CN115364059B - Cefpodoxime proxetil particles and preparation method thereof - Google Patents
Cefpodoxime proxetil particles and preparation method thereof Download PDFInfo
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- CN115364059B CN115364059B CN202211212895.6A CN202211212895A CN115364059B CN 115364059 B CN115364059 B CN 115364059B CN 202211212895 A CN202211212895 A CN 202211212895A CN 115364059 B CN115364059 B CN 115364059B
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- sucrose
- cefpodoxime proxetil
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- hydroxypropyl cellulose
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- LTINZAODLRIQIX-FBXRGJNPSA-N cefpodoxime proxetil Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(=O)OC(C)OC(=O)OC(C)C)C(=O)C(=N/OC)\C1=CSC(N)=N1 LTINZAODLRIQIX-FBXRGJNPSA-N 0.000 title claims abstract description 99
- 229960004797 cefpodoxime proxetil Drugs 0.000 title claims abstract description 95
- 239000002245 particle Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 229930006000 Sucrose Natural products 0.000 claims abstract description 101
- 239000005720 sucrose Substances 0.000 claims abstract description 101
- 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 100
- 238000000576 coating method Methods 0.000 claims abstract description 45
- 239000011248 coating agent Substances 0.000 claims abstract description 43
- 239000000463 material Substances 0.000 claims abstract description 35
- 239000008187 granular material Substances 0.000 claims abstract description 30
- 238000005550 wet granulation Methods 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 49
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 45
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 30
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 30
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 30
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 22
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 21
- 239000008101 lactose Substances 0.000 claims description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- 229960001375 lactose Drugs 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- PXEDJBXQKAGXNJ-QTNFYWBSSA-L disodium L-glutamate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](N)CCC([O-])=O PXEDJBXQKAGXNJ-QTNFYWBSSA-L 0.000 claims description 14
- 235000013923 monosodium glutamate Nutrition 0.000 claims description 14
- 229940073490 sodium glutamate Drugs 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 13
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 9
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 239000004094 surface-active agent Substances 0.000 claims description 9
- 108010011485 Aspartame Proteins 0.000 claims description 8
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 8
- 241000234295 Musa Species 0.000 claims description 8
- 235000018290 Musa x paradisiaca Nutrition 0.000 claims description 8
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 8
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 8
- 235000010357 aspartame Nutrition 0.000 claims description 8
- 239000000605 aspartame Substances 0.000 claims description 8
- 229960003438 aspartame Drugs 0.000 claims description 8
- 235000015165 citric acid Nutrition 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- 229960004106 citric acid Drugs 0.000 claims description 7
- 238000010298 pulverizing process Methods 0.000 claims description 7
- 238000007873 sieving Methods 0.000 claims description 7
- 239000000377 silicon dioxide Substances 0.000 claims description 7
- 235000012239 silicon dioxide Nutrition 0.000 claims description 7
- 229960002668 sodium chloride Drugs 0.000 claims description 7
- 235000002639 sodium chloride Nutrition 0.000 claims description 7
- 229960004793 sucrose Drugs 0.000 claims description 7
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 6
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 6
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 6
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000000853 adhesive Substances 0.000 claims description 4
- 230000001070 adhesive effect Effects 0.000 claims description 4
- -1 glidant Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000004147 Sorbitan trioleate Substances 0.000 claims description 2
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229960003943 hypromellose Drugs 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 235000019337 sorbitan trioleate Nutrition 0.000 claims description 2
- 229960000391 sorbitan trioleate Drugs 0.000 claims description 2
- 239000008119 colloidal silica Substances 0.000 claims 1
- 239000002075 main ingredient Substances 0.000 claims 1
- 125000000185 sucrose group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 52
- 229940079593 drug Drugs 0.000 abstract description 41
- 238000002474 experimental method Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000005286 illumination Methods 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- 239000007931 coated granule Substances 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 17
- 239000002994 raw material Substances 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000523 sample Substances 0.000 description 7
- 239000002671 adjuvant Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 235000019640 taste Nutrition 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000012738 dissolution medium Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000007908 dry granulation Methods 0.000 description 4
- 229960005191 ferric oxide Drugs 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 240000000111 Saccharum officinarum Species 0.000 description 3
- 235000007201 Saccharum officinarum Nutrition 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000000889 atomisation Methods 0.000 description 3
- 229960005090 cefpodoxime Drugs 0.000 description 3
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000010008 shearing Methods 0.000 description 3
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000003763 carbonization Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000001782 photodegradation Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- 235000016068 Berberis vulgaris Nutrition 0.000 description 1
- 241000335053 Beta vulgaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- DTYQLIDEZKYTTM-UHFFFAOYSA-M [Na+].Cl.[Cl-].NCC(O)=O Chemical compound [Na+].Cl.[Cl-].NCC(O)=O DTYQLIDEZKYTTM-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000010000 carbonizing Methods 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 238000004073 vulcanization Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- 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
- 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
- A61K9/1629—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
- 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
-
- 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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- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to cefpodoxime proxetil particles and a preparation method thereof, and relates to the field of pharmaceutical preparations. According to the research, the cefpodoxime proxetil particles prepared after the sucrose coating are obviously improved in stability. The finding reason is that the compatibility of the sucrose and cefpodoxime proxetil bulk drug is poor under the conditions of high temperature and illumination. The prepared sucrose coated granules are subjected to wet granulation with bulk drugs and other auxiliary materials, wherein cefpodoxime proxetil and the coated sucrose are not in direct contact in the wet granulation production process and the granule storage period, so that the stability of the cefpodoxime proxetil granules is improved. Experiments prove that the effect is good.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to cefpodoxime proxetil particles and a preparation method thereof.
Background
Cefpodoxime proxetil, english name Cefpodoxime Proxetil, chemical name (6R, 7R) -3-methoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- [ (Z) -methoxyimino]Acetamido group]-8-oxo-5-thia-1-azabicyclo [4.2.0]Oct-2-ene-2-carboxylic acid- (RS) -1- (isopropoxycarbonyloxy) ethyl ester of formula C 21 H 27 N 5 O 9 S 2， Molecular weight 557.60, structural formula as follows:
cefpodoxime proxetil belongs to beta-lactam antibiotics and is suitable for infection caused by sensitive bacteria. The original research company is Japanese first Sanco Co., ltd., the first time the tablet is marketed in Japanese 1989, and the dry syrup is marketed in 1991; dry suspensions and tablets were subsequently approved for sale in france, the united states, and the united kingdom. The product is absorbed by intestinal tract after oral administration, and is converted into active cefpodoxime in vivo to enter blood circulation. The medicine is mainly used for treating pneumonia, acute bronchitis, sphagitis, tonsillitis, pyelonephritis, cystitis, gonorrhea urethritis, skin soft tissue infection and the like caused by sensitive bacteria clinically. The present dosage forms comprise dispersible tablets, film coated tablets, capsules, dry suspensions and granules.
The cefpodoxime proxetil bulk drug has poor stability, and gradually undergoes double bond transformation under the influence of temperature and humidity, and the side chain is partially hydrolyzed, so that the stability of the cefpodoxime proxetil preparation is a difficult point.
Patent CN 103142506 of Tianjin medicine group jin kang medicine Co., ltd discloses cefpodoxime proxetil granules and a preparation method thereof, wherein raw materials and auxiliary materials are mixed, and dry granulation is carried out, so that the preparation is stable and controllable in quality.
Patent CN 108261404 of Tianjin double-major medical science and technology Co-Ltd discloses a pharmaceutical composition containing cefpodoxime proxetil, which avoids factors such as moisture, high temperature and the like and solves the problems of hydrolysis or oxidative degradation of raw materials by a dry granulation process.
Patent CN105963269 of Qilu animal health products Co-Ltd discloses a cefpodoxime proxetil flavor chewable tablet and a preparation method thereof, wherein the method adopts Eudragit ® The particles of the cefpodoxime proxetil raw material are subjected to fluidized bed coating, and the purpose of improving the stability of the cefpodoxime proxetil is achieved by isolating the direct contact of the cefpodoxime proxetil and the flavoring agent.
Patent CN 104771368 applied by Shijia four-medicine limited company discloses quick release of cefpodoxime proxetil and a preparation method thereof, wherein the method is to dissolve the cefpodoxime proxetil in ethanol, raise lactose proportion through wet granulation, and improve product stability. Wherein the patent shown in example 1 of the patent uses 1460g of lactose anhydrous and 241g of sucrose, and the weight ratio of lactose anhydrous to sucrose is 6:1. lactose is an excellent filler or diluent, but is expensive, sucrose is often used instead of lactose in industrial application, and the large amount of lactose is not advantageous in industrial production, so that the pharmaceutical cost is increased, the competitiveness is reduced, and the burden of patients is increased.
In the prior art, although the stability of the cefpodoxime proxetil preparation is improved through a dry granulation process, a raw material medicine coating process and a wet granulation process after the raw material medicine is dissolved in a proper solvent, the raw material medicine is subjected to special treatment or adopts the dry granulation process in the production process, and the production process is complicated or the use of auxiliary materials is high in price and unsuitable for production, so that key factors influencing the stability of the preparation are required to be searched, the defects of the prior art are overcome, a proper preparation process is selected aiming at the factors, the stability of the cefpodoxime proxetil preparation is improved, and meanwhile, the dissolution rate of the product is ensured.
Disclosure of Invention
The invention aims to provide cefpodoxime proxetil particles and a preparation method thereof, which aim to solve the problems that the raw material medicines need special treatment or have high requirements on equipment and the production process is complicated.
The cefpodoxime proxetil granule consists of cefpodoxime proxetil serving as a main drug, a diluent, a disintegrating agent, an adhesive, a surfactant, a glidant, a lubricant, a flavoring agent, essence and the like.
The cefpodoxime proxetil particles are characterized in that the sucrose coating material is any one of hydroxypropyl cellulose, ethyl cellulose, hypromellose and polyethylene glycol.
The cefpodoxime proxetil particles are characterized in that the sucrose coating is 0.5-15% (weight percentage) of the weight of the sucrose.
More preferably, the sucrose coating is 0.5% to 2.5% by weight of sucrose.
The preparation method is further prepared into granules through the following steps:
the preparation process comprises the following steps:
1) Pulverizing sucrose, sieving with 60 mesh sieve; weighing other auxiliary materials for standby;
2) Preparing ethanol solution of hydroxypropyl cellulose for coating;
3) Sucrose coating: adding sucrose with the prescription amount into a fluidized bed, and coating with hydroxypropyl cellulose ethanol solution;
4) Wet granulation: cefpodoxime proxetil, coated sucrose, diluent, disintegrating agent, adhesive, surfactant, flavoring agent and the like are subjected to wet granulation, drying and granule finishing;
5) Total mixing: and adding a glidant, a lubricant and essence into the dry particles to carry out total mixing to obtain cefpodoxime proxetil particles.
In the cefpodoxime proxetil particles, sucrose is coated with hydroxypropyl cellulose, and the weight gain of the coating is 0.5% -2.5%;
the diluent is lactose;
the disintegrating agent is carboxymethylcellulose calcium;
the adhesive is sodium carboxymethyl cellulose;
the surfactant is sorbitan trioleate;
the glidant is silicon dioxide;
the lubricant is talcum powder;
the flavoring agent is citric acid, aspartame, sodium chloride, or sodium glutamate;
the essence is banana essence.
The formulation of cefpodoxime proxetil granule unit dosage form is shown in table 1 below:
table 1 shows the formulation of cefpodoxime proxetil granule unit dosage form
Further illustratively, the formulation composition of the cefpodoxime proxetil granule unit dosage form is shown in Table 2 below:
table 2 shows the composition of prescriptions 1-5
The preparation process comprises the following steps:
1) Pulverizing sucrose, citric acid and sodium glutamate, and sieving with 60 mesh sieve; weighing other auxiliary materials for standby;
2) Preparing ethanol solution of hydroxypropyl cellulose for coating;
3) Sucrose coating: adding sucrose with the prescription amount into a fluidized bed, and coating with hydroxypropyl cellulose ethanol solution;
4) Wet granulation: cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropyl cellulose, citric acid, aspartame, sodium chloride, sodium glutamate and yellow ferric oxide are subjected to wet granulation, drying and granule finishing;
5) Total mixing: adding silicon dioxide, talcum powder and banana essence into the dry particles for total mixing to obtain cefpodoxime proxetil particles.
Further preferred is the following:
the preparation process comprises the following steps:
1) Pulverizing sucrose, citric acid and sodium glutamate, and sieving with 60 mesh sieve; weighing other auxiliary materials for standby;
2) Preparing 75% ethanol solution with hydroxypropyl cellulose concentration of 1.5%, stirring to dissolve, and coating;
3) Sucrose coating: adding sucrose with the prescription amount into a fluidized bed, and coating with hydroxypropyl cellulose ethanol solution;
setting the air inlet temperature to be 35-50 ℃ and the air inlet quantity to be 25-40 m 3 And (3) carrying out sucrose coating, wherein the atomization pressure is 1.5-3.0 MPa, and the liquid supply speed is 3.5-7 r/min. Drying the fluidized bed after coating until the water content is less than 3.0%, and taking out for later use;
4) Wet granulation: adding cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropyl cellulose, citric acid, aspartame, sodium chloride, sodium glutamate and ferric oxide into a wet granulator, stirring for 180 r/min, and shearing for 120 r/min to carry out wet granulation; drying the wet granules to <3.0%;
5) Total mixing: adding silicon dioxide, talcum powder and banana essence into the dry particles for total mixing to obtain cefpodoxime proxetil particles.
Further preferred is the following:
wherein: when the sucrose is coated with hydroxypropyl cellulose in the step 3), the coating accounts for 0.5-15% of the weight of the sucrose;
the concentration of the hydroxypropyl cellulose used for the sucrose coating is 0.5-5 percent of 75-95 percent ethanol solution with weight and volume ratio;
step 3) drying the sucrose coating until the moisture is below 3.0%;
step 4), drying the granules after wet granulation until the moisture content is below 3.0%;
the present patent application is further illustrated by the following experiments:
a series of experiments prove that the sucrose is coated with the hydroxypropyl cellulose, and the prepared sucrose coated granules are subjected to wet granulation with the bulk drug and other auxiliary materials, wherein cefpodoxime proxetil and the coated sucrose are not in direct contact in the wet granulation production process and the storage period of the granule, so that the stability of the cefpodoxime proxetil granules can be improved, the granules are not bitter, and the granules are quick-release granules.
Experiment one: compatibility test of raw and auxiliary materials
Because of more auxiliary materials in the product, after the auxiliary materials are grouped, the raw material medicines are respectively and uniformly mixed with each group of auxiliary materials, and then are respectively spread into thin layers with the thickness of less than 5mm in a culture dish. The specific groupings of adjuvants are shown in Table 3 below:
TABLE 3 grouping of auxiliary materials
Note that: the dosage of the auxiliary materials is the same as that corresponding to Table 1
Cefpodoxime proxetil bulk drug and filling agent sucrose, lactose or total mixed auxiliary materials according to the weight ratio of 1:5; the cefpodoxime proxetil bulk drug is mixed with the auxiliary material 3 or the auxiliary material 4 according to the weight ratio of 20:1, and the mixture is uniform; sample numbers are shown in the following table; each sample was spread in a petri dish as a thin layer < 5mm thick.
TABLE 4 grouping of auxiliary materials
The above samples were left to stand at high temperature (60.+ -. 2 ℃) and under light (4500 lx.+ -. 500 lx) for 30 days, and samples were taken on days 10 and 30, respectively, to determine the relevant substances. The test data are shown in the following table:
TABLE 5 compatibility test results of cefpodoxime proxetil crude drug and adjuvant (60 ℃ C.+ -2 ℃ C.)
TABLE 6 compatibility test results of cefpodoxime proxetil crude drug with adjuvant (light (4500 lx.+ -. 500 lx))
Note that: n.d.: not detected.
The experimental results show that the cefpodoxime proxetil bulk drug has poor stability under the conditions of high temperature (60+/-2 ℃) and illumination (4500 lx+/-500 lx); the bulk drug and sucrose (sample 1) are placed for 10 days and 30 days under the conditions of high temperature and illumination, and the increment of the impurity C+B-II+D-I and the total impurity is larger than that of the bulk drug (sample 6); the bulk drug and other auxiliary materials (samples 2-4) are placed for 10 days and 30 days under the conditions of high temperature and illumination, and the increment amplitude of impurities C+B-II+D-I and total impurities is lower than that of cefpodoxime proxetil bulk drug; the total auxiliary material +cefpodoxime proxetil (sample 5) contains sucrose, so that the increase range of impurities C+B-II+D-I and total impurities is larger than that of other auxiliary materials (samples 2-4), and the stability is reduced due to the existence of the sucrose, but the total auxiliary material has a protective effect on the bulk drug and is slightly lower than the impurities of the bulk drug. Wherein impurity B is a process impurity, impurity C is a thermal degradation impurity, and impurity D is a photodegradation impurity; in conclusion, the key auxiliary material affecting the stability of cefpodoxime proxetil bulk drug in the prescription is sucrose.
Note that: the structural formula of the impurities is as follows:
experiment II: compatibility test of raw and auxiliary materials (II)
The sucrose extraction raw materials are two types: sugarcane and beet; the sucrose preparation process has two kinds: sulfidizing (sulfur dioxide decolorizing), carbonizing (active carbon decolorizing). Wherein, the sucrose extracted from the sugarcane has better property and purity; the sucrose impurities prepared by the carbonization process are slightly lower. To sum up, the compatibility of sucrose and cefpodoxime proxetil raw material medicines which are extracted from sugarcane and produced by two preparation processes of vulcanization and carbonization is examined.
Cefpodoxime proxetil bulk drug and filling sucrose, total mixed auxiliary materials according to the weight ratio of 1:5; uniformly mixing; sample numbers are shown in the following table; each sample was spread in a petri dish as a thin layer < 5mm thick.
TABLE 7 corresponding adjuvants for each group of samples
The above samples were left to stand at high temperature (60.+ -. 2 ℃) and under light (4500 lx.+ -. 500 lx) for 30 days, and samples were taken on days 10 and 30, respectively, to determine the relevant substances. The test data are shown in the following table:
table 8 compatibility test results of cefpodoxime proxetil crude drug and adjuvant (60 ℃ C.+ -2 ℃ C.)
TABLE 9 compatibility test results of cefpodoxime proxetil crude drug with adjuvant (light (4500 lx.+ -. 500 lx))
Note that: n.d.: not detected.
The experimental results show that the raw material medicine and the sucrose prepared by the two preparation processes are placed for 10 days and 30 days under the conditions of high temperature and illumination, and the increment amplitude of the impurity C+B-II+D-I and the total impurity is basically consistent and is larger than that of the raw material medicine; the sucrose which illustrates different preparation processes has basically the same influence on the stability of the bulk drug, so that the compatibility problem of the sucrose and the bulk drug needs to be solved from the process perspective.
The beneficial effects are that:
through intensive research, the inventor unexpectedly discovers that the stability of cefpodoxime proxetil particles prepared after sucrose coating is obviously improved, and the dissolution meets the requirements.
Specifically:
the inventor has found by accident through a plurality of experiments that only the filling agent sucrose is mixed with cefpodoxime proxetil, namely: after sucrose and the bulk drug are in direct contact, the mixture is placed for 30 days under the conditions of high temperature (60+/-2 ℃) or illumination (4500 lx+/-500 lx), and the total impurity growth amplitude is larger than that of the bulk drug, wherein the impurity C+B-II+D-I is the process impurity, the impurity C is the thermal degradation impurity, the impurity D is the photodegradation impurity, and the sucrose is a key factor affecting the stability of cefpodoxime proxetil.
The original ground drug (ORELOX) is sucrose and lactose (about 20:1 by weight), both of which act as diluents, with lactose being a minor fraction. CN 104771368 is designed to solve the problem of low dissolution rate of the preparation when dissolved in water. The cefpodoxime proxetil and the surfactant are uniformly dispersed on the surface and inside of particles after the particles are granulated and dried, when the pharmaceutical preparation is added into an aqueous dissolution medium, water-soluble auxiliary materials and part of the cefpodoxime proxetil are rapidly dissolved, the surfactant can be rapidly distributed on the surface of the rest undissolved medicines, the special hydrophilic groups of the surfactant are outwards stretched to combine with water molecules, the hydrophobic groups surround the surfaces of the cefpodoxime proxetil molecules, and the medicine molecules are separated one by one, so that the gelation trend of the medicines can be effectively avoided, and the dissolution of the cefpodoxime proxetil is accelerated. The experimental results examined mainly the effect of the surfactant. Because the surfactant is added in the prescription, the sucrose and lactose of the original ground medicament cannot be diluted well, and particularly under the condition of most sucrose amount, the sucrose and lactose are difficult to granulate, so the sucrose and lactose are changed into the components with the weight ratio of 6:1 as a diluent. Thus, although neither the original study nor CN 104771368 included sucrose and lactose, neither demonstrated the effect of sucrose on stability, nor did it have technical implications.
In the invention, the sucrose is coated by adopting a proper coating material and process, and the coated sucrose can be isolated from the bulk drug, so as to achieve the purpose of improving the stability of cefpodoxime proxetil particles. Specifically: the sucrose is subjected to film coating by the hydroxypropyl cellulose, and the prepared sucrose coated particles are subjected to wet granulation with bulk drugs and other auxiliary materials, wherein cefpodoxime proxetil and the coated sucrose are not in direct contact in the wet granulation production process and the granule storage period, so that the purpose of improving the stability of the cefpodoxime proxetil particles is achieved.
Detailed Description
The beneficial effects of the invention are further illustrated by the following experiments. However, the present invention is not limited to the following embodiments, and those skilled in the art, on the basis of the present invention, may make equivalent substitutions or variations without departing from the spirit and scope of the present invention.
EXAMPLE 1 preparation of cefpodoxime proxetil particles (prescriptions 1-3)
The formulation of the cefpodoxime proxetil granule unit preparation is shown in the following table:
table 10 formulations of prescriptions 1-3
The preparation process comprises the following steps:
1) Pulverizing sucrose, citric acid and sodium glutamate, and sieving with 60 mesh sieve; weighing other auxiliary materials for standby;
2) Preparing 75% ethanol solution with hydroxypropyl cellulose concentration of 1.5%, stirring to dissolve, and coating;
3) Sucrose coating: adding sucrose with the prescription amount into a fluidized bed, and coating with hydroxypropyl cellulose ethanol solution;
setting the air inlet temperature to be 35-50 ℃ and the air inlet quantity to be 25-40 m 3 And (3) carrying out sucrose coating, wherein the atomization pressure is 1.5-3.0 MPa, and the liquid supply speed is 3.5-7 r/min. And after the coating is finished, drying the fluidized bed until the water content is less than 3.0%, and taking out for standby.
4) Wet granulation: adding cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropyl cellulose, citric acid, aspartame, sodium chloride, sodium glutamate and ferric oxide into a wet granulator, stirring for 180 r/min, and shearing for 120 r/min to carry out wet granulation; the wet granules were dried to <3.0%.
5) Total mixing: adding silicon dioxide, talcum powder and banana essence into the dry particles for total mixing to obtain cefpodoxime proxetil particles.
Example 2 preparation of cefpodoxime proxetil particles (prescriptions 4-5)
Table 11 formulations of prescriptions 4-5
The preparation process comprises the following steps:
1) Pulverizing sucrose, citric acid and sodium glutamate, and sieving with 60 mesh sieve; weighing other auxiliary materials for standby;
2) Preparing 75% ethanol solution with hydroxypropyl cellulose concentration of 1.5%, stirring to dissolve, and coating;
3) Sucrose coating: adding sucrose with the prescription amount into a fluidized bed, and coating with hydroxypropyl cellulose ethanol solution;
setting the air inlet temperature to be 35-50 ℃ and the air inlet quantity to be 25-40 m 3 And (3) carrying out sucrose coating, wherein the atomization pressure is 1.5-3.0 MPa, and the liquid supply speed is 3.5-7 r/min. Drying the fluidized bed after coating until the water content is less than 3.0%, and taking out for later use;
4) Wet granulation: adding cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropyl cellulose, citric acid, aspartame, sodium chloride, sodium glutamate and ferric oxide into a wet granulator, stirring for 180 r/min, and shearing for 120 r/min to carry out wet granulation; drying the wet granules to <3.0%;
5) Total mixing: adding silicon dioxide, talcum powder and banana essence into the dry particles for total mixing to obtain cefpodoxime proxetil particles.
Comparative example 1 (sucrose was not coated with hydroxypropyl cellulose)
The sucrose uncoated comparative example was prepared as in prescription example 1, with the following preparation process:
1) Pulverizing sucrose, citric acid and sodium glutamate, and sieving with 60 mesh sieve; weighing other auxiliary materials for standby;
2) Wet granulation: cefpodoxime proxetil, sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropyl cellulose, citric acid, aspartame, sodium chloride, sodium glutamate and ferric oxide are subjected to wet granulation, drying and granule finishing;
3) Total mixing: adding silicon dioxide, talcum powder and banana essence into the dry particles for total mixing to obtain cefpodoxime proxetil particles.
Preparation method of comparative example 2 CN 104771368
Table 12 CN 104771368 prescriptions
The preparation process comprises the following steps:
1) Taking the prescription amount of cefpodoxime proxetil and polyoxyethylene hydrogenated castor oil to dissolve in absolute ethyl alcohol to obtain a mixture I;
2) Placing anhydrous lactose, sucrose and carboxymethylcellulose calcium into a fluidized bed, uniformly mixing, slowly spraying the mixture I, granulating, and drying at 30 ℃ in the fluidized bed to obtain a mixture II;
3) Adding xanthan gum, citric acid, talcum powder and orange essence into the mixture II, mixing, and packaging.
Example 3: mouthfeel detection
5 samples of the above prescription 1, prescription 2, prescription 3, comparative example, and control (cefpodoxime proxetil dry suspension, trade name: ORELOX, underwriter: SANOFI-AVENTIS FRANCE) were taken in 6 unit dosage amounts, each dispersed in a proper amount of room temperature water, and were orally taken for 20s by 6 volunteers, and the drug administration process was simulated, and the taste detection results were shown in the following table:
table 13 results of taste tests for prescription examples, control examples, and control medicines
From the above taste detection results, the taste correction agents selected in the prescription examples and the comparative examples can effectively mask the bitter taste of cefpodoxime proxetil, and the taste is equivalent to that of the control drug.
Example 4: dissolution check
The above-mentioned prescription 1, prescription 2, prescription 3, comparative example, and control drug (cefpodoxime proxetil dry suspension, trade name: ORELOX, underwriter: SANOFI-AVENTIS FRANCE) were measured by a dissolution and release rate measurement method (general rule 0931, second method) under the condition that 6 unit dosage amounts were taken respectively, and the cefpodoxime proxetil dry suspension was prepared according to the second part of the "Chinese pharmacopoeia". Glycine-sodium chloride-hydrochloric acid solution (pH 3.0) [ glycine 54.5g and sodium chloride 42.6g are taken, put into a 1000ml measuring flask, added with 500ml of water to dissolve, slowly added with 14.2ml of hydrochloric acid, cooled, diluted to scale with water and shaken well to serve as stock solution. 50ml of the stock solution was taken, water was added to 900ml (if necessary, pH was adjusted to 3.0.+ -. 0.1 using 10mol/L sodium hydroxide solution) and 900ml was taken as a dissolution medium, the rotation speed was 75 revolutions per minute, and the procedure was followed, and sampling was carried out over 45 minutes. Taking out proper amount of the dissolved solution, filtering, precisely measuring proper amount of the subsequent filtrate, and quantitatively diluting with a dissolution medium to prepare a solution containing about 11 mug of cefpodoxime in each 1 ml. Taking a proper amount of cefpodoxime proxetil reference substance, precisely weighing, adding a proper amount of methanol for dissolution, and quantitatively diluting with a dissolution medium to prepare a solution containing about 11 mug of cefpodoxime in each 1 ml. Taking the sample solution and the reference substance solution, measuring absorbance at 259nm wavelength respectively according to ultraviolet-visible spectrophotometry (generally 0401), and calculating the dissolution amount of each bag. The test data are shown in the following table.
Table 14 results of the test for dissolution of the prescription, control and control (unit:%)
As is clear from the above-mentioned results of the dissolution test, the dissolution rates of the 3 sucrose-coated weight-gaining samples according to the present invention were substantially uniform at 45 minutes, as compared with the comparative example and the control drug, and all of the samples were in accordance with the predetermined (70% of the labeled amount).
Example 5: stability test results
The above-mentioned prescription 1, prescription 2, prescription 3, comparative example, and control drug (cefpodoxime proxetil dry suspension, trade name: ORELOX, underwriter: SANOFI-AVENTIS FRANCE) were subjected to 5 samples, and placed under accelerated conditions of 40 ℃ + -2 ℃ and 75% + -5% relative humidity for 6 months, respectively, and the relevant substances were sampled and measured, and the detection data are shown in the following table.
Table 15 results of detection of substances related to the prescription examples, the control examples, and the control medicines (unit:%)
As shown by the detection results of the related substances, the 3 sucrose coating weight-gaining samples of the invention are placed for 6 months under the acceleration condition that the temperature is 40+/-2 ℃ and the relative humidity is 75+/-5%, and the impurity C+B-II+D-I and the total impurity increase slowly, which are in accordance with the regulations, are equivalent to the comparison drug. The sucrose uncoated comparative example was close to the limit (4.0%) for impurity C+B-II+D-I when left under the above accelerated conditions for 3 months and exceeded the limit (4.0%) for impurity C+B-II+D-I when left for 6 months. By the sucrose coating process, the sucrose is isolated from the raw material medicines, so that the stability can be obviously improved, and the stability of the cefpodoxime proxetil granules is equivalent to that of the control medicines; the taste and the dissolution rate are consistent with those of the control medicine, so that the invention has outstanding substantive characteristics and remarkable progress and has practicability.
Claims (10)
1. A cefpodoxime proxetil granule comprises cefpodoxime proxetil granule, which comprises cefpodoxime proxetil as main ingredient, diluent, disintegrating agent, adhesive, surfactant, glidant, lubricant, correctant, and essence; the diluent is sucrose and lactose, wherein the sucrose is coated sucrose.
2. Cefpodoxime proxetil particles according to claim 1, characterized in that the sucrose coating material is selected from any one of hydroxypropyl cellulose, ethyl cellulose, hypromellose, polyethylene glycol.
3. Cefpodoxime proxetil particles according to claim 2, wherein the sucrose coating is 0.5% to 15% by weight of sucrose.
4. A cefpodoxime proxetil particle according to claim 3, wherein the sucrose coating is 0.5% to 2.5% by weight of sucrose.
5. The cefpodoxime proxetil particles according to claim 4, wherein the sucrose coating material is hydroxypropyl cellulose, and the unit formulation comprises the following components:
6. Cefpodoxime proxetil particles according to claim 5, characterized in that they are obtained according to the following preparation steps:
1) Pulverizing sucrose, citric acid and sodium glutamate, and sieving with 60 mesh sieve; weighing other auxiliary materials for standby;
2) Preparing ethanol solution of hydroxypropyl cellulose for coating;
3) Sucrose coating: adding sucrose with the prescription amount into a fluidized bed, and coating with hydroxypropyl cellulose ethanol solution;
4) Wet granulation: cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropyl cellulose, citric acid, aspartame, sodium chloride, sodium glutamate and yellow ferric oxide are subjected to wet granulation, drying and granule finishing;
5) Total mixing: adding silicon dioxide, talcum powder and banana essence into the dry particles for total mixing to obtain cefpodoxime proxetil particles.
7. The method for preparing cefpodoxime proxetil particles according to claim 6, wherein when sucrose is coated with hydroxypropyl cellulose in step 3), the coating is 0.5% -15% of the weight of sucrose.
8. The method for preparing cefpodoxime proxetil particles according to claim 6, wherein the sucrose coating is performed with a solution of hydroxypropyl cellulose in 75% to 95% ethanol at a concentration of 0.5% to 5% by weight/volume.
9. The method for preparing cefpodoxime proxetil particles according to claim 6, wherein step 3) is performed after coating the sucrose and drying to a moisture content of less than 3.0%.
10. The method for preparing cefpodoxime proxetil granules according to claim 6, wherein the wet granulation granules in step 4) are dried to a moisture content of less than 3.0%.
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