Cefixime granules and a method for preparing the same

Abstract

The application discloses cefixime granules and a preparation method thereof, and the granules contain cefixime, a filling agent, a binder, a wetting agent, a flavoring agent and pharmaceutically acceptable adjuvants, wherein the filling agent is a calcium hydrogen phosphate-hydroxyethyl cellulose compound. The cefixime granules prepared by the method have the advantages of simple preparation method, stable quality under the conditions of moisture and heat, no degradation, no impurities, good suspension performance, good dissolution performance, long-term storage with qualified and stable quality, simple preparation process and suitability for industrial mass production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and in particular to a cefixime granule and its preparation method. Background Technology

[0002] Cefixime is a white to pale yellow crystalline powder, odorless with a slight characteristic odor. It is readily soluble in methanol and dimethyl sulfoxide, slightly soluble in acetone, sparingly soluble in ethanol, and practically insoluble in water, ethyl acetate, ether, and hexane. Its chemical structural formula is:

[0003]

[0004] Cefixime granules contain cefixime as their main ingredient, a third-generation cephalosporin antibiotic. It effectively inhibits β-lactamases and Gram-negative bacteria, exhibiting a broad antibacterial spectrum, strong antibacterial activity, and high efficacy. Compared to other cephalosporins, cefixime granules have lower nephrotoxicity. Cefixime demonstrates good antibacterial activity against Gram-positive and Gram-negative microorganisms, Moraxella catarrhalis, Escherichia coli, Proteus mirabilis, and Neisseria gonorrhoeae, making it suitable for treating infections in the respiratory, urinary, and biliary tracts caused by susceptible bacteria.

[0005] Cefixime is a third-generation cephalosporin developed by Fujisawa Pharmaceutical Co., Ltd. of Japan, and was launched in Japan in 1987. The formulation of cefixime granules includes cefixime, white sugar, hydroxypropyl cellulose, tragacanth gum, orange oil, dextrin, gum arabic, and sunset yellow. Cefixime is unstable and easily degraded under humid and hot conditions, and the quality stability of such products on the market is generally poor. Furthermore, the use of a swing granulation process to prepare cefixime granules often results in a large particle size distribution and a high proportion of fine powder, leading to uneven dispersion of cefixime within the granules and affecting subsequent dissolution behavior.

[0006] Chinese patent ZL201010176154.8 discloses a cephalosporin suspension granule. The formulation of the cephalosporin suspension granule includes active pharmaceutical ingredients, excipients, suspending agents, disintegrants, flavoring agents, coloring agents, stabilizers, binders, and flavorings. By adding a certain amount of disintegrants and suspending agents to the formulation and using fluidized bed drying technology, it can ensure the dissolution of the active ingredients and give the solution a good suspension effect.

[0007] Chinese patent ZL202110773379.X discloses a cefixime drug, comprising cefixime and a dispersant, wherein the dispersant is cellulose-lactose. Utilizing cellulose-lactose to effectively disperse the raw materials improves the mixing uniformity and compressibility of the materials, thereby increasing the product yield and stability. Simultaneously, it enables rapid release of the product in multiple media, improving its bioavailability.

[0008] Chinese patent ZL201710154236.4 discloses a method for preparing cefixime dry suspension granules. The method involves dissolving a pH adjuster in a solution, spraying it onto the surface of intermediate cefixime dry suspension granules, drying the solution, and finally adding a solubilizer and flavoring agent, mixing thoroughly to obtain the cefixime dry suspension granules. This patented method increases the stability of the formulation by adjusting the pH value. However, its drawback is that spraying the solution onto the surface of the intermediate cefixime dry suspension granules can easily lead to excessively low local pH levels, making the cefixime raw material less stable in certain areas.

[0009] To overcome the shortcomings of cefixime, most existing technologies employ complex excipients or processes. While these solutions address issues such as cefixime's instability under wet and heat, easy degradation, and dissolution to some extent, the increased variety of excipients leads to an increase in unknown impurities, and the complex processes also increase production costs. Therefore, there is an urgent need to provide a cefixime granule drug that uses simpler excipients and processes, simultaneously addressing the problems of cefixime's instability under wet and heat, easy degradation, and dissolution. Summary of the Invention

[0010] In view of the shortcomings of the prior art, the purpose of this invention is to provide a cefixime granule and its preparation method. The formulation is simple, the preparation method is simple, and the obtained cefixime granules are stable, non-degradable, and have good dissolution performance and bioavailability.

[0011] To achieve the above objectives, this invention has conducted extensive experimental research and improvements on existing formulations and processes, and discovered that when using dicalcium phosphate-hydroxyethyl cellulose complex as a filler, in addition to achieving the filling function, it can also protect cefixime from degradation and maintain stability under humid and hot conditions.

[0012] Specifically, the present invention provides a cefixime granule, characterized in that the granule comprises cefixime, a filler, a binder, a wetting agent, a flavoring agent, and pharmaceutically acceptable excipients.

[0013] In this invention, the selection of filler is one of the key technical aspects for achieving the desired technical effect. The unstable structure of cefixime makes it highly susceptible to intermolecular polymerization. Existing process formulations result in rapid growth of impurities and polymers during production, forming sensitizing high-molecular-weight impurities. Polymerization reactions are particularly prone to occur under high temperature and humidity conditions, especially during granulation and drying. Temperatures exceeding 45°C can easily lead to dehydration of cefixime trihydrate, and high moisture content can cause polymer and related substances to exceed limits during storage. The dicalcium phosphate-hydroxyethyl cellulose complex, while acting as a filler, also forms a hydroxyethyl cellulose film on the surface of the cefixime active pharmaceutical ingredient. Under high temperature and humidity conditions, this reduces the loss of water of crystallization and prevents intermolecular polymerization reactions. If hydroxyethyl cellulose is used alone, it is easy to cause uneven material mixing. This is manifested in the increased particle size distribution and more fine powder when using the swing granulation process. However, if dicalcium phosphate is used in combination with hydroxyethyl cellulose, the hydroxyethyl cellulose can be fully mixed with cefixime during material filling, resulting in uniformly dispersed, stable and controllable particles. The hydroxyethyl cellulose and cefixime have more sufficient contact, resulting in better protective effect.

[0014] In this invention, the ratio of dicalcium phosphate to hydroxyethyl cellulose in the dicalcium phosphate-hydroxyethyl cellulose complex is one of the key technical factors for achieving the desired technical effect. As mentioned above, the dicalcium phosphate-hydroxyethyl cellulose complex, while providing a filling effect, also forms a hydroxyethyl cellulose film on the surface of the cefixime active pharmaceutical ingredient, preventing intermolecular polymerization. When the dicalcium phosphate content is high and the hydroxyethyl cellulose content is low, the hydroxyethyl cellulose cannot fully form a protective film on the cefixime active pharmaceutical ingredient. Conversely, when the dicalcium phosphate content is low and the hydroxyethyl cellulose content is high, the filling effect is poor, making granulation difficult. When the mass ratio of dicalcium phosphate to hydroxyethyl cellulose is 1-3.5:1, while ensuring the granulation effect of cefixime granules, a hydroxyethyl cellulose film is fully formed on the cefixime, effectively protecting cefixime from degradation under humid and hot conditions. Preferably, the mass ratio of dicalcium phosphate to hydroxyethyl cellulose is 3:1.

[0015] In this invention, the selection of the binder is one of the key technical aspects for achieving the desired technical effect. Existing formulations use hydroxypropyl cellulose as a binder, and tragacanth gum and gum arabic as suspending agents. However, tragacanth gum and gum arabic are prone to generating impurities during granulation due to humid and hot conditions. The reference formulation uses extrusion granulation, resulting in very fine particles with relatively easy moisture control. Currently, domestic extrusion equipment cannot cool down, and hydroxypropyl cellulose and flavoring agents tend to become sticky after heating during extrusion, making extrusion impossible. This invention selects low-viscosity hydroxypropyl methylcellulose as a binder, which has good adhesive properties and good compatibility with other excipients. When used in cefixime granules, it can replace tragacanth gum and gum arabic, providing a suspending and dispersing effect and avoiding the impurity generation caused by tragacanth gum and gum arabic during granulation due to humid and hot conditions. When the viscosity of low-viscosity hydroxypropyl methylcellulose is 100-300 cps, it is more conducive to forming uniform particles with suitable strength and effectively increasing the viscosity of the system, thus ensuring stable dispersion of cefixime granules in the liquid. Preferably, the viscosity of low-viscosity hydroxypropyl methylcellulose is 200 cps.

[0016] In this invention, the particle size of cefixime raw material is one of the key factors in achieving the technical effect. If the cefixime particle size is too small, the viscosity and electrostatic properties of the cefixime powder are significantly enhanced, resulting in poor material flowability during the preparation process. Furthermore, small cefixime particle size leads to a large specific surface area, increasing the contact points between cefixime and moisture, oxygen, heat, and other substances in the air, thereby accelerating the degradation rate of cefixime and causing poor quality stability of the formulation. If the cefixime particle size is too large, it is not conducive to the dissolution of cefixime particles, affecting release. A suitable particle size range not only improves the dissolution rate and increases particle quality, resulting in compact particles, reduced fine powder, and improved stability, but also enhances the dissolution rate and bioavailability. When the particle size range of cefixime is D90 = 40-90 μm, cefixime is easy to granulate, and the obtained cefixime particles are of stable quality and have better dissolution performance. Preferably, the particle size range of cefixime is D90 = 60-80 μm.

[0017] In this invention, the selection of the wetting agent is one of the key factors in achieving the technical effect. Ethanol is a polar organic compound with excellent wetting properties, effectively reducing surface tension and improving wetting performance. In pharmaceutical production, ethanol is used as a wetting agent to make the solution more easily penetrate into fine pores, thereby improving the quality and performance of the drug. Simultaneously, as a volatile organic solvent, ethanol, when mixed with water, forms a solution that easily evaporates without leaving residue. Therefore, using ethanol as a wetting agent can effectively avoid the effects of wetting agent residue. The higher the ethanol concentration, the lower the viscosity of the powder after wetting. When the formulation material has high water solubility, high viscosity, and high temperature, the ethanol concentration should be relatively high. Conversely, its concentration can be slightly lower. When the wetting agent is a water-ethanol solution, and the concentration of the water-ethanol solution is 30-60%, contact with the drug powder wets its surface, generating adhesion, and cefixime granules of a certain shape and size can be formed. Preferably, the concentration of the water-ethanol solution is 40%.

[0018] In this invention, flavoring agents are one of the key factors in achieving the technical effects. A suitable flavoring agent can reduce interference with the main active pharmaceutical ingredient, extend the shelf life of the drug, ensure easy and controllable drug quality, and improve the taste of the drug granules. When xylitol, sucrose, aspartame, erythritol, or sucralose are selected as flavoring agents, they cause the least interference with cefixime granules, and a small amount is sufficient to improve the taste of cefixime granules. Preferably, sucrose is the preferred flavoring agent.

[0019] In this invention, the selection of the formulation is one of the factors in achieving the technical effect. Specifically, increasing the amount of excipients is beneficial to increasing the possibility of granulation, but increasing the amount of excipients will lead to larger granule weight, which is not conducive to patient administration. Unless otherwise specified, the amount of active ingredient in the formulation of this invention is based on the mass of cefixime. When the mass fraction of cefixime is 1, the mass ratio of cefixime to filler is 1:0.4-0.8, the mass ratio of cefixime to binder is 1:0.3-0.7, the mass ratio of cefixime to wetting agent is 1:1.5-3.0, and the mass ratio of cefixime to flavoring agent is 1:15-20. Preferably, the mass ratio of cefixime to filler is 1:0.6, the mass ratio of cefixime to binder is 1:0.5, the mass ratio of cefixime to wetting agent is 1:2.0, and the mass ratio of cefixime to flavoring agent is 1:18.

[0020] Based on actual production conditions of the formulation, those skilled in the art know that the mass ratio between raw materials and excipients is allowed to have a certain error range, and the mass ratio error range described in this invention can be ±0.5%.

[0021] This invention also provides cefixime granules, comprising the following components. This formulation is a preferred technical solution of this invention, and simultaneously solves the problems of easy degradation and instability of cefixime granules under humid and hot conditions during the preparation process using swing granulation, resulting in a large amount of fine powder, uneven particle size, and impurity growth and release. The resulting preparation has excellent quality, good dissolution performance, and good long-term storage stability, meeting the requirements for pharmaceutical efficacy.

[0022] A cefixime granule comprises the following components:

[0023] name Quality Cefixime (D90 = 60-80 μm) 1 dicalcium phosphate-hydroxyethyl cellulose complex 0.6 Low-viscosity hydroxypropyl methylcellulose (viscosity 200 cps) 0.5 40% water-ethanol solution 2.0 sucrose 18

[0024] A second objective of this invention is to provide a method for preparing the aforementioned cefixime granules, the method comprising the following steps:

[0025] 1) Stir and mix dicalcium phosphate and hydroxyethyl cellulose evenly to obtain dicalcium phosphate-hydroxyethyl cellulose complex, for later use;

[0026] 2) Use a multi-purpose grinder to grind the sucrose. The grinding screen should be 120 mesh. Set aside.

[0027] 3) Place sucrose, cefixime, low-viscosity hydroxypropyl methylcellulose, and dicalcium phosphate-hydroxyethyl cellulose complex sequentially into a high-position wet mixing granulator, premix, pour in 40% ethanol aqueous solution containing Sunset Yellow, and granulate.

[0028] 4) Transfer the above soft material to a double-swing pellet mill, sieve it, and start the machine to perform swing pelleting;

[0029] 5) Place the granules after swaying granulation in a fluidized bed dryer and dry them. Set the inlet air temperature to 60℃ and dry them until the moisture content of the granules is ≤1%.

[0030] 6) Place the dried granules in a square sieve to sieve them, collect the middle layer of granules, and package them.

[0031] Cefixime granules are prepared using a swing granulation method. By precisely controlling the sieve aperture and swing amplitude, the size and shape of the granules can be precisely controlled, which helps to ensure the uniformity and consistency of cefixime granules, thereby improving the stability and efficacy of the drug.

[0032] Compared with the prior art, the present invention has the following outstanding advantages and beneficial effects:

[0033] 1) In this invention, dicalcium phosphate and hydroxyethyl cellulose are combined in a specific ratio as a composite filler. During the granulation process, the influence of environmental factors can be reduced, and the growth of impurities caused by high temperature and high humidity can be avoided. This reduces the occurrence of easy degradation and instability of the raw material. At the same time, the generation of fine powder is reduced during the use of swing granulation, ensuring that the particles are uniform and stable.

[0034] 2) This invention uses low-viscosity hydroxypropyl methylcellulose as a binder, which avoids the use of tragacanth gum and gum arabic, reduces impurities generated by the humid and hot environment during the granulation process of tragacanth gum and gum arabic, and achieves better dispersion while ensuring the dissolution and release of cefixime particles.

[0035] 3) The process of this invention is simple to operate, using a swing granulation method, and the preparation process is simple, suitable for large-scale industrial production and commercial production, and has great application value. Detailed Implementation

[0036] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0037] Example 1: Preparation of Cefixime Granules

[0038] name Dosage (g) Cefixime (D90 = 60-80 μm) 50.0 Calcium hydrogen phosphate 22.5 Hydroxyethyl cellulose 7.5 Low-viscosity hydroxypropyl methylcellulose (viscosity 200 cps) 25.0 Water-ethanol solution (40%) 100.0 sucrose 900.0

[0039] Preparation method:

[0040] 1) Stir and mix dicalcium phosphate and hydroxyethyl cellulose evenly to obtain dicalcium phosphate-hydroxyethyl cellulose complex, for later use;

[0041] 2) Use a multi-purpose grinder to grind the sucrose. The grinding screen should be 120 mesh. Set aside.

[0042] 3) Place sucrose, cefixime, low-viscosity hydroxypropyl methylcellulose, and dicalcium phosphate-hydroxyethyl cellulose complex sequentially into a high-position wet mixing granulator. Set the stirring paddle speed to 120-200 rpm and the cutter speed to 1200-2000 rpm. Premix for 300 seconds, then pour in a 40% ethanol aqueous solution containing Sunset Yellow and granulate.

[0043] 4) Transfer the above soft material to a double swing pellet mill, sieve it with a 24-mesh screen, and start the machine to perform swing pelleting;

[0044] 5) Place the granules after swaying granulation in a fluidized bed dryer for drying. Set the inlet air temperature to 60℃ and control the fan frequency to 25±5Hz according to the fluidization state of the material. Dry until the moisture content of the granules is ≤1%.

[0045] 6) Place the dried granules in a square sieve with mesh sizes of 30 mesh and 60 mesh to sieve the granules, collect the middle layer granules, and package them.

[0046] Example 2: Preparation of Cefixime Granules

[0047] name Dosage (g) Cefixime (D90 = 40-60 μm) 50.0 Calcium hydrogen phosphate 10.0 Hydroxyethyl cellulose 10.0 Low-viscosity hydroxypropyl methylcellulose (viscosity 100 cps) 15.0 Water-ethanol solution (30%) 75.0 sucrose 750.0

[0048] The preparation method is as described in Example 1.

[0049] Example 3: Preparation of Cefixime Granules

[0050] name Dosage (g) Cefixime (D90 = 80-90 μm) 50.0 Calcium hydrogen phosphate 31.0 Hydroxyethyl cellulose 9.0 Low-viscosity hydroxypropyl methylcellulose (viscosity 300 cps) 35.0 Water-ethanol solution (60%) 150.0 sucrose 1000.0

[0051] The preparation method is as described in Example 1.

[0052] Example 4: Preparation of Cefixime Granules

[0053] name Dosage (g) Cefixime (D90 = 60-80 μm) 50.0 Calcium hydrogen phosphate 15.0 Hydroxyethyl cellulose 10.0 Low-viscosity hydroxypropyl methylcellulose (viscosity 300 cps) 20.0 Water-ethanol solution (50%) 100.0 Sucralose 800.0

[0054] The preparation method is as described in Example 1.

[0055] Example 5: Preparation of Cefixime Granules

[0056] name Dosage (g) Cefixime (D90 = 60-80 μm) 50.0 Calcium hydrogen phosphate 23.0 Hydroxyethyl cellulose 12.0 Low-viscosity hydroxypropyl methylcellulose (viscosity 200 cps) 30.0 Water-ethanol solution (40%) 125.0 Xylitol 950.0

[0057] The preparation method is as described in Example 1.

[0058] Comparative Example 1: Preparation of Cefixime Granules

[0059] name Dosage (g) Cefixime (D90 = 60-80 μm) 50.0 Calcium hydrogen phosphate 5.0 Hydroxyethyl cellulose 10.0 Low-viscosity hydroxypropyl methylcellulose (viscosity 100 cps) 10.0 Water-ethanol solution (20%) 50.0 sucrose 700.0

[0060] The preparation method is as described in Example 1. In the formulation of Comparative Example 1, the amount of filler is relatively small, the proportion of dicalcium phosphate in the dicalcium phosphate-hydroxyethyl cellulose complex is relatively small, the amount of binder, wetting agent and flavoring agent is relatively small, and the concentration of water-ethanol solution is relatively low.

[0061] Comparative Example 2: Preparation of Cefixime Granules

[0062] name Dosage (g) Cefixime (D90 = 60-80 μm) 50.0 Calcium hydrogen phosphate 36.0 Hydroxyethyl cellulose 9.0 Hydroxypropyl methylcellulose (viscosity 500 cps) 40.0 Water-ethanol solution (70%) 175.0 sucrose 1100.0

[0063] The preparation method is as described in Example 1. In the formulation of Comparative Example 2, the amount of filler is relatively high. In the dicalcium phosphate-hydroxyethyl cellulose complex, the proportion of dicalcium phosphate is relatively large, the viscosity of hydroxypropyl methylcellulose is relatively high, the amount of binder, wetting agent, and flavoring agent is relatively high, and the concentration of water-ethanol solution is relatively high.

[0064] Preparation of cefixime granules (Comparative Example 3)

[0065] name Dosage (g) Cefixime (D90 = 60-80 μm) 50.0 Calcium hydrogen phosphate 30.0 Low-viscosity hydroxypropyl methylcellulose (viscosity 200 cps) 40.0 Water-ethanol solution (40%) 100.0 sucrose 900.0

[0066] The preparation method is as described in Example 1. In the formulation of Comparative Example 3, only dicalcium phosphate was used as the filler, and hydroxyethyl cellulose was not used.

[0067] Preparation of cefixime granules (Comparative Example 4)

[0068] name Dosage (g) Cefixime (D90 = 60-80 μm) 50.0 Hydroxyethyl cellulose 30.0 Low-viscosity hydroxypropyl methylcellulose (viscosity 200 cps) 25.0 Water-ethanol solution (40%) 100.0 sucrose 900.0

[0069] The preparation method is as described in Example 1. In the formulation of Comparative Example 4, only hydroxyethyl cellulose was used as the filler, and no dicalcium phosphate was used.

[0070] Preparation of cefixime granules (Comparative Example 5)

[0071] name Dosage (g) Cefixime (D90 = 60-80 μm) 50.0 Calcium hydrogen phosphate 22.5 Hydroxyethyl cellulose 7.5 Hydroxypropyl cellulose 25.0 water 100.0 sucrose 900.0

[0072] The preparation method is as described in Example 1. In the formulation of Comparative Example 5, hydroxypropyl cellulose is used as the adhesive and water is used as the wetting agent.

[0073] Preparation of cefixime granules (Comparative Example 6)

[0074] name Dosage (g) Cefixime (D90 = 100-120 μm) 50.0 Calcium hydrogen phosphate 22.5 Hydroxyethyl cellulose 7.5 Low-viscosity hydroxypropyl methylcellulose (viscosity 200 cps) 25.0 Water-ethanol solution (40%) 100.0 sucrose 900.0

[0075] The preparation method is as described in Example 1. In the formulation of Comparative Example 6, the cefixime particle size is relatively large.

[0076] Example 6

[0077] The cefixime granules prepared in Examples 1-5 and Comparative Examples 1-6 were subjected to quality testing, and the results are as follows:

[0078] Table 1 Quality Assessment of Cefixime Granules

[0079]

[0080] The results above show that the cefixime granules prepared in Examples 1-5 and Comparative Examples 1-6 have a stable granule yield of over 93% in Examples 1-5, while the yield in Comparative Example 1 is lower. Analysis indicates that the amounts of filler, binder, and wetting agent are insufficient, resulting in poor granulation and a lower granule yield. Furthermore, the ethanol concentration is low, the moisture content is high, and the amount of binder is insufficient, leading to poor dissolution and the inability to form uniform granules with suitable strength. The granules also have poor flowability and a rough texture. In Comparative Example 2, the amounts of filler, binder, and wetting agent are excessive, and the high viscosity of hydroxypropyl methylcellulose causes stickiness during granulation, preventing uniform mixing and resulting in poor granulation, a low yield, poor flowability, and a rough texture. In Comparative Example 3, only dicalcium phosphate was used as a filler, without hydroxyethyl cellulose, failing to form a hydroxyethyl cellulose protective film. Therefore, under humid and hot conditions, impurities increased. In Comparative Example 4, only hydroxyethyl cellulose was used as the filler, without the use of dicalcium phosphate. This resulted in the inability to form uniform particles, affecting the particle yield, poor flowability, and a coarse texture. In Comparative Example 5, hydroxypropyl cellulose was used as the binder, and water was used as the wetting agent. This resulted in poor dissolution and a high moisture content, further reducing the particle yield. In Comparative Example 6, the large particle size of cefixime affected dissolution, leading to a slightly poor dissolution effect and a coarse texture. Examples 1-5 represent the preferred solutions in this scheme. In Example 1, all parameters, including the types and proportions of excipients, are optimal. Using a dicalcium phosphate-hydroxyethyl cellulose composite as the filler and low-viscosity hydroxypropyl methyl cellulose as the binder ensures good compatibility with the excipients. This allows the cefixime to avoid the influence of environmental factors during granulation, preventing impurity growth under high temperature and humidity conditions. The overall combination of these factors allows the cefixime particles to achieve optimal performance during preparation.

[0081] Example 7

[0082] Take 100g of dried granules (before sieving) obtained from Examples 1-3 and Comparative Example 4 at mesh sizes of 20, 30, 60, and 120, and place them in sieve sleeves respectively. Vibrate evenly with both hands for 5 minutes, open the top cover, and weigh the granules on each sieve. Calculate the proportion of each particle size in the total material. The measured proportions of each particle size are shown in Table 2.

[0083] Table 2 Particle size distribution of finished product The results above show that the granules prepared by the formulation process described in Examples 1-3 have a particle size distribution that is basically within 60 mesh, with most particles between 30 and 60 mesh. The particle size distribution range is narrow, the particle size is uniform, and the granulation effect is good, which can meet the requirements of subsequent processes. In contrast, the granules prepared in Comparative Example 4 contain large particles and a lot of fine powder, and the particle distribution is uneven. Analysis shows that using hydroxyethyl cellulose alone easily leads to uneven material mixing. When using the swing granulation process, the particle size distribution increases, and there are more fine powder particles.

[0084] Example 8

[0085] The cefixime granules prepared in Example 1 of this invention were placed in a sealed and clean container and subjected to high temperature, high humidity, and light exposure tests under the following conditions:

[0086] High temperature: Placed at 60℃ for 10 days, samples were taken on the 5th and 10th days and tested according to the key stability test items. The test results were compared with those of day 0.

[0087] High humidity: Placed at 25℃ and relative humidity of 90%±5% for 10 days, samples were taken on the 5th and 10th days and tested according to the key stability test items. The test results were compared with those of 0 days.

[0088] Illumination: Placed under an illuminance of 4500 Lx for 10 days, samples were taken on the 5th and 10th days, and tests were conducted according to the key stability test items. The test results were compared with those of day 0.

[0089] The test results are shown in Table 3.

[0090] Table 3 Results of High Temperature and High Humidity Light Irradiation Test

[0091]

[0092] The results above show that the cefixime granules prepared in Example 1 have good stability in terms of moisture, dissolution, related substances, and labeled amounts under high temperature, high humidity, and light conditions. This indicates that in the dicalcium phosphate-hydroxyethyl cellulose complex, hydroxyethyl cellulose comes into contact with cefixime to form an effective protective film, protecting the raw materials from degradation under humid and hot conditions. Furthermore, dicalcium phosphate-hydroxyethyl cellulose and low-viscosity hydroxypropyl methylcellulose have good compatibility with other excipients and do not produce other impurities under humid and hot conditions.

[0093] Example 9 Accelerated Test

[0094] The cefixime granules prepared in Example 1 of this invention were placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the 1st, 2nd, 3rd, and 6th months, and the stability was tested according to the key test items. The test results are shown in Table 4.

[0095] Table 4 Accelerated Test Results The results above show that the cefixime granules prepared in Example 1 have good stability in terms of moisture, dissolution, related substances, and labeled amounts under the conditions of temperature 40℃±2℃ and relative humidity 75%±5%. This indicates that in the dicalcium phosphate-hydroxyethyl cellulose complex, hydroxyethyl cellulose can form an effective protective film when in contact with cefixime, protecting the raw material from degradation under humid and hot conditions. Furthermore, dicalcium phosphate-hydroxyethyl cellulose and low-viscosity hydroxypropyl methylcellulose have good compatibility with other excipients and will not produce other impurities during long-term storage, demonstrating good stability.

[0096] In summary, the cefixime granules prepared by this invention are simple to prepare, stable in quality under humid and hot conditions, do not degrade, are not prone to impurities, have good suspension properties, and also have good dissolution properties. They also maintain stable and qualified quality even after long-term storage.

[0097] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A cefixime granule, characterized in that, The granules contain cefixime, fillers, binders, wetting agents, flavoring agents, and pharmaceutically acceptable excipients. The filler is a dicalcium phosphate-hydroxyethyl cellulose complex. In the aforementioned dicalcium phosphate-hydroxyethyl cellulose complex, the mass ratio of dicalcium phosphate to hydroxyethyl cellulose is 1-3.5:

1. The adhesive is low-viscosity hydroxypropyl methylcellulose with a viscosity of 100-300 cps. The particle size range of the cefixime is D90 = 40-90 μm. The wetting agent is a water-ethanol solution with a concentration of 30-60%. The flavoring agents are xylitol, sucrose, aspartame, erythritol, and sucralose. The mass ratio of cefixime to filler is 1:0.4-0.8, the mass ratio of cefixime to adhesive is 1:0.3-0.7, the mass ratio of cefixime to wetting agent is 1:1.5-3.0, and the mass ratio of cefixime to flavoring agent is 1:15-20.

2. The cefixime granules according to claim 1, characterized in that, In the dicalcium phosphate-hydroxyethyl cellulose complex, the mass ratio of dicalcium phosphate to hydroxyethyl cellulose is 3:

1.

3. The cefixime granules according to claim 1, characterized in that, The adhesive has a viscosity of 200 cps.

4. The cefixime granules according to claim 1, characterized in that, The particle size range of the cefixime is D90 = 60-80 μm.

5. The cefixime granules according to claim 1, characterized in that, The concentration of the water-ethanol solution is 40%.

6. The cefixime granules according to claim 1, characterized in that, The flavoring agent is sucrose.

7. The cefixime granules according to claim 1, characterized in that, The mass ratio of cefixime to filler is 1:0.6, the mass ratio of cefixime to adhesive is 1:0.5, the mass ratio of cefixime to wetting agent is 1:2.0, and the mass ratio of cefixime to flavoring agent is 1:

18.

8. A cefixime granule, characterized in that, It contains the following components:

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