Cefcapene pivoxil hydrochloride fine granule and preparation method thereof

Abstract

The invention relates to a cefcapene pivoxil hydrochloride fine granule and a preparation method thereof. The cefcapene pivoxil hydrochloride fine granule comprises drug-containing taste-masking granules accounting for 50-56% of the total mass of the cefcapene pivoxil hydrochloride fine granule, sweet granules accounting for 41-47% of the total mass of the cefcapene pivoxil hydrochloride fine granule, sucrose stearate accounting for 0.5-2% of the total mass of the cefcapene pivoxil hydrochloride fine granule, and a wetting agent accounting for 0.5-3% of the total mass of the cefcapene pivoxil hydrochloride fine granule. Wherein the medicine-containing taste masking particles comprise cefcapene pivoxil hydrochloride. The cefcapene pivoxil hydrochloride fine granules disclosed by the invention are mainly used as a children preparation, can obviously mask bitter taste, can be dispersed and then settled in water without floating on the water surface or adhering to a water cup, and can obviously improve the stability of the preparation compared with the original developed preparation. Meanwhile, the preparation process used in the invention is easier for large-scale production, and the product is small in batch-to-batch difference and high in stability.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceuticals, and in particular relates to cefcapene pivoxil hydrochloride fine granules and a preparation method thereof. Background Art

[0002] In recent years, due to the increase in bacterial resistance and the limitations of clinical trials in children, there is a continuous demand for new antibiotics for children. Among the common pathogenic bacteria of bacterial infectious diseases in children, Gram-positive bacteria are mainly Staphylococcus aureus (S. aureus), Streptococcus pneumoniae, and coagulase-negative Staphylococci. Gram-negative bacteria are mainly Klebsiella, Pseudomonas aeruginosa, and Escherichia coli. Both the China Bacterial Resistance Monitoring Network and children's specialized hospitals show that the resistance rate of clinical isolates to commonly used antimicrobial drugs is slowly increasing, and there is a continuous demand for new antibiotics in clinical practice.

[0003] Cefuroxime belongs to the third generation of cephalosporin antibiotics and is a prodrug of the active ingredient cefuroxime. After oral administration, it is hydrolyzed by esterases in the digestive tract and the digestive tract wall to produce the active ingredient cefuroxime. Like other cephalosporin antibiotics, cefuroxime acts on the cell walls of sensitive bacteria, binds to bacterial penicillin-binding proteins, hinders the formation of mucopeptides, and prevents the synthesis of bacterial cell walls, thereby killing bacteria. Cefuroxime hydrochloride granules were developed by Shionogi of Japan and were launched in Japan as fine granules in June 1997. They are not available in the European Union and the United States. In September 2021, it obtained the Chinese import approval through priority review.

[0004] Fine granules are a unique dosage form in Japan. They are smaller in size than conventional granules and have less gritty feeling when taken orally, but have high bioavailability and few adverse reactions. They are added to an appropriate amount of water when used, usually to solve the problem of dysphagia in children and the elderly. Fine granules require that all particles pass through a No. 18 (850 μm) sieve and the retention rate of a No. 30 (500 μm) sieve does not exceed 10%.

[0005] The original patent CN102056610 mainly protects a suspension composition to improve the suspending and wettability of cefcapone hydrochloride particles in water, and polyoxyethylene (160) polyoxypropylene (30) glycol and hydrous silicon dioxide are preferred. Polyoxyethylene (160) polyoxypropylene (30) glycol has a low melting point, large and fluffy particles, and is easy to absorb moisture. It is prepared into suspension melt particles by melt granulation. The suspending agent has a low melting point and may be unstable during the accelerated stability period, and the preparation process is complicated, which ultimately leads to a long production process flow and complex process of the entire product.

[0006] There is another domestic patent CN110974803, which uses blank micro-pellets, centrifugally granulates cefuroxime hydrochloride, and then masks the bitter taste through coating. However, the micro-pellets are large in size, do not meet the standards of fine granules, are not suitable for infants and young children, and have not been proven to be bioequivalent to humans, so their pharmacokinetic properties and efficacy are questionable.

[0007] Cefcapone Hydrochloride Granules is a pediatric dosage form designed based on the drug's physical and chemical properties, antibacterial activity, and the characteristics of pediatric medication. The main advantage of this product is that the active ingredient has a low binding rate with plasma proteins, so the free drug concentration in the body is relatively high and shows strong broad-spectrum antibacterial activity. At the same time, the product dosage form is suitable for children, especially infants and young children, and has good medication compliance.

[0008] Therefore, it is urgent to develop more cefoperazone hydrochloride fine granules with excellent performance to provide more options for children's medication. Summary of the invention

[0009] The purpose of the present invention is to provide a cefcapone hydrochloride fine granules with different components and a preparation method thereof.

[0010] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0011] The first aspect of the present invention provides a cefcapene pivoxil hydrochloride fine granules, which include drug-containing taste-masking granules accounting for 50-56% of the total mass of the cefcapene pivoxil hydrochloride fine granules, sweet granules accounting for 41-47% of the total mass of the cefcapene pivoxil hydrochloride fine granules, sucrose stearate accounting for 0.5-2% of the total mass of the cefcapene pivoxil hydrochloride fine granules, and a wetting agent accounting for 0.5-3% of the total mass of the cefcapene pivoxil hydrochloride fine granules; wherein the drug-containing taste-masking granules include cefcapene pivoxil hydrochloride.

[0012] According to some specific embodiments, the drug-containing taste-masking granules account for 50%, 51%, 52%, 53%, 54%, 55% or 56% of the total mass of the cefcapone hydrochloride fine granules.

[0013] According to some specific embodiments, the sweet granules account for 41%, 42%, 43%, 44%, 45%, 46% or 47% of the total mass of the cefcapene pivoxil hydrochloride granules.

[0014] According to some specific embodiments, the sucrose stearate accounts for 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% or 2% of the total mass of the cefcapone hydrochloride granules.

[0015] According to some specific embodiments, the wetting agent accounts for 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9% or 3% of the total mass of the cefcapone hydrochloride granules.

[0016] According to some specific embodiments, the drug-containing taste-masking particles further include a waxy taste-masking material accounting for 1 to 10% of the total mass of the drug-containing taste-masking particles, for example, the waxy taste-masking material accounts for 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%. Further, the drug-containing taste-masking particles further include a waxy taste-masking material accounting for 1 to 5% of the total mass of the drug-containing taste-masking particles, thereby further reducing the hydrophobicity of the particles and improving the stability of the fine granules.

[0017] According to some specific embodiments, the drug-containing taste-masking particles further include a disintegrant accounting for 10 to 35% of the total mass of the drug-containing taste-masking particles, for example, the disintegrant accounts for 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34% or 35%. Further, the drug-containing taste-masking particles further include a disintegrant accounting for 10 to 20% of the total mass of the drug-containing taste-masking particles.

[0018] Further, the waxy taste-masking material is one or more of hydrogenated castor oil, glyceryl distearate and glyceryl behenate. Further, the waxy taste-masking material is hydrogenated castor oil.

[0019] Furthermore, the disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl starch. Further, the disintegrant is low-substituted hydroxypropyl cellulose.

[0020] According to some specific embodiments, the drug-containing taste-masking particles further include a filler accounting for 35-50% of the total mass of the drug-containing taste-masking particles. For example, the filler accounts for 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49% or 50%.

[0021] According to some specific embodiments, the drug-containing taste-masking particles further include a lubricant accounting for 1-2% of the total mass of the drug-containing taste-masking particles. For example, the lubricant accounts for 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9% or 2%.

[0022] According to some specific embodiments, the mass of the cefcapene pivoxil hydrochloride is 12-16% of the total mass of the cefcapene pivoxil hydrochloride fine granules, for example, 12%, 13%, 14%, 15%, 16%.

[0023] According to some specific embodiments, the wetting agent is one or more of colloidal silicon dioxide, talc, and sodium stearyl fumarate.

[0024] According to some specific embodiments, the sweet particles include a sweetener accounting for 90-96% of the total mass of the sweet particles. For example, the sweetener accounts for 90%, 91%, 92%, 93%, 94%, 95% or 96%.

[0025] According to some specific embodiments, the sweet particles include a binder accounting for 4-10% of the total mass of the sweet particles. For example, the binder accounts for 4%, 5%, 6%, 7%, 8%, 9% or 10%.

[0026] Furthermore, the sweetener is one or more of mannitol, sucralose, aspartame, and xylitol.

[0027] Furthermore, the binder is one or more of povidone, hydroxypropyl cellulose and hypromellose.

[0028] According to some specific embodiments, the cefcapone hydrochloride fine granules further include 0.1-1% of the total mass of the cefcapone hydrochloride fine granules. For example, the proportion of the flavor is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1%.

[0029] The second aspect of the present invention provides a method for preparing the cefcapone hydrochloride fine granules as described above, comprising the following steps:

[0030] (1) preparing drug-containing taste-masked granules by dry granulation process and melting process according to the formula amount;

[0031] (2) preparing sweet granules by wet granulation process according to the formula amount;

[0032] (3) According to the formula amount, the drug-containing taste-masking granules, the sweet granules, the sucrose stearate, and the wetting agent are uniformly mixed to prepare the cefcapone hydrochloride fine granules.

[0033] According to some specific embodiments, the detailed steps of the preparation method are as follows:

[0034] (1) Preparation of drug-containing taste-masked granules: premixing cefcapene hydrochloride within a certain particle size range with a waxy taste-masking material, a disintegrant, a filler and a lubricant, and mixing them uniformly to obtain a premixed powder; dry granulating the premixed powder according to certain parameters, controlling the particle size according to the requirements of fine granules, and obtaining dry granules; placing the dry granules in a fluidized bed for melt-masking to obtain drug-containing taste-masked granules;

[0035] (2) Preparation of sweet granules: premixing the sweetener and the binder, adding water for wet granulation, drying by a drying device, and finally passing through a sieve to prepare sweet granules;

[0036] (3) According to the yield of the drug-containing taste-masking granules, the sweet granules, surfactant, wetting agent and flavor are converted according to the formula, and finally cefcapone hydrochloride fine granules are prepared by mixing.

[0037] Furthermore, in step (1), the tableting speed of the dry granulation is controlled to be 10-15 Hz, the granulation speed is 18-22 Hz, and the pressure is 18-22 kg / cm 2 .

[0038] Furthermore, in step (1), the air inlet temperature during the melting process is controlled to be 70-120°C, and the air volume is initially 80-120m 3 / h, stop heating when the material temperature reaches 60-80℃.

[0039] The present invention prepares drug-containing taste-masking particles through a dry granulation process and a melting process, thereby masking the bitter taste of the drug and ensuring the stability of the drug. Furthermore, by combining sucrose stearate and a wetting agent, the suspension effect of the taste-masking particles in water is improved, and the stability of the product during the storage period is improved, which is more conducive to children's taking.

[0040] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0041] The cefcapone hydrochloride fine granules of the present invention are mainly used as children's preparations, can significantly mask the bitter taste, and can be dispersed first and then settled in water without floating on the water surface or adhering to the water cup. Compared with the original preparation, the stability of the preparation is significantly improved. At the same time, the preparation process used in the present invention is easier to scale up production, the batch difference of the product is small, and the stability is high. DETAILED DESCRIPTION

[0042] Cefuroxime hydrochloride tastes bitter. If it is made into fine granules, it needs to be taste-masked. However, by using particle taste-masking technology, the hydrophobicity of the particles will be significantly enhanced, causing the particles to float on the water surface, stick to the water cup or even the mouth when taken with water, ultimately leading to reduced drug intake and poor palatability.

[0043] The surfactant used in the original patent is sodium dodecyl sulfate or a nonionic surfactant containing a polyoxyethylene chain (polyoxyethylene (40) monostearate, polyoxyethylene hydrogenated castor oil 60 and polyoxyethylene (160) polyoxypropylene (30) glycol), and polyoxyethylene (160) polyoxypropylene (30) glycol, i.e., the poloxamer series, is preferred. The wetting agent used is hydrophilic hydrous silica. Since poloxamer is a fluffy, soft, large particle, it is not suitable for direct mixing or sieving, so it needs to be prepared into particles by melt granulation technology and then mixed, which makes the process more complicated.

[0044] To this end, the present invention develops a cefcapone hydrochloride fine granule (24 mesh: full amount passes; >35 mesh: <10%), simplifies its formula and production process, reduces preparation cost, masks the bitter taste of the drug, improves the moisturizing effect of the granules, ensures product quality and improves product stability and palatability, and finally puts it on the market as soon as possible to provide patients with more choices.

[0045] In order to achieve the purpose of the present invention, the main improvements of the present invention include: (1) The surfactant of the present invention is sucrose stearate, which is in powder form and can be compatible with a wetting agent. It can be mixed evenly through a simple mixing process, and the effect of improving the wettability of the drug-containing taste-masking particles can be achieved. Aggregation will not occur during the oral administration of the fine granules. At the same time, unexpectedly, the applicant unexpectedly discovered that the use of sucrose stearate as a surfactant can significantly improve the stability of cefuroxime hydrochloride fine granules while ensuring sufficient moisturizing effect; (2) Since cefuroxime hydrochloride is easily hydrolyzed when exposed to moisture and heat, in order to meet the standards of fine granules, it is necessary to use a repeated dry granulation process to prepare drug-containing taste-masking granules, and then use melting technology to achieve the final taste masking; (3) Due to the high loss of dry taste masking technology, it is necessary to prepare part of the flavor corrector (sweetener) through a wet granulation process, and finally form the final product through total mixing to improve the product yield; (4) A new type of surfactant is used to cooperate with the taste masking material to improve the wettability, suspension and stability of the product. The surfactant can achieve the above effects through a simple total mixing process.

[0046] According to the present invention, while simplifying the preparation process and improving efficiency, the particle size of the product is guaranteed and the bitterness is masked. The present application has also further conducted research on influencing factors, accelerated research and long-term research on the product. The results all show that the amount of related substances in the fine granules of the present application is better than the original patent disclosure data and the test results of the self-purchased original preparation; at the same time, the stability of dissolution during the stability period is better than the original preparation; the above two points can further extend the shelf life of the product. In addition, as a preparation to be marketed, the product of the present invention has passed the human bioequivalence study and is currently applying for marketing.

[0047] The present invention is further described below in conjunction with the examples. However, the present invention is not limited to the following examples. The implementation conditions used in the examples can be further adjusted according to the different requirements of specific use, and the implementation conditions not specified are conventional conditions in the industry. The technical features involved in each embodiment of the present invention can be combined with each other as long as they do not conflict with each other.

[0048] Unless otherwise specified, the reagents, instruments, etc. used in the following examples are all commercially available products commonly used in the art, or can also be prepared by conventional preparation methods in the art. The raw materials and auxiliary materials of the present invention can come from any supplier of reagents as long as they meet the pharmaceutical grade. For example, cefcapone hydrochloride comes from Suzhou Shengda Pharmaceutical Co., Ltd. In the present invention, unless otherwise specified, the content is mass content, "%" is mass percentage, and the number of parts is mass parts.

[0049] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article. Among them, the terms "optional" and "optional" all mean that they can be included or not (or can be included or not).

[0050] Example 1

[0051] Table 1

[0052]

[0053]

[0054] Cefcapene pivoxil hydrochloride fine granules were prepared from the components listed in Table 1 according to the following method.

[0055] Weigh cefoperazone hydrochloride, hydrogenated castor oil, low-substituted hydroxypropyl cellulose, mannitol and magnesium stearate into a mixer and mix for 10 minutes to obtain a premixed powder. Pour the premixed powder into a dry granulator, use a 1.0 mm screen, set the tableting speed to 12 Hz, the granulation speed to 20 Hz, and the pressure to 20 kg / cm 2 The granules were put into a swing granulator, sieved with a 40-mesh screen, and then sieved with an 80-mesh screen. The granules were granulated several times according to the amount of fine particles. The plain granules were put into a fluidized bed for melting and coating. The air inlet temperature was set to 100°C and the air volume was set to 100m / s. 3 / h, stop heating when the material temperature reaches 80℃, detect the loss on drying, and obtain drug-containing taste-masking granules; mix mannitol, sucralose and povidone, add water for wet granulation, dry in a fluidized bed, and sieve the whole granules with a 40-mesh screen to obtain sweet granules. Put the drug-containing taste-masking granules, sweet granules, sucrose stearate, sodium stearyl fumarate and flavors into a mixing barrel and mix for 15 minutes to obtain cefcapone hydrochloride fine granules.

[0056] Example 2

[0057] Table 2

[0058]

[0059]

[0060] Cefcapene pivoxil hydrochloride fine granules were prepared from the components listed in Table 2 according to the following method.

[0061] Weigh cefoperazone hydrochloride, glyceryl behenate, cross-linked polyvinylpyrrolidone, mannitol and magnesium stearate into a mixer and mix for 10 minutes to obtain a premixed powder. Pour the premixed powder into a dry granulator, use a 1.0 mm screen, set the tableting speed to 12 Hz, the granulation speed to 20 Hz, and the pressure to 20 kg / cm 2 The granules were put into the swing granulator, sized using a 40-mesh screen, and then sieved using an 80-mesh screen. The granules were granulated several times according to the amount of fine particles. The plain granules were put into the fluidized bed for melting and coating, and the air inlet temperature was set to 80°C and the air volume was set to 100m 3 / h, stop heating when the material temperature reaches 65℃, detect the drying loss, and obtain the drug-containing taste-masking granules; mix mannitol, sucralose and povidone, add water for wet granulation, dry in a fluidized bed, and sieve the whole granules with a 40-mesh screen to obtain sweet granules. Put the drug-containing taste-masking granules, sweet granules, sucrose stearate, colloidal silicon dioxide and flavors into a mixing barrel and mix for 15 minutes to obtain cefcapone hydrochloride fine granules.

[0062] Example 3

[0063] Table 3

[0064]

[0065] Cefcapene pivoxil hydrochloride fine granules were prepared from the components listed in Table 3 according to the following method.

[0066] Weigh cefoperazone hydrochloride, glyceryl distearate, cross-linked sodium carboxymethyl starch, mannitol and magnesium stearate into a mixer and mix for 10 minutes to obtain a premixed powder. Pour the premixed powder into a dry granulator, use a 1.0 mm screen, set the tableting speed to 12 Hz, the granulation speed to 20 Hz, and the pressure to 20 kg / cm 2 The granules were put into the swing granulator, sized using a 40-mesh screen, and then sieved using an 80-mesh screen. The granules were granulated several times according to the amount of fine particles. The plain granules were put into the fluidized bed for melting and coating, and the air inlet temperature was set to 75°C and the air volume was set to 100m 3 / h, stop heating when the material temperature reaches 60℃, detect the drying loss, and obtain the drug-containing taste-masking granules; mix mannitol, aspartame and hydroxypropyl methylcellulose, add water for wet granulation, dry in a fluidized bed, and sieve the whole granules with a 40-mesh screen to obtain sweet granules. Put the drug-containing taste-masking granules, sweet granules, sucrose stearate, colloidal silicon dioxide and flavors into a mixing barrel and mix for 15 minutes to obtain cefcapone hydrochloride fine granules.

[0067] Example 4

[0068] Table 4

[0069]

[0070] Cefcapene pivoxil hydrochloride fine granules were prepared from the components listed in Table 4 according to the following method.

[0071] Weigh cefoperazone hydrochloride, hydrogenated castor oil, low-substituted hydroxypropyl cellulose, mannitol and magnesium stearate into a mixer and mix for 10 minutes to obtain a premixed powder. Pour the premixed powder into a dry granulator, use a 1.0 mm screen, set the tableting speed to 12 Hz, the granulation speed to 20 Hz, and the pressure to 20 kg / cm 2 The granules were put into a swing granulator, sieved with a 40-mesh screen, and then sieved with an 80-mesh screen. The granules were granulated several times according to the amount of fine particles. The plain granules were put into a fluidized bed for melting and coating. The air inlet temperature was set to 100°C and the air volume was set to 100m / s. 3 / h, stop heating when the material temperature reaches 80℃, detect the drying loss, and obtain the drug-containing taste-masking granules; mix mannitol, sucralose and hydroxypropyl cellulose, add water for wet granulation, dry in a fluidized bed, and sieve the whole granules with a 40-mesh screen to obtain sweet granules. Put the drug-containing taste-masking granules, sweet granules, sucrose stearate, colloidal silicon dioxide and flavors into a mixing barrel and mix for 15 minutes to obtain cefcapone hydrochloride fine granules.

[0072] Example 5

[0073] Table 5

[0074]

[0075] Cefcapene pivoxil hydrochloride fine granules were prepared from the components listed in Table 5 according to the following method.

[0076] Weigh cefoperazone hydrochloride, hydrogenated castor oil, low-substituted hydroxypropyl cellulose, mannitol and magnesium stearate into a mixer and mix for 10 minutes to obtain a premixed powder. Pour the premixed powder into a dry granulator, use a 1.0 mm screen, set the tableting speed to 12 Hz, the granulation speed to 20 Hz, and the pressure to 20 kg / cm 2 The granules were put into a swing granulator, sieved with a 40-mesh screen, and then sieved with an 80-mesh screen. The granules were granulated several times according to the amount of fine particles. The plain granules were put into a fluidized bed for melting and coating. The air inlet temperature was set to 70°C and the air volume was set to 100m 3 / h, stop heating when the material temperature reaches 60℃, detect the loss on drying, and obtain drug-containing taste-masking granules; mix mannitol, sucralose and povidone, add water for wet granulation, dry in a fluidized bed, and sieve the whole granules with a 40-mesh screen to obtain sweet granules. Put the drug-containing taste-masking granules, sweet granules, sucrose stearate, talcum powder and flavors into a mixing barrel and mix for 15 minutes to obtain cefcapone hydrochloride fine granules.

[0077] Comparative Example 1

[0078] Table 6

[0079]

[0080]

[0081] Cefcapene pivoxil hydrochloride fine granules were prepared from the components listed in Table 6 according to the preparation method of Example 5.

[0082] Test Example 1: Evaluation of Suspensibility and Palatability in Water

[0083] About 0.5 g of the fine particles prepared in each embodiment and comparative example were placed in a 250 ml cup, and 150 ml of purified water was poured into the cup. The suspension and sedimentation state of the fine particles were visually observed, and the bitterness masking effect was evaluated by tasting. The experimental results are shown in Table 7. As can be seen from Table 7, in Comparative Example 1, sucrose stearate and wetting agent were not added, and most of the particles were suspended on the liquid surface, which was easy to adhere to the cup wall and even the oral cavity, thereby resulting in reduced drug intake and poor palatability. The fine particles of Examples 1 to 5 have improved wettability, especially Examples 1 to 4 have better wettability, and the particles are first dispersed in water and then settled at the bottom of the cup, and will not adhere to the cup wall and the oral cavity, which can better ensure drug intake and improve palatability.

[0084] Table 7

[0085]

[0086] Test Example 2: Evaluation of Critical Quality Attributes in Fine Granules

[0087] According to the relevant substance and polymer determination method in the import registration standard of cefuroxime hydrochloride granules (JX20190125), the relevant substances, polymers and solubility in the cefuroxime hydrochloride fine granules of the embodiments and comparative examples were studied. The experimental results are shown in Table 8, among which, comparative example 2 is the product of the original research Shionogi Company. The batch number is 0003.

[0088] Table 8

[0089]

[0090]

[0091] It can be seen from the test results of Examples 1 to 5 that the key quality indicators of the cefcapone hydrochloride fine granules prepared by the formulation and process of the present invention are better than those of the original preparation and meet the standards.

[0092] Test Example 3: Stability Study of Fine Granules

[0093] Example 1 and Comparative Example 2 used the same packaging and were placed under high temperature (60°C) conditions for 30 days, high humidity (92.5% RH) conditions for 30 days, and light conditions for 12 days, respectively. The test results are shown in Table 9 below.

[0094] Table 9

[0095]

[0096] In the study of the influencing factors of packaging, within 30 days of placement, the quality control indicators of Example 1 and Comparative Example 2 were most affected by temperature, and were almost unaffected by high humidity and light. Comparative Example 2 had significantly more related substances and polymer impurities than Example 1. Under high temperature conditions, the most significant change was dissolution, which was significantly reduced in Comparative Example 2, and the reduction in Comparative Example 2 exceeded 20% (unqualified) in 30 days, while Example 1 only reduced by 9.5%, still exceeding 75% (qualified). Therefore, the original research has higher requirements for use, storage and transportation, and the stability is also biased.

[0097] The packaging of Example 1 and Comparative Example 2 was removed, and the samples were placed under high temperature (60°C) conditions for 30 days, high humidity (92.5% RH) conditions for 30 days, and light conditions for 12 days, respectively. The test results are shown in Table 10. The content detection method is determined according to the import registration standard (JX20190125) of cefoperaxifen hydrochloride granules.

[0098] Table 10

[0099]

[0100] In the study of the influencing factors of unpacking, within 30 days of placement, the quality control indicators of Example 1 and Comparative Example 2 were most affected by temperature and humidity, and were almost unaffected by light. Under high temperature conditions, the growth rates of the related substances in Example 1 and Comparative Example 2 were consistent, but the amount of the related substances in Comparative Example 2 was significantly higher than that in Example 1, and the growth rate of the polymer in Example 1 was significantly lower than that in Comparative Example 2. Under high humidity conditions, the growth rate of the total impurities and polymers in Comparative Example 2 was significantly faster than that in Example 1, and the final amount was almost twice that of Example 1. The study of the influencing factors of unpacking shows that the stability of the product of the present invention is significantly better than that of the original preparation.

[0101] In addition, we also conducted accelerated tests on commercially available packaging for Example 1 and Comparative Example 2, and placed them under accelerated test conditions (40°C / 75%RH) for 6 months. The experimental results are shown in Table 11 below. The results show that the change range and amount of the relevant substances, polymers and dissolution of Example 1 are significantly better than those of Comparative Example 2.

[0102] Table 11

[0103]

[0104] Test Example 4: Human Bioequivalence Study

[0105] The key formula composition and process of the present invention are different from those of the original preparation, so the pharmacokinetic properties and efficacy in the human body may be affected. According to the requirements for drug marketing, the product of the present invention carried out bioequivalence tests before and after meals in healthy subjects, recruited 56 subjects, and the experimental results are shown in Table 12 below. The research results show that the product prepared by the formula and process of the present invention can ultimately be bioequivalent to the original marketed preparation under the conditions of ensuring the same taste masking and suspension effect as the original, lower related substances and polymers, and more stable dissolution stability.

[0106] Table 12

[0107]

[0108] The above detailed description of the present invention is intended to enable persons familiar with the art to understand the contents of the present invention and implement them. It does not limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A cefcapone hydrochloride fine granules, characterized in that: The invention comprises drug-containing taste-masking particles accounting for 50-56% of the total mass of the cefcapene pivoxil hydrochloride fine granules, sweet particles accounting for 41-47% of the total mass of the cefcapene pivoxil hydrochloride fine granules, sucrose stearate accounting for 0.5-2% of the total mass of the cefcapene pivoxil hydrochloride fine granules, and a wetting agent accounting for 0.5-3% of the total mass of the cefcapene pivoxil hydrochloride fine granules; wherein the drug-containing taste-masking particles comprise cefcapene pivoxil hydrochloride.

2. The cefcapone hydrochloride fine granules according to claim 1, characterized in that: The drug-containing taste-masking particles further include a waxy taste-masking material accounting for 1 to 10% of the total mass of the drug-containing taste-masking particles, and a disintegrant accounting for 10 to 35% of the total mass of the drug-containing taste-masking particles.

3. The cefcapone hydrochloride fine granules according to claim 2, characterized in that: The drug-containing taste-masking particles further include a waxy taste-masking material accounting for 1 to 5% of the total mass of the drug-containing taste-masking particles, and a disintegrant accounting for 10 to 20% of the total mass of the drug-containing taste-masking particles.

4. The cefcapone hydrochloride fine granules according to claim 2, characterized in that: The waxy taste-masking material is one or more of hydrogenated castor oil, glyceryl distearate and glyceryl behenate; the disintegrant is one or more of low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl starch.

5. The cefcapone hydrochloride fine granules according to claim 1 or 2, characterized in that: The drug-containing taste-masking particles further include a filler accounting for 35-50% of the total mass of the drug-containing taste-masking particles, and a lubricant accounting for 1-2% of the total mass of the drug-containing taste-masking particles.

6. The cefcapone hydrochloride fine granules according to claim 1, characterized in that: The mass of the cefcapone hydrochloride is 12-16% of the total mass of the cefcapone hydrochloride fine granules.

7. The cefcapone hydrochloride fine granules according to claim 1, characterized in that: The wetting agent is one or more of colloidal silicon dioxide, talc, and sodium stearyl fumarate.

8. The cefcapone hydrochloride fine granules according to claim 1, characterized in that: The sweet particles include a sweetener accounting for 90-96% of the total mass of the sweet particles, and a binder accounting for 4-10% of the total mass of the sweet particles.

9. The cefcapone hydrochloride fine granules according to claim 8, characterized in that: The sweetener is one or more of mannitol, sucralose, aspartame, and xylitol; the binder is one or more of povidone, hydroxypropyl cellulose, and hypromellose.

10. A method for preparing the cefcapone hydrochloride fine granules according to any one of claims 1 to 9, characterized in that: The steps include: (1) preparing drug-containing taste-masked granules by dry granulation process and melting process according to the formula amount; (2) preparing sweet granules by wet granulation process according to the formula amount; (3) According to the formula amount, the drug-containing taste-masking granules, the sweet granules, the sucrose stearate, and the wetting agent are uniformly mixed to prepare the cefcapone hydrochloride fine granules.

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