CN115607514B - Preparation method of cefdinir-containing particles - Google Patents
Preparation method of cefdinir-containing particles Download PDFInfo
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- CN115607514B CN115607514B CN202110805063.4A CN202110805063A CN115607514B CN 115607514 B CN115607514 B CN 115607514B CN 202110805063 A CN202110805063 A CN 202110805063A CN 115607514 B CN115607514 B CN 115607514B
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- 239000002245 particle Substances 0.000 title claims abstract description 127
- RTXOFQZKPXMALH-GHXIOONMSA-N cefdinir Chemical compound S1C(N)=NC(C(=N\O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 RTXOFQZKPXMALH-GHXIOONMSA-N 0.000 title claims abstract description 70
- 229960003719 cefdinir Drugs 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 239000008187 granular material Substances 0.000 claims abstract description 42
- 239000007779 soft material Substances 0.000 claims abstract description 25
- 239000005720 sucrose Substances 0.000 claims abstract description 24
- 239000000853 adhesive Substances 0.000 claims abstract description 23
- 230000001070 adhesive effect Effects 0.000 claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 20
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims abstract description 20
- 229930006000 Sucrose Natural products 0.000 claims abstract description 20
- 238000001035 drying Methods 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 17
- 238000002156 mixing Methods 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 15
- 239000004375 Dextrin Substances 0.000 claims abstract description 12
- 229920001353 Dextrin Polymers 0.000 claims abstract description 12
- 235000016623 Fragaria vesca Nutrition 0.000 claims abstract description 12
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims abstract description 12
- 235000019425 dextrin Nutrition 0.000 claims abstract description 12
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 11
- 235000012730 carminic acid Nutrition 0.000 claims abstract description 11
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 11
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 11
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 10
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 10
- 238000005507 spraying Methods 0.000 claims abstract description 8
- 241000220223 Fragaria Species 0.000 claims description 11
- 239000003814 drug Substances 0.000 abstract description 30
- 238000009835 boiling Methods 0.000 abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 10
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000007774 longterm Effects 0.000 abstract description 2
- 238000003860 storage Methods 0.000 abstract description 2
- 240000009088 Fragaria x ananassa Species 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 description 13
- 239000000080 wetting agent Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 9
- 238000001125 extrusion Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 4
- 229940106164 cephalexin Drugs 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 3
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 3
- 229960005361 cefaclor Drugs 0.000 description 3
- 229960003085 meticillin Drugs 0.000 description 3
- 239000004005 microsphere Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 2
- 229960002129 cefixime Drugs 0.000 description 2
- 239000011362 coarse particle Substances 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 206010001076 Acute sinusitis Diseases 0.000 description 1
- 241000589562 Brucella Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000221079 Euphorbia <genus> Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000588770 Proteus mirabilis Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000010397 acute frontal sinusitis Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 229940023064 escherichia coli Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- 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
- A61K9/1611—Inorganic compounds
-
- 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
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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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
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
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- 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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention relates to a preparation method of cefdinir-containing particles. The preparation method of the cefdinir-containing particles comprises the following steps: dissolving hydroxypropyl cellulose and carmine into 40% ethanol to prepare an adhesive; adding cefdinir, sucrose and dextrin into a wet granulator, uniformly mixing, spraying the prepared adhesive into the wet granulator, and uniformly stirring to obtain a soft material; putting the obtained soft material into a rotary extruder, extruding and granulating through a screen mesh with the aperture of 0.3mm to obtain wet granules; putting the obtained wet granules into a boiling dryer for drying, and finishing the granules through a sieve with the aperture of 0.5 mm; adding silicon dioxide and strawberry essence into the whole granule, and mixing uniformly. The cefdinir-containing particles prepared by the method have uniform size and small particle size, can be rapidly dissolved in water, have high medication compliance for patients, are convenient to take, and are very beneficial to the safety and long-term storage of clinical medicines.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and relates to a preparation method of cefdinir-containing particles.
Background
Cefdinir was first developed by the japanese euphorbia pharmaceutical industry, inc, and is a semisynthetic, broad-spectrum third generation oral cephalosporin that produces an antibacterial effect by inhibiting the synthesis of bacterial cell walls. The product has antibacterial activity to gram positive bacteria and gram negative bacteria, and is stable to most beta lactamase, and has wide antibacterial spectrum, high antibacterial activity, low toxicity and small side effect.
The cefdinir has strong antibacterial activity on gram-positive bacteria such as staphylococcus aureus, streptococcus pyogenes, pneumococcus and the like which are sensitive to the methicillin, and is higher than that of cefixime, cefaclor and cefalexin. Has moderate activity on methicillin-resistant staphylococcus aureus (MPSA) and streptococcus faecalis. Has stronger activity to gram negative bacteria such as escherichia coli, pneumobacillus and the like, is higher than cefaclor and cefalexin, is equivalent to cefalexin, and is also sensitive to klebsiella pneumoniae resistant to cefaclor and cefalexin, escherichia coli resistant to methicillin, proteus mirabilis, haemophilus influenzae and brucella mucositis. The cefdinir is obtained by modifying the structure of the third-generation cephalosporin cefixime, and has improved pharmacokinetic properties due to the modification of the structure, and is good in oral absorption property and suitable for being prepared into preparations for gastrointestinal tract absorption.
The cefdinir preparation is applied to clinic for nearly twenty years, and is mainly used for treating community-acquired pneumonia, acute exacerbation of chronic bronchitis, acute frontal sinusitis, pharyngitis/tonsillitis, acute bacterial otitis media, simple skin infection, tissue infection and the like of adults or children. Clinical application practice for many years shows that the medicine has the characteristics of good curative effect and high safety. In particular, the curative effect and safety of the medicine are fully proved in pediatric application, and the medicine is recommended by clinical guidelines of the American society of pediatrics.
Cefdinir raw material is yellowish powder, has poor water solubility, is easy to generate static electricity, is unstable under high temperature, high humidity and illumination conditions, and has the influence on safety and effectiveness due to the rise of related substances. In the industrial production process, local high temperature and high humidity can be generated in the one-step granulating process of the dry granulating process, the wet granulating process or the boiling granulating machine, and great challenges are brought to the stability of the cefdinir, so that the industrial problem that the production and preparation process with good stability, simplicity and high efficiency is found is solved. The cefdinir in the market at present has several dosage forms such as tablets, capsules, suspension, granules and the like, wherein the tablets and the capsules are not easy to swallow by children, the suspension is packaged in multiple doses, the doses are difficult to control and the administration is inconvenient, and the granules have the characteristics of large dispersity, convenient administration, good absorption and the like.
At present, the granules on the market in China are in a round shape or an irregular round shape, the diameter of round granules is more than 2mm, the diameter of cefdinir granules prepared by the preparation method can be controlled to be less than 0.3mm, and compared with the traditional screw extrusion granulating process, the porosity of the cefdinir granules prepared by the preparation method is obviously reduced, and the rotary extrudate is granulated according to the target particle size by the controllable particle size control process, so that the influence of the undersize extrudate particle size on taste masking effect is avoided, and the influence of the oversized particle size on the drug release speed and the gritty feel in the oral cavity is also avoided.
The inventors found that commercial granules generally have the problems of large particle size distribution (the particle size range is 600-2000 μm) and non-uniformity in research, while cefdinir granules of the invention have the advantages of small and uniform particle size and narrow particle size distribution, and the particle size range of the cefdinir granules is controlled to be 180-380 μm. Because cefdinir has the characteristic of being indissolvable in water, if the particle size of the particles is large, the particles of the cefdinir are difficult to dissolve when a patient takes the medicine, medicine residues are easy to exist in a medicine cup or an oral cavity after taking the medicine, so that the dissolution rate of the medicine and the blood concentration of the medicine after taking the medicine are fluctuated, and the absorption of the medicine is further influenced.
The granule prepared by the preparation method has smaller particle size and powder ratio, is convenient for split charging and easy to take, has smaller particle size, is easier to be uniformly mixed with powder medicament, has good content uniformity and higher bioavailability, has excellent dissolution characteristic, high yield and easy swallowing, is more suitable for children patients to take, and improves the medicine taking compliance of patients.
Disclosure of Invention
The invention aims to provide a preparation method of cefdinir-containing particles.
In view of this, in order to achieve the object of the present invention, the present invention adopts the following technical scheme:
a process for the preparation of cefdinir-containing granules, said process comprising the steps of:
first, preparation of an adhesive:
adding hydroxypropyl cellulose and carmine into a wetting agent, stirring and dissolving to obtain an adhesive;
secondly, preparing a soft material:
adding cefdinir, sucrose and dextrin into a wet granulator, uniformly mixing, spraying the adhesive into the wet granulator by using a spray gun, stirring at 300rpm and 3200rpm for 3min to obtain a soft material;
thirdly, preparing wet particles:
putting the soft material into a rotary extruder, extruding and granulating through a screen mesh with the aperture of 0.3mm to obtain wet granules;
fourth step, finishing:
adding the wet particles into a dryer, drying the wet particles in the dryer, and finishing the dried particles through a screen with the aperture of 0.5mm to obtain dry particles;
fifth, preparing a finished product:
and adding silicon dioxide and strawberry essence into the dry particles, and uniformly mixing to obtain a finished product containing cefdinir particles.
Preferably, the strawberry essence comprises 5 parts by weight of hydroxypropyl cellulose, 1 part by weight of carmine, 80 parts by weight of wetting agent, 50 parts by weight of cefdinir, 411 parts by weight of sucrose, 20 parts by weight of dextrin, 10 parts by weight of silicon dioxide and 10 parts by weight of strawberry essence.
Preferably, the wetting agent is 40% ethanol. In the present invention, a wetting agent is used for auxiliary granulation, and in the preparation of the binder, hydroxypropylcellulose is dissolved in the wetting agent together with carmine as a pigment to excite viscosity of sucrose as a subsequent additive, and in general, a volatile organic solvent is selected as the wetting agent, and in the present invention, 40% ethanol is preferable as the wetting agent.
Preferably, the particle diameter D90 of the cefdinir is 10-30 μm. According to the invention, the cefdinir with the particle size can be fully wrapped by the sucrose powder in the preparation process of the medicine to form the cefdinir-sucrose micro powder ball with the characteristic form, so that the cefdinir can be effectively protected from producing degradation impurities in the high-temperature environment in the extrusion granulation and drying processes, and the stability of the cefdinir in the technological process is improved.
Preferably, the sucrose has a particle size D90 of less than or equal to 80 μm. In the invention, the sucrose with the particle size and the dextrin are used for wrapping the cefdinir particles together, and then the cefdinir particles are wetted by the adhesive and are rotationally extruded to form a compact and firm protective layer, so that the stability of the cefdinir in high-temperature, high-humidity, illumination and other environments is improved. In addition, when the grain diameter D90 of the sucrose is smaller than or equal to 80 mu m, the sucrose powder under the grain diameter condition has larger surface area, and can be fully contacted with the cefdinir to form a cefdinir-sucrose microsphere with characteristic morphology in the mixing process, and after the adhesive is added, the cefdinir-sucrose microsphere absorbs moisture to excite the viscosity of the sucrose, so that the cefdinir is fully wrapped, and further the cefdinir-sucrose microsphere is formed.
Preferably, the dryer is a boiling dryer. In the invention, wet particles are required to be dried before finishing, and the wet particles with high water content are obtained by extruding the wet particles through a rotary extruder, for example, the wet particles are dried by using a common oven, so that the particles are easy to adhere to each other. The boiling dryer can uniformly keep the wet particles in a boiling state by using high-temperature air flow, and simultaneously quickly take away the moisture in the particles, so that the wet particles are dried. Because the wet particles are in a boiling state in the whole drying step, the contact area of the particles and hot air flow is large, and the moisture in the core of the wet particles can be rapidly taken away.
Preferably, the temperature of drying in the dryer is 80 ℃. In the granulation step of the wet granules of the present invention, the wet granules are dried, and in order to avoid the phenomenon of external drying and internal wetting after the wet granules are dried, a proper drying temperature is required to be set, and in the present invention, the preferable drying temperature is 80 ℃.
Preferably, the drying time in the dryer is 30min. In the preparation process of cefdinir-containing particles, if the wet particles are dried for too long, the hardness of the particles is too high, the stability of the medicine is also reduced, and the cefdinir-containing particles are not easy to be dissolved and absorbed rapidly when taken; if the drying time of the wet granules is too short, the granules are not dried to a sufficient extent, which is unfavorable for granule finishing, and in the invention, the drying time in the dryer is preferably 30min.
Preferably, the particle size of the cefdinir-containing finished product is less than or equal to 0.3mm. The medicine particles with the particle size can be rapidly dissolved in water and can be absorbed by a user more rapidly, so that the medication compliance of the user is improved.
In the invention, the soft material is extruded by a rotary extruder in the preparation of wet granules, and the common preparation process for preparing the granules is wet granulation, and granulation is carried out by using instruments and equipment such as a swinging extrusion granulator, a boiling granulator or simple sieving, and the like. The rotary extrusion granulating process used in the invention can extrude soft materials from a screen with the aperture of 0.3mm, and the screen aperture is small and the extrusion force is large, so that the local high temperature can be formed at the screen aperture due to the large extrusion force, and the sucrose and the dextrin can be melted for the second time, thereby effectively wrapping cefdinir, and the obtained granules have small particle size, firmness and large density, and can ensure that the main medicine is perfectly wrapped by the medicinal auxiliary materials in the extrusion process to form medicine-containing granules, so that the stability of the medicine-containing granules is greatly improved.
The invention has the beneficial effects that:
(1) The cefdinir-containing particles prepared by the preparation method disclosed by the invention are uniform in size and small in particle size, can be quickly absorbed, and are beneficial to improving the compliance of patients in taking.
(2) The cefdinir-containing particles prepared by the preparation method disclosed by the invention have the advantages of good stability and high safety, and are favorable for safe use and long-term storage of clinical medicines.
(3) The cefdinir-containing particles prepared by the preparation method disclosed by the invention are fragrant and sweet in taste, and can greatly improve the taking willingness of patients, especially children.
(4) According to the preparation method disclosed by the invention, the granules with small particle size and uniform size can be obtained by extruding and granulating through a rotary extruder, and the main drug cefdinir can be wrapped by the medicinal auxiliary material in the extruding process to form the cefdinir-containing granules, and meanwhile, the stability of the cefdinir-containing granules can be improved.
Detailed Description
The invention will be further understood by the following specific examples of the invention, which are given by way of illustration and are not intended to be limiting.
In the first to fifth embodiments of the present invention, sucrose is pulverized into powder having a particle diameter of 80 μm or less in advance and then added according to the preparation steps.
Example 1
The preparation method of the cefdinir-containing particles comprises the following steps:
first, preparation of an adhesive:
adding 5 parts of hydroxypropyl cellulose and 1 part of carmine into 80 parts of 40% ethanol, and stirring for dissolution to obtain an adhesive;
secondly, preparing a soft material:
adding 50 parts of cefdinir, 411 parts of sucrose and 20 parts of dextrin into a wet granulator, uniformly mixing, spraying an adhesive into the wet granulator by using a spray gun, stirring at 300rpm and 3200rpm for 3min to obtain a soft material;
thirdly, preparing wet particles:
putting the soft material into a rotary extruder, extruding and granulating through a screen mesh with the aperture of 0.3mm to obtain wet granules;
fourth step, finishing:
adding wet particles into a boiling dryer, drying the wet particles in the boiling dryer at 80 ℃ for 30min to enable the moisture of the particles to be less than 0.6%, and then finishing the dried particles through a sieve with the aperture of 0.5mm to obtain dry particles;
fifth, preparing a finished product:
adding 10 parts of silicon dioxide and 10 parts of strawberry essence into the dry particles, uniformly mixing, and subpackaging to obtain a cefdinir-containing particle finished product.
Example two
The preparation method of the cefdinir-containing particles comprises the following steps:
first, preparation of an adhesive:
adding 5 parts of hydroxypropyl cellulose and 1 part of carmine into 80 parts of 40% ethanol, and stirring for dissolution to obtain an adhesive;
secondly, preparing a soft material:
adding 50 parts of cefdinir, 411 parts of sucrose and 20 parts of dextrin into a wet granulator, uniformly mixing, spraying an adhesive into the wet granulator by using a spray gun, stirring at 300rpm and 3200rpm for 3min to obtain a soft material;
thirdly, preparing wet particles:
putting the soft material into a rotary extruder, extruding and granulating through a screen mesh with the aperture of 0.6mm to obtain wet granules;
fourth step, finishing:
adding wet particles into a boiling dryer, drying the wet particles in the boiling dryer at 80 ℃ for 30min to enable the moisture of the particles to be less than 0.6%, and then finishing the dried particles through a sieve with the aperture of 0.8mm to obtain dry particles;
fifth, preparing a finished product:
adding 10 parts of silicon dioxide and 10 parts of strawberry essence into the dry particles, uniformly mixing, and subpackaging to obtain a cefdinir-containing particle finished product.
Example III
The preparation method of the cefdinir-containing particles comprises the following steps:
first, preparation of an adhesive:
adding 5 parts of hydroxypropyl cellulose and 1 part of carmine into 80 parts of purified water, stirring and dissolving to obtain an adhesive;
secondly, preparing a soft material:
adding 50 parts of cefdinir, 411 parts of sucrose and 20 parts of dextrin into a wet granulator, uniformly mixing, spraying an adhesive into the wet granulator by using a spray gun, stirring at 300rpm and 3200rpm for 3min to obtain a soft material;
thirdly, preparing wet particles:
putting the soft material into a rotary extruder, extruding and granulating through a screen mesh with the aperture of 0.3mm to obtain wet granules;
fourth step, finishing:
adding wet particles into a boiling dryer, drying the wet particles in the boiling dryer at 80 ℃ for 50min to enable the moisture of the particles to be less than 0.6%, and then finishing the dried particles through a sieve with the aperture of 0.5mm to obtain dry particles;
fifth, preparing a finished product:
adding 10 parts of silicon dioxide and 10 parts of strawberry essence into the dry particles, uniformly mixing, and subpackaging to obtain a cefdinir-containing particle finished product.
Example IV
The preparation method of the cefdinir-containing particles comprises the following steps:
first, preparation of an adhesive:
adding 5 parts of hydroxypropyl cellulose and 1 part of carmine into 80 parts of 70% ethanol, and stirring for dissolution to obtain an adhesive;
secondly, preparing a soft material:
adding 50 parts of cefdinir, 411 parts of sucrose and 20 parts of dextrin into a wet granulator, uniformly mixing, spraying an adhesive into the wet granulator by using a spray gun, stirring at 300rpm and 3200rpm for 3min to obtain a soft material;
thirdly, preparing wet particles:
putting the soft material into a rotary extruder, extruding and granulating through a screen mesh with the aperture of 0.3mm to obtain wet granules;
fourth step, finishing:
adding wet particles into a boiling dryer, drying the wet particles in the boiling dryer at 80 ℃ for 30min to enable the moisture of the particles to be less than 0.6%, and then finishing the dried particles through a sieve with the aperture of 0.5mm to obtain dry particles;
fifth, preparing a finished product:
adding 10 parts of silicon dioxide and 10 parts of strawberry essence into the dry particles, uniformly mixing, and subpackaging to obtain a cefdinir-containing particle finished product.
Example five
The preparation method of the cefdinir-containing particles comprises the following steps:
first, preparation of an adhesive:
adding 5 parts of hydroxypropyl cellulose and 1 part of carmine into 80 parts of 40% ethanol, and stirring for dissolution;
secondly, preparing a soft material:
adding 50 parts of cefdinir, 411 parts of sucrose and 20 parts of dextrin into a wet granulator, uniformly mixing, spraying an adhesive into the wet granulator by using a spray gun, stirring at 300rpm and 3200rpm for 3min to obtain a soft material;
thirdly, preparing wet particles:
putting the soft material into a rotary extruder, extruding and granulating through a screen mesh with the aperture of 0.3mm to obtain wet granules;
fourth step, finishing:
adding wet particles into a boiling dryer, drying the wet particles in the boiling dryer at 50 ℃ for 106min to enable the moisture of the particles to be less than 0.6%, and then finishing the dried particles through a sieve with the aperture of 0.5mm to obtain dry particles;
fifth, preparing a finished product:
adding 10 parts of silicon dioxide and 10 parts of strawberry essence into the dry particles, uniformly mixing, and subpackaging to obtain a cefdinir-containing particle finished product.
Example six
Sample testing
The final products containing cefdinir granules prepared in examples one to five were left to stand under conditions of high temperature (60 ℃) and high humidity (92.5% RH), and after 10 days, the quality attributes of the samples in each example were measured, and the results are shown in Table 1:
wherein "dissolution time" in table 1: a single dose of cefdinir-containing particles (0.5 g) was poured into 50ml of water (water temperature 37 ℃ C.) and stirred at a rate of 2 cycles/sec for the time the particles were all dispersed.
Table 1 results of testing examples one to five
Analysis of sample test results
(1) As can be seen from the sample retention data of the samples of the first and second examples, the screen mesh (0.6 mm) of the second example is larger, and coarse particles on 40 meshes are more, so that 64.4% of the prepared sample is dissolved, the dissolution time of the prepared sample is long, the dissolution rate of the prepared sample is low, the particles are not easy to disperse and dissolve, the sample of the first example can be fully dispersed and dissolved within 60 seconds, the dissolution rate of the prepared sample within 15 minutes is more than 85%, and the curative effect of the medicine and the compliance of patients on taking the medicine are effectively improved.
(2) As can be seen from the sample retention data of the first sample and the third sample, when the third sample uses purified water as a wetting agent, the prepared particles have high water content, long drying time, overlarge particle hardness, 65% of coarse particles on 40 meshes, long dissolution time, obvious increase of related substances and poor stability. In the first embodiment, the cefdinir granules prepared by using 40% ethanol as a wetting agent have better stability and higher drug safety.
(3) As can be seen from the data of the samples of the first and fourth examples, when 70% ethanol was used as the wetting agent in the fourth example, the prepared particles were soft, the 80-mesh fine powder exceeded 20%, the dissolution rate exceeded fast, and the dissolution rate exceeded 90% for 15 min. Meanwhile, the particles have overlarge scattering property and adhesiveness, are inconvenient to split, are easy to cause unstable loading and cause inaccurate medicine taking dosage clinically.
(4) As can be seen from the sample retention data of the first sample and the fifth sample, the sample in the fifth sample is dried at 50 ℃ for 106min, the contents of impurities I, maximum single impurities, total impurities and the like in related substances in the sample after sample retention are obviously increased, the impurity content is over 1.5%, the sample drying time is too long, and the stability of the medicine is reduced.
(5) As is apparent from the particle size distribution data of the sample of examples, the sample prepared according to the method of the present invention has a particle size of more than 80% distributed in the range of 230 to 380. Mu.m, and no powder having a particle size of more than 425. Mu.m, but less than 180. Mu.m, accounts for less than 10%, so that the sample prepared according to the present invention has a small particle size and a more concentrated particle size distribution.
The above embodiments are merely embodiments of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the concept of the present invention belong to the protection scope of the present invention. It should be noted that modifications and adaptations to the invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be comprehended within the scope of the present invention.
Claims (3)
1. A process for the preparation of cefdinir-containing granules, characterized in that it comprises the steps of:
first, preparation of an adhesive:
adding hydroxypropyl cellulose and carmine into 40% ethanol, stirring and dissolving;
secondly, preparing a soft material:
adding cefdinir, sucrose and dextrin into a wet granulator, uniformly mixing, spraying the adhesive into the wet granulator, and uniformly stirring to obtain a soft material, wherein the particle size D90 of the cefdinir is 10-30 mu m, and the particle size D90 of the sucrose is smaller than or equal to 80 mu m;
thirdly, preparing wet particles:
putting the soft material into a rotary extruder, extruding and granulating through a screen mesh with the aperture of 0.3mm to obtain wet granules;
fourth step, finishing:
drying the wet particles in a dryer at 80 ℃ for 30min, drying the wet particles in the dryer, and finishing the dried particles by a screen with the aperture of 0.5mm to obtain dry particles;
fifth, preparing a finished product:
adding silicon dioxide and strawberry essence into the dry particles, and uniformly mixing to obtain a finished product containing cefdinir particles;
the strawberry essence comprises, by weight, 5 parts of hydroxypropyl cellulose, 1 part of carmine, 80 parts of 40% ethanol, 50 parts of cefdinir, 411 parts of sucrose, 20 parts of dextrin, 10 parts of silicon dioxide and 10 parts of strawberry essence.
2. A process for the preparation of cefdinir-containing granules as claimed in claim 1 wherein the dryer is a ebullating dryer.
3. The method for preparing cefdinir-containing granules according to claim 1, wherein the particle size of the cefdinir-containing granule finished product is less than or equal to 0.3mm.
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