WO2013174015A1 - Cefixime granule and preparation method thereof - Google Patents

Cefixime granule and preparation method thereof Download PDF

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Publication number
WO2013174015A1
WO2013174015A1 PCT/CN2012/076090 CN2012076090W WO2013174015A1 WO 2013174015 A1 WO2013174015 A1 WO 2013174015A1 CN 2012076090 W CN2012076090 W CN 2012076090W WO 2013174015 A1 WO2013174015 A1 WO 2013174015A1
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Prior art keywords
cefixime
sodium
diluent
mesh
binder
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PCT/CN2012/076090
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French (fr)
Chinese (zh)
Inventor
闫志刚
邓宝军
曾环想
王泳
赖振洪
李娟�
罗炳锋
范文峰
周向荣
权超
于晓阳
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深圳致君制药有限公司
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Priority to PCT/CN2012/076090 priority Critical patent/WO2013174015A1/en
Publication of WO2013174015A1 publication Critical patent/WO2013174015A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to the field of pharmaceutical preparations, and in particular to a cefixime granule and a preparation method thereof. Background technique
  • Cefixime is an oral third-generation cephalosporin antibiotic, chemical name: (6R, 7R)-7-[ (Z) -2- (2-amino-4-thiazolyl)-2- (carboxy carboxy oxyimino) acetylamino] -8-oxo-3-ethene-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trihydrate, chemistry Structure:
  • Cefixime is a white to pale yellow crystalline powder, tasteless, slightly specific odor, soluble in sterol, disulfoxide, slightly soluble in acetone, insoluble in ethanol, insoluble in water, ethyl acetate, ether In hexane.
  • Cefixime has broad antibacterial spectrum and strong antibacterial activity against Gram-positive microorganisms, Gram-negative microorganisms, Moraxella catarrhalis (including enzyme-producing strains), and Escherichia coli.
  • Neisseria gonorrhoeae including enzyme producing strains
  • catarrhalis Escherichia coli, Klebsiella, Serratia, Proteus and flu
  • bronchitis bronchi Dilatation, secondary infection of chronic respiratory infections, pneumonia; pyelonephritis, cystitis, gonococcal urethritis; cholestitis, cholangitis; scarlet fever; otitis media, sinusitis.
  • the present invention provides a cefixime granule and a preparation method thereof.
  • the Cefixime granule has good quality stability, suspension, content and bioavailability, and has a good taste of 4 , which is especially suitable for children and people with dysphagia, and the medication compliance is good.
  • the invention also provides a preparation method of cefixime granules, wherein cefixime is sprayed into a boiling auxiliary material in the form of a suspension for boiling granulation, so that the prepared granules have good content uniformity and mixing. Suspension, preparation method, single, especially suitable for industrial production.
  • the present invention provides the following technical solutions:
  • the invention provides a cefixime granule comprising the following components by weight: cefixime 1% ⁇ 20%, diluent 56% ⁇ 95%, buffer 0.5% ⁇ 10%, binder 0.5% ⁇ 10%, flavoring agent 0.1% ⁇ 5%.
  • the present invention provides a cefixime granule comprising, by weight percent, the following components: cefixime 5% ⁇ 10%, diluent 71% ⁇ 85%, buffer 3% ⁇ 10%, Adhesive 3% ⁇ 8%, flavoring agent 1% ⁇ 3%.
  • the present invention provides a cefixime granule which further comprises 0.1% to 5% by weight and/or 0.1% to 5% by weight of the pigment.
  • the diluent comprises one of sugar, starch, maltodextrin, lactose, mannitol, sorbitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch.
  • the diluent comprises one of sugar, starch, maltodextrin, lactose, mannitol, sorbitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch.
  • maltodextrin lactose
  • mannitol sorbitol
  • microcrystalline cellulose hydroxypropyl cellulose
  • sodium carboxymethyl starch kind or a mixture of two or more.
  • the buffering agent comprises a mixture of one or more of citric acid, sodium citrate, sodium hydrogen phosphate, sodium hydrogencarbonate, sodium carbonate, sodium phosphate.
  • the binder comprises one or a mixture of two or more of mercaptocellulose, polyvinylpyrrolidone, hydroxypropylcellulose, sodium carboxymethylcellulose.
  • the flavoring agent comprises a mixture of one or more of aspartame, sucrose, stevioside, neotame.
  • the fragrance comprises a mixture of one or more of strawberry flavor, pineapple flavor, orange flavor, cherry flavor, cantaloupe flavor, chocolate flavor.
  • the pigment includes a mixture of one or more of sunset yellow, sunset yellow lake, lemon yellow, lemon yellow lake, red fresh lake, and natural caramel.
  • the invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 1% ⁇ 20%, diluent 56% ⁇ 95%, buffer 0.5% ⁇ 10%, binder 0.5% ⁇ 10%, flavoring 0.1% ⁇ 5%.
  • Step 1 Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make 2% ⁇ 20% aqueous solution of the adhesive;
  • Step 2 Take cefixime, diluent, buffer and flavoring agent through 60 ⁇ 160 mesh sieve, preheat to 40 ⁇ 60 °C, add the binder aqueous solution to carry out one-step granulation, control the drying of materials.
  • the temperature is not higher than 60 ° C, and the granules are sieved through 10 mesh and 80 mesh respectively, and are obtained by inspection and dispensing.
  • the invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 1% ⁇ 20%, diluent 56% ⁇ 95%, buffer 0.5% ⁇ 10%, binder 0.5% ⁇ 10%, flavoring 0.1% ⁇ 5%, flavor 0.1% ⁇ 5%.
  • Step 1 Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make 2% ⁇ 20% aqueous solution of the adhesive;
  • Step 2 Take cefixime, diluent, buffer and flavoring agent through 60 ⁇ 160 mesh sieve, preheat to 40 ⁇ 60 °C, add the binder aqueous solution to carry out one-step granulation, control the drying of materials.
  • the temperature is not higher than 60 ° C, and the granules are sieved through 10 mesh and 80 mesh respectively, and are obtained by inspection and dispensing.
  • the invention also provides a method for preparing one-step granulation of cefixime granules, which comprises the following components by weight: cefixime 1% ⁇ 20%, diluent 56% ⁇ 95%, Buffer 0.5% ⁇ 10%, binder 0.5% ⁇ 10%, flavor 0.1% ⁇ 5%, pigment 0.1% ⁇
  • Step 1 Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make a 2% ⁇ 20% aqueous solution of the adhesive;
  • Step 2 Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials.
  • the temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
  • the invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 1% ⁇ 20%, diluent 56% ⁇ 95%, buffer 0.5% ⁇ 10%, binder 0.5% ⁇ 10%, flavoring 0.1% ⁇ 5%, flavor 0.1% ⁇ 5%, pigment 0.1% ⁇ 5%.
  • Step 1 Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make a 2% ⁇ 20% aqueous solution of the adhesive;
  • Step 2 Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials.
  • the temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
  • the invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 5% ⁇ 10%, diluent 71% ⁇ 85%, buffer 3% ⁇ 10%, binder 3% ⁇ 8%, flavoring agent 1% ⁇ 3%.
  • Step 1 Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make 2% ⁇ 20% aqueous solution of the adhesive;
  • Step 2 Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials.
  • the temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
  • the invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 5% ⁇ 10%, diluent 71% ⁇ 85%, buffer 3% ⁇ 10%, binder 3% ⁇ 8%, flavoring agent 1% ⁇ 3%, flavor 0.1% ⁇ 5%.
  • Step 1 Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make a 2% ⁇ 20% aqueous binder solution
  • Step 2 Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials.
  • the temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
  • the invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 5% ⁇ 10%, diluent 71% ⁇ 85%, buffer 3% ⁇ 10%, binder 3% ⁇ 8%, flavoring agent 1% ⁇ 3%, pigment 0.1% ⁇ 5%.
  • Step 1 Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make a 2% ⁇ 20% aqueous solution of the adhesive;
  • Step 2 Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials.
  • the temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
  • the invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 5% ⁇ 10%, diluent 71% ⁇ 85%, buffer 3% ⁇ 10%, binder 3% ⁇ 8%, flavoring agent 1% ⁇ 3%, flavor 0.1% ⁇ 5%, pigment 0.1% ⁇ 5%.
  • Step 1 Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make a 2% ⁇ 20% aqueous solution of the adhesive;
  • Step 2 Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials.
  • the temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
  • the invention provides a cefixime granule and a preparation method thereof.
  • the cefixime granule has good quality stability, suspension, uniformity of content, fast dissolving speed, and good mouthfeel. It is especially suitable for children and people with dysphagia, and the medication compliance is good.
  • the invention also provides a preparation method of cefixime granules, which comprises the steps of preparing one-step granulation, combining the four steps of mixing, soft material, rocking wet granules and boiling drying in the ordinary wet granulation process into one step.
  • the granulation process the equipment is reduced from the three equipments of the high-efficiency wet mixing granulator, the swinging granulator and the boiling dryer in the ordinary wet granulation process to one equipment of the fluidized bed, the operation method is simple, and the production efficiency is high. It is especially suitable for industrial production.
  • Figure 1 shows a flow chart of the wet granulation process
  • FIG. 2 is a flow chart showing the preparation process provided by the present invention. detailed description
  • the invention discloses a cefixime granule and a preparation method thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention.
  • the technique of the present invention is applied. Acceptable excipients are commercially available.
  • the cefixipin was passed through a 120 mesh sieve, and maltodextrin, starch, sodium citrate, citric acid, aspartame, pineapple flavor, and sunset yellow were passed through a 60 mesh sieve, and used.
  • the polyvinylpyrrolidone was dissolved in purified water to prepare a 15% aqueous solution, which was used.
  • the cefixipin was passed through a 100 mesh sieve, and lactose, sodium hydrogencarbonate, sodium carbonate, stevioside, strawberry flavor, and lemon yellow were passed through an 80 mesh sieve, and used.
  • the sodium carboxymethyl cellulose was dissolved in purified water to prepare a 5% aqueous solution, which was used.
  • the cefixipin was passed through a 160 mesh sieve, and the microcrystalline cellulose, sucrose, sodium hydrogen phosphate, sucralose, and chocolate flavor were respectively passed through a 60 mesh sieve and used.
  • the hydroxypropionin cellulose was dissolved in purified water to prepare a 5% aqueous solution, and the natural caramel was added and stirred uniformly to serve as a binder.
  • Cefixime was passed through a 120 mesh sieve, and sucrose, hydroxypropylcellulose, sodium citrate, citric acid, aspartame, sucralose, and orange flavor were passed through an 80 mesh sieve, and used.
  • the thiol cellulose and the polyvinylpyrrolidone were dissolved together in purified water to prepare a 3% aqueous solution, which was used.
  • the cefixime was passed through a 100 mesh sieve, and mannitol, hydroxypropylcellulose, sodium hydrogen phosphate, sodium phosphate, aspartame, and lemon yellow lake were sieved through a 60 mesh sieve, respectively.
  • the polyvinylpyrrolidone was dissolved in purified water to prepare a 20% aqueous solution, which was used.
  • the cefixum was passed through a 160 mesh sieve, and sorbitol, sodium carboxymethyl starch, sodium hydrogencarbonate, sodium carbonate, aspartame, cantaloupe flavor, and red radix red radiant were respectively passed through a 60 mesh sieve and used.
  • the hydroxypropionin was dissolved in purified water to prepare a 2% aqueous solution, which was used.
  • the cefixime was passed through a 120 mesh sieve, and starch, sorbitol, sodium citrate, citric acid, and stevioside were passed through a 60 mesh sieve, and used.
  • the sodium carboxymethyl cellulose was dissolved in purified water to prepare a 5% aqueous solution, which was used.
  • Comparative Example Commercially available cefixime granules; After investigation and analysis, the current commercial products are obtained by wet granulation.
  • Example 6 1 1 1 1 1 1 1 1 1
  • Example 8 1 1 1 1 1 1 1 1 Comparative Example 0.3 0.2 0.3 0.1 0.2 0.2
  • the cefixime granules were more suspending than the comparative examples. Comparative test of content homology:
  • the cefixime particles of Examples 1 to 8 which were granulated in one step and the comparative examples were respectively subjected to accelerated stability test (40 ° C ⁇ 2 ° C, relative humidity 75% ⁇ 5%, respectively, during the test period). Samples were taken at the end of the first month, 2 months, 3 months, and 6 months. The percentage of the amount of cefixime indicated and the relative percentage of related substances were determined. The results are shown in Table 4.
  • Example 1 100.6 0.17 0.83
  • Example 2 101.1 0.21 0.89
  • Example 3 99.9 0.2 0.94
  • Example 4 100.3 0.19 0.85
  • Example 5 99.8 0.15 0.75
  • Example 6 99.3 0.49 1.65
  • Example 8 99.3 0.39 1.57 Comparative Example 97.9 0.60 2.41
  • Example 2 100.0 0.51 1.93
  • Example 3 99.2 0.47 1.88
  • Example 4 99.1 0.56 1.90
  • Example 5 98.4 0.48 1.87
  • Example 6 98.7 0.57 1.96
  • Example 8 99.0 0.50 1.89
  • Example 1 98.0 0.58 2.20
  • Example 2 98.3 0.69 2.56
  • Example 3 97.7 0.64 2.47
  • Example 4 98.5 0.53 2.19
  • Example 1 The study of cefixime granules was reported in the 2005 issue of the Journal of Modern Applied Pharmacy, 2005. Therefore, the formulation in Example 1 was prepared by reference to the conventional wet granulation process reported in the literature. , details as follows:

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Abstract

The present invention provides a cefixime granule and a preparation method of the cefixime granule. The cefixime granule comprises the following components by weight percentage: 1-20% of cefixime, 56-95% of diluent, 0.5-10% of adhesive and 0.1-5% of flavoring. The preparation method of the cefixime granule is using aqueous solutions of the adhesive to further pelletize the cefixime, the diluent, buffer agent and the flavoring that are respectively sifted, which are then dried, granulated, checked and subpackaged.

Description

一种头孢克肟颗粒及其制备方法 技术领域  Cefixime granule and preparation method thereof
本发明涉及药物制剂领域,特别涉及一种头孢克肟颗粒剂及其制备方 法。 背景技术  The present invention relates to the field of pharmaceutical preparations, and in particular to a cefixime granule and a preparation method thereof. Background technique
头孢克肟 （Cefixime ) 是一种口服的第三代头孢菌素抗生素， 化 学名称： （6R, 7R)-7-[ (Z) -2- (2-氨基 -4-噻唑基 )-2- ( 羧曱氧亚氨基 ) 乙酰氨基] -8-氧代 -3-乙烯 -5-硫杂 -1-氮杂双环 [4.2.0]辛 -2-烯 -2-羧酸三 水合物， 化学结构式：  Cefixime is an oral third-generation cephalosporin antibiotic, chemical name: (6R, 7R)-7-[ (Z) -2- (2-amino-4-thiazolyl)-2- (carboxy carboxy oxyimino) acetylamino] -8-oxo-3-ethene-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trihydrate, chemistry Structure:
Figure imgf000002_0001
分子式： C16H15N507S2'3H20, 分子量： 507.50。
Figure imgf000002_0001
Molecular formula: C 16 H 15 N 5 0 7 S 2 '3H 2 0, molecular weight: 507.50.
头孢克肟为白色至淡黄色结晶性粉末， 无味， 具轻微特异臭， 易 溶于曱醇、 二曱亚砜， 略溶于丙酮， 难溶于乙醇， 几不溶于水、 醋酸 乙酯、 乙醚、 己烷中。 头孢克肟作为第三代口服头孢菌素类抗生素， 具 有抗菌谱广、 抗菌活性强， 对革兰氏阳性微生物、 革兰氏阴性微生物、 卡 他莫拉菌 （包括产酶株）、 大肠杆菌、 奇异变形杆菌、 淋球菌 （包括产酶 株） 均有良好的抗菌活性， 对多数 β内酰胺酶稳定以及副作用小等优点。 适用于对头孢克肟敏感菌的链球菌属 （肠球菌除外）、 肺炎球菌、 淋 球菌、 卡他布兰汉球菌、 大肠杆菌、 克雷伯杆菌属、 沙雷菌属、 变形 杆菌属及流感杆菌等引起的下列细菌感染性疾病： 支气管炎、 支气管 扩张症， 慢性呼吸系统感染疾病的继发感染， 肺炎； 肾盂肾炎、 膀胱 炎、 淋球菌性尿道炎； 胆嚢炎、 胆管炎； 猩红热； 中耳炎、 副鼻窦炎 等。 Cefixime is a white to pale yellow crystalline powder, tasteless, slightly specific odor, soluble in sterol, disulfoxide, slightly soluble in acetone, insoluble in ethanol, insoluble in water, ethyl acetate, ether In hexane. As a third-generation oral cephalosporin antibiotic, Cefixime has broad antibacterial spectrum and strong antibacterial activity against Gram-positive microorganisms, Gram-negative microorganisms, Moraxella catarrhalis (including enzyme-producing strains), and Escherichia coli. Proteus mirabilis, Neisseria gonorrhoeae (including enzyme producing strains) have good antibacterial activity, and are stable to most β-lactamases and have few side effects. Suitable for Streptococcus (except Enterococcus), pneumococcal, Neisseria gonorrhoeae, K. catarrhalis, Escherichia coli, Klebsiella, Serratia, Proteus and flu The following bacterial infectious diseases caused by bacilli, etc.: bronchitis, bronchi Dilatation, secondary infection of chronic respiratory infections, pneumonia; pyelonephritis, cystitis, gonococcal urethritis; cholestitis, cholangitis; scarlet fever; otitis media, sinusitis.
但是， 头孢克肟颗粒剂的普通湿法制粒工艺， 在生产过程中往往 会产生较硬的粒子， 导致不能快速溶散， 颗粒混悬性不好， 而且颗粒 细粉往往较多， 需要通过过 除去， 导致生产的头孢克肟颗粒成品收 率较低， 且口感不好， 不利于儿童给药。 发明内容  However, the common wet granulation process of cefixime granules tends to produce harder particles in the production process, resulting in inability to dissolve quickly, poor particle suspension, and often more fine particles. Removal, resulting in the production of cefaclor granules, the yield of the finished product is low, and the taste is not good, which is not suitable for children. Summary of the invention
有鉴于此，本发明提供一种头孢克肟颗粒剂及其制备方法。该头孢克 肟颗粒剂具有很好的质量稳定性、 混悬性、 含量均勾性、 生物利用度， 同 时具有 4艮好的口感， 特别适合儿童及吞咽困难的人群， 用药顺应性好。 本 发明还提供了一种头孢克肟颗粒的制备方法，将头孢克肟以混悬液的形式 喷入到沸腾的辅料中进行沸腾制粒,使得制出的颗粒具有良好的含量均匀 性以及混悬性， 制备方法筒单， 特别适合工业化生产。  In view of the above, the present invention provides a cefixime granule and a preparation method thereof. The Cefixime granule has good quality stability, suspension, content and bioavailability, and has a good taste of 4 ,, which is especially suitable for children and people with dysphagia, and the medication compliance is good. The invention also provides a preparation method of cefixime granules, wherein cefixime is sprayed into a boiling auxiliary material in the form of a suspension for boiling granulation, so that the prepared granules have good content uniformity and mixing. Suspension, preparation method, single, especially suitable for industrial production.
为了实现上述发明目的， 本发明提供以下技术方案：  In order to achieve the above object, the present invention provides the following technical solutions:
本发明提供的一种头孢克肟颗粒剂， 其按重量百分数计包括以下组 分： 头孢克肟 1%~20%、 稀释剂 56% ~ 95%、 緩沖剂 0.5% ~ 10%、 粘合 剂 0.5% ~ 10%、 矫味剂 0.1% ~ 5%。  The invention provides a cefixime granule comprising the following components by weight: cefixime 1%~20%, diluent 56%~95%, buffer 0.5%~10%, binder 0.5% ~ 10%, flavoring agent 0.1% ~ 5%.
优选地，本发明提供的一种头孢克肟颗粒剂，其按重量百分数计包括 以下组分： 头孢克肟 5% ~ 10%、 稀释剂 71% ~ 85%、 緩沖剂 3% ~ 10%、 粘合剂 3% ~ 8%、 矫味剂 1% ~ 3%。  Preferably, the present invention provides a cefixime granule comprising, by weight percent, the following components: cefixime 5% ~ 10%, diluent 71% ~ 85%, buffer 3% ~ 10%, Adhesive 3% ~ 8%, flavoring agent 1% ~ 3%.
本发明提供的一种头孢克肟颗粒剂， 其按重量百分数计还包括香精 0.1% ~ 5%和 /或色素 0.1% ~ 5%。  The present invention provides a cefixime granule which further comprises 0.1% to 5% by weight and/or 0.1% to 5% by weight of the pigment.
本发明提供的一种头孢克肟颗粒剂中， 稀释剂包括 糖、 淀粉、 麦芽 糊精、 乳糖、 甘露醇、 山梨醇、 微晶纤维素、 羟丙纤维素、 羧曱基淀粉钠 中的一种或者两者以上的混合物。  In a cefixime granule provided by the present invention, the diluent comprises one of sugar, starch, maltodextrin, lactose, mannitol, sorbitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium carboxymethyl starch. Kind or a mixture of two or more.
本发明提供的一种头孢克肟颗粒剂中，緩沖剂包括枸橼酸、枸橼酸钠、 磷酸氢钠、 碳酸氢钠、 碳酸钠、 磷酸钠中的一种或两者以上的混合物。 本发明提供的一种头孢克肟颗粒剂中，粘合剂包括曱基纤维素、聚乙 烯吡咯烷酮、羟丙曱纤维素、羧曱基纤维素钠中的一种或两者以上的混合 物。 In a cefixime granule provided by the present invention, the buffering agent comprises a mixture of one or more of citric acid, sodium citrate, sodium hydrogen phosphate, sodium hydrogencarbonate, sodium carbonate, sodium phosphate. In a cefixime granule provided by the present invention, the binder comprises one or a mixture of two or more of mercaptocellulose, polyvinylpyrrolidone, hydroxypropylcellulose, sodium carboxymethylcellulose.
本发明提供的一种头孢克肟颗粒剂中，矫味剂包括阿司帕坦、三氯蔗 糖、 甜菊甙、 纽甜中的一种或两者以上的混合物。  In a cefixime granule provided by the present invention, the flavoring agent comprises a mixture of one or more of aspartame, sucrose, stevioside, neotame.
本发明提供的一种头孢克肟颗粒剂中，香精包括草莓香精、菠萝香精、 橙子香精、樱桃香精、哈密瓜香精、巧克力香精中的一种或两者以上的混 合物。  In a cefixime granule provided by the present invention, the fragrance comprises a mixture of one or more of strawberry flavor, pineapple flavor, orange flavor, cherry flavor, cantaloupe flavor, chocolate flavor.
本发明提供的一种头孢克肟颗粒剂中，色素包括日落黄、日落黄色淀、 柠檬黄、柠檬黄色淀、 赤鲜红色淀、 天然焦糖中的一种或两者以上的混合 物。  In a cefixime granule provided by the present invention, the pigment includes a mixture of one or more of sunset yellow, sunset yellow lake, lemon yellow, lemon yellow lake, red fresh lake, and natural caramel.
本发明还提供了一种头孢克肟颗粒剂的一步制粒制备方法，配方按重 量百分数计包括以下组分： 头孢克肟 1%~20%、 稀释剂 56% ~ 95%、 緩沖 剂 0.5% ~ 10%、 粘合剂 0.5% ~ 10%、 矫味剂 0.1% ~ 5%。  The invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 1%~20%, diluent 56%~95%, buffer 0.5% ~ 10%, binder 0.5% ~ 10%, flavoring 0.1% ~ 5%.
步骤 1： 取粘合剂过 60 ~ 160 目筛， 溶于水中配制成 2% ~ 20%的粘 合剂水溶液；  Step 1: Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make 2% ~ 20% aqueous solution of the adhesive;
步骤 2: 取头孢克肟、 稀释剂、 緩沖剂、 矫味剂分别过 60 ~ 160目筛 处理， 预热至 40 ~ 60°C , 加入所述粘合剂水溶液进行一步制粒， 控制物 料干燥温度不高于 60°C ,分别经过 10目、 80目筛整粒，检验、分装即得。  Step 2: Take cefixime, diluent, buffer and flavoring agent through 60~160 mesh sieve, preheat to 40 ~ 60 °C, add the binder aqueous solution to carry out one-step granulation, control the drying of materials. The temperature is not higher than 60 ° C, and the granules are sieved through 10 mesh and 80 mesh respectively, and are obtained by inspection and dispensing.
本发明还提供了一种头孢克肟颗粒剂的一步制粒制备方法，配方按重 量百分数计包括以下组分： 头孢克肟 1%~20%、 稀释剂 56% ~ 95%、 緩沖 剂 0.5% ~ 10%、粘合剂 0.5% ~ 10%、矫味剂 0.1% ~ 5%、香精 0.1% ~ 5%。  The invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 1%~20%, diluent 56%~95%, buffer 0.5% ~ 10%, binder 0.5% ~ 10%, flavoring 0.1% ~ 5%, flavor 0.1% ~ 5%.
步骤 1 : 取粘合剂过 60 - 160 目筛， 溶于水中配制成 2% ~ 20%的粘 合剂水溶液；  Step 1: Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make 2% ~ 20% aqueous solution of the adhesive;
步骤 2: 取头孢克肟、 稀释剂、 緩沖剂、 矫味剂分别过 60 ~ 160目筛 处理， 预热至 40 ~ 60°C , 加入所述粘合剂水溶液进行一步制粒， 控制物 料干燥温度不高于 60°C ,分别经过 10目、 80目筛整粒，检验、分装即得。  Step 2: Take cefixime, diluent, buffer and flavoring agent through 60~160 mesh sieve, preheat to 40 ~ 60 °C, add the binder aqueous solution to carry out one-step granulation, control the drying of materials. The temperature is not higher than 60 ° C, and the granules are sieved through 10 mesh and 80 mesh respectively, and are obtained by inspection and dispensing.
本发明还提供了一种头孢克肟颗粒剂的一步制粒的制备方法，配方其 按重量百分数计包括以下组分： 头孢克肟 1%~20%、 稀释剂 56% ~ 95%、 緩沖剂 0.5% ~ 10%、粘合剂 0.5% ~ 10%、矫味剂 0.1% ~ 5%、 色素 0.1% ~The invention also provides a method for preparing one-step granulation of cefixime granules, which comprises the following components by weight: cefixime 1%~20%, diluent 56%~95%, Buffer 0.5% ~ 10%, binder 0.5% ~ 10%, flavor 0.1% ~ 5%, pigment 0.1% ~
5%。 5%.
步骤 1: 取粘合剂过 60- 160 目筛， 溶于水中配制成 2% ~ 20%的粘 合剂水溶液；  Step 1: Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make a 2% ~ 20% aqueous solution of the adhesive;
步骤 2: 取头孢克肟、 稀释剂、 緩沖剂、 矫味剂分别过 60 ~ 160目筛 处理， 预热至 40~60°C, 加入所述粘合剂水溶液进行一步制粒， 控制物 料干燥温度不高于 60°C,分别经过 10目、 80目筛整粒，检验、分装即得。  Step 2: Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials. The temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
本发明还提供了一种头孢克肟颗粒剂的一步制粒制备方法，配方按重 量百分数计包括以下组分： 头孢克肟 1%~20%、 稀释剂 56% ~ 95%、 緩沖 剂 0.5% ~ 10%、粘合剂 0.5% ~ 10%、矫味剂 0.1% ~ 5%、香精 0.1% ~ 5%、 色素 0.1% ~5%。  The invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 1%~20%, diluent 56%~95%, buffer 0.5% ~ 10%, binder 0.5% ~ 10%, flavoring 0.1% ~ 5%, flavor 0.1% ~ 5%, pigment 0.1% ~ 5%.
步骤 1: 取粘合剂过 60- 160 目筛， 溶于水中配制成 2% ~ 20%的粘 合剂水溶液；  Step 1: Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make a 2% ~ 20% aqueous solution of the adhesive;
步骤 2: 取头孢克肟、 稀释剂、 緩沖剂、 矫味剂分别过 60 ~ 160目筛 处理， 预热至 40~60°C, 加入所述粘合剂水溶液进行一步制粒， 控制物 料干燥温度不高于 60°C,分别经过 10目、 80目筛整粒，检验、分装即得。  Step 2: Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials. The temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
本发明还提供了一种头孢克肟颗粒剂的一步制粒制备方法，配方按重 量百分数计包括以下组分： 头孢克肟 5% ~ 10%、 稀释剂 71% ~ 85%、 緩 沖剂 3% ~ 10%、 粘合剂 3% ~ 8%、 矫味剂 1% ~ 3%。  The invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 5% ~ 10%, diluent 71% ~ 85%, buffer 3% ~ 10%, binder 3% ~ 8%, flavoring agent 1% ~ 3%.
步骤 1： 取粘合剂过 60 ~ 160 目筛， 溶于水中配制成 2% ~ 20%的粘 合剂水溶液；  Step 1: Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make 2% ~ 20% aqueous solution of the adhesive;
步骤 2: 取头孢克肟、 稀释剂、 緩沖剂、 矫味剂分别过 60 ~ 160目筛 处理， 预热至 40~60°C, 加入所述粘合剂水溶液进行一步制粒， 控制物 料干燥温度不高于 60°C,分别经过 10目、 80目筛整粒，检验、分装即得。  Step 2: Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials. The temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
本发明还提供了一种头孢克肟颗粒剂的一步制粒制备方法，配方按重 量百分数计包括以下组分： 头孢克肟 5% ~ 10%、 稀释剂 71% ~ 85%、 緩 沖剂 3% ~ 10%、 粘合剂 3%~8%、 矫味剂 1%~3%、 香精 0.1%~5%。  The invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 5% ~ 10%, diluent 71% ~ 85%, buffer 3% ~ 10%, binder 3%~8%, flavoring agent 1%~3%, flavor 0.1%~5%.
步骤 1: 取粘合剂过 60- 160 目筛， 溶于水中配制成 2% ~ 20%的粘 合剂水溶液； 步骤 2: 取头孢克肟、 稀释剂、 緩沖剂、 矫味剂分别过 60 ~ 160目筛 处理， 预热至 40~60°C, 加入所述粘合剂水溶液进行一步制粒， 控制物 料干燥温度不高于 60°C,分别经过 10目、 80目筛整粒，检验、分装即得。 Step 1: Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make a 2% ~ 20% aqueous binder solution; Step 2: Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials. The temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
本发明还提供了一种头孢克肟颗粒剂的一步制粒制备方法，配方按重 量百分数计包括以下组分： 头孢克肟 5% ~ 10%、 稀释剂 71% ~ 85%、 緩 沖剂 3% ~ 10%、 粘合剂 3% ~ 8%、 矫味剂 1% ~ 3%、 色素 0.1% ~ 5%。  The invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 5% ~ 10%, diluent 71% ~ 85%, buffer 3% ~ 10%, binder 3% ~ 8%, flavoring agent 1% ~ 3%, pigment 0.1% ~ 5%.
步骤 1: 取粘合剂过 60- 160 目筛， 溶于水中配制成 2% ~ 20%的粘 合剂水溶液；  Step 1: Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make a 2% ~ 20% aqueous solution of the adhesive;
步骤 2: 取头孢克肟、 稀释剂、 緩沖剂、 矫味剂分别过 60 ~ 160目筛 处理， 预热至 40~60°C, 加入所述粘合剂水溶液进行一步制粒， 控制物 料干燥温度不高于 60°C,分别经过 10目、 80目筛整粒，检验、分装即得。  Step 2: Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials. The temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
本发明还提供了一种头孢克肟颗粒剂的一步制粒制备方法，配方按重 量百分数计包括以下组分： 头孢克肟 5% ~ 10%、 稀释剂 71% ~ 85%、 緩 沖剂 3% ~ 10%、 粘合剂 3%~8%、 矫味剂 1%~3%、 香精 0.1%~5%、 色 素 0·1%~5%。  The invention also provides a one-step granulation preparation method of cefixime granules, the formula comprising the following components by weight percentage: cefixime 5% ~ 10%, diluent 71% ~ 85%, buffer 3% ~ 10%, binder 3%~8%, flavoring agent 1%~3%, flavor 0.1%~5%, pigment 0.1%~5%.
步骤 1: 取粘合剂过 60- 160 目筛， 溶于水中配制成 2% ~ 20%的粘 合剂水溶液；  Step 1: Take the adhesive through a 60-160 mesh sieve and dissolve it in water to make a 2% ~ 20% aqueous solution of the adhesive;
步骤 2: 取头孢克肟、 稀释剂、 緩沖剂、 矫味剂分别过 60 ~ 160目筛 处理， 预热至 40~60°C, 加入所述粘合剂水溶液进行一步制粒， 控制物 料干燥温度不高于 60°C,分别经过 10目、 80目筛整粒，检验、分装即得。  Step 2: Take cefixime, diluent, buffer, and flavoring agent through 60-160 mesh sieves, preheat to 40-60 ° C, add the binder aqueous solution for one-step granulation, and control the drying of materials. The temperature is not higher than 60 ° C, and it is sifted through 10 mesh and 80 mesh sieves respectively, and it is obtained by inspection and dispensing.
本发明提供一种头孢克肟颗粒剂及其制备方法。该头孢克肟颗粒剂具 有很好的质量稳定性、 混悬性、 含量均匀性， 溶散速度快， 同时具有很好 的口感， 特别适合儿童及吞咽困难的人群， 用药顺应性好。 本发明还提供 了一种头孢克肟颗粒的制备方法， 使用一步制粒的制备方法， 将普通湿 法制粒工艺中的混合、 制软材、 摇摆制湿颗粒、 沸腾干燥四个步骤合 并为一步制粒工艺， 使用设备则由普通湿法制粒工艺中的高效湿法混 合制粒机、摇摆式颗粒机及沸腾干燥机三个设备减少至流化床一个设 备， 操作方法筒单， 生产效率高， 特别适合工业化生产。 附图说明 The invention provides a cefixime granule and a preparation method thereof. The cefixime granule has good quality stability, suspension, uniformity of content, fast dissolving speed, and good mouthfeel. It is especially suitable for children and people with dysphagia, and the medication compliance is good. The invention also provides a preparation method of cefixime granules, which comprises the steps of preparing one-step granulation, combining the four steps of mixing, soft material, rocking wet granules and boiling drying in the ordinary wet granulation process into one step. The granulation process, the equipment is reduced from the three equipments of the high-efficiency wet mixing granulator, the swinging granulator and the boiling dryer in the ordinary wet granulation process to one equipment of the fluidized bed, the operation method is simple, and the production efficiency is high. It is especially suitable for industrial production. DRAWINGS
图 1示湿法制粒工艺流程图；  Figure 1 shows a flow chart of the wet granulation process;
图 2示本发明提供的制备工艺流程图。 具体实施方式  Figure 2 is a flow chart showing the preparation process provided by the present invention. detailed description
本发明公开了一种头孢克肟颗粒剂及其制备方法，本领域技术人员可 以借鉴本文内容， 适当改进工艺参数实现。特别需要指出的是， 所有类似 的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在 本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员 明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行 改动或适当变更与组合， 来实现和应用本发明技术。 可接受的辅料均可由市场购得。  The invention discloses a cefixime granule and a preparation method thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied. Acceptable excipients are commercially available.
下面结合实施例， 进一步阐述本发明： 实施例 1 头孢克肟颗粒剂的制备  The invention will be further illustrated by the following examples: Example 1 Preparation of cefixime granules
组分 重量 ( g )  Component weight ( g )
头孢克肟 1000  Cefixime 1000
蔗糖 16000  Sucrose 16000
羟丙纤维素 1000  Hydroxypropyl cellulose 1000
枸橼酸钠 200  Sodium citrate 200
枸橼酸 200  Tannic acid 200
聚乙烯吡咯烷酮 1000  Polyvinylpyrrolidone 1000
纽甜 100  New sweet 100
橙子香精 300  Orange Flavor 300
巧克力香精 100  Chocolate Essence 100
制成 20000包  Made of 20000 packs
工艺： Process:
取头孢克肟过 120目筛， 蔗糖、 羟丙纤维素、 枸橼酸钠、 枸橼酸、 聚 乙烯吡咯烷酮、 纽甜、 橙子香精、 巧克力香精分别过 60目筛， 备用。 将 聚乙烯吡咯烷酮溶于纯化水中配制成 15%的水溶液， 备用。 Take cefixime through a 120 mesh sieve, sucrose, hydroxypropylcellulose, sodium citrate, citric acid, poly The vinylpyrrolidone, neotame, orange flavor, and chocolate flavor were passed through a 60 mesh sieve, and used. The polyvinylpyrrolidone was dissolved in purified water to prepare a 15% aqueous solution, which was used.
称取处方量的已过筛的头孢克肟、 蔗糖、 羟丙纤维素、 枸橼酸钠、 枸 橼酸、 纽甜一起投入到流化床中干混、 预热至物料温度达 50°C开始喷入 粘合剂溶液进行制粒。 制粒完成后进行干燥， 控制物料温度不高于 60°C 沸腾干燥。将干颗粒用 10目和 80目筛进行筛分整粒，并与与处方量的已 过筛的橙子香精、 巧克力香精一起投入到混合机中混合均匀， 取样检验， 合格后进行分装、 包装， 即得成品。 实施例 2 头孢克肟颗粒剂的制备  Weigh the prescribed amount of sieved cefixime, sucrose, hydroxypropylcellulose, sodium citrate, citric acid, neotame, and put it into the fluidized bed for dry mixing, preheating until the temperature of the material reaches 50 °C. The injection of the binder solution is started for granulation. Drying after granulation is completed, and the temperature of the controlled material is not higher than 60 ° C. Boiling and drying. The dry granules are sieved and sifted with 10 mesh and 80 mesh sieves, and mixed with the prescribed amount of sieved orange flavor and chocolate flavor into the mixer for uniform mixing, sampling and inspection, and then subpackaged and packaged after passing the test. , that is, the finished product. Example 2 Preparation of Cefixime Granules
组分 重量 ( g )  Component weight ( g )
头孢克肟 1000  Cefixime 1000
麦芽糊精 2500  Maltodextrin 2500
淀粉 5000  Starch 5000
枸橼酸钠 150  Sodium citrate 150
枸橼酸 150  Tannic acid 150
聚乙烯吡咯烷酮 800  Polyvinylpyrrolidone 800
阿司帕坦 200  Aspartan 200
菠萝香精 100  Pineapple flavor 100
曰落黄 100  Fallen Yellow 100
制成 20000包  Made of 20000 packs
工艺： Process:
将头孢克肟过 120目筛， 麦芽糊精、 淀粉、 枸橼酸钠、 枸橼酸、 阿司 帕坦、 菠萝香精、 日落黄分别过 60目筛， 备用。 将聚乙烯吡咯烷酮溶于 纯化水中配制成 15%的水溶液， 备用。  The cefixipin was passed through a 120 mesh sieve, and maltodextrin, starch, sodium citrate, citric acid, aspartame, pineapple flavor, and sunset yellow were passed through a 60 mesh sieve, and used. The polyvinylpyrrolidone was dissolved in purified water to prepare a 15% aqueous solution, which was used.
称取处方量的已过筛的头孢克肟、 麦芽糊精、 淀粉、 枸橼酸钠、 枸橼 酸、阿司帕坦、 日落黄一起投入到流化床中干混、预热至物料温度达 45 °C 开始喷入粘合剂溶液进行制粒。制粒完成后进行干燥，控制物料温度不高 于 60°C沸腾干燥。 将干颗粒用 10目和 80目筛进行筛分整粒， 并与处方 量的已过筛的菠萝香精一起投入到混合机中混合均匀，取样检验，合格后 进行分装、 包装， 即得成品。 实施例 3 头孢克肟颗粒剂的制备 Weigh the prescribed amount of sieved cefixime, maltodextrin, starch, sodium citrate, citric acid, aspartame, and sunset yellow into the fluidized bed for dry mixing and preheating to the temperature of the material. The binder solution was sprayed at 45 ° C for granulation. After the granulation is completed, drying is carried out, and the temperature of the material is controlled to be no higher than 60 ° C to be boiled and dried. Dry granules are sieved and sized with 10 mesh and 80 mesh sieves, and prescribed The amount of the sieved pineapple flavor is put into the mixer and mixed evenly, sampled and tested, and after being qualified, the product is packaged and packaged to obtain the finished product. Example 3 Preparation of Cefixime Granules
组分 重量 ( g )  Component weight ( g )
头孢克肟 1500  Cefixime 1500
乳糖 6000  Lactose 6000
碳酸氢钠 500  Sodium bicarbonate 500
碳酸钠 400  Sodium carbonate 400
羧曱基纤维素钠 800  Carboxymethyl cellulose sodium 800
甜菊甙 300  Stevia 300
草莓香精 300  Strawberry Flavor 300
杵樣黄 100  杵like yellow 100
制成 10000包  Made of 10,000 packs
工艺： Process:
将头孢克肟过 100目筛， 乳糖、 碳酸氢钠、 碳酸钠、 甜菊甙、 草莓香 精、 柠檬黄分别过 80目筛， 备用。 将羧曱基纤维素钠溶于纯化水中配制 成 5%的水溶液， 备用。  The cefixipin was passed through a 100 mesh sieve, and lactose, sodium hydrogencarbonate, sodium carbonate, stevioside, strawberry flavor, and lemon yellow were passed through an 80 mesh sieve, and used. The sodium carboxymethyl cellulose was dissolved in purified water to prepare a 5% aqueous solution, which was used.
称取处方量的已过筛的头孢克肟、乳糖、碳酸氢钠、碳酸钠、甜菊甙、 柠檬黄一起投入到流化床中干混、 预热至物料温度达 40°C开始喷入粘合 剂溶液进行制粒。 制粒完成后进行干燥， 控制物料温度不高于 60°C沸腾 干燥。将干颗粒用 10目和 80目筛进行筛分整粒，并与处方量的已过筛的 草莓香精一起投入到混合机中混合均匀， 取样检验，合格后进行分装、 包 装， 即得成品。 实施例 4 头孢克肟颗粒剂的制备  Weigh the prescribed amount of sifted cefixime, lactose, sodium bicarbonate, sodium carbonate, stevioside, and tartrazine into the fluidized bed for dry mixing, preheating until the temperature of the material reaches 40 °C and start to stick into the paste. The mixture solution is granulated. After the granulation is completed, the drying is carried out, and the temperature of the controlled material is not higher than 60 ° C and boiled and dried. The dry granules are sieved and sifted with 10 mesh and 80 mesh sieves, and put into the mixer together with the prescribed amount of sifted strawberry flavor, mixed and sampled, sampled and tested, and then packaged and packaged after being qualified, that is, the finished product is obtained. . Example 4 Preparation of Cefixime Granules
组分 重量（g )  Component weight (g)
头孢克肟 2000  Cefixime 2000
微晶纤维素 2400 3000 Microcrystalline cellulose 2400 3000
氢钠 1000  Sodium hydrogen 1000
聚乙烯吡咯烷酮 450  Polyvinylpyrrolidone 450
三氯蔗糖 300  Sucralose 300
巧克力香精 150  Chocolate Essence 150
天然焦糖 500  Natural Caramel 500
制成 10000包  Made of 10,000 packs
工艺: Process:
将头孢克肟过 160目筛， 微晶纤维素、 蔗糖、 磷酸氢钠、 三氯蔗糖、 巧克力香精分别过 60目筛， 备用。 将羟丙曱纤维素溶于纯化水中配制成 5%的水溶液， 天然焦糖加入搅拌均匀， 作为粘合剂， 备用。  The cefixipin was passed through a 160 mesh sieve, and the microcrystalline cellulose, sucrose, sodium hydrogen phosphate, sucralose, and chocolate flavor were respectively passed through a 60 mesh sieve and used. The hydroxypropionin cellulose was dissolved in purified water to prepare a 5% aqueous solution, and the natural caramel was added and stirred uniformly to serve as a binder.
称取处方量的已过筛的头孢克肟、 微晶纤维素、 蔗糖、磷酸氢钠、 三 氯蔗糖一起投入到流化床中干混， 预热至物料温度达 60°C开始喷入粘合 剂溶液进行制粒。 制粒完成后进行干燥， 控制物料温度不高于 60°C沸腾 干燥。将干颗粒用 10目和 80目筛筛分整粒，并与处方量的已过筛的巧克 力香精一起投入到混合机中混合均匀，取样检验，合格后进行分装、包装， 即得成品。 实施例 5头孢克肟颗粒剂的制备  Weigh the prescribed amount of sieved cefixime, microcrystalline cellulose, sucrose, sodium hydrogen phosphate, and sucralose into a fluidized bed for dry mixing, preheat until the material temperature reaches 60 ° C and start to spray into the paste. The mixture solution is granulated. After the granulation is completed, the drying is carried out, and the temperature of the controlled material is not higher than 60 ° C and boiled and dried. The dry granules are sieved with 10 mesh and 80 mesh sieves, and put into a mixer with a prescribed amount of sieved chocolate flavor to be evenly mixed, sampled and tested, and then packaged and packaged after being qualified to obtain a finished product. Example 5 Preparation of Cefixime Granules
组分 重量 ( g )  Component weight ( g )
头孢克肟 1000  Cefixime 1000
蔗糖 12000  Sucrose 12000
羟丙纤维素 2200  Hydroxypropyl cellulose 2200
枸橼酸钠 900  Sodium citrate 900
枸橼酸 900  Tannic acid 900
曱基纤维素 1000  Mercapto cellulose 1000
聚乙烯吡咯烷酮 500  Polyvinylpyrrolidone 500
阿司帕坦 300  Aspartan 300
三氯蔗糖 600 橙子香精 600 Sucralose 600 Orange Flavor 600
制成 20000包  Made of 20000 packs
工艺： Process:
将头孢克肟过 120目筛， 蔗糖、 羟丙纤维、 枸橼酸钠、 枸橼酸、 阿司 帕坦、 三氯蔗糖、 橙子香精分别过 80目筛， 备用。 将曱基纤维素和聚乙 烯吡咯烷酮一起溶于纯化水中配制成 3%的水溶液， 备用。  Cefixime was passed through a 120 mesh sieve, and sucrose, hydroxypropylcellulose, sodium citrate, citric acid, aspartame, sucralose, and orange flavor were passed through an 80 mesh sieve, and used. The thiol cellulose and the polyvinylpyrrolidone were dissolved together in purified water to prepare a 3% aqueous solution, which was used.
称取处方量的已过筛的头孢克肟、 蔗糖、 羟丙纤维、 枸橼酸钠、 枸橼 酸、 阿司帕坦、 三氯蔗糖一起投入到流化床中干混， 预热至物料温度达 55°C开始喷入粘合剂溶液进行制粒。制粒完成后进行干燥，控制物料温度 不高于 60°C沸腾干燥。 将干颗粒用 10目和 80目筛筛分整粒， 并与处方 量的已过筛的橙子香精一起投入到混合机中混合均匀，取样检验，合格后 进行分装、 包装， 即得成品。 实施例 6 头孢克肟颗粒剂的制备  Weigh the prescribed amount of sieved cefixime, sucrose, hydroxypropylcellulose, sodium citrate, citric acid, aspartame, and sucralose into a fluidized bed for dry mixing and preheat to the material. The binder solution was sprayed at a temperature of 55 ° C for granulation. After the granulation is completed, it is dried to control the temperature of the material to be no higher than 60 ° C. The dry granules are sieved with 10 mesh and 80 mesh sieves, and mixed with the prescribed amount of sieved orange flavor into a mixer to be uniformly mixed, sampled and tested, and then packaged and packaged to obtain a finished product. Example 6 Preparation of Cefixime Granules
组分 重量（g )  Component weight (g)
头孢克肟 500  Cefixime 500
甘露醇 38850  Mannitol 38850
羟丙纤维素 5000  Hydroxypropyl cellulose 5000
磷酸氢钠 250  Sodium hydrogen phosphate 250
騎酸 ] 250  Riding acid ] 250
聚乙烯吡咯烷酮 5000  Polyvinylpyrrolidone 5000
阿司帕坦 100  Aspartan 100
4宁檬黄色淀 50  4 Ning lemon yellow lake 50
制成 10000包  Made of 10,000 packs
工艺： Process:
将头孢克肟过 100目筛， 甘露醇、 羟丙纤维素、 磷酸氢钠、 磷酸钠、 阿司帕坦、 柠檬黄色淀分别过 60目筛 备用。 将聚乙烯吡咯烷酮溶于纯 化水中配制成 20%的水溶液， 备用。  The cefixime was passed through a 100 mesh sieve, and mannitol, hydroxypropylcellulose, sodium hydrogen phosphate, sodium phosphate, aspartame, and lemon yellow lake were sieved through a 60 mesh sieve, respectively. The polyvinylpyrrolidone was dissolved in purified water to prepare a 20% aqueous solution, which was used.
称取处方量的已过筛的头孢克肟、 甘露醇、 羟丙纤维素、 磷酸氢钠、 磷酸钠、 阿司帕坦、柠檬黄色淀一起投入到流化床中干混， 预热至物料温 度达 50°C开始喷入粘合剂溶液进行制粒。 制粒完成后进行干燥， 控制物 料温度不高于 60°C沸腾干燥。 将干颗粒用 10目和 80目筛筛分整粒， 得 到的 10目与 80目之间的颗粒， 取样检验， 合格后进行分装、 包装， 即得 成品。 实施例 7 头孢克肟颗粒剂的制备 Weigh the prescribed amount of sieved cefixime, mannitol, hydroxypropylcellulose, sodium hydrogen phosphate, Sodium phosphate, aspartame, and lemon yellow lake were put together into a fluidized bed for dry mixing, and preheated until the temperature of the material reached 50 ° C, and the binder solution was sprayed for granulation. After the granulation is completed, the drying is carried out, and the temperature of the material is controlled to be not higher than 60 ° C to be boiled and dried. The dry granules are sieved by 10 mesh and 80 mesh sieves to obtain granules between 10 mesh and 80 mesh, which are sampled and tested, and then packaged and packaged after being qualified to obtain a finished product. Example 7 Preparation of Cefixime Granules
组分 重 f ( g  Component weight f ( g
头孢克肟 1000  Cefixime 1000
山梨醇 37500  Sorbitol 37500
羧曱淀粉钠 10000  Carboxyammonium starch 10000
碳酸氢钠 100  Sodium bicarbonate 100
碳酸钠 150  Sodium carbonate 150
羟丙曱纤维素 250  Hydroxypropyl cellulose 250
阿司帕坦 50  Aspartan 50
哈密瓜香精 50  Cantaloupe Flavor 50
赤藓红色淀 900  Red Oak Red Lake 900
制成 10000包  Made of 10,000 packs
工艺： Process:
将头孢克肟过 160目筛， 山梨醇、 羧曱淀粉钠、 碳酸氢钠、 碳酸钠、 阿司帕坦、 哈密瓜香精、 赤藓红色淀分别过 60目筛， 备用。 将羟丙曱纤 维素溶于纯化水中配制成 2%的水溶液， 备用。  The cefixum was passed through a 160 mesh sieve, and sorbitol, sodium carboxymethyl starch, sodium hydrogencarbonate, sodium carbonate, aspartame, cantaloupe flavor, and red radix red radiant were respectively passed through a 60 mesh sieve and used. The hydroxypropionin was dissolved in purified water to prepare a 2% aqueous solution, which was used.
称取处方量的已过筛的头孢克肟山梨醇、羧曱淀粉钠、碳酸氢钠、碳 酸钠、 阿司帕坦、 赤藓红色淀一起投入到流化床中干混，预热至物料温度 达 45°C开始喷入粘合剂溶液进行制粒。 制粒完成后进行干燥， 控制物料 温度不高于 60°C沸腾干燥。 将干颗粒用 10目和 80目筛筛分整粒， 并与 处方量的已过筛的哈密瓜香精一起投入到混合机中混合均匀， 取样检验， 合格后进行分装、 包装， 即得成品。 实施例 8 头孢克肟颗粒剂的制备 Weigh the prescribed amount of sieved cefixime sorbitol, sodium carboxymethyl starch, sodium bicarbonate, sodium carbonate, aspartame, red peony red lake into the fluidized bed for dry mixing, preheating to the material The binder solution was sprayed at a temperature of 45 ° C for granulation. After the granulation is completed, the drying is carried out, and the temperature of the material is controlled to be not higher than 60 ° C to be boiled and dried. The dry granules are sieved and sifted with 10 mesh and 80 mesh sieves, and mixed with the prescribed amount of sifted cantaloupe flavor into a mixer to be uniformly mixed, sampled and tested, and then packaged and packaged after being qualified to obtain a finished product. Example 8 Preparation of Cefixime Granules
组分 重量 ( g )  Component weight ( g )
头孢克肟 1000  Cefixime 1000
淀粉 2000  Starch 2000
山梨醇 5800  Sorbitol 5800
枸橼酸钠 200  Sodium citrate 200
枸橼酸 200  Tannic acid 200
羧曱基纤维素钠 300  Carboxymethyl cellulose sodium 300
甜菊甙 500  Stevia 甙 500
制成 20000包  Made of 20000 packs
工艺: Process:
将头孢克肟过 120目筛， 淀粉、 山梨醇、 枸橼酸钠、 枸橼酸、 甜菊甙 分别过 60 目筛， 备用。 将羧曱基纤维素钠溶于纯化水中配制成 5%的水 溶液， 备用。  The cefixime was passed through a 120 mesh sieve, and starch, sorbitol, sodium citrate, citric acid, and stevioside were passed through a 60 mesh sieve, and used. The sodium carboxymethyl cellulose was dissolved in purified water to prepare a 5% aqueous solution, which was used.
称取处方量的已过筛的头孢克肟、淀粉、 山梨醇、枸橼酸钠、枸橼酸、 甜菊甙一起投入到流化床中干混、 预热至物料温度达 40°C开始喷入粘合 剂溶液进行制粒。 制粒完成后进行干燥， 控制物料温度不高于 60°C沸腾 干燥。将干颗粒用 10目和 80目筛进行筛分整粒，得到的 10目与 80目之 间的颗粒， 取样检验， 合格后进行分装、 包装， 即得成品。 实施例 9对比试验  Weigh the prescribed amount of sifted cefixime, starch, sorbitol, sodium citrate, citric acid, and stevioside into the fluidized bed for dry mixing, preheating until the temperature of the material reaches 40 °C. The binder solution was granulated. After the granulation is completed, the drying is carried out, and the temperature of the controlled material is not higher than 60 ° C and boiled and dried. The dry granules are sieved and sized by 10 mesh and 80 mesh sieves, and the obtained granules between 10 mesh and 80 mesh are sampled and tested. After passing the test, the product is packaged and packaged to obtain the finished product. Example 9 Comparative Test
对比例： 市售的头孢克肟颗粒； 经调研分析， 目前的市售品均采用湿 法制粒工艺制得。  Comparative Example: Commercially available cefixime granules; After investigation and analysis, the current commercial products are obtained by wet granulation.
溶散性：  Dissolution:
分别取一步制粒的实施例 1~8 的头孢克肟颗粒与对比例 2.0g加入到 40ml水中， 以 60rpm搅拌速度搅拌至颗粒全部溶散， 计录时间 （时间越 短表明颗粒溶散的越快） 。 试验数据见表 1。
Figure imgf000014_0002
The cefixime granules of Examples 1 to 8 which were separately granulated in one step were added to 40 ml of water in a ratio of 2.0 g, and stirred at a stirring speed of 60 rpm until the particles were completely dissolved, and the recording time (the shorter the time, the more the particles were dispersed). Fast). The test data is shown in Table 1.
Figure imgf000014_0002
结果表明， 本发明一步制粒的实施例 1~8 的头孢克肟颗粒与对比例 相比， 溶散速度明显加快。 沉降体积比：  The results showed that the dissolution rate of the cefixime granules of the examples 1 to 8 of the one-step granulation of the present invention was significantly accelerated as compared with the comparative example. Settling volume ratio:
分别取一步制粒的实施例 1~8的头孢克肟颗粒与对比例， 按照中国药 典 2010年版附录 I 0项下沉降体积比进行混悬性对比检查试验， 试验数 据见表 2。  The cefixime granules of Examples 1 to 8 which were separately granulated were compared with the comparative examples, and the suspension comparison test was carried out according to the sedimentation volume ratio of Appendix I of the Chinese Pharmacopoeia 2010 edition. The test data is shown in Table 2.
表 2 沉降体积比对比结果  Table 2 Settlement volume ratio comparison results
Figure imgf000014_0001
实施例 6 1 1 1 1 1 1 实施例 Ί 1 1 1 1 1 1 实施例 8 1 1 1 1 1 1 对比例 0.3 0.2 0.3 0.1 0.2 0.2 结果清楚地表明本发明一步制粒的实施例 1~8 的头孢克肟颗粒与对 比例相比， 混悬性更好。 含量均勾性对比试验：
Figure imgf000014_0001
Example 6 1 1 1 1 1 1 Example Ί 1 1 1 1 1 1 Example 8 1 1 1 1 1 1 Comparative Example 0.3 0.2 0.3 0.1 0.2 0.2 The results clearly show Examples 1 to 8 of the one-step granulation of the present invention. The cefixime granules were more suspending than the comparative examples. Comparative test of content homology:
实施例 1至 8制得的头孢克肟颗粒和对比例按照中国药典 2010版二 部附录 X Ε含量均匀度检查法项下方法进行检查并计算 A+1.45S , 试验 数据见下表 3。 表 3 含量均匀性比较表  The cefixime granules and the comparative examples prepared in Examples 1 to 8 were inspected according to the method of the Chinese Pharmacopoeia 2010 Edition, Appendix X, Ε Content Uniformity Checking Method, and A+1.45S was calculated, and the test data is shown in Table 3 below. Table 3 Comparison of content uniformity
Figure imgf000015_0001
Figure imgf000015_0001
结果清楚地表明本发明实施例 1至 8与对比例相比， 含量均匀性明显 提1¾。 质量稳定性：  The results clearly show that the content uniformity of the inventive examples 1 to 8 is significantly higher than that of the comparative examples. Quality stability:
分别取一步制粒的实施例 1~8的头孢克肟颗粒与对比例，行了加速稳 定性试验（40°C±2°C、 相对湿度 75%±5%条件下放置， 分别于试验期间 第 1个月、 2个月、 3个月、 6个月末取样一次）， 测定头孢克肟标示量的 百分含量和有关物质相对百分含量， 结果详见表 4。 The cefixime particles of Examples 1 to 8 which were granulated in one step and the comparative examples were respectively subjected to accelerated stability test (40 ° C ± 2 ° C, relative humidity 75% ± 5%, respectively, during the test period). Samples were taken at the end of the first month, 2 months, 3 months, and 6 months. The percentage of the amount of cefixime indicated and the relative percentage of related substances were determined. The results are shown in Table 4.
表 4加速试验稳定性比较  Table 4 Comparison of accelerated test stability
时间 有关物质 （ % )  Time related substance ( % )
样品名 含量（％ )  Sample name content (%)
(月） 单个最大（ % ) 总杂质 （％ ) 实施例 1 100.6 0.17 0.83 实施例 2 101.1 0.21 0.89 实施例 3 99.9 0.2 0.94 实施例 4 100.3 0.19 0.85 实施例 5 99.8 0.15 0.75 (Month) Single Maximum (%) Total Impurity (%) Example 1 100.6 0.17 0.83 Example 2 101.1 0.21 0.89 Example 3 99.9 0.2 0.94 Example 4 100.3 0.19 0.85 Example 5 99.8 0.15 0.75
0 实施例 6 100.2 0.22 0.86 0 Example 6 100.2 0.22 0.86
实施例 Ί 99.6 0.14 0.69 实施例 8 99.9 0.16 0.73 对比例 100.5 0.32 0.99 实施例 1 99.9 0.31 1.58 实施例 2 100.2 0.45 1.63 实施例 3 99.5 0.41 1.49 实施例 4 99.8 0.39 1.28 EXAMPLES Ί 99.6 0.14 0.69 Example 8 99.9 0.16 0.73 Comparative Example 100.5 0.32 0.99 Example 1 99.9 0.31 1.58 Example 2 100.2 0.45 1.63 Example 3 99.5 0.41 1.49 Example 4 99.8 0.39 1.28
1 实施例 5 99.1 0.37 1.49 1 Example 5 99.1 0.37 1.49
实施例 6 99.3 0.49 1.65 实施例 Ί 98.7 0.27 1.39 实施例 8 99.3 0.39 1.57 对比例 97.9 0.60 2.41 实施例 1 98.9 0.46 1.85 实施例 2 100.0 0.51 1.93 实施例 3 99.2 0.47 1.88 实施例 4 99.1 0.56 1.90 Example 6 99.3 0.49 1.65 Example Ί 98.7 0.27 1.39 Example 8 99.3 0.39 1.57 Comparative Example 97.9 0.60 2.41 Example 1 98.9 0.46 1.85 Example 2 100.0 0.51 1.93 Example 3 99.2 0.47 1.88 Example 4 99.1 0.56 1.90
2 实施例 5 98.4 0.48 1.87 实施例 6 98.7 0.57 1.96 实施例 Ί 98.5 0.36 1.64 实施例 8 99.0 0.50 1.89 对比例 96.4 0.79 3.06 实施例 1 98.0 0.58 2.20 实施例 2 98.3 0.69 2.56 实施例 3 97.7 0.64 2.47 实施例 4 98.5 0.53 2.19 实施例 5 97.6 0.61 2.312 Example 5 98.4 0.48 1.87 Example 6 98.7 0.57 1.96 Example Ί 98.5 0.36 1.64 Example 8 99.0 0.50 1.89 Comparative Example 96.4 0.79 3.06 Example 1 98.0 0.58 2.20 Example 2 98.3 0.69 2.56 Example 3 97.7 0.64 2.47 Example 4 98.5 0.53 2.19 Example 5 97.6 0.61 2.31
3 实施例 6 97.5 0.65 2.47 3 Example 6 97.5 0.65 2.47
实施例 Ί 97.3 0.52 2.15 实施例 8 98.4 0.69 2.42 对比例 95.0 0.85 3.82 实施例 1 96.8 0.71 3.51 实施例 2 97.2 0.80 3.11 实施例 3 97.0 0.73 3.46 实施例 4 97.4 0.64 3.32 实施例 5 96.7 0.76 3.53 EXAMPLES Ί 97.3 0.52 2.15 Example 8 98.4 0.69 2.42 Comparative Example 95.0 0.85 3.82 Example 1 96.8 0.71 3.51 Example 2 97.2 0.80 3.11 Example 3 97.0 0.73 3.46 Example 4 97.4 0.64 3.32 Example 5 96.7 0.76 3.53
6 实施例 6 96.7 0.82 3.46 6 Example 6 96.7 0.82 3.46
实施例 Ί 96.8 0.69 3.19 实施例 8 96.1 0.83 3.80 对比例 94.5 0.93 5.63 表 4结果表明， 经 6个月加速稳定性试验， 一步制粒的实施例 1~8 的头孢克肟颗粒与对比例中的头孢克肟标示量的百分含量和有关物质相 对百分含量均仍在合格范围内， 但相比较， 对比例比一步制粒的实施例 1-8的头孢克肟颗粒中的头孢标示量的百分含量下降相对较多；对比例单 个杂质和总杂质的增加量均较大。 实施例 10 口感评价 EXAMPLES 6.8 96.8 0.69 3.19 Example 8 96.1 0.83 3.80 Comparative Example 94.5 0.93 5.63 The results in Table 4 show that one-step granulation of the ceft gram particles of Examples 1-8 in the one-step accelerated stability test and the comparative example The percentage of the indicated amount of cefixime and the relative percentage of the relevant substances were still within the acceptable range, but the comparative examples were compared with the cephalosporin indicating amount in the cefotaxime particles of Examples 1-8 in one-step granulation. The percentage content decreased relatively more; the increase of single impurity and total impurity in the comparative example was larger. Example 10 Evaluation of taste
在深圳地区分别随机选取各年龄段患者总共 180名，按照年龄分为 6 组， 每组 30名被调查者， 对本发明实施例 1~8的头孢克肟颗粒以及对比 例进行口感评价， 评价标准见表 5 , 评价结果见表 6。 表 5 口感评价标准  A total of 180 patients of all ages were randomly selected in Shenzhen, and were divided into 6 groups according to age. Each group of 30 respondents evaluated the taste of the cefixime granules and the comparative examples of the present inventions 1-8. See Table 5 and the evaluation results are shown in Table 6. Table 5 taste evaluation criteria
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0001
Figure imgf000018_0002
由调查结果显示，受试者对本发明一步制粒的头孢克肟颗粒的口感满 意率远高于对比例的口感满意率。 实施例 11 工艺评价 The results of the investigation showed that the satisfaction rate of the taste of the one-step granulated cefacruzil granules of the present invention was much higher than that of the comparative examples. Example 11 Process Evaluation
2005年《中国现代应用药学杂志》第 22卷第 1期中报道了头孢克肟 颗粒剂的研究， 因此将实施例 1中的处方，参照文献中报道的普通湿法制 粒工艺制得头孢克肟颗粒， 具体如下：  The study of cefixime granules was reported in the 2005 issue of the Journal of Modern Applied Pharmacy, 2005. Therefore, the formulation in Example 1 was prepared by reference to the conventional wet granulation process reported in the literature. , details as follows:
组分 重量 ( g )  Component weight ( g )
头孢克肟 1000  Cefixime 1000
蔗糖 16000  Sucrose 16000
羟丙纤维素 1000  Hydroxypropyl cellulose 1000
枸橼酸钠 200  Sodium citrate 200
枸橼酸 200  Tannic acid 200
聚乙烯吡咯烷酮 1000  Polyvinylpyrrolidone 1000
纽甜 100  New sweet 100
橙子香精 300  Orange Flavor 300
巧克力香精 100  Chocolate Essence 100
制成 20000包  Made of 20000 packs
工艺：  Process:
1、 将头孢克肟、 蔗糖、 羟丙纤维素、 枸橼酸钠、 枸橼酸、 纽甜、 橙 子香精、 巧克力香精分别过 80目筛， 备用。  1. Pass cefixime, sucrose, hydroxypropylcellulose, sodium citrate, citric acid, neotame, orange flavor, and chocolate flavor through an 80 mesh sieve, and set aside.
3、 称取处方量的已过筛的头孢克肟、 蔗糖、 羟丙纤维素、 枸橼酸钠、 枸橼酸、 纽甜一起投入到高速搅拌制粒机中混合均勾， 加入粘合剂溶液 进行制软材， 然后制湿颗粒， 在 50°C的热空气中进行沸腾干燥。 3. Weigh the prescribed amount of sieved cefixime, sucrose, hydroxypropylcellulose, sodium citrate, citric acid, neotame, and put them into a high-speed mixing granulator. The solution was made into a soft material, and then the pellet was wetted and subjected to boiling drying in hot air at 50 °C.
4、 喷入处方量的已过筛的橙子香精、 巧克力香精， 混合均匀， 用 18 目筛、 80目筛整粒， 取样检验， 合格后进行分装、 包装， 即得成品。 以实施例 1~8的一步制粒工艺与上述普通湿法制粒工艺的相关参数及 颗粒成品率进行对比评价， 评价数据见表 7。 表 7 —步制粒工艺与现有湿法制粒技术的对比优势说明 4. Spray the prescribed amount of sifted orange flavor and chocolate flavor, mix evenly, use 18-mesh sieve, 80-mesh sieve to granulate, sample and test, and then pack and pack after passing the product. The one-step granulation process of Examples 1 to 8 was compared with the relevant parameters of the above-mentioned conventional wet granulation process and the particle yield, and the evaluation data is shown in Table 7. Table 7 - Comparison of the advantages of the step granulation process and the existing wet granulation technology
Figure imgf000020_0001
Figure imgf000020_0001
以上对本发明所提供的一种头孢克肟颗粒及其制备方法进行了详细 实施例的说明只是用于帮助理解本发明的方法及其核心思想。 应当指出， 对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对 本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保 护范围内。 The above description of the detailed description of a cefixime granule and a method for preparing the same provided by the present invention is only for aiding in understanding the method of the present invention and its core idea. It should be noted that those skilled in the art can make various modifications and changes to the present invention without departing from the spirit and scope of the invention.
-I- -I-

Claims

权 利 要 求 Rights request
1、 一种头孢克肟颗粒剂， 其特征在于， 其按重量百分数计包括以下 组分： 头孢克肟 1% ~ 20%、 稀释剂 56% ~ 95%、 緩沖剂 0.5% ~ 10%、 粘 合剂 0.5% ~ 10%、 矫味剂 0.1% ~ 5%。 1. A cefixime granule, characterized in that it includes the following components by weight percentage: cefixime 1% ~ 20%, diluent 56% ~ 95%, buffer 0.5% ~ 10%, viscosity Mixture 0.5% ~ 10%, flavoring agent 0.1% ~ 5%.
2、 根据权利要求 1所述的头孢克肟颗粒剂， 其特征在于， 其按重量 百分数计包括以下组分： 头孢克肟 5% ~ 10%、 稀释剂 71% ~ 85%、 緩沖 剂 3% ~ 10%、 粘合剂 3% ~ 8%、 矫味剂 1% ~ 3%。 2. Cefixime granules according to claim 1, characterized in that it includes the following components in weight percentage: cefixime 5% ~ 10%, diluent 71% ~ 85%, buffer 3% ~ 10%, binder 3% ~ 8%, flavoring agent 1% ~ 3%.
3、 根据权利要求 1所述的头孢克肟颗粒剂， 其特征在于， 其按重量 百分数计还包括香精 0.1 % ~ 5% 3. The cefixime granule according to claim 1, characterized in that it also includes 0.1% to 5% of essence by weight percentage.
4、 根据权利要求 1所述的头孢克肟颗粒剂， 其特征在于， 其按重量 百分数计还包括色素 0.1% ~ 5%。 4. The cefixime granule according to claim 1, characterized in that it also includes 0.1% to 5% of pigment by weight percentage.
5、 根据权利要求 1头孢克肟颗粒， 其特征在于， 所述稀释剂包括蔗 糖、 淀粉、 麦芽糊精、 乳糖、甘露醇、 山梨醇、微晶纤维素、 羟丙纤维素、 羧曱基淀粉钠中的一种或者两者以上的混合物。 5. Cefixime granules according to claim 1, characterized in that the diluent includes sucrose, starch, maltodextrin, lactose, mannitol, sorbitol, microcrystalline cellulose, hydroxypropyl cellulose, and carboxymethyl starch One or a mixture of two or more sodium.
6、 根据权利要求 1头孢克肟颗粒， 其特征在于， 所述緩沖剂包括枸 橼酸、 枸橼酸钠、 磷酸氢钠、 碳酸氢钠、 碳酸钠、 磷酸钠中的一种或两者 以上的混合物。 6. Cefixime granules according to claim 1, characterized in that the buffering agent includes one or more of citric acid, sodium citrate, sodium hydrogen phosphate, sodium bicarbonate, sodium carbonate and sodium phosphate. mixture.
7、 根据权利要求 1头孢克肟颗粒， 其特征在于， 所述粘合剂包括曱 基纤维素、 聚乙烯吡咯烷酮、 羟丙曱纤维素、羧曱基纤维素钠中的一种或 两者以上的混合物。 7. Cefixime granules according to claim 1, characterized in that the binder includes one or more of methylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. mixture.
8、 根据权利要求 1头孢克肟颗粒， 其特征在于， 所述矫味剂包括阿 司帕坦、 三氯蔗糖、 甜菊甙、 纽甜中的一种或两者以上的混合物。 8. Cefixime granules according to claim 1, characterized in that the flavoring agent includes one or a mixture of two or more of aspartame, sucralose, stevioside and neotame.
9、 一种头孢克肟颗粒剂的制备方法， 其特征在于， 按重量百分数计 包括以下组分： 9. A method for preparing cefixime granules, characterized in that it includes the following components in terms of weight percentage:
头孢克肟 1%~20%、 稀释剂 56% ~ 95%、 緩沖剂 0.5% ~ 10%、 粘合 剂 0.5% ~ 10%、 矫味剂 0.1% ~ 5%; Cefixime 1% ~ 20%, diluent 56% ~ 95%, buffer 0.5% ~ 10%, binder 0.5% ~ 10%, flavoring agent 0.1% ~ 5%;
步骤 1 : 取粘合剂过 60 - 160 目筛， 溶于水中配制成 2% ~ 20%的粘 合剂水溶液； 步骤 2: 取头孢克肟、 稀释剂、 緩沖剂、 矫味剂分别过 60 ~ 160目筛 处理， 预热至 40~60°C, 加入所述粘合剂水溶液进行一步制粒， 控制物 料干燥温度不高于 60°C,分别经过 10目、 80目筛整粒，检验、分装即得。 Step 1: Pass the adhesive through a 60-160 mesh sieve, dissolve it in water to prepare a 2% ~ 20% adhesive aqueous solution; Step 2: Pass cefixime, diluent, buffer and flavoring agent through 60~160 mesh sieve respectively, preheat to 40~60°C, add the binder aqueous solution for one-step granulation, and control the drying of the materials The temperature should not be higher than 60°C, and then sieved through 10-mesh and 80-mesh sieves, inspected, and packaged.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023148316A1 (en) * 2022-02-03 2023-08-10 Basf Se Magnesium diacetate x 4h 2o and/or magnesium dichloride x 6h 2o and/or magnesium sulfate x 7h 2o and/or disodium sulfate x 10 h 2o and/or sodium thiosulfate x 5h 2o and/or na 3po 4 x 12 h 2o and/or na 2hpo 4 x 12h 2o/7h 2o and/or sodium acetate x 3h 2o as granulating aid

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1526390A (en) * 2003-03-03 2004-09-08 浙江仙琚制药股份有限公司 Piduomode granule and its prepn

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1526390A (en) * 2003-03-03 2004-09-08 浙江仙琚制药股份有限公司 Piduomode granule and its prepn

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN WEIHONG ET AL.: "The Pharmaceutical Study on Suspending Granules of Cefixime.", DISSERTATION OF MASTER OF DEGREE OF GUANGZHOU UNIVERSITY OF CHINESE MEDICINE., August 2011 (2011-08-01) *
WANG LEI ET AL.: "The research and preparation of cefixime granules.", THE CHINESE JOURNAL OF MODERN APPLIED PHARMACY., vol. 22, no. 1, February 2005 (2005-02-01) *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023148316A1 (en) * 2022-02-03 2023-08-10 Basf Se Magnesium diacetate x 4h 2o and/or magnesium dichloride x 6h 2o and/or magnesium sulfate x 7h 2o and/or disodium sulfate x 10 h 2o and/or sodium thiosulfate x 5h 2o and/or na 3po 4 x 12 h 2o and/or na 2hpo 4 x 12h 2o/7h 2o and/or sodium acetate x 3h 2o as granulating aid

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