Cefixime granules and preparation method thereof

Abstract

The invention discloses cefixime granules and a preparation method thereof, the granules comprise cefixime, a filler, an adhesive, a wetting agent, a flavoring agent and pharmaceutically acceptable auxiliary materials, and the filler is a calcium hydrophosphate-hydroxyethyl cellulose compound. The cefixime granules prepared by the invention are simple in preparation method, stable in quality, non-degradable, not easy to generate impurities, better in suspension performance, better in dissolution performance, qualified and stable in quality after long-term storage, simple in preparation process and suitable for industrial mass production under damp and hot conditions.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical preparations, and in particular to cefixime granules and a preparation method thereof. Background Art

[0002] Cefixime is a white to light yellow crystalline powder, tasteless, with a slight specific odor, easily soluble in methanol and dimethyl sulfoxide, slightly soluble in acetone, poorly soluble in ethanol, almost insoluble in water, ethyl acetate, ether, and hexane. The chemical structure is:

[0003]

[0004] The main ingredient of Cefixime Granules is Cefixime, which is a third-generation cephalosporin antibiotic that can effectively inhibit β-lactamase and Gram-negative bacteria. It has a broad antibacterial spectrum, strong antibacterial activity, and high efficacy. Compared with other cephalosporin drugs, Cefixime Granules have lower nephrotoxicity. Cefixime has good antibacterial activity against Gram-positive and Gram-negative microorganisms, Moraxella catarrhalis, Escherichia coli, Proteus mirabilis, and Neisseria gonorrhoeae, and is suitable for the treatment of infections in the respiratory, urinary, and biliary tracts caused by sensitive bacteria.

[0005] Cefixime is a third-generation cephalosporin product developed by Fujisawa Pharmaceutical Co., Ltd. of Japan and was launched in Japan in 1987. The prescription of cefixime granules is cefixime, sugar, hydroxypropyl cellulose, tragacanth gum, orange oil, dextrin, gum arabic, and sunset yellow. Cefixime is unstable and easily degraded under hot and humid conditions. The quality stability of such products on the market is generally poor. In addition, the use of the swing granulation process to prepare cefixime granules is prone to problems such as large particle size distribution and more fine powder in the particles, which leads to uneven dispersion of cefixime in the particles and affects the subsequent dissolution behavior.

[0006] Chinese patent ZL201010176154.8 discloses a cephalosporin suspension granule, the prescription composition of the cephalosporin suspension granule includes active pharmaceutical ingredients, excipients, suspending agents, disintegrants, flavoring agents, colorants, stabilizers, adhesives, and flavors. By adding a certain amount of disintegrants and suspending agents to the prescription and using fluidized bed drying technology, the dissolution of the active ingredients can be ensured and the solution can have a good suspending effect.

[0007] Chinese patent ZL202110773379.X discloses a cefixime drug, including cefixime and a dispersant, wherein the dispersant is cellulose-lactose. Cellulose-lactose is used to disperse the raw materials well, effectively improve the mixing uniformity of the materials, improve the compressibility of the materials, thereby improving the yield and stability of the product, and at the same time, the product can be quickly released in multiple media, thereby improving the bioavailability of the product.

[0008] Chinese patent ZL201710154236.4 discloses a method for preparing cefixime dry suspension granules, which comprises dissolving a pH regulator in a solution, spraying the solution on the surface of the cefixime dry suspension intermediate granules, drying the solution, adding a solubilizer and a flavoring agent, and mixing the mixture evenly to obtain cefixime dry suspension granules. The patent scheme increases the stability of the preparation by adjusting the pH value, but its disadvantage is that spraying the solution on the surface of the cefixime dry suspension intermediate granules may easily lead to a low local pH value, and the local cefixime raw material may become more unstable.

[0009] In order to overcome the defects of cefixime, most of the existing technologies use complex excipients or processes. Although the above solutions solve the problems of cefixime being unstable under damp heat, easy to degrade and dissolve to a certain extent, the increase in the types of excipients will lead to the increase of unknown impurities, and the complex process will also lead to the increase of production costs. Therefore, it is urgent to provide a cefixime granule drug, which uses relatively simple excipients and processes, and can solve the problems of cefixime being unstable under damp heat, easy to degrade and dissolve at the same time. Summary of the invention

[0010] In view of the deficiencies in the prior art, the object of the present invention is to provide a cefixime granule and a preparation method thereof, which has a simple prescription composition and a simple preparation method, and the obtained cefixime granule is stable, does not degrade, and has good dissolution performance and bioavailability.

[0011] To achieve the above-mentioned purpose, the present invention has conducted a large number of experimental studies and improvements on the existing formulations and processes, and found that when using calcium hydrogen phosphate-hydroxyethyl cellulose complex as a filler, in addition to achieving the filling function, it can also protect cefixime from degradation under hot and humid conditions and maintain stability.

[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 a pharmaceutically acceptable excipient.

[0013] In the present invention, the selection of filler is one of the important technical keys to achieve the technical effect. The instability of the cefixime structure is very easy to cause intermolecular polymerization. The existing process prescription increases impurities and polymers rapidly during the production process, forming high-molecular impurities with sensitization. The high-molecular polymerization reaction is very easy to occur under high temperature and high humidity conditions, especially in the granulation and drying process. The temperature exceeds 45°C, which easily leads to the dehydration of cefixime trihydrate. High water content easily leads to excessive polymers and related substances during storage. The calcium hydrogen phosphate-hydroxyethyl cellulose complex forms a hydroxyethyl cellulose film on the surface of the cefixime raw material while having a filling effect. Cefixime reduces the loss of crystal water under high temperature and high humidity conditions and avoids intermolecular polymerization. If hydroxyethyl cellulose is used alone, it is easy to produce material unevenness during material mixing, which is reflected in the fact that when using the swing granulation process, the particle size distribution is enlarged and there are more fine powder particles. If calcium hydrogen phosphate and hydroxyethyl cellulose are used in combination, the hydroxyethyl cellulose can be fully and evenly mixed with cefixime during material filling to obtain evenly dispersed, stable and controllable particles. The hydroxyethyl cellulose is in more complete contact with cefixime, and the protective effect is better.

[0014] In the present invention, the ratio of calcium hydrogen phosphate to hydroxyethyl cellulose in the calcium hydrogen phosphate-hydroxyethyl cellulose complex is one of the important technical keys to achieve the technical effect. As described above, the calcium hydrogen phosphate-hydroxyethyl cellulose complex forms a hydroxyethyl cellulose film on the surface of the cefixime raw material while having a filling effect, thereby avoiding intermolecular polymerization. When the calcium hydrogen phosphate content is high and the hydroxyethyl cellulose content is low, the hydroxyethyl cellulose cannot fully form a protective film on the cefixime raw material, and when the calcium hydrogen phosphate content is low and the hydroxyethyl cellulose content is high, the filling effect is poor and it is difficult to granulate. When the mass ratio of calcium hydrogen 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 cefixime, effectively protecting cefixime from degradation under hot and humid conditions. Preferably, the mass ratio of calcium hydrogen phosphate to hydroxyethyl cellulose is 3:1.

[0015] In the present invention, the selection of adhesive is one of the important technical keys to achieve technical effects. In the existing process prescription, hydroxypropyl cellulose is used as an adhesive, and tragacanth gum and gum arabic are used as suspending agents. Tragacanth gum and gum arabic are prone to produce impurities due to hot and humid conditions during granulation. The reference preparation adopts extrusion granulation, and the particles are very fine and the moisture is relatively well controlled. At present, the domestic extrusion equipment cannot cool down, and hydroxypropyl cellulose and flavoring agents are prone to stickiness after heating during the extrusion process and cannot be extruded. The present invention selects low-viscosity hypromellose as an adhesive, which has good bonding function and good compatibility with other excipients. It can be used in cefixime granules to replace tragacanth gum and gum arabic, and play a suspending and dispersing effect, avoiding tragacanth gum and gum arabic from easily producing impurities due to hot and humid conditions during granulation. When the viscosity of low-viscosity hypromellose is 100-300cps, it is more conducive to forming uniform particles with suitable strength, and effectively increasing the viscosity of the system so that the cephalosporin granules are stably dispersed in the liquid. Preferably, the low viscosity hypromellose has a viscosity of 200 cps.

[0016] In the present invention, the particle diameter of cefixime raw material is one of the key factors to realize technical effect. Cefixime particle diameter is too low, and the viscosity and electrostatic property of cefixime powder are obviously enhanced, resulting in poor material fluidity in the process of preparation, and cefixime particle diameter is small, and specific surface area is large, and the contact point of cefixime with moisture, oxygen, heat and other materials in the air also increases thereupon, thereby accelerating the degradation rate of cefixime, causing poor quality stability of the preparation product. Cefixime particle diameter is too large, which is unfavorable for the dissolution of cefixime granules and affects release. Suitable particle diameter range can not only improve dissolution rate, but also improve the quality of granules, and granules are firm, and fine powder is reduced, while improving stability, dissolution rate and bioavailability are improved. When the particle size range of cefixime is D90=40-90 μm, cefixime is easy to granulate, and the obtained cefixime granules have stable quality and excellent dissolution performance. Preferably, the particle size range of cefixime is D90=60-80 μm.

[0017] In the present invention, the selection of wetting agent is one of the key factors to achieve the technical effect. Ethanol is a polar organic substance with good wetting properties, which can effectively reduce surface tension and improve wetting properties. In the production of medicines, ethanol is used as a wetting agent, which can make the solution easier to enter into fine pores, thereby improving the quality and performance of the medicine. At the same time, ethanol is a volatile organic solvent, and the solution formed after mixing with water is easy to volatilize and will not remain. Therefore, ethanol, as a wetting agent, can effectively avoid the influence of wetting agent residue. The higher the ethanol concentration, the lower the viscosity of the powder after being wetted. When the prescription material is highly water-soluble, highly viscous, and the temperature is high, the ethanol concentration should be relatively high. On the contrary, 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%, through contact with the drug powder, its surface is wetted, adhesion is generated, and cefixime particles of a certain shape and size can be made. Preferably, the concentration of the water-ethanol solution is 40%.

[0018] In the present invention, flavoring agent is one of the important factors for achieving technical effect. Suitable flavoring agent can reduce the interference and effect on the main raw material drug, prolong the shelf life of the drug, reach the effect of easy control of drug quality and improve the mouthfeel of drug granules. When the flavoring agent selects xylitol, sucrose, aspartame, erythritol, sucralose, the interference for cefixime granules is the least, and the cefixime granules mouthfeel can be improved with a small amount, and preferably, the flavoring agent is sucrose.

[0019] In the present invention, the selection of prescription is one of the factors realizing technical effect.Specifically, the increase of auxiliary material dosage is conducive to increasing the possibility of granulation, but the increase of auxiliary material dosage can cause the particle weight to be larger, which is unfavorable for patients to take.If not otherwise specified, the effective ingredient dosage in the formulation prescription of the present invention is all based on the cefixime mass, when the cefixime mass parts is 1, 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, 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 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.

[0020] According to the actual production conditions of the preparations, it is well known to those skilled in the art that the mass ratio of raw materials and auxiliary materials is allowed to have a certain error range, and the error range of the mass ratio in the present invention may be ±0.5%.

[0021] The present invention also provides a cefixime granule, comprising the following components. The prescription is a preferred technical solution of the present invention, and simultaneously solves the problems of easy degradation, instability, more fine powder, uneven particles, impurity growth and release of the cefixime granules under hot and humid conditions during the preparation process using swing granulation. The obtained preparation has excellent quality, good dissolution performance, good long-term storage stability, and meets the medicinal effect.

[0022] A cefixime granule comprising the following components:

[0023] name Mass Cefixime (D90 = 60-80 μm) 1 Dicalcium Phosphate-Hydroxyethylcellulose Complex 0.6 Low viscosity Hydroxypropyl methylcellulose (viscosity 200cps) 0.5 40% water-ethanol solution 2.0 sucrose 18

[0024] The second object of the present invention is to provide a method for preparing the aforementioned cefixime granules, the method comprising the following steps:

[0025] 1) stirring and mixing calcium hydrogen phosphate and hydroxyethyl cellulose to obtain a calcium hydrogen phosphate-hydroxyethyl cellulose complex for later use;

[0026] 2) Use a universal grinder to grind sucrose, the grinding screen is 120 mesh, and set aside;

[0027] 3) placing sucrose, cefixime, low-viscosity hydroxypropyl methylcellulose, and calcium hydrogen phosphate-hydroxyethyl cellulose complex in a high-position wet mixing granulator in sequence, premixing, pouring in 40% ethanol aqueous solution containing sunset yellow, and granulating;

[0028] 4) Transfer the soft material to a double swing granulator, sieve it, and start the machine for swing granulation;

[0029] 5) Dry the granules after swing granulation in a fluidized bed dryer, set the air inlet temperature at 60°C, and dry until the moisture content of the granules is ≤1%;

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

[0031] Cefixime granules are prepared using the swing granulation method. By precisely controlling the aperture and swing amplitude of the sieve, the size and shape of the particles can be precisely controlled, which helps to ensure the uniformity and consistency of the 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 the present invention, calcium hydrogen 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, the growth of impurities under high temperature and high humidity conditions can be avoided, the degradation of raw materials and the instability can be reduced, and at the same time, the generation of fine powder can be reduced during the swing granulation process, ensuring uniform and stable particles.

[0034] 2) The present invention uses low-viscosity hypromellose as a binder, which can avoid the use of tragacanth gum and gum arabic, reduce impurities generated by the hot and humid environment during the granulation of tragacanth gum and gum arabic, achieve a better dispersion effect, and ensure the dissolution and release of cefixime granules.

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

[0036] The present invention is further described in detail below with reference to examples, but the embodiments of the present invention are 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 200cps) 25.0 Water-ethanol solution (40%) 100.0 sucrose 900.0

[0039] Preparation method:

[0040] 1) stirring and mixing calcium hydrogen phosphate and hydroxyethyl cellulose to obtain a calcium hydrogen phosphate-hydroxyethyl cellulose complex for later use;

[0041] 2) Use a universal grinder to grind sucrose, the grinding screen is 120 mesh, and set aside;

[0042] 3) placing sucrose, cefixime, low-viscosity hydroxypropyl methylcellulose, and calcium hydrogen phosphate-hydroxyethyl cellulose complex in a high-position wet mixing granulator in sequence, setting the stirring blade speed to 120-200 rpm and the cutting blade speed to 1200-2000 rpm, premixing for 300 seconds, pouring in 40% ethanol aqueous solution containing sunset yellow, and granulating;

[0043] 4) The soft material is transferred to a double swing granulator, sieved, the mesh size is 24, and the machine is started for swing granulation;

[0044] 5) Place the granules after swing granulation in a boiling dryer and dry them. Set the air inlet temperature to 60°C. According to the fluidization state of the material, control the fan frequency to 25±5Hz and dry them until the moisture content of the granules is ≤1%;

[0045] 6) Place the dried granules on a square granule sieve with mesh sizes of 30 and 60 respectively, sieve the granules, collect the granules in the middle layer, 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 100cps) 15.0 Water-ethanol solution (30%) 75.0 sucrose 750.0

[0048] The preparation method is the same as 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 300cps) 35.0 Water-ethanol solution (60%) 150.0 sucrose 1000.0

[0051] The preparation method is the same as 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 300cps) 20.0 Water-ethanol solution (50%) 100.0 Sucralose 800.0

[0054] The preparation method is the same as 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 200cps) 30.0 Water-ethanol solution (40%) 125.0 Xylitol 950.0

[0057] The preparation method is the same as 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 100cps) 10.0 Water-ethanol solution (20%) 50.0 sucrose 700.0

[0060] The preparation method is as in Example 1. In the prescription of Comparative Example 1, the amount of filler used is relatively small, the proportion of calcium hydrogen phosphate in the calcium hydrogen phosphate-hydroxyethyl cellulose composite is relatively small, the amounts of binder, wetting agent and flavoring agent used are 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 500cps) 40.0 Water-ethanol solution (70%) 175.0 sucrose 1100.0

[0063] The preparation method is as in Example 1. In the prescription of Comparative Example 2, the amount of filler used is too much, the proportion of calcium hydrogen phosphate in the calcium hydrogen phosphate-hydroxyethyl cellulose composite is relatively large, the viscosity of hydroxypropyl methylcellulose is relatively high, the amount of binder, wetting agent and flavoring agent used is too much, and the concentration of water-ethanol solution is relatively high.

[0064] Comparative Example 3 Preparation of Cefixime Granules

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

[0066] The preparation method is the same as that in Example 1. In the prescription of Comparative Example 3, only calcium hydrogen phosphate is used as the filler, and hydroxyethyl cellulose is not used.

[0067] Comparative Example 4 Preparation of Cefixime Granules

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

[0069] The preparation method is the same as that in Example 1. In the prescription of Comparative Example 4, only hydroxyethyl cellulose is used as the filler, and calcium hydrogen phosphate is not used.

[0070] Comparative Example 5 Preparation of Cefixime Granules

[0071] name Dosage(g) Cefixime (D90 = 60-80 μm) 50.0 Calcium Hydrogen Phosphate 22.5 Hydroxyethyl Cellulose 7.5 Hydroxypropylcellulose 25.0 water 100.0 sucrose 900.0

[0072] The preparation method is the same as that in Example 1. In the prescription of Comparative Example 5, hydroxypropyl cellulose is used as the binder and water is used as the wetting agent.

[0073] Comparative Example 6 Preparation of Cefixime Granules

[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 200cps) 25.0 Water-ethanol solution (40%) 100.0 sucrose 900.0

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

[0076] Example 6

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

[0078] Table 1 Quality inspection of cefixime granules

[0079]

[0080] As can be seen from the above results, the cefixime granules prepared by embodiments 1-5 and comparative examples 1-6 have a granule yield of more than 93% for embodiments 1-5, while the yield of comparative example 1 is low. It can be seen from the analysis that the amount of filler, binder, and wetting agent is small, and the granulation effect is not good, which leads to a low granule yield, and the ethanol concentration is low, the water content is large, the amount of binder is small, the dissolution effect is not good, and uniform granules with suitable strength cannot be formed, the fluidity is poor, and the granules have a rough taste. In comparative example 2, the amount of filler, binder, and wetting agent is large, and the viscosity of hydroxypropyl methylcellulose is large, and stickiness occurs during the granulation process, and the particles cannot be uniformly mixed, and the granulation effect is not good, so the yield is low, the fluidity is poor, and the granules have a rough taste. In comparative example 3, the amount of filler only uses calcium hydrogen phosphate, and hydroxyethyl cellulose is not used, and a hydroxyethyl cellulose protective film cannot be formed, so under hot and humid conditions, impurities increase. In comparative example 4, the amount of filler only adopts hydroxyethyl cellulose, does not use calcium hydrogen phosphate, can not form uniform particles, affect particle yield, poor fluidity, particle mouthfeel is coarse. In comparative example 5, binder uses hydroxypropyl cellulose, and wetting agent is water, and dissolution effect is poor, and moisture content is large, and wetting effect is poor, and particle yield reduces. In comparative example 6, cefixime particle diameter is large, affects dissolution, and therefore, dissolution effect is slightly poor, and particle mouthfeel is coarse simultaneously. Embodiment 1-5 is the preferred scheme in this scheme, and various parameters in embodiment 1, including the type and ratio of auxiliary materials, are all most preferably, as adopting calcium hydrogen phosphate-hydroxyethyl cellulose complex as filler, low viscosity hydroxypropyl methylcellulose as binder, better match with each auxiliary material, make cefixime in granulation process, can avoid environmental factors influence, avoid causing the growth of impurities under the environment of high temperature and high humidity, overall combination, make cefixime granules can reach optimum in preparation process.

[0081] Example 7

[0082] Take 100g of the dried granules (before sieving) obtained in Examples 1-3 and Comparative Example 4 with 20 mesh, 30 mesh, 60 mesh, and 120 mesh, and put them into the sieve sleeves respectively. Use both hands to shake for 5 minutes, open the top cover, weigh the granules on each level of sieve, and calculate the proportion of each part of granules in the total material amount. The proportion of the particle size of each part is shown in Table 2.

[0083] Table 2 Particle size distribution of finished products From the above results, it can be seen that the granules prepared by the prescription process described in Examples 1-3 have a particle size distribution of less than 60 mesh, and most of the particles are between 30 mesh 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. However, the granules prepared in Comparative Example 4 have large particles, a lot of fine powder, and uneven particle distribution. Analysis shows that the use of hydroxyethyl cellulose alone is prone to uneven material mixing. When using the swing granulation process, the particle size distribution is enlarged and there are more fine powder particles.

[0084] Example 8

[0085] Take the cefixime granules prepared in Example 1 of the present invention, put them in a sealed and clean container, and perform a high temperature, high humidity and illumination test. The test conditions are as follows:

[0086] High temperature: Place at 60℃ for 10 days, take samples on the 5th and 10th days, test according to the key stability inspection items, and compare the test results with those on day 0.

[0087] High humidity: Place at 25℃ and relative humidity of 90%±5% for 10 days, take samples on the 5th and 10th days, test according to key stability inspection items, and compare the test results with those on day 0.

[0088] Lighting: Place under an illumination of 4500Lx for 10 days, take samples on the 5th and 10th days, test according to the key stability inspection items, and compare the test results with those on day 0.

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

[0090] Table 3 High temperature and high humidity light test results

[0091]

[0092] From the above results, it can be seen that the cefixime granules prepared in Example 1 have good stability in terms of moisture, solubility, related substances and labeled amount under high temperature, high humidity and light conditions, indicating that in the calcium hydrogen phosphate-hydroxyethyl cellulose composite, hydroxyethyl cellulose contacts with cefixime to form an effective protective film to protect the raw materials from degradation under hot and humid conditions, and calcium hydrogen phosphate-hydroxyethyl cellulose and low-viscosity hypromellose have good compatibility with other excipients and will not produce other impurities under hot and humid conditions.

[0093] Example 9 Accelerated Test

[0094] The cefixime granules prepared in Example 1 of the present invention were placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months, and samples were taken at the end of the first, second, third and sixth months, respectively, and the stability key inspection items were measured. The test results are shown in Table 4.

[0095] Table 4 Accelerated test results From the above results, it can be seen that the cefixime granules prepared in Example 1 have good stability in terms of moisture, solubility, related substances and labeled amount under the conditions of temperature 40°C±2°C and relative humidity 75%±5%, indicating that in the calcium hydrogen phosphate-hydroxyethyl cellulose composite, hydroxyethyl cellulose contacts with cefixime to form an effective protective film to protect the raw materials from degradation under hot and humid conditions, and calcium hydrogen phosphate-hydroxyethyl cellulose and low-viscosity hypromellose have good compatibility with other excipients, and will not produce other impurities under long-term storage, and have good stability.

[0096] In summary, the cefixime granules prepared by the present invention are simple to prepare, have stable quality, are not degraded, are not prone to produce impurities under wet and hot conditions, have good suspension performance, and have good dissolution performance, and have qualified and stable quality during long-term storage.

[0097] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A cefixime granule, characterized in that, The granules contain cefixime, a filler, a binder, a wetting agent, a flavoring agent and pharmaceutically acceptable excipients, wherein the filler is a calcium hydrogen phosphate-hydroxyethyl cellulose complex.

2. The cefixime granules according to claim 1, characterized in that In the calcium hydrogen phosphate-hydroxyethyl cellulose composite, the mass ratio of calcium hydrogen phosphate to hydroxyethyl cellulose is 1-3.5:1, preferably 3:

1.

3. The cefixime granules according to claim 1, characterized in that, The binder is low-viscosity hypromellose with a viscosity of 100-300 cps, preferably 200 cps.

4. The cefixime granules according to claim 1, characterized in that The particle size range of the cefixime is D90=40-90 μm, preferably D90=60-80 μm.

5. The cefixime granules according to claim 1, characterized in that, The wetting agent is a water-ethanol solution, and the concentration of the water-ethanol solution is 30-60%, preferably 40%.

6. The cefixime granules according to claim 1, characterized in that, The flavor corrector is xylitol, sucrose, aspartame, erythritol, sucralose, preferably sucrose.

7. The cefixime granules according to claim 1, characterized in that, The mass ratio of cefixime to the filler is 1:0.4-0.8, the mass ratio of cefixime to the binder is 1:0.3-0.7, the mass ratio of cefixime to the wetting agent is 1:1.5-3.0, and the mass ratio of cefixime to the flavoring agent is 1:15-20. Preferably, the mass ratio of cefixime to the filler is 1:0.6, the mass ratio of cefixime to the binder is 1:0.5, the mass ratio of cefixime to the wetting agent is 1:2.0, and the mass ratio of cefixime to the flavoring agent is 1:

18.

8. A cefixime granule, characterized in that: Contains the following ingredients: 。 9. The method for preparing cefixime granules according to any one of claims 1 to 8, characterized in that: The steps include: 1) stirring and mixing calcium hydrogen phosphate and hydroxyethyl cellulose to obtain a calcium hydrogen phosphate-hydroxyethyl cellulose complex for later use; 2) Use a universal grinder to grind sucrose, the grinding screen is 120 mesh, and set aside; 3) placing sucrose, cefixime, low-viscosity hydroxypropyl methylcellulose, and calcium hydrogen phosphate-hydroxyethyl cellulose complex in a high-position wet mixing granulator in sequence, premixing, pouring in 40% ethanol aqueous solution containing sunset yellow, and granulating; 4) Transfer the soft material to a double swing granulator, sieve it, and start the machine for swing granulation; 5) Dry the granules after swing granulation in a fluidized bed dryer, set the air inlet temperature at 60°C, and dry until the moisture content of the granules is ≤1%; 6) Place the dried granules on a square granule sieve, sieve the granules, collect the granules in the middle layer, and package them.

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