CN115364059A - Cefpodoxime proxetil particles and preparation method thereof - Google Patents
Cefpodoxime proxetil particles and preparation method thereof Download PDFInfo
- Publication number
- CN115364059A CN115364059A CN202211212895.6A CN202211212895A CN115364059A CN 115364059 A CN115364059 A CN 115364059A CN 202211212895 A CN202211212895 A CN 202211212895A CN 115364059 A CN115364059 A CN 115364059A
- Authority
- CN
- China
- Prior art keywords
- sucrose
- cefpodoxime proxetil
- coating
- particles
- cefpodoxime
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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 100
- 229960004797 cefpodoxime proxetil Drugs 0.000 title claims abstract description 97
- 239000002245 particle Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 229930006000 Sucrose Natural products 0.000 claims abstract description 103
- 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 102
- 239000005720 sucrose Substances 0.000 claims abstract description 98
- 238000000576 coating method Methods 0.000 claims abstract description 49
- 239000011248 coating agent Substances 0.000 claims abstract description 47
- 239000000463 material Substances 0.000 claims abstract description 40
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 30
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 30
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 30
- 239000008187 granular material Substances 0.000 claims abstract description 25
- 238000005550 wet granulation Methods 0.000 claims abstract description 20
- 229960004793 sucrose Drugs 0.000 claims description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
- 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
- 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
- 238000000034 method Methods 0.000 claims description 21
- 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 20
- 238000002156 mixing Methods 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 239000008101 lactose Substances 0.000 claims description 19
- 229960001375 lactose Drugs 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- 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 13
- 235000013923 monosodium glutamate Nutrition 0.000 claims description 13
- 229940073490 sodium glutamate Drugs 0.000 claims description 13
- 229960004106 citric acid Drugs 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- 238000009472 formulation Methods 0.000 claims description 11
- 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
- 239000004094 surface-active agent Substances 0.000 claims description 9
- 235000015165 citric acid Nutrition 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- 108010011485 Aspartame Proteins 0.000 claims description 7
- 235000018290 Musa x paradisiaca Nutrition 0.000 claims description 7
- 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 7
- 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 7
- 229960003438 aspartame Drugs 0.000 claims description 7
- 235000010357 aspartame Nutrition 0.000 claims description 7
- 239000000605 aspartame Substances 0.000 claims description 7
- 229940084030 carboxymethylcellulose calcium 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
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 6
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 6
- -1 glidant Substances 0.000 claims description 6
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 6
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 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
- 239000000853 adhesive Substances 0.000 claims description 4
- 230000001070 adhesive effect Effects 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 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
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 239000011361 granulated particle Substances 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
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 240000005561 Musa balbisiana Species 0.000 claims 1
- 229960003943 hypromellose Drugs 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 55
- 229940079593 drug Drugs 0.000 abstract description 45
- 238000012360 testing method Methods 0.000 abstract description 14
- 238000005286 illumination Methods 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- 239000007931 coated granule Substances 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 238000011160 research Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 description 25
- 239000002994 raw material Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 241000234295 Musa Species 0.000 description 6
- 238000002474 experimental 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
- 238000003763 carbonization Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 235000019640 taste Nutrition 0.000 description 4
- 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 3
- 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
- 229960004977 anhydrous lactose Drugs 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 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
- 238000007908 dry granulation Methods 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 238000010008 shearing Methods 0.000 description 3
- 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 2
- 241000894006 Bacteria Species 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 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
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000004042 decolorization Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 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 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000001782 photodegradation Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000005987 sulfurization reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000004073 vulcanization Methods 0.000 description 2
- 239000000230 xanthan gum Substances 0.000 description 2
- 229920001285 xanthan gum Polymers 0.000 description 2
- 229940082509 xanthan gum Drugs 0.000 description 2
- 235000010493 xanthan gum Nutrition 0.000 description 2
- OVGUTKULXVYHIJ-FJWTYUKWSA-N 1-propan-2-yloxycarbonyloxyethyl (6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-3-ene-2-carboxylate Chemical compound COCC1=CS[C@@H]2[C@H](NC(=O)C(=N/OC)\c3csc(N)n3)C(=O)N2C1C(=O)OC(C)OC(=O)OC(C)C OVGUTKULXVYHIJ-FJWTYUKWSA-N 0.000 description 1
- 241000219310 Beta vulgaris subsp. vulgaris Species 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
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical group 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 description 1
- 235000021536 Sugar beet Nutrition 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
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 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
- 239000004067 bulking agent Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000007941 film coated tablet Substances 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
- 208000001786 gonorrhea Diseases 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 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
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 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
- 238000005259 measurement Methods 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 229910010271 silicon carbide Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000012085 test solution Substances 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
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain 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
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to cefpodoxime proxetil particles and a preparation method thereof, and relates to the field of pharmaceutical preparations. The research shows that the stability of the cefpodoxime proxetil particles prepared after the sucrose coating is obviously improved. The finding reason is that the compatibility of the sucrose and the cefpodoxime proxetil bulk drug is poor under the conditions of high temperature and illumination, and the sucrose and the bulk drug are isolated by coating the sucrose with hydroxypropyl cellulose. The prepared sucrose-coated granules are subjected to wet granulation with bulk drugs and other auxiliary materials, wherein the cefpodoxime proxetil and the coated sucrose are not in direct contact in the production process of wet granulation and the storage period of the granules, so that the stability of the cefpodoxime proxetil granules is improved. The test proves that the effect is good.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, and in particular relates to cefpodoxime proxetil particles and a preparation method thereof.
Background
Cefpodoxime Proxetil, having the name Cefpodoxime Proxetil in English and the chemical name (6R, 7R) -3-methoxymethyl-7- [2- (2-amino-4-thiazolyl) -2- [ (Z) -methoxyimino group]Acetylamino group]-8-oxo-5-thia-1-azabicyclo [4.2.0]Oct-2-ene-2-carboxylic acid- (RS) -1- (isopropoxyformyloxy) ethyl ester, 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 former company is the first three-in-one corporation of japan, the first marketed tablet in 1989 of japan, and the dry syrup in 1991; subsequent French, USA, UK approved for marketing dry suspensions and tablets. The product can be absorbed by intestinal tract after oral administration, and can be converted into active cefpodoxime after deesterification in vivo and enter blood circulation. The traditional Chinese medicine composition 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 in clinic. The existing preparation forms comprise dispersible tablets, film-coated tablets, capsules, dry suspensions and granules.
The cefpodoxime proxetil bulk drug has poor stability, gradually undergoes double bond transformation under the influence of temperature and humidity, and the side chain part is hydrolyzed, so that the stability of the cefpodoxime proxetil preparation is difficult.
CN 103142506 applied by Tianjin pharmaceutical group Jinkang pharmaceutical Co., ltd discloses cefpodoxime proxetil granules and a preparation method thereof.
The patent CN 108261404 applied by Tianjin Shuangshuo medicine science and technology company Limited discloses a pharmaceutical composition containing cefpodoxime proxetil, and the method avoids factors such as moisture, high temperature and the like through a dry granulation process, and solves the problem of hydrolysis or oxidative degradation of raw material medicines.
The patent CN105963269 applied by Qilu animal health products Limited company discloses cefpodoxime proxetil flavor chewable tablets and a preparation method thereof, and the method adopts
Carrying out fluidized bed coating on the particles containing the cefpodoxime proxetil raw material to isolate the cefpodoxime proxetil from the corrigentThe contact achieves the aim of improving the stability of the cefpodoxime proxetil, but because the particles of the cefpodoxime proxetil raw material are coated, the release and the like of the cefpodoxime proxetil raw material are limited, and the bioavailability is influenced.
The patent CN 104771368 applied by Shijiazhuang four-drug Co., ltd discloses a cefpodoxime proxetil quick release and a preparation method thereof, the cefpodoxime proxetil is dissolved in ethanol, the proportion of lactose is increased by wet granulation, and the product stability is improved. In the patent, the weight ratio of anhydrous lactose to sucrose is 6:1. lactose is an excellent filler or diluent, but the price is high, sucrose is often used for replacing lactose in industrial application, and the large-amount use of lactose has no advantage in industrial production, so that the pharmaceutical cost is increased, the competitiveness is reduced, and the burden of patients is increased.
Although the stability of the cefpodoxime proxetil preparation is improved by a dry granulation process, a bulk drug coating process and a wet granulation process after the bulk drug is dissolved in a proper solvent in the prior art, the bulk drug needs to be specially treated or the dry granulation process is adopted in the production process, the production process is more complicated or the used auxiliary materials are high in price and are not suitable for production, so that key factors influencing the stability of the preparation need to be searched, the defects of the prior art are overcome, the proper preparation process is selected for the factors, the stability of the cefpodoxime proxetil preparation is improved, and the dissolution speed of the product is ensured.
Disclosure of Invention
The invention aims to provide cefpodoxime proxetil particles and a preparation method thereof, and solves the problems that 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 as main medicine component, diluent, disintegrating agent, adhesive, surfactant, flow aid, lubricant, corrective, essence, etc.
The cefpodoxime proxetil particles are characterized in that the sucrose coating material is selected from any one of hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose and polyethylene glycol.
The cefpodoxime proxetil granule is characterized in that the sucrose coating accounts for 0.5-15 percent (weight percentage) of the weight of sucrose.
More preferably, the sucrose coating is 0.5 to 2.5 wt% of the sucrose.
Further preparing into granules by the following steps:
the preparation process comprises the following steps:
1) Pulverizing sucrose, and sieving with 60 mesh sieve; weighing other auxiliary materials for later use;
2) Preparing an ethanol solution of hydroxypropyl cellulose for coating;
3) And (3) coating sucrose: adding sucrose in a formula amount into a fluidized bed, and coating with a hydroxypropyl cellulose ethanol solution;
4) And (3) wet granulation: carrying out wet granulation, drying and granule finishing on cefpodoxime proxetil, coated sucrose, a diluent, a disintegrating agent, an adhesive, a surfactant, a flavoring agent and the like;
5) Total mixing: and adding a flow aid, a lubricant and essence into the dry granules for total mixing to prepare the cefpodoxime proxetil granules.
In the cefpodoxime proxetil particles, sucrose is coated by hydroxypropyl cellulose, and the weight gain of the coating is 0.5-2.5%.
The diluent is lactose;
the disintegrant 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 and sodium glutamate;
the essence is banana essence.
The cefpodoxime proxetil granule unit preparation formula composition is shown in the following table 1:
table 1 shows the unit formulation of cefpodoxime proxetil particles
Further illustrating, the formulation composition of the cefpodoxime proxetil particle unit formulation is shown in table 2 below:
table 2 shows the compositions of the formulations 1 to 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 later use;
2) Preparing an ethanol solution of hydroxypropyl cellulose for coating;
3) And (3) coating with cane sugar: adding sucrose in a formula amount into a fluidized bed, and coating with a hydroxypropyl cellulose ethanol solution;
4) And (3) wet granulation: wet granulating, drying and finishing cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, citric acid, aspartame, sodium chloride, sodium glutamate and yellow ferric oxide;
5) Total mixing: and adding silicon dioxide, talcum powder and banana essence into the dry particles to carry out total mixing to prepare the cefpodoxime proxetil particles.
Further preferred mode:
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 later use;
2) Preparing 75% ethanol solution with hydroxypropyl cellulose concentration of 1.5%, stirring to dissolve, and coating;
3) And (3) coating with cane sugar: adding sucrose in a formula amount into a fluidized bed, and coating with a hydroxypropyl cellulose ethanol solution;
the air inlet temperature is set to be 35-50 ℃, and the air inlet volume is 25-40 m 3 The sucrose coating is carried out at the atomization pressure of 1.5-3.0 MPa and the liquid supply speed of 3.5-7 r/min. After the coating is finished, drying the coating by a fluidized bed until the moisture content is below 3.0 percent, and taking out the coating for later use.
4) And (3) wet granulation: adding cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, citric acid, aspartame, sodium chloride, sodium glutamate and yellow ferric oxide into a wet granulating machine, stirring for 180 r/min, and shearing for 120 r/min to perform wet granulation; the wet granulate was dried to <3.0%.
5) Total mixing: and adding silicon dioxide, talcum powder and banana essence into the dry particles to carry out total mixing to prepare the cefpodoxime proxetil particles.
Further preferred mode:
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 sucrose coating uses 75-95% ethanol solution with hydroxypropyl cellulose concentration of 0.5-5% weight volume ratio.
And 3) drying the coated sucrose until the moisture content is less than 3.0%.
And 4) drying the wet-granulated particles 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 sucrose is firstly subjected to film coating by hydroxypropyl cellulose, and the prepared sucrose-coated granules are then subjected to wet granulation with bulk drugs and other auxiliary materials, wherein cefpodoxime proxetil and coated sucrose are not directly contacted in the production process of wet granulation and the storage period of the granules, so that the stability of the cefpodoxime proxetil granules can be improved, and the granules are bitter-free and quick-release granules.
Experiment one: compatibility test of raw materials and auxiliary materials
Because the auxiliary materials are more in the product, the auxiliary materials are grouped, the raw material medicines are respectively and uniformly mixed with each group of auxiliary materials, and then the raw material medicines are respectively placed in a culture dish to be spread into thin layers with the thickness of less than 5 mm. The specific grouping of the excipients is shown in table 3 below.
TABLE 3 grouping of adjuvants
Note: the dosage of the auxiliary materials is the same as the dosage corresponding to the table 1
The cefpodoxime proxetil bulk drug and filler sucrose, lactose or total mixed auxiliary materials according to the weight ratio of 1: 5; mixing the cefpodoxime proxetil raw material medicine with the auxiliary material 3 or the auxiliary material 4 according to the weight ratio of 20:1, and uniformly mixing; sample numbers are shown in the following table; each sample was spread in a thin layer < 5mm thick in a petri dish.
TABLE 4 grouping of excipients
The samples were allowed to stand at high temperature (60 ℃ C. + -2 ℃ C.) and under light (4500 lx. + -. 500 lx) for 30 days, and samples were taken on days 10 and 30 to determine the substances. The test data are shown in the following table.
TABLE 5 compatibility test results (60 ℃. + -. 2 ℃) of cefpodoxime proxetil raw material drug and auxiliary materials
TABLE 6 compatibility test results (illumination (4500 lx +/-500 lx))
Note: N.D.: it was 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 the sucrose (sample 1) are placed for 10 days and 30 days under the conditions of high temperature and illumination, and the increase range of impurities C + B-II + D-I and total impurities is larger than that of the bulk drug (sample 6); the crude 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 of impurities C + B-II + D-I and total impurities is lower than that of the crude drug of cefpodoxime proxetil; the total auxiliary material and cefpodoxime proxetil (sample 5) contain 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), the stability is reduced due to the existence of sucrose, but the total auxiliary materials also have a protective effect on the bulk drugs, and the total auxiliary materials are slightly lower than the impurities of the raw materials. Wherein the impurity B is a process impurity, the impurity C is a thermal degradation impurity, and the impurity D is a photodegradation impurity; in conclusion, sucrose is the key auxiliary material affecting the stability of cefpodoxime proxetil bulk drug in the formula.
Note: the structural formula of the impurities is as follows:
impurity D
Experiment two: compatibility test of raw materials and auxiliary materials
The extraction raw materials of sucrose are two types: sugar cane, sugar beet; there are two processes for preparing sucrose: sulfurization (sulfur dioxide decolorization), carbonization (activated carbon decolorization). Wherein the sucrose extracted from sugarcane has better properties and purity; the sucrose prepared by the carbonization process has slightly low impurity. In conclusion, the compatibility of sucrose and cefpodoxime proxetil bulk drug produced by two preparation processes of sulfuration and carbonization from sugarcane extraction is investigated.
Mixing cefpodoxime proxetil raw material medicine, filler sucrose and total mixed auxiliary materials according to the weight ratio of 1: 5; mixing uniformly; sample numbers are shown in the following table; each sample was spread in a thin layer < 5mm thick in a petri dish.
TABLE 7 respective groups of samples containing corresponding adjuvants
| Serial number | Name of raw and auxiliary materials |
| Sample 1 | Cefpodoxime proxetil + sucrose (Carborundum) |
| Sample 2 | Cefpodoxime proxetil + sucrose (sulfurized) |
| Sample 3 | Cefpodoxime proxetil + total mixed auxiliary material (carbonization) |
| Sample 4 | Cefpodoxime proxetil + mixed auxiliary material (vulcanization) |
| Sample 5 | Cefpodoxime proxetil |
| Sample 6 | Total mixed auxiliary material (carbonization) |
| Sample 7 | Total mixed auxiliary material (vulcanization) |
The samples were allowed to stand at high temperature (60 ℃ C. + -2 ℃ C.) and under light (4500 lx. + -. 500 lx) for 30 days, and samples were taken on days 10 and 30 to determine the substances. The test data are shown in the following table.
TABLE 8 compatibility test results (60 ℃. + -. 2 ℃) of cefpodoxime proxetil raw material drug and auxiliary materials
TABLE 9 compatibility test results (illumination (4500 lx +/-500 lx))
Note: N.D.: it was not detected.
From the experimental results, the raw material medicines and the cane sugar prepared by the two preparation processes are placed for 10 days and 30 days under the conditions of high temperature and illumination, the increase amplitudes of the impurities C + B-II + D-I and the total impurities are basically consistent and are both larger than those of the raw material medicines; the results show that the sucrose prepared by different preparation processes has basically the same influence on the stability of the bulk drug, so the problem of compatibility of the two needs to be solved from the process perspective.
Has the advantages that:
the inventor has found through intensive research that the stability of cefpodoxime proxetil particles prepared after sucrose coating is obviously improved, and meanwhile, the dissolution meets the requirement.
Specifically, the method comprises the following steps:
the inventors have discovered, by chance and after numerous experiments, that only the bulking agent sucrose is mixed with cefpodoxime proxetil, namely: after the sucrose is directly contacted with the bulk drug, the mixture is placed for 30 days under the conditions of high temperature (60 +/-2 ℃) or illumination (4500 +/-500 lx), and the increase range of the impurities C + B-II + D-I and the total impurities is larger than that of the bulk drug, wherein the impurity B is a process impurity, the impurity C is a thermal degradation impurity, and the impurity D is a photo degradation impurity, which indicates that the sucrose is a key factor influencing the stability of cefpodoxime proxetil.
The original drug of the study (oreloc) was sucrose and lactose (about 20 weight ratio 1), both of which served as diluents, with lactose being a minor component. CN 104771368 aims at solving the problem that the preparation is low in dissolution when dissolved in water. The cefpodoxime proxetil and the surfactant are uniformly dispersed on the surface and inside the particles after granulation and drying, when the medicinal preparation is added into an aqueous dissolution medium, the water-soluble auxiliary material and part of cefpodoxime proxetil are quickly dissolved, the surfactant can be quickly distributed on the surface of the residual undissolved medicament, a specific hydrophilic group of the surfactant extends outwards to combine with water molecules, a hydrophobic group surrounds the surface of the cefpodoxime proxetil, and the medicament molecules are separated one by one, so that the tendency of gelation of the medicament can be effectively avoided, and the dissolution of the cefpodoxime proxetil is accelerated. The experimental results mainly examine the influence of the surfactant. Because the prescription is added with the surfactant, the sucrose and the lactose of the original medicine cannot be diluted well, and particularly, the sucrose and the lactose are difficult to granulate under the condition of large sucrose amount, so the weight ratio of the sucrose to the lactose is changed to 6:1 as a diluent. Thus, although either the original drug or CN 104771368 includes sucrose and lactose, neither of them describes the effect of sucrose on stability, nor has any technical implication.
The sucrose is coated by using a proper coating material and process, and the coated sucrose can be isolated from the bulk drugs so as to achieve the purpose of improving the stability of cefpodoxime proxetil particles. Specifically, the method comprises the following steps: according to the preparation method, sucrose is firstly subjected to film coating by using hydroxypropyl cellulose, and the prepared sucrose coated particles are subjected to wet granulation with raw material medicines and other auxiliary materials, wherein the cefpodoxime proxetil and the coated sucrose are not in direct contact in the production process of wet granulation and the storage period of the particles, so that the purpose of improving the stability of the cefpodoxime proxetil particles is achieved.
Detailed Description
The advantageous effects of the present invention are further illustrated by the following experiments. It is not limited to the following embodiments, and those skilled in the art can make equivalents and changes without departing from the spirit of the invention.
EXAMPLE 1 preparation of cefpodoxime proxetil particles (recipes 1-3)
The composition of the cefpodoxime proxetil particle unit preparation formula is shown as the following table:
TABLE 10 formulations 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 later use;
2) Preparing 75% ethanol solution with hydroxypropyl cellulose concentration of 1.5%, stirring to dissolve, and coating;
3) And (3) coating with cane sugar: adding sucrose in a formula amount into a fluidized bed, and coating with a hydroxypropyl cellulose ethanol solution;
the air inlet temperature is set to be 35-50 ℃, and the air inlet volume is 25-40 m 3 The sucrose coating is carried out at the atomization pressure of 1.5-3.0 MPa and the liquid supply speed of 3.5-7 r/min. After the coating is finished, drying the coating by a fluidized bed until the moisture content is below 3.0 percent, and taking out the coating for later use.
4) And (3) wet granulation: adding cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, citric acid, aspartame, sodium chloride, sodium glutamate and yellow ferric oxide into a wet granulator, stirring for 180 r/min, and shearing for 120 r/min to perform wet granulation; the wet granulate was dried to <3.0%.
5) Total mixing: and adding silicon dioxide, talcum powder and banana essence into the dry particles to carry out total mixing to prepare the cefpodoxime proxetil particles.
EXAMPLE 2 preparation of cefpodoxime proxetil particles (recipes 4-5)
TABLE 11 formulations 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 later use;
2) Preparing 75% ethanol solution with hydroxypropyl cellulose concentration of 1.5%, stirring to dissolve, and coating;
3) And (3) coating with cane sugar: adding sucrose in the formula amount into a fluidized bed, and coating with hydroxypropyl cellulose ethanol solution;
the air inlet temperature is set to be 35-50 ℃, and the air inlet volume is 25-40 m 3 The sucrose coating is carried out at the atomizing pressure of 1.5 to 3.0MPa and the liquid supply speed of 3.5 to 7 r/min. After coating, drying the coating by a fluidized bed until the water content is below 3.0 percent, and taking out for later use.
4) And (3) wet granulation: adding cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, citric acid, aspartame, sodium chloride, sodium glutamate and yellow ferric oxide into a wet granulating machine, stirring for 180 r/min, and shearing for 120 r/min to perform wet granulation; the wet granulate was dried to <3.0%.
5) Total mixing: and adding silicon dioxide, talcum powder and banana essence into the dry particles for total mixing to prepare the cefpodoxime proxetil particles.
Comparative example 1 (sucrose without hydroxypropylcellulose coating)
The sucrose uncoated comparative example was prepared according to the same formulation as in formulation example 1, and the preparation process was as follows:
1) Pulverizing sucrose, citric acid and sodium glutamate, and sieving with 60 mesh sieve; weighing other auxiliary materials for later use;
2) And (3) wet granulation: carrying out wet granulation, drying and granule finishing on cefpodoxime proxetil, sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, citric acid, aspartame, sodium chloride, sodium glutamate and yellow ferric oxide;
3) Total mixing: and adding silicon dioxide, talcum powder and banana essence into the dry particles to carry out total mixing to prepare the cefpodoxime proxetil particles.
Comparative example 2 preparation of CN 104771368
Table 12 recipe of CN 104771368
| Name of raw and auxiliary materials | Prescription |
| Cefpodoxime proxetil | 135g |
| Anhydrous lactose | 1400g |
| Sucrose | 240g |
| Calcium carboxymethylcellulose | 45g |
| Xanthan gum | 10g |
| Citric acid | 5g |
| Polyoxyethylene hydrogenated castor oil | 135g |
| Anhydrous ethanol | 600ml |
| Talcum powder | 20g |
| Orange essence | 10g |
The preparation process comprises the following steps:
1) Dissolving the cefpodoxime proxetil and polyoxyethylene hydrogenated castor oil in the anhydrous ethanol according to the prescription amount to obtain a first mixture;
2) Uniformly mixing anhydrous lactose, sucrose and calcium carboxymethylcellulose in a fluidized bed, slowly spraying the mixture I, granulating, and drying at 30 ℃ in the fluidized bed to obtain a mixture II;
3) And adding xanthan gum, citric acid, talcum powder and orange essence into the mixture II, mixing and subpackaging.
Example 3: taste detection
5 samples of the prescription 1, the prescription 2, the prescription 3, the comparative example and the reference drug (cefpodoxime proxetil dry suspension, trade name: ORELOX, the carrier: SANOFI-AVENTIS FRANCE) are respectively taken for 6 unit doses, the samples are respectively dispersed in water at a proper room temperature, 6 volunteers are asked to hold the samples for 20s, the taking process of the drugs is simulated, and the taste detection results are shown in the following table:
TABLE 13 oral sensation test results of prescription example, control example and control drug
According to the taste detection results, the flavoring agents selected in the prescription examples and the comparative examples can effectively cover the bitter taste of cefpodoxime proxetil, and the taste is equivalent to that of a reference medicament.
Example 4: dissolution test
In the above formula 1, formula 2, formula 3, comparative example, and control drug (cefpodoxime proxetil dry suspension, trade name: ORELOX, support company: SANOFI-AVENTIS FRANCE), 5 samples were taken, and 6 unit dosage was measured according to the dissolution and release determination method (second method of 0931, general rules) in the second part of the Chinese pharmacopoeia, namely, in the term of cefpodoxime proxetil dry suspension. Glycine-sodium chloride-hydrochloric acid solution (pH 3.0) [ 54.5g glycine and 42.6g sodium chloride were taken and placed in a 1000ml measuring flask, 500ml water was added to dissolve, 14.2ml hydrochloric acid was slowly added, cooling was allowed to stand, diluted to the mark with water, shaken up to a stock solution. Taking 50ml of stock solution, adding water to 900ml (adjusting pH to 3.0 + -0.1 with 10mol/L sodium hydroxide solution if necessary) 900ml as dissolution medium, rotating at 75 rpm, and sampling at 45min according to the method. Taking a proper amount of the dissolution liquid, filtering, precisely taking a proper amount of the subsequent filtrate, and quantitatively diluting with a dissolution medium to prepare a solution containing about 11 mu g of cefpodoxime in each 1 ml. Taking a proper amount of cefpodoxime proxetil as a reference substance, precisely weighing, adding a proper amount of methanol for dissolving, and quantitatively diluting with a dissolution medium to prepare a solution containing about 11 mu g of cefpodoxime in each 1 ml. Taking the test solution and the reference solution, respectively measuring absorbance at 259nm wavelength by ultraviolet-visible spectrophotometry (general formula 0401), and calculating the elution amount of each bag. The test data are shown in the following table.
Table 14 prescription example, control example, and test results of dissolution of control drug (unit:%)
| Sample (I) | Prescription 1 | Prescription 2 | Prescription 3 | Comparative example 1 | Comparative example 2 | Contrast drug |
| Sample No. 1 | 98.4 | 97.6 | 98.2 | 97.5 | 98.0 | 97.5 |
| Sample 2 | 96.1 | 97.2 | 96.8 | 98.7 | 96.6 | 95.6 |
| Sample 3 | 95.7 | 96.1 | 98.1 | 98.5 | 97.4 | 99.5 |
| Sample 4 | 96.3 | 96.7 | 96.8 | 97.6 | 96.8 | 98.4 |
| Sample No. 5 | 95.2 | 96.8 | 97.8 | 97.8 | 97.1 | 96.7 |
| Sample No. 6 | 97.1 | 98.5 | 97.7 | 98.1 | 97.9 | 98.5 |
| Mean value of | 96.5 | 97.2 | 97.6 | 98.0 | 97.3 | 97.7 |
| RSD | 1.18 | 0.86 | 0.64 | 0.50 | 0.59 | 1.43 |
From the dissolution rate test results, the dissolution rates of the 3 sucrose-coated weight-increased samples of the invention are basically consistent at 45min and all meet the requirements (70% of the marked amount) compared with the comparative example and the control drug.
Example 5: stability test results
5 samples of the above-mentioned formulation 1, formulation 2, formulation 3, comparative example and control drug (cefpodoxime proxetil dry suspension, trade name: ORELOX, carrier: SANOFI-AVENTIS FRANCE) were placed under accelerated conditions of 40 ℃. + -. 2 ℃ and 75%. + -. 5% relative humidity for 6 months, and samples were taken to measure the relevant substances, and the measurement data are shown in the following table.
TABLE 15 recipe examples, control examples, and test results of substances related to control drugs (unit:%)
According to the detection results of the related substances, the 3 sucrose-coated weight-gaining samples in the invention are placed for 6 months under the accelerated conditions of 40 ℃ plus or minus 2 ℃ and 75% plus or minus 5% of relative humidity, and impurities C + B-II + D-I and total impurities slowly increase and are in accordance with the regulations and equivalent to the control drugs. The sucrose uncoated comparative example was found to have the impurity C + B-II + D-I approaching the limit (4.0%) when left under the above accelerated conditions for 3 months, and the impurity C + B-II + D-I exceeded the limit (4.0%) when left for 6 months. By adopting the sucrose coating process, sucrose is isolated from the bulk drug, so that the stability can be obviously improved, and the stability of cefpodoxime proxetil granules is equivalent to that of a reference drug; the mouth feel and the dissolution rate are consistent with those of a contrast 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 as main ingredient, diluent, disintegrating agent, adhesive, surfactant, glidant, lubricant, correctant and essence; the preparation is characterized in that the diluent is sucrose and lactose, wherein the sucrose is coated sucrose.
2. The cefpodoxime proxetil granulate according to claim 1 wherein the sucrose coating material is selected from any one of hydroxypropyl cellulose, ethyl cellulose, hypromellose, polyethylene glycol.
3. A cefpodoxime proxetil granulate according to claim 2 wherein the sucrose coating comprises 0.5 to 15% by weight of sucrose.
4. A cefpodoxime proxetil granulate according to claim 3 wherein the sucrose coating comprises 0.5% to 2.5% by weight of sucrose.
5. The cefpodoxime proxetil particles of claim 4 wherein the sucrose coating material is hydroxypropylcellulose and the unit formulation is as follows:
6. cefpodoxime proxetil particles according to claim 5, obtained by the following preparation steps:
1) Pulverizing sucrose, citric acid and sodium glutamate, and sieving with 60 mesh sieve; weighing other auxiliary materials for later use;
2) Preparing an ethanol solution of hydroxypropyl cellulose for coating;
3) And (3) coating sucrose: adding sucrose in a formula amount into a fluidized bed, and coating with a hydroxypropyl cellulose ethanol solution;
4) And (3) wet granulation: wet granulating, drying and finishing cefpodoxime proxetil, coated sucrose, lactose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, hydroxypropylcellulose, citric acid, aspartame, sodium chloride, sodium glutamate and yellow ferric oxide;
5) Total mixing: and adding silicon dioxide, talcum powder and banana essence into the dry particles for total mixing to prepare the cefpodoxime proxetil particles.
7. The method for preparing cefpodoxime proxetil particles according to claim 6 wherein the sucrose in step 3) is coated with hydroxypropylcellulose in an amount of 0.5-15% by weight of sucrose.
8. The method for preparing cefpodoxime proxetil particles according to claim 6 wherein the sucrose coating uses a 75-95% ethanol solution with a hydroxypropyl cellulose concentration of 0.5-5% w/v.
9. The method for preparing cefpodoxime proxetil particles according to claim 6 wherein the sucrose coating of step 3) is dried to a moisture content of less than 3.0%.
10. The method for preparing cefpodoxime proxetil particles according to claim 6 wherein the wet granulated particles of step 4) are dried to a moisture content of less than 3.0%.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104174023A (en) * | 2014-08-15 | 2014-12-03 | 河北菲尼斯生物技术有限公司 | Pharmaceutical composition capable of improving stability of ambroxol hydrochloride |
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