solution with pH 1.2.

[0034] Example 2 The composition of cefaclor sustained-release tablets comprises the following components in the tablet core: 70 parts of cefaclor with a particle size d (0.9) of 45 μm; 2 parts of sucrose; 7 parts of hydroxypropyl cellulose; 20 parts of hydroxypropyl methylcellulose (standard viscosity 25 mPa·s); 1 part of magnesium stearate; and a coating layer comprising 3 parts of film coating powder.

[0035] The preparation method is as follows: (1) One-step granulation: First, weigh 70g of cefaclor (particle size d(0.9) = 45μm), 2g of sucrose, 7g of hydroxypropyl cellulose, and 20g of hydroxypropyl methylcellulose (standard viscosity 25mPa·s), and pour these materials directly into the fluidized bed. Then, prepare a 5% hydroxypropyl cellulose aqueous solution as a binder solution for one-step granulation. During the granulation process, the inlet air temperature is controlled at 50℃, the material temperature is controlled at 30℃, the exhaust air temperature is controlled at 28℃, and the spray atomization pressure is 0.3MPa. After granulation, dry the material until the moisture content does not exceed 5.0%, and then remove it from the pot.

[0036] (2) Granulation and mixing: The material discharged from the fluidized bed is granulated through a 15-mesh sieve, and then 1g of magnesium stearate is added. The mixture is then mixed in a three-dimensional mixer for 5 minutes to obtain an intermediate.

[0037] (3) Tableting: The intermediate is added to a rotary tablet press for tableting. The tablets are made according to the specification of 0.375g (calculated as cefaclor) of cefaclor sustained-release tablets, with the weight of each tablet controlled at 535mg and the hardness controlled at 160N.

[0038] (4) Coating: The pressed sheets are coated in a conventional coating pan using an aqueous dispersion of film coating powder, and the coating weight gain is controlled to be 3%.

[0039] Example 3 The composition of cefaclor sustained-release tablets comprises the following components in the tablet core: 80 parts of cefaclor with a particle size d (0.9) of 120 μm; 3.5 parts of mannitol; 3.5 parts of povidone; 15 parts of hydroxypropyl methylcellulose (standard viscosity 100 mPa·s); 1 part of magnesium stearate; 0.5 parts of colloidal silica; and a coating layer comprising 4 parts of film coating powder.

[0040] The preparation method is as follows: (1) One-step granulation: First, weigh 80g of cefaclor (particle size d(0.9) = 120μm), 3.5g of mannitol, 3.5g of povidone, and 15g of hydroxypropyl methylcellulose (standard viscosity 100mPa·s), and directly draw these materials into the fluidized bed. Then, use purified water as a binder solution for one-step granulation, with the inlet air temperature controlled at 75℃, the material temperature controlled at 45℃, the exhaust air temperature controlled at 40℃, and the spray atomization pressure at 0.5MPa. After granulation, dry the material until the moisture content does not exceed 4.0%, and then remove it from the pot.

[0041] (2) Granulation and mixing: The material discharged from the fluidized bed is granulated through a 10-mesh sieve, and then 1g of magnesium stearate and 0.5g of colloidal silica are added. The mixture is then mixed in a double cone mixer for 7 minutes to obtain an intermediate.

[0042] (3) Tableting: The intermediate is added to a rotary tablet press for tableting. The tablets are made according to the specification of 0.375g (calculated as cefaclor) of cefaclor sustained-release tablets, with the weight of each tablet controlled at 470mg and the hardness controlled at 200N.

[0043] (4) Coating: The pressed sheets are coated in a high-efficiency coating machine using an aqueous dispersion of film coating powder, and the coating weight gain is controlled to be 4%.

[0044] Example 4 The composition of cefaclor sustained-release tablets comprises the following components in the tablet core: 75 parts of cefaclor with a particle size d(0.9) of 60 μm; 7 parts of sucrose; 3 parts of hydroxypropyl methylcellulose (standard viscosity 2 mPa·s); 18 parts of hydroxypropyl methylcellulose (standard viscosity 150 mPa·s); 1 part of magnesium stearate; 0.5 parts of silica; and a coating layer comprising 3.5 parts of film coating powder.

[0045] The preparation method is as follows: (1) One-step granulation: First, weigh 75g of cefaclor (particle size d(0.9) = 60μm), 7g of sucrose, 3g of hydroxypropyl methylcellulose (standard viscosity 2mPa·s), and 18g of hydroxypropyl methylcellulose (standard viscosity 150mPa·s), and pour these materials directly into the fluidized bed. Then, prepare a 3% aqueous solution of hydroxypropyl methylcellulose (standard viscosity 2mPa·s) as a binder solution for one-step granulation. During the granulation process, the inlet air temperature is controlled at 60℃, the material temperature is controlled at 35℃, the exhaust air temperature is controlled at 32℃, and the spray atomization pressure is 0.35MPa. After granulation, dry the material until the moisture content does not exceed 5.5%, and then remove it from the pot.

[0046] (2) Granulation and mixing: The material discharged from the fluidized bed is granulated through a 30-mesh sieve, and then 1g of magnesium stearate and 0.5g of silicon dioxide are added. The mixture is mixed in a V-type mixer for 6 minutes to obtain an intermediate.

[0047] (3) Tableting: The intermediate is added to a rotary tablet press for tableting. The tablets are made according to the specification of 0.375g (calculated as cefaclor) of cefaclor sustained-release tablets, with the weight of each tablet controlled at 500mg and the hardness controlled at 150N.

[0048] (4) Coating: The pressed sheets are coated in a conventional coating pan using an aqueous dispersion of film coating powder, and the coating weight gain is controlled to be 3.5%.

[0049] Example 5 The composition of cefaclor sustained-release tablets comprises the following components in the tablet core: 78 parts of cefaclor with a particle size d (0.9) of 100 μm; 5 parts of microcrystalline cellulose; 4 parts of hydroxypropyl cellulose; 12 parts of hydroxypropyl methylcellulose (standard viscosity 60 mPa·s); 1 part of magnesium stearate; and a coating layer comprising 5.5 parts of film coating powder.

[0050] The preparation method is as follows: (1) One-step granulation: First, weigh 78g of cefaclor (particle size d(0.9) = 100μm), 5g of microcrystalline cellulose, 4g of hydroxypropyl cellulose, and 12g of hydroxypropyl methylcellulose (standard viscosity 60mPa·s), and directly draw these materials into the fluidized bed. Then, use purified water as a binder solution for one-step granulation, wherein the inlet air temperature is controlled at 85℃, the material temperature is controlled at 50℃, the exhaust air temperature is controlled at 45℃, and the spray atomization pressure is 0.55MPa. After granulation, dry the material until the moisture content does not exceed 3.8%, and then remove it from the pot.

[0051] (2) Granulation and mixing: The material discharged from the fluidized bed is granulated through a 25-mesh sieve, and then 1g of magnesium stearate is added. The mixture is mixed in a double cone mixer for 10 minutes to obtain an intermediate.

[0052] (3) Tableting: The intermediate is added to a rotary tablet press for tableting. The tablets are made according to the specification of 0.375g (calculated as cefaclor) of cefaclor sustained-release tablets, with the weight of each tablet controlled at 480mg and the hardness controlled at 220N.

[0053] (4) Coating: The pressed sheets are coated in a high-efficiency coating machine using an aqueous dispersion of film coating powder, and the coating weight gain is controlled to be 5.5%.

[0054] Example 6 The composition of cefaclor sustained-release tablets comprises the following components in the tablet core: 73 parts of cefaclor with a particle size d (0.9) of 40 μm; 4 parts of sucrose; 6 parts of hydroxypropyl cellulose; 16 parts of sodium alginate; 1 part of magnesium stearate; and a coating layer comprising 4.5 parts of film coating powder.

[0055] The preparation method is as follows: (1) One-step granulation: First, weigh 73g of cefaclor (particle size d(0.9) = 40μm), 4g of sucrose, 6g of hydroxypropyl cellulose, and 16g of sodium alginate, and pour these materials directly into the fluidized bed. Then, prepare a 4% hydroxypropyl cellulose aqueous solution as a binder solution for one-step granulation. During the granulation process, the inlet air temperature is controlled at 55℃, the material temperature is controlled at 32℃, the exhaust air temperature is controlled at 30℃, and the spray atomization pressure is 0.25MPa. After granulation, dry the material until the moisture content does not exceed 6.0%, and then remove it from the pot.

[0056] (2) Granulation and mixing: The material discharged from the fluidized bed is granulated through a 12-mesh sieve, and then 1g of magnesium stearate is added. The mixture is mixed in a three-dimensional mixer for 9 minutes to obtain an intermediate.

[0057] (3) Tableting: The intermediate is added to a rotary tablet press for tableting. The tablets are made according to the specification of 0.375g (calculated as cefaclor) of cefaclor sustained-release tablets, with the weight of each tablet controlled at 515mg and the hardness controlled at 130N.

[0058] (4) Coating: The pressed sheets are coated in a conventional coating pan using an aqueous dispersion of film coating powder, and the coating weight gain is controlled to be 4.5%.

[0059] 3. Comparative Example To demonstrate the superiority of the technical solution of the present invention, the following comparative examples were designed: Comparative Example 1: High-shear wet granulation of aqueous solution The composition of cefaclor sustained-release tablets comprises the following components in the tablet core: 75 parts of cefaclor with a particle size d (0.9) of 85 μm; 3 parts of sucrose; 5 parts of hydroxypropyl cellulose; 20.5 parts of hydroxypropyl methylcellulose (standard viscosity 5 mPa·s); 1.5 parts of magnesium stearate; and a coating layer comprising 5 parts of film coating powder.

[0060] The composition has the same component ratio as in Example 1, but the preparation method uses high-shear wet granulation of aqueous solution, as detailed below: (1) Add 75g of cefaclor (particle size d(0.9) is 85μm), 3g of sucrose, 5g of hydroxypropyl cellulose and 20.5g of hydroxypropyl methylcellulose (standard viscosity 5mPa·s) to a high shear wet granulator, premix for 5 minutes, with the stirring paddle speed at 3r / s and the cutter speed at 18r / s.

[0061] (2) Add an appropriate amount of purified water to the material within 2 minutes to make soft material. Adjust the stirring speed to 4r / s and the cutting speed to 18r / s. The soft material making time is about 5 minutes.

[0062] (3) The prepared wet granules are wet-sized by passing them through a 10-mesh sieve and then dried in a fluidized bed. The moisture content at the drying endpoint is controlled to be no higher than 6.5%.

[0063] (4) The dried granules are granulated by passing them through a 20-mesh sieve, and 1.5g of magnesium stearate is added and mixed for 5 minutes to obtain an intermediate.

[0064] (5) Add the intermediate to a rotary tablet press for tableting. The tablets are made according to the specification of 0.375g (calculated as cefaclor) of cefaclor sustained-release tablets, with a single tablet weight of 500mg and a hardness of 180N.

[0065] (6) The pressed raw film is coated in a high-efficiency coating machine using an aqueous dispersion of film coating powder, and the coating weight gain is controlled to be 5%.

[0066] Comparative Example 2: Wet Granulation with Organic Solvents The composition of cefaclor sustained-release tablets comprises the following components in the tablet core: 74.5 parts of cefaclor with a particle size d(0.9) of 90 μm; 5 parts of mannitol; 2 parts of acrylic resin L100-55; 15 parts of hydroxypropyl methylcellulose (standard viscosity 40 mPa·s); 2 parts of hydroxypropyl cellulose; 1 part of magnesium stearate; 0.5 parts of stearic acid; and a coating layer comprising 5 parts of film coating powder.

[0067] The preparation method is as follows: (1) First, dissolve 2g of acrylic resin L100-55 and 2g of hydroxypropyl cellulose in an appropriate amount of 95% ethanol to prepare an organic solution.

[0068] (2) Add 74.5g of cefaclor (particle size d(0.9) is 90μm), 5g of mannitol and 15g of hydroxypropyl methylcellulose (standard viscosity 40mPa·s) to a high-shear wet granulator and mix for 5 minutes.

[0069] (3) Add the above organic solution to the mixture for wet granulation. Make soft material for about 5 minutes and then wet granulate through a 15-mesh sieve.

[0070] (4) Place the wet particles in a fluidized bed to dry, and control the moisture content at the drying endpoint to be no higher than 5.0%.

[0071] (5) The dried granules are granulated by passing them through a 20-mesh sieve. 1g of magnesium stearate and 0.5g of stearic acid are added and mixed for 5 minutes to obtain an intermediate.

[0072] (6) Add the intermediate to a rotary tablet press for tableting. The tablets are made according to the specification of 0.375g (calculated as cefaclor) of cefaclor sustained-release tablets, with a single tablet weight of 505mg and a hardness of 170N.

[0073] (7) Coat the pressed sheets in a conventional coating pan using an aqueous dispersion of film coating powder, and control the coating weight gain to 5%.

[0074] Comparative Example 3: Direct compression of powder into tablets The composition of cefaclor sustained-release tablets comprises the following components in the tablet core: 75 parts of cefaclor with a particle size d (0.9) of 85 μm; 3 parts of sucrose; 5 parts of hydroxypropyl cellulose; 20.5 parts of hydroxypropyl methylcellulose (standard viscosity 5 mPa·s); 1.5 parts of magnesium stearate; and a coating layer comprising 5 parts of film coating powder.

[0075] The composition has the same component ratio as in Example 1, but the preparation method uses direct compression of powder into tablets, as detailed below: (1) Add 75g of cefaclor (particle size d(0.9) is 85μm), 3g of sucrose, 5g of hydroxypropyl cellulose, and 20.5g of hydroxypropyl methylcellulose (standard viscosity 5mPa·s) to a V-type mixer and mix for 15 minutes.

[0076] (2) Add 1.5g magnesium stearate and continue mixing for 5 minutes to obtain a mixed powder.

[0077] (3) Add the mixed powder directly to a rotary tablet press for tableting, and try to compress it according to the specification of 0.375g (calculated as cefaclor) of cefaclor sustained-release tablets.

[0078] Note: In actual operation, due to the poor flowability of the material, the tableting process could not be carried out smoothly, and therefore the cefaclor sustained-release tablets could not be successfully prepared.

[0079] 4. Testing and Evaluation To evaluate the effectiveness of the technical solution of the present invention, a series of tests were conducted on the above embodiments and comparative examples, including granulation yield, release rate determination, content determination, moisture determination, related substances determination, and accelerated stability test.

[0080] 4.1 Granulation Yield Test The pelleting yield test was evaluated by calculating the weight ratio of the material before and after pelleting, and the results are shown in Table 1.

[0081] Table 1 Comparison of granulation yields from different preparation methods As shown in Table 1, the fluidized bed one-step granulation method of this invention achieves a granulation yield of over 99.5%, significantly higher than that of the aqueous high-shear wet granulation method in Comparative Example 1 (83.2%) and the organic solvent wet granulation method in Comparative Example 2 (91.4%). This is mainly because the one-step granulation process of this invention avoids losses caused by material stickiness during wet granulation. In particular, in the aqueous high-shear wet granulation method, cefaclor easily forms a sticky substance upon contact with water, leading to significant material adhesion to the equipment surface and losses during wet granulation. Comparative Example 3, due to its direct powder compression, suffers from poor material flowability, making tableting difficult and therefore unsuitable for preparing cefaclor sustained-release tablets.

[0082] 4.2 Release Rate Test According to the second method (paddle method) of the General Chapter IV of the 2020 edition of the Chinese Pharmacopoeia, hydrochloric acid solution with pH 1.2 was used as the dissolution medium, and the rotation speed was 100 r / min. The percentage of drug release at different time points (1h, 2h, 4h) was measured, and the results are shown in Table 2.

[0083] Table 2. Release rate test results of products prepared by different methods Note: The acceptable standard for release rate is that the release of each tablet at 1h, 2h, and 4h should be 20%~40%, 40%~75%, and above 80% of the labeled amount, respectively.

[0084] As shown in Table 2, the cefaclor sustained-release tablets prepared in all embodiments of the present invention meet the release rate requirements, and the release behavior is closely related to the amount and type of sustained-release material. In Examples 1-6, the release rate slows down when the amount of hydroxypropyl methylcellulose increases or the viscosity increases; the release rate accelerates when the amount of filler or pore-forming agent increases. This indicates that the technical solution of the present invention can effectively regulate the drug release behavior by rationally proportioning the sustained-release material and the filler or pore-forming agent.

[0085] Although Comparative Examples 1 and 2 also met the sustained-release requirements, Comparative Example 1, due to its high-shear wet granulation process using aqueous solution, had higher particle density and thus a relatively slower release. Comparative Example 2, with the addition of acrylic resin as a release modifier, had a relatively faster release, approaching the upper limit of the standard. Comparative Example 3 was not suitable for release testing because it could not be successfully prepared into tablets.

[0086] 4.3 Content, moisture and related substances tests According to the content determination method for cefaclor tablets in the 2020 edition of the Chinese Pharmacopoeia, the content of each sample was determined by high performance liquid chromatography; the moisture content was determined by the Karl Fischer method; and the content of related substances was determined according to the related substances test method for cefaclor tablets. The results are shown in Table 3.

[0087] Table 3. Test results of content, moisture and related substances of products prepared by different methods As shown in Table 3, the cefaclor sustained-release tablets prepared in each embodiment of the present invention all have a content in the range of 98.0% to 102.0%, which meets the requirements; the moisture content is controlled between 3.5% and 5.8%, and the content of related substances is all below 0.12%. In contrast, Comparative Example 1 uses high-shear wet granulation with aqueous solution. Due to the longer contact time of the material in water, the hydrolysis of cefaclor increases, resulting in a lower content (97.8%) and a higher content of related substances (0.12%). Although the content of Comparative Example 2 meets the requirements (99.7%), the use of organic solvent granulation may lead to residual solvent problems, and the content of related substances is the highest (0.15%), which may be related to the contact of cefaclor with organic solvents during the preparation process.

[0088] 4.4 Accelerated stability test The prepared samples were subjected to accelerated stability testing at 40℃ / 75%RH. The changes in related substance content and drug content were measured at 0 days, 15 days and 30 days, and the results are shown in Table 4.

[0089] Table 4 Accelerated stability test results The results showed that the cefaclor sustained-release tablets prepared using the present invention had significantly lower levels of related substances on day 0 than the comparative schemes, especially Example 5, which had only 0.07%, while Comparative Examples 1 and 2 had 0.12% and 0.15%, respectively. After accelerated stability testing, Examples 1-6 all showed excellent stability, with Examples 3 and 5 being the most outstanding.

[0090] In Example 3 (80 parts cefaclor, 15 parts hydroxypropyl methylcellulose 100 mPa·s), after 30 days, the related substances increased to only 0.51%, and the content remained at 99.5%. In Example 5 (78 parts cefaclor, 12 parts hydroxypropyl methylcellulose 60 mPa·s), after 30 days, the related substances were 0.48%, and the content was 99.3%. In contrast, in Comparative Example 1 (high-shear wet granulation of aqueous solution), the related substances were as high as 0.95% after 30 days, and the content decreased to 96.5%. Although Comparative Example 2 (wet granulation of organic solvent) showed better stability than Comparative Example 1, it was still inferior to the examples of this invention.

[0091] These results fully demonstrate that the one-step granulation process of the present invention effectively inhibits the hydrolysis of the β-lactam ring by reducing the contact time between cefaclor and water, while the rational formulation design (especially the amount and viscosity selection of the sustained-release material) further enhances product stability. Differences between the examples also indicate that the amount of sustained-release material, viscosity, and product moisture content have a significant impact on stability, with medium viscosity (60-100 mPa·s) hydroxypropyl methylcellulose combined with an appropriate amount of filler achieving the best stability performance.

[0092] Overall, this invention significantly improves the stability of cefaclor extended-release tablets through synergistic optimization of the formulation and process, providing important technical support for the industrial production of this drug.

[0093] 4.5 Process Efficiency Assessment To evaluate the process efficiency of different preparation methods, the total production time, cleaning time, and personnel requirements for each preparation method were recorded, and the results are shown in Table 5.

[0094] Table 5 Comparison of process efficiency of different preparation methods As shown in Table 5, the fluidized bed one-step granulation process of this invention is significantly superior to the comparative preparation method in terms of total production time, cleaning time, and personnel requirements. In particular, compared to Comparative Example 2 (organic solvent wet granulation), the total production time is reduced by approximately 42%, the cleaning time by approximately 47%, and the personnel requirements are reduced by 50%. This is mainly attributed to the simplicity of the one-step granulation process of this invention, which eliminates the need for additional high-shear wet granulation and wet sizing steps, while avoiding the use of difficult-to-clean acrylic resins and organic solvents, thus greatly simplifying the production process and cleaning procedures.

[0095] The superiority of the technical solution of this invention mainly stems from the following technical mechanisms: This invention utilizes hydroxypropyl methylcellulose (HMC) with a specific viscosity (2~200 mPa·s) as a sustained-release material, combined with a water-soluble filler / porogen (such as sucrose), to form a unique sustained-release system. As a hydrophilic polymer, HMC forms a gel layer upon contact with gastrointestinal fluids, controlling drug release through diffusion and erosion mechanisms. Simultaneously, the water-soluble filler forms microporous channels during dissolution, increasing the contact area between the release medium and drug molecules, thereby achieving an ideal sustained-release effect.

[0096] The particle size of cefaclor is controlled within the range of 40–130 μm, ensuring uniform distribution of the drug within the hydrophilic gel matrix and avoiding burst release caused by local aggregation. Simultaneously, this particle size range also facilitates the formation of ideal particle morphology during one-step fluidized bed granulation, improving particle flowability and tableting performance.

[0097] In the fluidized bed one-step granulation process of this invention, cefaclor and excipients are contacted with atomized water or an aqueous solution in a suspended state, forming granules which are then rapidly dried. The short contact time between the drug and water throughout the process reduces the risk of hydrolysis of the cefaclor β-lactam ring. Simultaneously, the material is in motion within the fluidized bed, avoiding material adhesion and agglomeration that easily occur in high-shear wet granulation, significantly improving the granulation yield.

[0098] Furthermore, the porous and loose particles formed by one-step fluidized bed granulation are beneficial for drug release; while the relatively dense particles formed by high-shear wet granulation are not conducive to the penetration of the release medium, which may lead to a slower release rate. This also explains why the release rate of Comparative Example 1 (high-shear wet granulation of aqueous solution) was lower than that of Example 1 at all time points.

[0099] The technical solution of this invention achieves optimized preparation of cefaclor sustained-release tablets through the synergistic effect of the formulation components and the preparation process. Specifically, hydroxypropyl methylcellulose, as a sustained-release material, uniformly encapsulates drug particles during a one-step fluidized bed granulation process, forming a preliminary sustained-release framework; water-soluble fillers such as sucrose form a uniformly distributed pore structure in the fluidized bed; and temperature, pressure, and moisture control during the granulation process ensure appropriate particle size distribution and moisture content, thereby affecting tableting performance and drug stability.

[0100] This prescription-process synergy not only simplifies the production process but also improves the consistency and stability of product quality, which is one of the key innovations of this invention.

[0101] Through the above embodiments and comparative experiments, the present invention demonstrates the following innovative points and unexpected technical effects: This invention is the first to achieve the preparation of cefaclor sustained-release tablets using a simple formulation (≤4 types of tablet core excipients) combined with a one-step fluidized bed granulation process, successfully solving the problems of complex formulations and cumbersome processes in existing technologies. In particular, it avoids the use of difficult-to-clean materials such as acrylic resin and organic solvents, which reduces production costs and eliminates safety hazards. This synergistic innovation of formulation and process represents a significant technological advancement.

[0102] The one-step granulation process of this invention achieves a granulation yield of over 99.5%, far exceeding that of traditional aqueous solution high-shear wet granulation (83.2%) and organic solvent wet granulation (91.4%). This effect exceeds expectations, significantly reducing production costs and improving batch-to-batch consistency, thus ensuring product quality.

[0103] The cefaclor sustained-release tablets prepared according to this invention exhibited excellent performance in accelerated stability testing, with significantly lower increases and decreases in related substances compared to the comparative sample after 30 days. This result demonstrates that the technical solution of this invention effectively improves the long-term stability of the product by reducing the degradation risk of cefaclor during preparation, representing a significant technological breakthrough for β-lactam antibiotic formulations.

[0104] The technical solution of this invention has excellent process adaptability, capable of adapting to hydroxypropyl methylcellulose of different viscosities and different types of fillers / porogens, providing greater flexibility for pharmaceutical formulation production. Furthermore, due to its simple process and high degree of continuity, it is particularly suitable for large-scale industrial continuous manufacturing under the current centralized drug procurement framework, resulting in significant economic and social benefits.

[0105] The cefaclor sustained-release tablet composition and its preparation method provided by this invention have a simple formulation and efficient process, which can well meet the needs of large-scale industrial production. This method avoids the use of organic solvents, reducing environmental pollution; simplifies the process flow, lowers production costs; improves product stability, and extends product shelf life. Therefore, this invention has significant industrial applicability and promotional value.

Claims

1. A composition for cefaclor sustained-release tablets, characterized in that, The composition comprises: Chip core, the chip core comprising the following components: 70-80 parts of cefaclor, wherein the particle size d(0.9) of the cefaclor is 40-130 μm; 1 to 10 parts of filler and / or porogen; 1-10 parts adhesive; 10-30 portions of sustained-release material; 0.3 to 5 parts of lubricant and / or flow aid; The coating layer comprises 2 to 10 parts of film coating powder.

2. The composition according to claim 1, characterized in that, The filler and / or pore-forming agent is selected from one or more of sucrose, mannitol, microcrystalline cellulose, povidone, starch, dextrin, and hydroxypropyl cellulose; the binder is selected from one or two of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone; the sustained-release material is selected from one or two of hydroxypropyl methylcellulose, sodium alginate, and chitosan; and the lubricant and / or flow aid is selected from one or more of magnesium stearate, stearic acid, sodium stearate fumarate, silica, and colloidal silica.

3. The composition according to claim 2, characterized in that, The filler and / or pore-forming agent is sucrose; the binder is hydroxypropyl cellulose; the sustained-release material is hydroxypropyl methylcellulose; and the lubricant and / or flow aid is magnesium stearate.

4. The composition according to claim 2 or 3, characterized in that, When the sustained-release material includes hydroxypropyl methylcellulose, the standard viscosity of the hydroxypropyl methylcellulose is 2~200 mPa·s.

5. The composition according to any one of claims 1-4, characterized in that, The amount of the filler and / or pore-forming agent is 2-7 parts; the amount of the binder is 3-8 parts; the amount of the slow-release material is 15-25 parts; the amount of the lubricant and / or flow aid is 0.5-2 parts; the film coating powder is a film coating powder with HPMC, HPC, PVA, talc or titanium dioxide as the film material, and the amount of the film coating powder is 3-5.5 parts.

6. A method for preparing the cefaclor sustained-release tablet composition according to any one of claims 1-5, characterized in that, The method includes the following steps: (1) One-step granulation: Weigh the raw materials and excipients according to the prescription amount for the tablet core, and directly suck or pour the raw materials and excipients into a fluidized bed for one-step granulation with water or an aqueous solution of binder. During the one-step granulation process, the inlet air temperature is controlled between 40 and 90°C, the material temperature and / or exhaust air temperature is controlled between 25 and 65°C, the liquid spraying atomization pressure is 0.2 to 0.6 MPa, and the moisture content of the dried material is controlled to not exceed 6.5%. (2) Granulation and / or total blend: The material exiting the fluidized bed is granulated or directly mixed with lubricant and / or flow aid to obtain an intermediate. (3) Tableting: The intermediate is added to a tablet press for tableting. The tablets are made according to the specification of 0.375g (calculated as cefaclor), and the weight of a single tablet is controlled at 480~600mg, and the hardness is controlled at 100~240N. (4) Coating: The pressed raw film is coated, and the weight gain of the coating is controlled to be 3-5.5%.

7. The method according to claim 6, characterized in that, In step (1), the adhesive is selected from one or two of hydroxypropyl cellulose, hydroxypropyl methylcellulose and povidone.

8. The method according to claim 6, characterized in that, In step (2), if granulation is performed, the granulation is carried out using an 8-40 mesh sieve or a sieve or equipment with an aperture of 0.3-2.5 mm.

9. The method according to claim 6, characterized in that, In step (2), the mixing time is 5 to 10 minutes.

10. The method according to claim 6, characterized in that, The lubricant and / or flow aid is selected from one or more of magnesium stearate, stearic acid, sodium stearate fumarate, silica and colloidal silica, preferably magnesium stearate or magnesium stearate combined with another lubricant or flow aid.

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