CN101711741A - Cefixime submicro-emulsion solid preparation and novel application thereof - Google Patents
Cefixime submicro-emulsion solid preparation and novel application thereof Download PDFInfo
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- CN101711741A CN101711741A CN200910229884A CN200910229884A CN101711741A CN 101711741 A CN101711741 A CN 101711741A CN 200910229884 A CN200910229884 A CN 200910229884A CN 200910229884 A CN200910229884 A CN 200910229884A CN 101711741 A CN101711741 A CN 101711741A
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- Prior art keywords
- cefixime
- emulsion
- solid preparation
- submicro
- granule
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Links
- 229960002129 cefixime Drugs 0.000 title claims abstract description 89
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 title claims abstract description 89
- 238000002360 preparation method Methods 0.000 title claims abstract description 61
- 239000000839 emulsion Substances 0.000 title claims abstract description 58
- 239000007787 solid Substances 0.000 title claims abstract description 28
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 238000004945 emulsification Methods 0.000 claims abstract description 6
- 239000008187 granular material Substances 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 20
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 14
- 239000002775 capsule Substances 0.000 claims description 12
- 239000007957 coemulsifier Substances 0.000 claims description 12
- 229920001993 poloxamer 188 Polymers 0.000 claims description 11
- 229940044519 poloxamer 188 Drugs 0.000 claims description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 206010017553 Furuncle Diseases 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 229920002472 Starch Polymers 0.000 claims description 9
- 230000001154 acute effect Effects 0.000 claims description 9
- 229960003964 deoxycholic acid Drugs 0.000 claims description 9
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000008107 starch Substances 0.000 claims description 9
- 235000019698 starch Nutrition 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 229920003081 Povidone K 30 Polymers 0.000 claims description 8
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 7
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 7
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000007919 dispersible tablet Substances 0.000 claims description 7
- 235000010445 lecithin Nutrition 0.000 claims description 7
- 239000000787 lecithin Substances 0.000 claims description 7
- 229940067606 lecithin Drugs 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 239000007779 soft material Substances 0.000 claims description 7
- 229940083466 soybean lecithin Drugs 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 208000003512 furunculosis Diseases 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 6
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 6
- 239000002671 adjuvant Substances 0.000 claims description 5
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- -1 polyoxyethylene Polymers 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 239000008215 water for injection Substances 0.000 claims description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 4
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 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 description 4
- 238000013019 agitation Methods 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 4
- 238000004132 cross linking Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000012530 fluid Substances 0.000 claims description 4
- 238000012856 packing Methods 0.000 claims description 4
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- 235000012239 silicon dioxide Nutrition 0.000 claims description 4
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 239000003826 tablet Substances 0.000 claims description 4
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 239000004375 Dextrin Substances 0.000 claims description 3
- 229920001353 Dextrin Polymers 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- 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 3
- 229930195725 Mannitol Natural products 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- 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 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 229960003943 hypromellose Drugs 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229920001983 poloxamer Polymers 0.000 claims description 3
- 229960000502 poloxamer Drugs 0.000 claims description 3
- 229940085605 saccharin sodium Drugs 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 238000001694 spray drying Methods 0.000 claims description 3
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 239000008118 PEG 6000 Substances 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 235000019219 chocolate Nutrition 0.000 claims description 2
- 235000012000 cholesterol Nutrition 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 2
- WUIJQWLICXXNNE-UHFFFAOYSA-L disodium;octyl phosphate Chemical compound [Na+].[Na+].CCCCCCCCOP([O-])([O-])=O WUIJQWLICXXNNE-UHFFFAOYSA-L 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- 238000005469 granulation Methods 0.000 claims description 2
- 230000003179 granulation Effects 0.000 claims description 2
- 235000013336 milk Nutrition 0.000 claims description 2
- 239000008267 milk Substances 0.000 claims description 2
- 210000004080 milk Anatomy 0.000 claims description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 238000007873 sieving Methods 0.000 claims description 2
- 239000002002 slurry Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 238000005516 engineering process Methods 0.000 abstract description 6
- 230000001804 emulsifying effect Effects 0.000 abstract 1
- 238000002386 leaching Methods 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 9
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 6
- 229960002727 cefotaxime sodium Drugs 0.000 description 6
- 210000003780 hair follicle Anatomy 0.000 description 6
- 230000001476 alcoholic effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 3
- 206010040047 Sepsis Diseases 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 239000004530 micro-emulsion Substances 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 2
- 206010067482 No adverse event Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 208000033809 Suppuration Diseases 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 210000001217 buttock Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 208000037920 primary disease Diseases 0.000 description 2
- 208000013223 septicemia Diseases 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000036269 ulceration Effects 0.000 description 2
- ZTCPYEZGLNHNBH-UHFFFAOYSA-N 2-methyloct-2-enoic acid trihydrate Chemical compound O.O.O.CC(=CCCCCC)C(=O)O ZTCPYEZGLNHNBH-UHFFFAOYSA-N 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 208000004020 Brain Abscess Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 101710116957 D-alanyl-D-alanine carboxypeptidase Proteins 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000000680 avirulence Effects 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 201000007262 cavernous sinus thrombosis Diseases 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 210000000589 cicatrix Anatomy 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
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- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000001786 gonorrhea Diseases 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000003448 neutrophilic effect Effects 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 208000009146 rhinoscleroma Diseases 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 210000001732 sebaceous gland Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 210000000106 sweat gland Anatomy 0.000 description 1
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- 208000000143 urethritis Diseases 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
The invention relates to a cefixime submicro-emulsion solid preparation and a novel application thereof, in particular to a solid preparation of cefixime processed by micro-emulsification and a novel application thereof. The cefixime submicro-emulsion solid preparation comprises cefixime, an emulsifying agent and an emulsifying aid agent, wherein the active component of the cefixime is processed by applying a micro-emulsification technology. The stability is enhanced, the solubility is increased, and the problem of low leaching degree is solved.
Description
Technical field
The present invention relates to a kind of cefixime submicro-emulsion solid preparation and new application the thereof, be specifically related to the solid preparation and new application the thereof of the cefixime of a kind of process microemulsified processing, belong to medical technical field.
Background technology
Furuncle is because the acute festering type that antibacterial is invaded caused single hair follicle and affiliated sebaceous gland thereof from hair follicle or sweat gland infects, and is the inflammation of a kind of acute festering type hair follicle and hair follicle surrounding tissue, the local inflammatory infiltration tuberosity that forms.Single person is called furuncle, and multiple repeatedly person is called furunculosis.Primary disease is more common in hot season, and often the position that is often rubbed with head, face, neck, oxter and buttocks etc. is common in underfed children's or diabetics for seeing more.Be initially the inflammatory pimple the same with hair follicle, increasing gradually becomes pink or kermesinus infiltration tuberosity, tool pain and tenderness.Through the downright bad deliquescing of suppurating of 2-3 days posterior tubercles, form the pus infections, there is fluctuation in central authorities, and purulent core is arranged, and form a crateriform hole behind the ulceration, have the pus ripple to overflow frequently.After purulent core and slough discharge, pain is paused and is subtracted, and the inflammation redness disappears gradually, about 1-2 week healing, local residual cicatrix.The patient can be with General Symptomies such as fever and headache, whole body discomfort, lymphadenectasis.Body constitution weak person even can cause pyemia or septicemia.The lighter is ulceration not, and the inflammation scleroma absorbs gradually disappears.Primary disease can betide any position of whole body, especially easily betides neck, face, scalp, axillary fossa and buttocks etc. and locates.Betide facial person, especially near the furuncle nose easily causes cavernous sinus thrombophlebitis, brain abscess or septicemia.Use cefotaxime sodium at present clinically, every day 50～100mg/kg, quiet at twice, bring misery and trouble to patient and family members, inquire into a kind of convenience, effective method is treated has certain clinical meaning, therefore, we use the acute furunculosis of cefixime capsule for treating children's skin.
Cefixime, chemical name is: (6R, 7R)-7[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxylic methoxy amido imide) acetamido]-3-ethylene-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid trihydrate, molecular formula: C
16H
15N
5O
7S
23H
2O, molecular weight: 507.50, structural formula is:
Cefixime is a third generation oral cephalosporin, has a broad antifungal spectrum, most enterobacteriaceae lactobacteriaceaes such as micrococcus scarlatinae, streptococcus pneumoniae, streptococcus agalactiae, gonococcus, hemophilus influenza, mora mucositis bacterium and escherichia coli, pneumobacillus had good antibacterial activity, highly stable to beta-lactamase, with penicillin-binding protein 3,1a and 1b high affinity is arranged, make the bacteria cell wall biosynthesis block, antibacterial is dissolved rapidly, death.Clinically pharyngitis, tonsillitis, acute bronchitis and acute episode of chronic bronchitis due to the sensitive organism, otitis media, urinary tract infection, simple property gonorrheas (cervicitis or urethritis) etc. of being used for the treatment of more.At present, the listing preparation of cefixime has tablet, capsule, granule, dispersible tablet, dry suspension, slow releasing tablet and slow releasing capsule, its poor stability, and dissolution is low to be insoluble problem always.
Patent documentation CN101401810A discloses a kind of cefixime dispersible tablet and preparation method thereof, take by weighing cefixime earlier, starch, microcrystalline Cellulose, partial cross-linked polyvidone, partial cross-linked sodium carboxymethyl cellulose, part low-substituted hydroxypropyl cellulose, mix homogeneously, add 5% 30 POVIDONE K 30 BP/USP, 30 alcoholic solution system soft materials, cross the 18-24 mesh sieve and granulate, wet granular carries out drying under 50-80 ℃ of condition, with 18-24 mesh sieve granulate, add remaining polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose, magnesium stearate and micropowder silica gel mixing, tabletting promptly gets cefixime dispersible tablet.Patent documentation CN 1850087A discloses a kind of effervescent tablet and method for making thereof that contains cefixime, by cefixime 25-400mg and pharmaceutically acceptable acid-base pair, filler, binding agent, disintegrating agent, lubricant, compositions such as sweeting agent and correctives.
It is exactly that long-term shelf-stability is poor that there is a general character problem in above-mentioned patent, and dissolution is low, the prescription that can not satisfy the prescriptive period.
Summary of the invention
The object of the present invention is to provide a kind of cefixime submicro-emulsion solid preparation and new application the thereof, specifically, the solid preparation of the cefixime that the process microemulsified is handled and new application the thereof, the cefixime solid preparation poor stability of present listing, the problem that dissolution is low have well been solved, and can be used for preparation treatment children's acute furunculosis medicine, obtained gratifying technique effect.
The inventor attempts it is prepared into submicronized emulsion.But in our test, a lot of emulsifying agents commonly used and co-emulsifier can not form emulsion with cefixime in water for injection, can't obtain qualified product.But after hundreds of tests, we find that unexpectedly emulsifying agent uses the combination of lecithin and poloxamer, particularly soybean lecithin and poloxamer 188, when co-emulsifier uses sodium deoxycholate, can obtain satisfied product.Use micro-emulsion technology like this cefixime raw material handled, greatly improve the stability of cefixime, and significantly improved the dissolution of preparation.
Technical scheme provided by the invention is as follows:
The invention provides a kind of cefixime submicron emulsion granule, it is made up of cefixime, emulsifying agent, co-emulsifier, wherein counts 1 part of cefixime by weight, emulsifying agent 2.5-10 part, co-emulsifier 0.8-5 part.
Above-mentioned described cefixime submicron emulsion granule, wherein emulsifying agent is selected from one or more in lecithin, tween, poloxamer 188,30 POVIDONE K 30 BP/USP 30, polyvinyl alcohol, sodium lauryl sulphate, cholesterol, peregal, gelatin, polyoxyethylene hydrogenated Oleum Ricini, the glyceryl monostearate, the combination of preferably lecithin and poloxamer 188, more preferably lecithin and poloxamer 188 weight ratios are 2.2: 1～1.3: 1 combination, and most preferably soybean lecithin and poloxamer 188 weight ratios are 1.8: 1 combination.
Above-mentioned described cefixime submicron emulsion granule, co-emulsifier is selected from one or more in n-butyl alcohol, ethylene glycol, ethanol, propylene glycol, glycerol, polyglycerin ester, mono-octyl phosphate sodium salt, NaGC, the sodium deoxycholate, is preferably sodium deoxycholate.
The present invention also provides a kind of preparation cefixime submicron emulsion particulate method, comprise the steps: emulsifying agent and co-emulsifier are added in the water for injection, add the cefixime mix homogeneously again, 70-90 ℃ of heating in water bath is stirred to molten condition, adopts tissue mincer's shear agitation, gets colostric fluid, again through high pressure dispersing emulsification machine circulating emulsion, emulsion, lyophilization or spray drying then obtain the submicron emulsion granule of cefixime.
In one embodiment, in the said method, wherein emulsifying agent is the combination of soybean lecithin and poloxamer 188, and co-emulsifier is a sodium deoxycholate.
The technical scheme that the present invention solves also comprises:
A kind of cefixime submicro-emulsion solid preparation, be made up of above-mentioned described cefixime submicron emulsion granule and pharmaceutically acceptable other adjuvants, preferred described cefixime submicro-emulsion solid preparation is granule, tablet, capsule, dispersible tablet or dry suspension.
Above-mentioned described solid preparation, wherein said adjuvant is not particularly limited, can be the pharmaceutical necessities of solid preparation commonly used in the pharmaceutics, specifically make: 1 part of cefixime submicron emulsion granule, diluent 0.2-5 part, disintegrating agent 0-3 part by following component by weight, binding agent 0-0.5 part, correctives 0-5 part, aromatic 0-0.3 part, lubricant 0-0.5 part.
As preferably, wherein said diluent is selected from one or more in microcrystalline Cellulose, lactose, starch, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, the calcium hydrogen phosphate; Described disintegrating agent is selected from one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the dried starch; Described binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, hypromellose, starch slurry, sodium carboxymethyl cellulose, the syrup; Described correctives is selected from one or more in sucrose, Aspartane, saccharin sodium, the steviosin; Described aromatic is selected from one or more in Fructus Citri tangerinae XIANGFEN, Fructus Fragariae Ananssae XIANGFEN, chocolate XIANGFEN, Herba Menthae XIANGFEN, the milk XIANGFEN; Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate etc.
Further, the present invention also provides the preparation method of above-mentioned described cefixime submicro-emulsion solid preparation, and it comprises the steps: (1) with the pulverizing of cefixime submicron emulsion granule, and 80 mesh sieves are standby excessively; (2) diluent, disintegrating agent, correctives are pulverized, crossed 80 mesh sieves, mix, standby; (3) with above-mentioned supplementary material mix homogeneously, add binding agent, aromatic system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate; (4) dried granules is carried out packing or tabletting, make cefixime submicro-emulsion solid preparation.
Those skilled in the art are to be understood that, above-mentioned preparation and preparation method thereof only is illustrative, can cefixime submicron emulsion granule of the present invention be made similar or different solid preparations with any known prior art, this is in the technical scope of this area.
The present invention also provides above-mentioned cefixime submicro-emulsion solid preparation to be used for the treatment of application in the children's acute furunculosis medicine in preparation.
The present invention makes cefixime submicron emulsion granule by specific adjuvant and supplementary material proportioning thereof, cefixime submicron emulsion granule provided by the invention and cefixime solid preparation, and compared with prior art, major advantage is as follows:
(1) active component cefixime application micro-emulsion technology is handled, and has improved stability, has increased dissolubility, has solved the low problem of dissolution;
(2) used emulsifying agent, co-emulsifier degradation in vivo, avirulence and the non-immunogenicity of micro-emulsion technology, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(3) production technology is simple, and cost is low, can industrial-scale production.
The specific embodiment
Further specify the present invention by the following examples, but should not be construed as limitation of the present invention.
The particulate preparation of embodiment 1 cefixime submicron emulsion
160.7g soybean lecithin, 89.3g poloxamer 188 and 80g sodium deoxycholate are added in the 2500ml water for injection, add 100g cefixime mix homogeneously again, 86 ℃ of heating in water bath are stirred to molten condition, adopt the shear agitation 20min of tissue mincer, rotating speed 12000r/min, colostric fluid, again through high pressure dispersing emulsification machine circulating emulsion 5 times, emulsion, deep bid lyophilization then, pulverize, obtain the submicron emulsion granule 396.6g of cefixime, yield 92.2%.
The particulate preparation of embodiment 2 cefixime submicron emulsion
642.9g soybean lecithin, 357.1g poloxamer 188 and 500g sodium deoxycholate are added in the 9000ml water for injection, add 100g cefixime mix homogeneously again, 75 ℃ of heating in water bath are stirred to molten condition, adopt the shear agitation 15min of tissue mincer, rotating speed 13000r/min, get colostric fluid, again through high pressure dispersing emulsification machine circulating emulsion 5 times, emulsion, spray drying then, obtain the submicron emulsion granule 1467g of cefixime, yield 91.7%.
The preparation of embodiment 3 cefixime sheets
44.2g cefixime submicron emulsion granule, 56g pregelatinized Starch, 70g lactose and the 9g low-substituted hydroxypropyl cellulose of embodiment 1 preparation are crossed 80 mesh sieves respectively, mix homogeneously then, add 8% 30 POVIDONE K 30 BP/USP, 3070% alcoholic solution 30ml system soft material, 20 mesh sieves are granulated, 55 ℃ of oven dry, 20 mesh sieve granulate add 1.8g magnesium stearate mix homogeneously again, tabletting makes the cefixime sheet.
The capsular preparation of embodiment 4 cefiximes
45.1g cefixime submicron emulsion granule, 40g starch, the 10g carboxymethylstach sodium of embodiment 1 preparation are crossed 80 mesh sieves respectively, mix homogeneously then, add 3% 30 POVIDONE K 30 BP/USP, 3080% alcoholic solution 20ml system soft material, 20 mesh sieves are granulated, 60 ℃ of oven dry, 20 mesh sieve granulate add 2.5g colloidality silicon dioxide and 2.8g Pulvis Talci mix homogeneously again, filled capsules makes the cefixime capsule.
The preparation of embodiment 5 cefixime dispersible tablets
43.6g cefixime submicron emulsion granule, 20g dextrin, 30g dried starch, 11g Aspartane, 8g cross-linking sodium carboxymethyl cellulose and the 6g polyvinylpolypyrrolidone of embodiment 1 preparation are crossed 80 mesh sieves respectively, mix homogeneously then, add 2% 30 POVIDONE K 30 BP/USP, 30 40% alcoholic solution 20ml system soft material, 20 mesh sieves are granulated, 60 ℃ of oven dry, 20 mesh sieve granulate add 0.8g magnesium stearate and 1.2g colloidality silicon dioxide mix homogeneously again, tabletting makes cefixime dispersible tablet.
The particulate preparation of embodiment 6 cefiximes
43.8g cefixime submicron emulsion granule, 65g sucrose, 20g sorbitol and the 8g saccharin sodium of embodiment 1 preparation are crossed 80 mesh sieves respectively, mix homogeneously then, add 2% hypromellose, 20% alcoholic solution 20ml system soft material, 20 mesh sieves are granulated, 55 ℃ of oven dry, 20 mesh sieve granulate, packing makes the cefixime granule.
The preparation of embodiment 7 cefixime dry suspension
164.7g cefixime submicron emulsion granule, 184g sucrose, 57g mannitol, the 20g Fructus Fragariae Ananssae XIANGFEN of embodiment 2 preparation are crossed 80 mesh sieves respectively, mix homogeneously then, packing makes the cefixime dry suspension.
Test example 1 dissolution detects
The sample for preparing among the sample of embodiment of the invention 3-5 preparation and the patent documentation CN101401810A is carried out dissolution detection, result such as table 1.
Table 1 dissolution testing result
Can find out by The above results, the sample dissolution of embodiment preparation is significantly improved among the embodiment sample of the present invention's preparation and the patent documentation CN101401810A, and the sample dissolution of embodiment of the invention preparation after 6 months does not almost change, the sample dissolution of patent documentation CN101401810A embodiment preparation descends obviously, proved absolutely the present invention improve dissolution and stable aspect superiority.
Test example 2 study on the stability
With the sample of embodiment of the invention 3-7 and patent documentation CN101401810A, patent documentation CN1850087A preparation under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test and investigate, the results are shown in Table 2;
Table 2 accelerated test result
Found that by above bigger variation takes place the sample character of patent documentation CN101401810A and CN1850087A embodiment preparation when quickening March, June, related substance raises, and content and dissolution obviously reduce; And the every detection index of sample of embodiment of the invention 3-7 preparation does not all have obvious variation.Illustrated that the present invention is at the superiority that improves aspect stable.
Prepare before 3 clinical trials of test example
1, physical data 57 routine patients are from the acute onset of outpatient service prescription on individual diagnosis, have heating, many places cutaneous manifestations and be single hair follicle and surrounding tissue thereof red, swollen, hot, suppurate, but each scope is no more than diameter 2cm, heating body temperature fluctuates in 38.2 ℃～41 ℃, neutrophilic granulocyte 48 examples that raise are divided into two groups, cefixime capsule for treating group 29 examples at random, wherein male 16 examples, women 13 examples; Matched group cefotaxime sodium for injection 28 examples, wherein male 16 examples, women 12 examples.Two groups of patient ages, sex, course of disease there was no significant difference have comparability.
2, Therapeutic Method treatment group gives the cefixime capsule 8mg/kgd of the embodiment of the invention 4 preparations
-1, q12h.Matched group gives cefotaxime sodium, 50～100mg/kgd
-1,, quiet at twice.Test example 4 clinical test results
1, clinical efficacy cefixime capsule for treating group and cefotaxime sodium matched group curative effect relatively do not have significant difference between two groups, see Table 3.
Table 3 cefixime capsule for treating group and cefotaxime sodium matched group clinical efficacy are relatively
2, untoward reaction treatment group has no adverse reaction, and matched group has 3 examples that slight gastrointestinal reaction takes place, and comprising: abdominal discomfort, stool are rare, all therapy discontinued not.
To sum up, acute furunculosis 29 examples of cefixime capsule for treating children's skin of the present invention preparation, and compare with quiet of cefotaxime sodium, clinical efficacy is satisfied, and has no adverse reaction after the medication.Because oral cefixime every day twice, safety, convenient can alleviate misery and burden that intravenous drip arrives to infant and the head of a family, a kind of ideal method of can yet be regarded as.
Claims (9)
1. a cefixime submicro-emulsion solid preparation is characterized in that being made up of cefixime submicron emulsion granule and other adjuvants, and wherein cefixime submicron emulsion granule is counted by weight by 1 part of cefixime, emulsifying agent 2.5-10 part, co-emulsifier 0.8-5 part.
2. cefixime submicron emulsion granule according to claim 1, wherein emulsifying agent is selected from one or more in lecithin, tween, poloxamer 188,30 POVIDONE K 30 BP/USP 30, polyvinyl alcohol, sodium lauryl sulphate, cholesterol, peregal, gelatin, polyoxyethylene hydrogenated Oleum Ricini, the glyceryl monostearate, the combination of preferably lecithin and poloxamer 188, more preferably lecithin and poloxamer 188 weight ratios are 2.2: 1～1.3: 1 combination, and most preferably soybean lecithin and poloxamer 188 weight ratios are 1.8: 1 combination.
3. cefixime submicron emulsion granule according to claim 1, it is characterized in that co-emulsifier is selected from one or more in n-butyl alcohol, ethylene glycol, ethanol, propylene glycol, glycerol, polyglycerin ester, mono-octyl phosphate sodium salt, NaGC, the sodium deoxycholate, is preferably sodium deoxycholate.
4. particulate preparation method of the described cefixime submicron emulsion of claim 1-3, it is characterized in that comprising the steps: emulsifying agent and co-emulsifier are added in the water for injection, add the cefixime mix homogeneously again, 70-90 ℃ of heating in water bath is stirred to molten condition, adopts tissue mincer's shear agitation, gets colostric fluid, again through high pressure dispersing emulsification machine circulating emulsion, emulsion, lyophilization or spray drying then obtain the submicron emulsion granule of cefixime; More preferably emulsifying agent is soybean lecithin and poloxamer 188, and co-emulsifier is a sodium deoxycholate.
5. cefixime submicro-emulsion solid preparation, it is characterized in that being made up of each described cefixime submicron emulsion granule of claim 1-3 and pharmaceutically acceptable other adjuvants, preferred described cefixime submicro-emulsion solid preparation is granule, tablet, capsule, dispersible tablet or dry suspension.
6. cefixime submicro-emulsion solid preparation according to claim 5, it is characterized in that described solid preparation is to be made by following component by weight: 1 part of cefixime submicron emulsion granule, diluent 0.2-5 part, disintegrating agent 0-3 part, binding agent 0-0.5 part, correctives 0-5 part, aromatic 0-0.3 part, lubricant 0-0.5 part.
7. cefixime submicro-emulsion solid preparation according to claim 6, its feature are that also described diluent is selected from one or more in microcrystalline Cellulose, lactose, starch, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, the calcium hydrogen phosphate; Described disintegrating agent is selected from one or more in carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, the dried starch; Described binding agent is selected from one or more in 30 POVIDONE K 30 BP/USP 30, hypromellose, starch slurry, sodium carboxymethyl cellulose, the syrup; Described correctives is selected from one or more in sucrose, Aspartane, saccharin sodium, the steviosin; Described aromatic is selected from one or more in Fructus Citri tangerinae XIANGFEN, Fructus Fragariae Ananssae XIANGFEN, chocolate XIANGFEN, Herba Menthae XIANGFEN, the milk XIANGFEN; Described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate etc.
8. method for preparing the described cefixime submicro-emulsion solid preparation of claim 5-7, it comprises the steps: that (1) pulverize cefixime submicron emulsion granule, crosses 80 mesh sieves, and is standby; (2) diluent, disintegrating agent, correctives are pulverized, crossed 80 mesh sieves, mix, standby; (3) with above-mentioned supplementary material mix homogeneously, add binding agent, aromatic system soft material, the granulation of sieving, oven dry, the adding mix lubricant is even, granulate; (4) dried granules is carried out packing or tabletting, make cefixime submicro-emulsion solid preparation.
9. be used for the treatment of application in the medicine of children's acute furunculosis according to the described cefixime submicro-emulsion solid preparation of claim 5-7 in preparation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198104A (en) * | 2011-05-16 | 2011-09-28 | 王万玉 | Cefixime freeze-dried powder injection and preparation method thereof |
| CN103655486A (en) * | 2013-12-12 | 2014-03-26 | 人福医药集团股份公司 | Sirolimus micro-emulsion particles and preparation method and application thereof |
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2009
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102198104A (en) * | 2011-05-16 | 2011-09-28 | 王万玉 | Cefixime freeze-dried powder injection and preparation method thereof |
| CN103655486A (en) * | 2013-12-12 | 2014-03-26 | 人福医药集团股份公司 | Sirolimus micro-emulsion particles and preparation method and application thereof |
| CN103655486B (en) * | 2013-12-12 | 2015-08-12 | 人福医药集团股份公司 | Sirolimus microemulsion particles and its preparation method and application |
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