Cefixime granules and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to cefixime granules and a preparation method thereof. The cefixime granules provided by the invention are prepared from cefixime, a dissolution-promoting and stability-maintaining agent and pharmaceutically acceptable auxiliary materials, wherein the dissolution-promoting and stability-maintaining agent is a combination of sodium caprylate and meglumine; meanwhile, the dissolution-promoting stability-maintaining agent and the cefixime are subjected to a specific pretreatment process, and then the cefixime particles are prepared through a wet granulation process. According to the technical scheme, the dissolution performance and the stability of the cefixime granules are synergistically optimized, and the preparation process is simple, convenient and controllable, does not need to depend on a special high-energy-consumption process, has relatively high industrial feasibility and is beneficial to large-scale production and market promotion.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical preparations, and particularly relates to a cefixime granule and a preparation method thereof. BACKGROUND

[0002] Cefixime, as a third-generation oral cephalosporin antibiotic, has broad-spectrum antibacterial activity, and its mechanism of action is to achieve bactericidal effect by inhibiting the biosynthesis of bacterial cell wall. The drug shows good antibacterial effect on various gram-positive bacteria and gram-negative bacteria, especially on enterobacteriaceae bacteria such as Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis, and Haemophilus influenzae and Neisseria gonorrhoeae, and is widely used in the treatment of respiratory tract infections (such as bronchitis and pneumonia), urinary system infections (such as pyelonephritis and cystitis), biliary tract infections (such as cholecystitis and cholangitis) and otolaryngological infections caused by sensitive bacteria.

[0003] Granules, as one of the important dosage forms of oral preparations, have the characteristics of convenient administration, rapid disintegration and absorption, and easy dose control, and are particularly suitable for children, the elderly and patients with difficulty in swallowing, so cefixime granules are particularly widely used in clinical pediatrics and primary medical care. However, the inherent physicochemical properties of cefixime bring double challenges to the development of granules: firstly, poor stability, as a BCS class 4 drug, it is prone to degradation in a humid and hot environment, producing cefixime open-loop substances and other allergenic related substances, resulting in content decrease and safety risk; secondly, poor dissolution performance, the drug is difficult to dissolve in water and has low permeability, and if the granules are not fully disintegrated and dispersed, problems such as low bioavailability and efficacy fluctuation are prone to occur. In order to solve the above problems, the industry has carried out a number of studies and formed related patent technologies, but there are still obvious limitations.

[0004] In the prior art, the improvement schemes for cefixime granules are diversified, but none of them can simultaneously achieve optimal improvement of dissolution and stability. For example, Chinese Patent CN201711124739.3 discloses a cefixime granule, which uses airflow pulverization to make cefixime into nano fine powder, and uses an “intermediate granule + suspension liquid” step-by-step granulation process to improve the dissolution and stability to some extent. However, the stability improvement depends on the specific ratio of fructose-mannitol, and the airflow pulverization process has high energy consumption and is difficult to control in industrialization. Meanwhile, the preparation of xanthan gum suspension requires strict control of stirring speed (1000-1300 r / min), and batch-to-batch uniformity problems are likely to occur. Chinese Patent CN202411826190.2 uses calcium hydrogen phosphate-hydroxyethyl cellulose complex as a filler to form a protective film on the surface of the drug by using hydroxyethyl cellulose, thereby solving the problem of wet heat degradation. Although this scheme optimizes the stability, the ratio of calcium hydrogen phosphate and hydroxyethyl cellulose in the complex needs to be accurately controlled at 1-3.5:1, otherwise problems such as granule adhesion or insufficient protection are likely to occur. Moreover, low-viscosity hydroxypropyl methyl cellulose binder at high concentration is likely to cause differences in granule dissolution speed, which cannot meet the stringent requirements of clinical dissolution consistency. Chinese Patent CN202411378112.0 uses boiling drying instead of traditional oven drying, and uses a composite flavor containing a thickening agent to reduce impurity generation during the drying process. However, this scheme still mainly uses sucrose as the diluent, which is prone to moisture absorption under high humidity, leading to delayed granule disintegration. Moreover, after long-term contact between the trace amount of aldehyde components in the flavor and cefixime, there is still a risk of unknown single impurity increase. The dissolution improvement of this scheme only depends on the optimization of the drying process, and the problem is not solved from the essence of drug dispersion, so the improvement range is limited.

[0005] In summary, the existing technologies either improve the stability by using special excipients but sacrifice the universality of the process, or improve the dissolution by using a single process but the effect is not long-lasting, or have industrialization bottlenecks and long-term storage risks. Therefore, there is an urgent need to develop a cefixime granule that does not rely on special excipients, has a simple and controllable process, and can significantly improve the dissolution and long-term stability. SUMMARY

[0006] To overcome the defects in the prior art that cefixime granules cannot simultaneously achieve optimal improvement of dissolution and stability, the purpose of the present application is to provide a cefixime granule that simultaneously achieves the synergistic optimization of dissolution performance, solubility, and stability by using a specific combination of solubilizing and stabilizing agents and a pretreatment process.

[0007] The cefixime granule of the present application comprises effective ingredient cefixime, solubilizing and stabilizing agents, and pharmaceutically acceptable excipients, and the components are as follows in terms of weight parts: Active ingredients: cefixime 50-200 parts by weight; solubilizing and stabilizing agent: total amount is 30-130 parts by weight, which is a complex combination of sodium caprylate and meglumine, wherein sodium caprylate is 10-50 parts by weight, and meglumine is 20-80 parts by weight. The complex combination is the key component to solve the poor dissolution performance and low stability of cefixime, and the synergistic effect of the two can not only improve the water solubility and dispersibility of the drug, but also inhibit the degradation of cefixime in a humid and hot environment. Pharmaceutically acceptable adjuvants: including 100-500 parts by weight of a filler, 5-30 parts by weight of a disintegrant, 1-10 parts by weight of a lubricant, 5-40 parts by weight of a binder, and 1-20 parts by weight of a flavoring agent; wherein the filler is selected from at least one of lactose, mannitol, dextrin, microcrystalline cellulose, starch, and pregelatinized starch; the disintegrant is selected from at least one of sodium carboxymethyl starch, cross-linked povidone, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose; the lubricant is selected from at least one of magnesium stearate, microcrystalline silica, talc, stearic acid, and polyethylene glycol 6000; the binder is selected from at least one of povidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, starch paste, and gelatin; and the flavoring agent is selected from at least one of steviol glycoside, aspartame, sucrose, citric acid, and orange flavor.

[0008] To maximize the effect of the solubilizing and stabilizing agent, the present application adopts a specific pretreatment process for cefixime and the solubilizing and stabilizing agent: wet grinding sodium caprylate and meglumine with a small amount of purified water at 5-15 DEG C for 5-15 min, vacuum drying, then adding cefixime for dry grinding for 5-10 min to obtain a uniform mixed powder.

[0009] The cefixime granules of the present application are prepared by a wet granulation process, and the specific steps include: (1) Adjuvant pretreatment: pass the filler, disintegrant, binder, and flavoring agent through a 80-100 mesh pharmaceutical sieve respectively, remove impurities and ensure uniform particle size.

[0010] (2) Soft material preparation: mix the pretreated cefixime-solubilizing and stabilizing agent mixed powder with the filler, disintegrant, and flavoring agent in a high-efficiency wet granulator for 5-10 minutes, then slowly spray the diluted binder, and stir until the soft material forms a soft mass that can be held together and scattered by a light touch.

[0011] (3) Granulation and drying: extrude and granulate the soft material through a swing granulator equipped with an 18-20 mesh screen, vacuum dry or fluid bed dry the initial granules at 60-70 DEG C to a moisture content of ≤2.0%, cool to room temperature, and then pass through an 18 mesh sieve to obtain the final granules.

[0012] (4) Total mixing and packaging: add the lubricant to the granules, mix in a three-dimensional motion mixer for 3-5 minutes, and finally package in a pharmaceutical composite film bag or an aluminum-plastic blister according to the specified dosage.

[0013] Compared with the prior art, the technical effect of the present application is that: (1) The stability is significantly improved, and the safety is more guaranteed. The pretreatment process of low-temperature wet grinding and dry grinding after the specific combination of the solubilizing and stabilizing agent sodium caprylate and meglumine can significantly enhance the stability of cefixime granules in a humid and hot environment.

[0014] (2) The dissolution performance is comprehensively optimized, and the bioavailability is better. The present application solves the inherent problem of poor solubility and poor dispersibility of cefixime in water through the synergistic effect of the solubilizing and stabilizing agent and the optimization of the pretreatment process. The prepared granules not only have a significantly accelerated dissolution rate, but also have a significantly improved final dissolution degree.

[0015] (3) The solubility meets the pharmacopoeia standard, and the drug applicability is stronger. The cefixime granules prepared by the present application meet the solubility requirements of soluble granules in the Chinese Pharmacopoeia, and can smoothly complete the process from dispersion to complete solubilization under the specified test conditions without obvious block agglomerates or visible foreign matters.

[0016] (4) The process is simple and controllable, and the industrialization feasibility is higher. The present application uses a conventional wet granulation process without relying on special and high-energy consumption processes such as airflow pulverization and high-speed stirring to prepare a suspension. By optimizing the combination of the solubilizing and stabilizing agent and the pretreatment process, the above performance improvement can be achieved. The process is simple to operate, effectively solves the problems of poor process universality, high industrialization control difficulty and high production cost in the prior art, and is more suitable for large-scale industrial production and market promotion and application. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 : The dissolution curve of cefixime granules. DETAILED DESCRIPTION

[0018] In order to make the purpose, technical scheme of the present application more clear, the following embodiments are used to further illustrate the present application, but the protection scope of the present application is not limited to these embodiments, and the embodiments are only used to explain the present application. Those skilled in the art should understand that any changes or equivalent replacements without departing from the concept of the present application are included in the protection scope of the present application.

[0019] Example 1: Cefixime granules Formula: Preparation method: (1) Pretreatment of active ingredients and solubilizing and stabilizing agent: take the solubilizing and stabilizing agent, wet it with a small amount of purified water, wet grind at 8℃, vacuum dry, then add cefixime, dry grind to uniform powder, and reserve.

[0020] (2) Pretreatment of other excipients: Take the filler, disintegrant, binder, flavoring agent, respectively, through 80-100 mesh sieve, ready for use.

[0021] (3) Soft material preparation: Mix the cefixime and the mixed powder of the solubility promoting and stability maintaining agent, add the filler, disintegrant, flavoring agent, and place in the high efficiency wet granulator for 5-10 minutes of pre-mixing. Dilute the binder with water, slowly spray into the material under stirring, until the soft material is formed, which can be held together by hand, and scattered by light touch.

[0022] (4) Granulation: Put the soft material into the swing granulator equipped with 18-20 mesh screen, extrude and granulate, collect the primary granules and remove the blocky material.

[0023] (5) Drying: Place the primary granules in the vacuum drying oven or the boiling drying machine, dry at 60-70°C and turn regularly, until the moisture content is ≤2.0%, take out and cool to room temperature.

[0024] (6) Granulation: Dry the granules through 18 mesh screen for granulation, and break the clumps for standby use.

[0025] (7) Total mixing: Place the granules after granulation in the three-dimensional motion mixer, add the lubricant and mix for 3-5 minutes.

[0026] (8) Dose and packaging: Use the granule packaging machine to package the total mixed granules according to the specified dose, and use the pharmaceutical composite film bag or aluminum-plastic blister packaging.

[0027] Example 2 Cefixime granules Formulation: Preparation method: (1) Pretreatment of active ingredients and solubility promoting and stability maintaining agent: Take the solubility promoting and stability maintaining agent, wet with a small amount of purified water, place in a 5°C wet grinding, vacuum dried, add cefixime, dry grinding to uniform powder, ready for use.

[0028] (2) Pretreatment of other excipients: Take the filler, disintegrant, binder, flavoring agent, respectively, through 80-100 mesh sieve, ready for use.

[0029] (3) Soft material preparation: Mix the cefixime and the mixed powder of the solubility promoting and stability maintaining agent, add the filler, disintegrant, flavoring agent, and place in the high efficiency wet granulator for 5-10 minutes of pre-mixing. Dilute the binder with water, slowly spray into the material under stirring, until the soft material is formed, which can be held together by hand, and scattered by light touch.

[0030] (4) Granulation: Put the soft material into the swing granulator equipped with 18-20 mesh screen, extrude and granulate, collect the primary granules and remove the blocky material.

[0031] (5) Drying: Place the primary granules in a vacuum drying oven or a boiling drying machine, dry at 60-70°C and turn over periodically until the moisture content is ≤2.0%, then take out and cool to room temperature.

[0032] (6) Granule sizing: Sift the dried granules through an 18-mesh screen to size, and use the broken lumps for later use.

[0033] (7) Total mixing: Place the sized granules in a three-dimensional motion mixer, add the lubricant and mix for 3-5 minutes.

[0034] (8) Dose separation and packaging: Separate the total-mixed granules into the prescribed doses using a granule separating machine, and use pharmaceutical composite film bags or aluminum-plastic blister packs.

[0035] Example 3 Cefixime granules Formulation: Preparation method: (1) Pretreatment of active ingredient and solubility-maintaining agent: Wet the solubility-maintaining agent with a small amount of purified water, grind it in a wet manner at 15°C, and then add cefixime after drying in a vacuum. Dry-grind until a uniform powder is obtained, and reserve it for later use.

[0036] (2) Pretreatment of other excipients: Sift the fillers, disintegrants, binders, and flavorings through 80-100-mesh pharmaceutical screens, respectively, and reserve them for later use.

[0037] (3) Soft material preparation: Mix the cefixime and solubility-maintaining agent powders with the fillers, disintegrants, and flavorings, and pre-mix them in a high-efficiency wet granulator for 5-10 minutes. Dilute the binder with water, and slowly spray it into the material while stirring until a soft material that can be formed into a ball and crumbles at a light touch is obtained.

[0038] (4) Granulation: Place the soft material into a swinging granulator equipped with an 18-20-mesh screen, and extrude it to form primary granules. Collect the primary granules and remove the lumpy material.

[0039] (5) Drying: Place the primary granules in a vacuum drying oven or a boiling drying machine, dry at 60-70°C and turn over periodically until the moisture content is ≤2.0%, then take out and cool to room temperature.

[0040] (6) Granule sizing: Sift the dried granules through an 18-mesh screen to size, and use the broken lumps for later use.

[0041] (7) Total mixing: Place the sized granules in a three-dimensional motion mixer, add the lubricant and mix for 3-5 minutes.

[0042] (8) Dose separation and packaging: Separate the total-mixed granules into the prescribed doses using a granule separating machine, and use pharmaceutical composite film bags or aluminum-plastic blister packs.

[0043] Example 4 Cefixime granules Formulation: Preparation method: (1) Pretreatment of active ingredient and solubility stabilizer: take the solubility stabilizer, add a small amount of purified water to wet, wet grinding at 10°C, vacuum drying, then add cefixime, dry grinding to uniform powder, ready for use.

[0044] (2) Pretreatment of other excipients: take the filler, disintegrant, binder, flavoring agent, respectively through 80-100 mesh pharmaceutical sieve, ready for use.

[0045] (3) Soft material preparation: mix the cefixime and solubility stabilizer powder, add the filler, disintegrant, flavoring agent, and pre-mix in the high-efficiency wet granulator for 5-10 minutes. Dilute the binder with water and slowly spray into the material under stirring until it forms a soft material that can be held together and scattered by light touch.

[0046] (4) Granulation: put the soft material into the swinging granulator equipped with 18-20 mesh screen, extrude and granulate, collect the primary granules and remove the lumpy material.

[0047] (5) Drying: place the primary granules in a vacuum drying oven or a boiling dryer, dry at 60-70°C and turn regularly until the moisture content is ≤2.0%, then take out and cool to room temperature.

[0048] (6) Granulation: dry the granules through 18 mesh screen, break the lumps and reserve for use.

[0049] (7) Total mixing: place the granules after granulation in a three-dimensional motion mixer, add the lubricant and mix for 3-5 minutes.

[0050] (8) Dose and packaging: use the granule packaging machine to package the total mixed granules according to the specified dose, and use pharmaceutical composite film bags or aluminum-plastic blister packaging.

[0051] Comparative Example 1 Cefixime Granules Formulation: Preparation method: same as Example 1.

[0052] Comparative Example 2 Cefixime Granules Formulation: Preparation method: same as Example 1.

[0053] Comparative Example 3 Cefixime Granules Formulation: Preparation method: same as Example 1.

[0054] Comparative Example 4: Cefixime Granules formula: Preparation method: Same as in Example 1.

[0055] Comparative Example 5: Cefixime Granules formula: Preparation method: Same as in Example 1.

[0056] Comparative Example 6 Cefixime Granules Formula: Same as Example 1.

[0057] Preparation method: (1) Pretreatment of active ingredients and solubilizing stabilizer: Mix the solubilizing stabilizer with cefixime and grind it into a uniform powder by dry grinding for later use.

[0058] (2)~(8): Same as Example 1.

[0059] Comparative Example 7: Cefixime Granules Formula: Same as Example 1.

[0060] Preparation method: (1) Pretreatment of active ingredients and solubilizing stabilizer: Take the solubilizing stabilizer, add a small amount of purified water to moisten it, place it at 25~30℃ for wet grinding, vacuum dry it, add cefixime, dry grind it into a uniform powder, and set it aside.

[0061] (2)~(8): Same as Example 1.

[0062] Dissolution and stability of cefixime granules Accelerated test conditions: 40℃±2℃, relative humidity 75±5%, 6 months.

[0063] The content of cefixime is determined according to the high performance liquid chromatography method (general rule 0512) in the Chinese Pharmacopoeia. The test sample solution: take the content in the dosage difference item (about equivalent to 50 mg of cefixime, calculated as C16H15N5O7S2) and accurately weigh, put it into a 250 ml volumetric flask, add the mobile phase to dissolve and dilute to the mark, shake well, filter, and take the filtrate. The control sample solution: take the cefixime control sample, accurately weigh, add the mobile phase to dissolve and quantitatively dilute to prepare a solution containing about 0.2 mg of cefixime (calculated as C16H15N5O7S2) per 1 ml. The system suitability solution: take the cefixime control sample, add water to dissolve and dilute to prepare a solution containing about 1 mg per 1 ml, heat on a boiling water bath for 45 minutes, and cool. The chromatographic conditions: use octadecylsilane bonded silica gel as the filler; use tetrabutylammonium hydroxide solution (take 10% tetrabutylammonium hydroxide solution 25 ml, add water 1000 ml, shake well, and adjust the pH value to 7.0 with 1.5 mol / L phosphoric acid solution) - acetonitrile (72:28) as the mobile phase; the detection wavelength is 254 nm; the column temperature is 40 DEG C; the injection volume is 20 μl. The system suitability requirements: in the chromatogram of the system suitability solution, the peaks of the cefixime (E) isomer and cefixime appear in order, and the separation degree between the peak of the cefixime (E) isomer and the peak of cefixime should meet the requirements. The determination method: accurately take the test sample solution and the control sample solution, respectively inject into the liquid chromatograph, and record the chromatogram. The content of C16H15N5O7S2 in the test sample is calculated by the peak area according to the external standard method.

[0064] Table 1: cefixime content of accelerated test From the cefixime content of the accelerated test in Table 1, it can be seen that the cefixime granules prepared in Examples 1-4 have a significantly better cefixime content retention effect under the accelerated test conditions than the comparative examples 1-7 and the commercially available preparation, and exhibit better stability. The cefixime content of each comparative example decreases more greatly due to the replacement of the type of the solubility-promoting and stability-maintaining agent, the single use, or the change of the pretreatment process of the solubility-promoting and stability-maintaining agent and cefixime, and the stability is not as good as that of Examples 1-4.

[0065] Dissolution was determined according to the method of dissolution and release determination (general rule 0931 second method) in the Chinese Pharmacopoeia. The dissolution conditions were as follows: 900 ml of phosphate buffer (pH 7.2) (take 6.8 g of potassium dihydrogen phosphate, dissolve in water, adjust the pH value to 7.2 with 1 mol / L sodium hydroxide solution, and dilute with water to 1000 ml) was used as the dissolution medium, the rotation speed was 50 revolutions per minute, and the sample was taken after 30 minutes according to the law. Test solution: Take the dissolution liquid, filter, accurately take the filtrate, and dilute with the dissolution medium to prepare a solution containing about 10 μg of cefixime (calculated as C16H15N5O7S2) per 1 ml. The control solution: take the cefixime control sample, accurately weigh, dissolve and dilute to prepare a solution containing about 10 μg per 1 ml (if necessary, first dissolve with a small amount of methanol, the amount of methanol should not exceed 0.1% of the total volume of the control solution). Determination method: take the test solution and the control solution, and measure the absorbance at a wavelength of 288 nm by ultraviolet-visible spectrophotometry (general rule 0401), and calculate the dissolution amount per package.

[0066] Table 2 dissolution of cefixime granules Table 2 shows that the dissolution rate and final dissolution degree of cefixime granules of examples 1-4 of the present application are significantly better than those of comparative examples 1-7 and commercial preparations during the dissolution process, and the dissolution performance is outstanding. It is proved that the combination of the dissolution-promoting and stability-maintaining agent and the pretreatment process plays a key role in improving the dissolution performance of the granules.

[0067] The experiment was carried out according to the method of solubility test of soluble granules in the general rule 0104 of the Chinese Pharmacopoeia, to determine whether it meets the quality requirements of soluble granules. 200 mL of purified water at 45°C±2°C was measured with a measuring cylinder, and poured into a beaker. 1 part of the sample to be tested was quickly poured into the above beaker, the magnetic stirrer was turned on, and the rotation speed was adjusted to 300 r / min. The solubility was observed at 1 min, 3 min and 5 min.

[0068] Table 3 solubility of cefixime granules Table 3 shows that the cefixime granules of examples 1-4 of the present application can complete the process of dispersion to complete solubility as expected, and meet the solubility quality requirements of soluble granules. The specific dissolution-promoting and stability-maintaining agent combination and pretreatment process used in the present application provides a guarantee for the good solubility of the granules.

Claims

1. Cefixime granules, characterized in that, The cefixime granules are formulated by 50-200 parts by weight of cefixime, 30-130 parts by weight of a solubility-maintaining stabilizer, and pharmaceutically acceptable excipients; the solubility-maintaining stabilizer is a combination of sodium caprylate and meglumine.

2. The cefixime granules according to claim 1, characterized by, The pharmaceutically acceptable excipients are selected from multiple kinds of fillers, disintegrants, lubricants, binders, and flavoring agents; the fillers are 100-500 parts by weight, the disintegrants are 5-30 parts by weight, the lubricants are 1-10 parts by weight, the binders are 5-40 parts by weight, and the flavoring agents are 1-20 parts by weight.

3. The cefixime granules according to claim 1, characterized by, The sodium caprylate is 10-50 parts by weight, and the meglumine is 20-80 parts by weight.

4. The cefixime granules according to claim 1, characterized by, The fillers are selected from at least one of lactose, mannitol, dextrin, microcrystalline cellulose, starch, and pregelatinized starch.

5. The cefixime granules according to claim 1, wherein The disintegrants are selected from at least one of sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, and cross-linked sodium carboxymethyl cellulose.

6. The cefixime granules according to claim 1, wherein The lubricants are selected from at least one of magnesium stearate, micro-powder silica gel, talc, stearic acid, and polyethylene glycol 6000.

7. The cefixime granules according to claim 1, wherein The binders are selected from at least one of povidone, hydroxypropyl cellulose, sodium carboxymethyl cellulose, starch paste, and gelatin.

8. The cefixime granules according to claim 1, wherein The flavoring agents are selected from at least one of stevioside, aspartame, sucrose, citric acid, and orange essence.

9. The cefixime granules according to claim 1, wherein The processing method of the solubility-maintaining stabilizer and cefixime is as follows: the sodium caprylate and meglumine are wetted with appropriate purified water, wet-grinded at 5-15°C, vacuum-dried, added with cefixime, and dry-grinded to obtain the product.

10. The cefixime granules according to claim 1, wherein The preparation method of the cefixime granules is wet granulation.

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