Preparation method of cefcapene pivoxil hydrochloride particles

Abstract

The invention provides a preparation method of cefcapene pivoxil hydrochloride granules, and belongs to the technical field of preparation of pharmaceutical preparations. The preparation method comprises the following steps: S1, putting drug-containing taste-masking particles containing cefcapene pivoxil hydrochloride hydrate into a fluidized bed, adjusting the temperature to 35-45 DEG C, and adding a poloxamer 188 solution by adopting fluidized bed bottom spraying to obtain drug-containing particles of which the surfaces are coated with poloxamer; s2, mixing the silicon dioxide, the ferric oxide, the corn starch and the essence, adding the medicated particles and the sweet particles, and mixing to obtain a product. According to the method, the production process is simplified, the production cost is reduced, the production cycle is shortened, a small amount of poloxamer can be quickly dissolved and uniformly distributed on the surfaces of particles, the effect of reducing surface tension can be better exerted, drug-containing particles are prevented from gathering and floating, the drug stability is effectively improved, and the bioavailability is improved. And the drug release amount is not more than 6% according to the release amount reported by the original research drug, and the taste masking effect is good.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a method for preparing cefoperazone hydrochloride granules. Background Technology

[0002] Cefcaptin hydrochloride granules are a third-generation cephalosporin antibiotic developed by Shionogi & Co., Ltd. of Japan. It is an important pediatric antibiotic. Its active precursor is cefcaptin ester, which is converted into the active ingredient cefcaptin in the digestive tract after oral administration. It exerts its bactericidal effect by inhibiting the synthesis of cell walls in susceptible bacteria.

[0003] Cefcaptin hydrochloride has the following characteristics: First, it has poor solubility, is difficult to dissolve in water, and becomes viscous when it comes into contact with water. This characteristic hinders the dissolution of the main drug component, thus adversely affecting the absorption of the drug in the body; Second, it has an extremely strong bitter taste, which is so intense that traditional sweeteners and flavorings cannot mask it, causing serious problems for children taking this drug orally.

[0004] The original drug's invention patent CN102056610B discloses a preparation process for cefoperazone hydrochloride granules involving multiple granulation processes, including dry granulation, fluidized bed melt coating, wet granulation, and hot-melt granulation. This process is complex, has a long production cycle, and low efficiency. The hot-melt granulation process is particularly problematic. Since the amount of material requiring hot-melt granulation (such as poloxamer 188 and silica) is only 1% of the total batch size, large-scale hot-melt granulation machines in general production workshops are unsuitable for this product. Small-scale hot-melt granulation machines or separate purchase of finished raw materials are necessary, increasing production costs and posing a risk of uneven mixing during the addition process. Domestic invention patent CN 119700665A primarily addresses this by changing the type of lubricant, allowing the lubricant to be directly mixed with the drug-containing granules and sweetener, reducing the hot-melt granulation process. However, due to the small amount of lubricant used, the risk of uneven mixing remains. Summary of the Invention This invention provides a method for preparing cefcapine hydrochloride granules, which optimizes the preparation method of cefcapine hydrochloride granules, simplifies the preparation process, shortens the production cycle, reduces production equipment, and increases the uniformity of surfactant.

[0005] This invention proposes a method for preparing cefoperazone hydrochloride granules, comprising the following steps: S1. Place the drug-containing granules containing cefcapine hydrochloride hydrate into a fluidized bed, adjust the temperature to 35-45℃, and add poloxamer 188 solution by bottom spraying the fluidized bed to obtain drug-containing granules coated with poloxamer on the surface. S2. Mix silicon dioxide, ferric oxide, corn starch, and flavoring, then add the medicated granules and sweetener granules, mix, and obtain the product.

[0006] Furthermore, in S1, when using fluidized bed bottom spraying, the fan speed is 1200-2000 r / min; the atomization pressure is 1.0-1.6 bar; and the spray peristaltic pump speed is 1-3 r / min. Furthermore, S1 satisfies at least one of the following conditions: (1) The mass concentration of poloxamer 188 solution is (10~20) g / 100 mL; (2) The mass ratio of cefcapine hydrochloride hydrate to poloxamer 188 is 70:2. Furthermore, in S1, the drug-masked granules containing cefoperazone hydrochloride hydrate are prepared from the following raw materials in parts by weight: Cefcaptin hydrochloride hydrate, 70 parts; Low-substituted hydroxypropyl cellulose, 66 parts; Hydrogenated castor oil, 72 parts; Maltitol, 50 parts; Mannitol, 14 parts; Magnesium stearate, 9 parts.

[0007] Furthermore, in S1, the drug-masked granules containing cefoperazone hydrochloride hydrate are prepared by the following steps: a) Cefcapine hydrochloride hydrate, low-substituted hydroxypropyl methylcellulose, mannitol, maltitol, magnesium stearate, and 50% hydrogenated castor oil are mixed to obtain a premixed powder; the premixed powder is then fed into a dry granulation machine to obtain granules. b) The particles obtained in step a) are sieved through a 30-80 mesh sieve to obtain raw particles; the raw particles are put into a fluidized bed, and when the temperature in the fluidized bed rises to above 83°C, the remaining hydrogenated castor oil is added for melt coating. After coating is completed, the temperature is lowered to obtain drug-masked particles containing cefoperazone hydrochloride hydrate. Furthermore, a) satisfies at least one of the following conditions: (1) Use a universal mixer for mixing; during mixing, the speed is 15-20 r / min and the time is 10-15 min; (2) The process parameters of the dry granulation machine are: screen aperture 0.8-1.0mm, feeding speed 10-15Hz, tableting speed 8-10Hz, granulation speed 12-15Hz, and pressure 20-60kg / cm. b) satisfies at least one of the following conditions: (1) When the fluidized bed is running, the inlet air temperature is 100-130℃; (2) When the fluidized bed is running, the fan speed is 1200-2000 r / min.

[0008] Further, in S2, the sweetener particles are prepared from the following raw materials in parts by weight: Aspartame, 8 portions Xylitol, 93 parts Mannitol, 94 parts Hydroxypropyl cellulose, 8 parts Pregelatinized starch, 6 parts.

[0009] Further, in S2, the sweet granules are prepared by the following steps: A) Hydroxypropyl cellulose is added to water to prepare a hydroxypropyl cellulose solution, which is then used as an adhesive; B) Mix aspartame, mannitol, xylitol, and pregelatinized starch in a wet granulator, add the above-mentioned binder, granulate, granulate by a granulator, and dry in a fluidized bed to obtain sweet granules.

[0010] Furthermore, in S2, silicon dioxide, ferric oxide, corn starch, and flavoring are prepared in the following weight proportions: Flavoring, 1 part; Ferric oxide, 0.5 parts; Cornstarch, 3.5 parts; Silicon dioxide, 3 parts.

[0011] Furthermore, calculated per bag, The medicated granules were prepared from the following raw materials by weight: Cefcaptin hydrochloride hydrate, 70 mg; Low-substituted hydroxypropyl cellulose, 66 mg; Hydrogenated castor oil, 72 mg; Maltitol, 50mg; Mannitol, 14 mg; Magnesium stearate, 9 mg; Poloxamer 188, 2 mg; Sweetener granules are prepared from the following raw materials by weight: Aspartame, 8 mg; Xylitol, 93 mg; Mannitol, 94 mg; Hydroxypropyl cellulose, 8 mg; Pregelatinized starch, 6 mg; Ferric oxide, corn starch, flavoring, and silicon dioxide are prepared from the following raw materials by weight: Flavoring, 1mg; Ferric oxide, 0.5 mg; Corn starch, 3.5 mg; Silicon dioxide, 3 mg.

[0012] This invention has the following advantages: The method for preparing cefoperazone hydrochloride granules proposed in this invention uses the same formulation and dosage as the original formulation. Through a specific preparation method, poloxamer is coated onto the surface of the drug-containing granules. This method directly eliminates the need for the hot-melt granulation steps of the surfactant poloxamer 188 and silica in the original formulation, thereby simplifying the production process, reducing production costs, and shortening the production cycle. It ensures that a small amount of poloxamer 188 dissolves rapidly and is evenly distributed on the granule surface, better reducing surface tension and preventing the drug-containing granules from agglomerating and floating, effectively improving drug stability. Moreover, the drug release amount is consistent with the reported release amount of the original drug, which does not exceed 6%, and the taste masking effect is excellent. Detailed Implementation

[0013] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Unless otherwise specified, the embodiments and features in the embodiments of the present invention can be combined with each other.

[0014] This invention provides a method for preparing cefoperazone hydrochloride granules, comprising the following steps: S1. Place the drug-containing granules containing cefcapine hydrochloride hydrate into a fluidized bed, adjust the temperature to 35-45℃, and add poloxamer 188 solution by bottom spraying the fluidized bed to obtain drug-containing granules coated with poloxamer on the surface. S2. Mix silicon dioxide, ferric oxide, corn starch and flavoring, add medicated granules and sweet granules, mix to obtain the product.

[0015] In the preparation method of cefoperazone hydrochloride granules proposed in this invention, poloxamer 188 is coated onto the surface of the drug-containing granules through bottom spraying in a fluidized bed under specific conditions. This directly eliminates the need for the hot-melt granulation step of the surfactant in the original formulation, thereby simplifying the production process, reducing costs, and shortening the production cycle. Simultaneously, it ensures that a small amount of poloxamer dissolves rapidly and is evenly distributed on the granule surface, better reducing surface tension and preventing the drug-containing granules from agglomerating and floating, effectively improving drug stability. Furthermore, the drug release still meets the reported release level of no more than 6% for the original drug, and the taste masking effect is excellent.

[0016] In existing research, due to the poor solubility of cefoperazone hydrochloride and its viscous consistency upon contact with water, no one has used an aqueous solution of the surfactant poloxamer 188 for spraying drug-containing particles. However, the inventors of this application have discovered through extensive research that by controlling the spraying concentration and spraying conditions of the poloxamer 188 solution, a uniform and effective distribution of poloxamer 188 on the particle surface can be achieved. Furthermore, the cefoperazone hydrochloride particles dissolve rapidly in water without floating, and exhibit excellent taste masking effects.

[0017] In this embodiment of the invention, in S1, when using fluidized bed bottom spraying, the temperature of the material is 35-45°C. This temperature is conducive to the rapid evaporation of moisture while leaving poloxamer 188 on the particle surface.

[0018] In one embodiment of the present invention, in S1, when using fluidized bed bottom spraying, the fan speed is 1200-2000 r / min; the atomization pressure is 1.0-1.6 bar; and the spray peristaltic pump speed is 1-3 r / min. In this embodiment of the present invention, by controlling the conditions of fluidized bed bottom spraying, poloxamer 188 solution can be rapidly and uniformly sprayed onto the surface of drug-containing particles. In this way, the surfactant poloxamer 188 can be effectively coated onto the surface of drug-containing particles to exert its surfactant effect.

[0019] In one embodiment of the present invention, in S1, the mass concentration of the poloxamer 188 solution is (10~20) g / 100 mL. That is, the mass concentration of the poloxamer 188 solution is 10%-20%. When the concentration is too low for coating, the release of cefoperazone ester in the masking particles is higher, which can reduce the masking effect of hydrogenated castor oil. When the concentration is too high for coating, although the release of the masking particles is not affected, the drug-containing particles float, indicating that the solution volume is too small, the coating time is short, and the poloxamer is unevenly distributed, which reduces the lubricating effect of poloxamer 188.

[0020] In one embodiment of the present invention, in S1, the mass ratio of cefcapine hydrochloride hydrate to poloxamer 188 is 70:2. In one embodiment of the present invention, in S1, the drug-masked granules containing cefoperazone hydrochloride hydrate are prepared from the following raw materials in parts by weight: Cefcaptin hydrochloride hydrate, 70 parts; Low-substituted hydroxypropyl cellulose, 66 parts; Hydrogenated castor oil, 72 parts; Maltitol, 50 parts; Mannitol, 14 parts; Magnesium stearate, 9 parts.

[0021] In a preferred embodiment of the present invention, in S1, the drug-masked granules containing cefoperazone hydrochloride hydrate are prepared by the following steps: a) Cefcapine hydrochloride hydrate, low-substituted hydroxypropyl methylcellulose, mannitol, maltitol, magnesium stearate, and 50% hydrogenated castor oil are mixed to obtain a premixed powder; the premixed powder is then fed into a dry granulation machine to obtain granules. b) The particles obtained in step a) are sieved through a 30-80 mesh sieve to obtain raw particles; the raw particles are put into a fluidized bed, and when the temperature in the fluidized bed rises to above 83°C, the remaining hydrogenated castor oil is added for melt coating. After coating is completed, the temperature is lowered to obtain drug-masked particles containing cefoperazone hydrochloride hydrate. Preferably, in step a), the cefcapine hydrochloride hydrate is cefcapine hydrochloride hydrate that has passed through a 100-mesh sieve.

[0022] Preferably, in step a), a universal mixer is used for mixing; during mixing, the speed is 15-20 r / min and the time is 10-15 min.

[0023] Preferably, in step a), the process parameters of the dry granulator are: screen aperture 0.8-1.0mm, feeding speed 10-15Hz, tableting speed 8-10Hz, granulation speed 12-15Hz, and pressure 20-60kg / cm.

[0024] Preferably, in step b), the inlet air temperature of the fluidized bed is 100°C and the fan speed is 1200-2000 r / min.

[0025] In a preferred embodiment of the present invention, in step S2, the sweetener particles are prepared from the following raw materials in parts by weight: Aspartame, 8 portions Xylitol, 93 parts Mannitol, 94 parts Hydroxypropyl cellulose, 8 parts Pregelatinized starch, 6 parts.

[0026] In a preferred embodiment of the present invention, in step S2, the sweet granules are prepared by the following steps: A) Hydroxypropyl cellulose is added to water to prepare a hydroxypropyl cellulose solution, which is then used as an adhesive; B) Mix aspartame, mannitol, xylitol, and pregelatinized starch in a wet granulator, add the above-mentioned binder, granulate, granulate by a granulator, and dry in a fluidized bed to obtain sweet granules.

[0027] Preferably, in step A), the mass concentration of the hydroxypropyl cellulose solution is 10 g / 100 mL.

[0028] Preferably, in step B), the granulation is specifically performed using a granulator.

[0029] Preferably, in step B), the drying is specifically performed using a fluidized bed.

[0030] In a preferred embodiment of the present invention, in step S2, silicon dioxide, ferric oxide, corn starch, and flavoring are prepared in the following weight proportions: Flavoring, 1 part; Ferric oxide, 0.5 parts; Cornstarch, 3.5 parts; Silicon dioxide, 3 parts.

[0031] Preferably, the flavoring is at least one of strawberry flavoring and milk flavoring.

[0032] In a preferred embodiment of the present invention, the calculation is based on each bag: The medicated granules were prepared from the following raw materials by weight: Cefcaptin hydrochloride hydrate, 70 mg; Low-substituted hydroxypropyl cellulose, 66 mg; Hydrogenated castor oil, 72 mg; Maltitol, 50mg; Mannitol, 14 mg; Magnesium stearate, 9 mg; Poloxamer 188 2mg; Sweetener granules are prepared from the following raw materials by weight: Aspartame, 8 mg; Xylitol, 93 mg; Mannitol, 94 mg; Hydroxypropyl cellulose, 8 mg; Pregelatinized starch, 6 mg; Ferric oxide, corn starch, flavoring, and silicon dioxide are prepared from the following raw materials by weight: Flavoring, 1mg; Ferric oxide, 0.5 mg; Corn starch, 3.5 mg; Silicon dioxide, 3 mg.

[0033] The present invention will now be described in detail with reference to the embodiments.

[0034] Example 1 A method for preparing cefcapine hydrochloride granules

[0035] Cefcapine hydrochloride granules were prepared according to the following steps, based on the components and dosages listed above: 1) Weigh the prescribed amount of cefoperazone hydrochloride hydrate (obtained after passing through a 100-mesh sieve) and 50% of hydrogenated castor oil, low-substituted hydroxypropyl cellulose, mannitol, maltitol, and magnesium stearate into a mixer. Mix for 10 minutes at a speed of 20 r / min to obtain a premixed powder. Pour the premixed powder into a dry granulator using a 1.0 mm sieve. Set the feeding speed to 10 Hz, the tableting speed to 8 Hz, the granulation speed to 15 Hz, and the pressure to 40 ± 20 kg / cm. Sieve the dry granules to select 30-80 mesh particles. Add the granules to a fluidized bed. Set the inlet air temperature to 100℃ and the fan speed to 1500 r / min. When the temperature reaches above 83℃, add the remaining hydrogenated castor oil for melt coating to obtain medicated granules. Then begin cooling. 2) Poloxamer 188 was added to an appropriate amount of water to prepare a Poloxamer 188 solution with a concentration of 20g / 100mL. When the drug-containing particles obtained in step (1) were cooled to 35-45℃, the Poloxamer 188 solution was added to the bottom spray of the fluidized bed. The fan speed was 1500 r / min; the atomization pressure was 1.2 bar; and the spray peristaltic pump speed was 2 r / min, to obtain drug-containing particles with Poloxamer coated on the surface. 3) Hydroxypropyl cellulose was added to water to obtain a hydroxypropyl cellulose solution with a mass concentration of 10 g / 100 mL, which was used as a binder. The prescribed amounts of aspartame, mannitol, xylitol, and pregelatinized starch were mixed in a wet granulator, and the binder was added to granulate. The granules were then granulated by a granulator and dried in a fluidized bed to obtain sweet granules. 4) Mix silicon dioxide, ferric oxide, corn starch, and flavoring, then add the drug-containing granules and sweet granules to obtain the finished product of cefoperazone hydrochloride granules. Example 2 A method for preparing cefcapine hydrochloride granules Same as Example 1, except that the mass concentration of the poloxamer 188 solution is 15 g / 100 mL (mass concentration of 15%).

[0036] Example 3 A method for preparing cefcapine hydrochloride granules Same as Example 1, except that the mass concentration of the poloxamer 188 solution is 20 g / 100 mL (mass concentration of 20%).

[0037] Comparative Example 1 A method for preparing cefcapine hydrochloride granules Same as Example 1, except that the mass concentration of the poloxamer 188 solution is 8 g / 100 mL (mass concentration of 8%). Comparative Example 2 A method for preparing cefcapine hydrochloride granules Same as Example 1, except that the mass concentration of the poloxamer 188 solution is 22 g / 100 mL (mass concentration of 22%).

[0038] Comparative Example 3 A method for preparing cefcapine hydrochloride granules

[0039] 1) Weigh the prescribed amount of cefoperazone hydrochloride, 50% of the amount of hydrogenated castor oil, low-substituted hydroxypropyl cellulose, mannitol, and magnesium stearate into a mixer. Mix for 10 minutes at 20 rpm to obtain a premixed powder. Pour the premixed powder into a dry granulator using a 1.0 mm sieve. Set the feeding speed to 10 Hz, the tableting speed to 8 Hz, the granulation speed to 15 Hz, and the pressure to 40 ± 20 kg / cm. Sieve the dry granules to select 30-80 mesh particles. Add the granules to a fluidized bed. Set the inlet air temperature to 100℃ and the blower speed to 1200-2000 rpm. When the temperature reaches above 83℃, add the remaining hydrogenated castor oil for melt coating to obtain medicated granules. 2) Add a portion of hydroxypropyl cellulose and poloxamer to an appropriate amount of water to make the mass concentration of the hydroxypropyl cellulose solution 10 g / 100 mL and the concentration of the poloxamer 188 solution 10 g / 100 mL. Disperse and dissolve to prepare a binder. Add the remaining hydroxypropyl methylcellulose, aspartame, mannitol, xylitol, and pregelatinized starch in the prescribed amount to a wet granulator and mix. Add the binder and granulate. Granulate the granules and dry them in a fluidized bed to obtain sweet granules. 3) Mix silicon dioxide, ferric oxide, corn starch, and flavoring, then add the drug-containing granules and sweet granules and mix together to obtain the finished product of cefcaptin hydrochloride granules. Comparative Example 4 Cefcaptin hydrochloride granules were prepared by referring to the original drug's invention patent (CN102056610B).

[0040] 1) Weigh the prescribed amount of cefoperazone hydrochloride, 50% of the amount of hydrogenated castor oil, low-substituted hydroxypropyl cellulose, mannitol, and magnesium stearate into a mixer. Mix for 10 minutes at a speed of 20 r / min to obtain a premixed powder. Pour the premixed powder into a dry granulator using a 1.0 mm sieve. Set the feeding speed to 10 Hz, the tableting speed to 8 Hz, the granulation speed to 15 Hz, and the pressure to 40 ± 20 kg / cm. Sieve the dry granules to select 50 mesh particles. Feed the granules into a fluidized bed. Set the inlet air temperature to 100℃ and the blower speed to 1500 r / min. When the temperature reaches above 83℃, add the remaining hydrogenated castor oil for melt coating to obtain medicated granules. 2) Disperse and dissolve 50% of the hydroxypropyl cellulose in an appropriate amount of water to prepare a binder (mass concentration of 10 g / 100 mL). Add the remaining 50% of the hydroxypropyl methylcellulose, aspartame, mannitol, xylitol, and pregelatinized starch to a wet granulator and mix. Add the binder and granulate. Granulate the granules using a granulator and dry them in a fluidized bed to obtain sweet granules. 3) Poroxam 188 is crushed to a suitable particle size, added to a silica hot melt granulator for mixing, and heated to 55-65℃. After hot melt granulation and sieving, surfactant particles are obtained. 4) Mix ferric oxide and corn starch to obtain colorant granules, and mix silicon dioxide and fragrance to obtain fragrance powder; 5) Mix the sweet granules and colorant granules, add the drug-containing granules and mix evenly, then add the surfactant granules and mix, add the fragrance powder and mix evenly to obtain the finished product of cefoperazone hydrochloride granules.

[0041] Experimental Example 1 The distribution of Poloxamer 188 was studied. The uniformity of poloxamer content in the samples obtained in Examples 1-3 and Comparative Examples 1-4 was tested using gel chromatography-evaporative light detection. The chromatographic column was an Ultrahydrogel water-soluble gel column (7.8 × 300 mm, 250 Å), and the mobile phase was acetonitrile-water. The test results are shown in Table 1.

[0042] Table 1

[0043] The test results from Examples 1 to 3 show that poloxamer 188 can be sprayed onto the surface of drug-containing particles through fluidized bed coating, and it can be evenly distributed on the surface of drug-containing particles.

[0044] Comparative Example 1 uses an 8% poloxamer 188 solution for coating, which also allows poloxamer 188 to be evenly distributed in the formulation. However, the long coating time can easily cause the drug-containing particles to break, affecting the taste masking effect.

[0045] When Comparative Example 2 was coated with a 22% poloxamer 188 solution, the uniformity of its distribution on the particle surface was poor due to the small amount of poloxamer 188 solution.

[0046] In Comparative Example 3, when poloxamer 188 was added as a binder to sweet granules during wet granulation, poloxamer 188 could be evenly distributed in the formulation. However, the sweet granules needed to dissolve and release poloxamer 188 before it could exert its effect of wetting the drug-containing granules.

[0047] Comparative Example 4 used the original formulation preparation process. Poloxamer and an equal amount of silica were melt-granulated separately and then mixed with other drug-containing granules, sweet granules, and colored granules. Because poloxamer 188 and silica have large differences in volume, particle size distribution, and flowability, the mixing uniformity of the two after melt granulation was poor, resulting in a worse uniformity of poloxamer 188 content in the formulation compared to the example.

[0048] Experimental Example 2 Study on the solubility, taste masking effect, and drug release performance of cefoperazone hydrochloride granules The appearance of cefoperazone hydrochloride granules prepared in Examples 1-3, Comparative Examples 1-4, and the original formulation was compared. The lubricating effect of poloxamer was evaluated by the dispersion and dissolution state of the finished granules in water at 37±0.5℃. The effect of the poloxamer addition method on the taste masking effect of the drug-containing granules was evaluated by the amount of drug released from the drug granules in water at 37±0.5℃ within 60 seconds. The results are shown in Table 2.

[0049] Table 2

[0050] The test results from Examples 1-3, Comparative Example 4 of the original patented process, and the reference formulation show that the cefoperazone hydrochloride granules prepared by spraying 10-20% poloxamer 188 solution onto the surface of drug-containing particles via fluidized bed coating have similar appearance, solubility and dispersion in water, and taste masking effect to the reference formulation and Comparative Example 4 of the original process.

[0051] When Comparative Example 1 was coated with 8% poloxamer 188 solution, the masking particles did not float, but the release of cefoperazone ester in the masking particles was relatively high, indicating that a poloxamer 188 solution of less than 10% can reduce the masking effect of hydrogenated castor oil.

[0052] In Comparative Example 2, when a 20% poloxamer 188 solution was used for coating, although the amount of masked particles released was similar to that in Examples 1-3, the drug-containing particles floated. This indicates that when the coating solution was higher than 20% poloxamer 188, the solution volume was too small, the coating time was too short, the poloxamer was unevenly distributed, and the lubricating effect of poloxamer 188 was reduced.

[0053] In Comparative Example 3, when poloxamer 188 was added to sweetened granules, cefcapine hydrochloride granules showed a small amount or brief floating during dissolution and dispersion. This indicates that poloxamer 188 needs to disintegrate and release poloxamer in the sweetened granules before it can exert a lubricating effect, thus the release of the drug-containing granules is relatively slow.

[0054] Experimental Example 3 Stability study of cefcapine hydrochloride particles The influencing factors of cefcapine hydrochloride particles prepared in Examples 1-3, Comparative Examples 1-4 and the original formulation were investigated for 30 days at 40°C and 75%±5% humidity. The total impurities and polymers in the samples were detected by high performance liquid chromatography and molecular exclusion method. The results are shown in Table 3.

[0055] Table 3

[0056] The test results from Examples 1-3 and Comparative Example 4 of the original patented process show that the cefoperazone hydrochloride granules prepared by spraying 10-20% poloxamer 188 solution onto the surface of drug-containing particles via fluidized bed coating exhibit a similar increasing trend in related substances as the comparative example 4 of the original patented process. However, since the original formulation was a sample produced for 8 months, the related substances in the 0-day and 30-day samples were both higher. When the drug-containing particles in Comparative Example 1 were encapsulated with 8% poloxamer 188 solution, the stability of the product decreased, and the levels of related substances were higher than those in Examples 1-3 at both 0 days and 30 days.

[0057] When Comparative Example 2 used a solution containing more than 22% poloxamer 188 to encapsulate the drug-containing particles, it did not affect the stability of cefcapine hydrochloride granules.

[0058] Comparative Example 3: Adding poloxamer 188 to sweet granules did not affect the stability of cefcapine hydrochloride granules.

[0059] Test Example 4 In vitro dissolution test The formulation of the product in this invention embodiment is the same as that of the reference formulation, and the amount of excipients is similar. Dissolution curves of Examples 1-3, Comparative Examples 1-4, and the reference formulation in water (main medium) at a paddle speed of 50 r / min were used to evaluate the pharmaceutical consistency between the patented product and the reference formulation. The results are shown in Table 4. Table 4

[0060] The test results from Examples 1-3 and Comparative Example 4 of the original patented process show that the cefoperazone hydrochloride fine granules prepared by spraying 10-20% poloxamer 188 solution onto the surface of drug-containing particles via fluidized bed coating have dissolution curves with F2 values ​​greater than 50, namely 68, 74, and 76, respectively, which meet the requirements. The release trend is not significantly different from that of the original patented process (Comparative Example 1: F2 value 72) and is consistent with the dissolution curve of the original formulation.

[0061] Comparative Example 1, coated with 8% poloxamer 188 solution, showed a faster dissolution rate and lower similarity to the reference formulation. This indicates that a concentration of less than 10% poloxamer 188 solution may impair the encapsulation effect of hydrogenated castor oil, leading to faster release of the active pharmaceutical ingredient.

[0062] Comparative Example 2 was coated with a 22% poloxamer 188 solution. The dissolution rate of the sample was similar to that of the reference formulation and close to the F2 values ​​of Examples 1-3. This indicates that coating the drug-containing particles with a solution higher than 20% poloxamer 188 only changes the initial dispersion state of the particles after they are immersed in water and has little effect on the subsequent dissolution and release.

[0063] Comparative Example 3 showed that adding poloxamer to the sweetened granules had no effect on the dissolution curve of cefoperazone hydrochloride granules. The dissolution rate of the sample was similar to that of the reference formulation and close to the F2 values ​​of Examples 1-3. This indicates that adding poloxamer to the sweetened granules only changes the initial dispersion state of the drug-containing granules after they are added to water and has little effect on the subsequent dissolution and release.

[0064] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing cefoperazone hydrochloride granules, characterized in that, Includes the following steps: S1. Place the drug-containing granules containing cefcapine hydrochloride hydrate into a fluidized bed, adjust the temperature to 35-45℃, and add poloxamer 188 solution by bottom spraying the fluidized bed to obtain drug-containing granules coated with poloxamer on the surface. S2. Mix silicon dioxide, ferric oxide, corn starch, and flavoring, then add the medicated granules and sweetener granules, mix, and obtain the product.

2. The preparation method according to claim 1, characterized in that, In step S1, when using fluidized bed bottom spraying, the fan speed is 1200-2000 r / min; the atomization pressure is 1.0-1.6 bar; and the spray peristaltic pump speed is 1-3 r / min.

3. The preparation method according to claim 1, characterized in that, S1 satisfies at least one of the following conditions: (1) The mass concentration of poloxamer 188 solution is (10~20) g / 100 mL; (2) The mass ratio of cefcapine hydrochloride hydrate to poloxamer 188 is 70:

2.

4. The preparation method according to claim 1, characterized in that, In S1, the drug-masked granules containing cefoperazone hydrochloride hydrate were prepared from the following raw materials in parts by weight: Cefcaptin hydrochloride hydrate, 70 parts; Low-substituted hydroxypropyl cellulose, 66 parts; Hydrogenated castor oil, 72 parts; Maltitol, 50 parts; Mannitol, 14 parts; Magnesium stearate, 9 parts.

5. The preparation method according to claim 4, characterized in that, In S1, the drug-masked granules containing cefoperazone hydrochloride hydrate are prepared by the following steps: a) Cefcapine hydrochloride hydrate, low-substituted hydroxypropyl methylcellulose, mannitol, maltitol, magnesium stearate, and 50% hydrogenated castor oil are mixed to obtain a premixed powder; the premixed powder is then fed into a dry granulation machine to obtain granules. b) The particles obtained in step a) are sieved through a 30-80 mesh sieve to obtain raw particles; the raw particles are put into a fluidized bed, and when the temperature in the fluidized bed rises to above 83°C, the remaining hydrogenated castor oil is added for melt coating. After coating is completed, the temperature is lowered to obtain drug-masked particles containing cefoperazone hydrochloride hydrate.

6. The preparation method according to claim 5, characterized in that, a) satisfies at least one of the following conditions: (1) Use a universal mixer for mixing; during mixing, the speed is 15-20 r / min and the time is 10-15 min; (2) The process parameters of the dry granulation machine are: screen aperture 0.8-1.0mm, feeding speed 10-15Hz, tableting speed 8-10Hz, granulation speed 12-15Hz, and pressure 20-60kg / cm. b) satisfies at least one of the following conditions: (1) When the fluidized bed is running, the inlet air temperature is 100-130℃; (2) When the fluidized bed is running, the fan speed is 1200-2000 r / min.

7. The preparation method according to claim 1, characterized in that, In S2, the sweetener particles are prepared from the following raw materials in parts by weight: Aspartame, 8 portions Xylitol, 93 parts Mannitol, 94 parts Hydroxypropyl cellulose, 8 parts Pregelatinized starch, 6 parts.

8. The preparation method according to claim 7, characterized in that, In S2, the sweet granules are prepared by the following steps: A) Hydroxypropyl cellulose is added to water to prepare a hydroxypropyl cellulose solution, which is then used as an adhesive; B) Mix aspartame, mannitol, xylitol, and pregelatinized starch in a wet granulator, add the above-mentioned binder, granulate, granulate by a granulator, and dry in a fluidized bed to obtain sweet granules.

9. The preparation method according to claim 1, characterized in that, In S2, silicon dioxide, ferric oxide, corn starch, and flavoring are prepared in the following weight proportions: Flavoring, 1 part; Ferric oxide, 0.5 parts; Cornstarch, 3.5 parts; Silicon dioxide, 3 parts.

10. The preparation method according to claim 1, characterized in that, Calculated per bag, The medicated granules were prepared from the following raw materials by weight: Cefcaptin hydrochloride hydrate, 70 mg; Low-substituted hydroxypropyl cellulose, 66 mg; Hydrogenated castor oil, 72 mg; Maltitol, 50mg; Mannitol, 14 mg; Magnesium stearate, 9 mg; Poloxamer 188, 2 mg; Sweetener granules are prepared from the following raw materials by weight: Aspartame, 8 mg; Xylitol, 93 mg; Mannitol, 94 mg; Hydroxypropyl cellulose, 8 mg; Pregelatinized starch, 6 mg; Ferric oxide, corn starch, flavoring, and silicon dioxide are prepared from the following raw materials by weight: Flavoring, 1mg; Ferric oxide, 0.5 mg; Corn starch, 3.5 mg; Silicon dioxide, 3 mg.

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