CN101721371B - Cefetamet pivoxil hydrochloride submicron emulsion solid preparation and new application thereof - Google Patents
Cefetamet pivoxil hydrochloride submicron emulsion solid preparation and new application thereof Download PDFInfo
- Publication number
- CN101721371B CN101721371B CN2009102299661A CN200910229966A CN101721371B CN 101721371 B CN101721371 B CN 101721371B CN 2009102299661 A CN2009102299661 A CN 2009102299661A CN 200910229966 A CN200910229966 A CN 200910229966A CN 101721371 B CN101721371 B CN 101721371B
- Authority
- CN
- China
- Prior art keywords
- cefetamet pivoxil
- pivoxil hydrochloride
- submicron emulsion
- solid preparation
- granule
- 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.)
- Expired - Fee Related
Links
- DASYMCLQENWCJG-XUKDPADISA-N cefetamet pivoxil Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DASYMCLQENWCJG-XUKDPADISA-N 0.000 title claims abstract description 103
- 229950000726 cefetamet pivoxil Drugs 0.000 title claims abstract description 103
- 239000000839 emulsion Substances 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 66
- 239000007787 solid Substances 0.000 title claims abstract description 25
- 208000003167 cholangitis Diseases 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- 239000000314 lubricant Substances 0.000 claims abstract description 8
- 239000003085 diluting agent Substances 0.000 claims abstract description 7
- 239000008187 granular material Substances 0.000 claims description 44
- 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 32
- 239000000203 mixture Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 235000012000 cholesterol Nutrition 0.000 claims description 16
- 238000004945 emulsification Methods 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims description 12
- 229960003964 deoxycholic acid Drugs 0.000 claims description 12
- 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 12
- 229920001993 poloxamer 188 Polymers 0.000 claims description 12
- 229940044519 poloxamer 188 Drugs 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 229920002472 Starch Polymers 0.000 claims description 8
- 238000013019 agitation Methods 0.000 claims description 8
- 239000007919 dispersible tablet Substances 0.000 claims description 8
- 239000012530 fluid Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- 239000008215 water for injection Substances 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 7
- 239000002775 capsule Substances 0.000 claims description 7
- 238000001694 spray drying Methods 0.000 claims description 7
- 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 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 229920003081 Povidone K 30 Polymers 0.000 claims description 5
- 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 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 238000012856 packing Methods 0.000 claims description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 5
- 239000007779 soft material Substances 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 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 4
- 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 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 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
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 229940107161 cholesterol Drugs 0.000 claims description 4
- 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 4
- 239000008101 lactose Substances 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- -1 Aspartane Chemical compound 0.000 claims description 3
- 239000004375 Dextrin Substances 0.000 claims description 3
- 229920001353 Dextrin Polymers 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 3
- 238000004132 cross linking Methods 0.000 claims description 3
- 235000019425 dextrin Nutrition 0.000 claims description 3
- 238000005469 granulation Methods 0.000 claims description 3
- 230000003179 granulation Effects 0.000 claims description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 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 2
- 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 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
- 239000008118 PEG 6000 Substances 0.000 claims description 2
- 229920002584 Polyethylene Glycol 6000 Polymers 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
- 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
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 229960003943 hypromellose Drugs 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
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 2
- 229940085605 saccharin sodium Drugs 0.000 claims description 2
- 238000007873 sieving Methods 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 239000002002 slurry Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 claims 2
- 230000001154 acute effect Effects 0.000 abstract description 5
- 239000000853 adhesive Substances 0.000 abstract 1
- 230000001070 adhesive effect Effects 0.000 abstract 1
- 239000000796 flavoring agent Substances 0.000 abstract 1
- 235000013355 food flavoring agent Nutrition 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 239000003995 emulsifying agent Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 210000000481 breast Anatomy 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 239000004382 Amylase Substances 0.000 description 3
- 102000013142 Amylases Human genes 0.000 description 3
- 108010065511 Amylases Proteins 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 235000019418 amylase Nutrition 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000001804 emulsifying effect Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000005360 mashing Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 2
- 206010009866 Cold sweat Diseases 0.000 description 2
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 210000001953 common bile duct Anatomy 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 210000003786 sclera Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 206010000097 Abdominal tenderness Diseases 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- NGFKTFCPPHBWOS-AMWHJWHASA-N C(C(C)(C)C)(=O)[O].CC1=C(N2C(C(C2SC1)NC(\C(=N/OC)\C=1N=C(SC1)N)=O)=O)C(=O)O Chemical compound C(C(C)(C)C)(=O)[O].CC1=C(N2C(C(C2SC1)NC(\C(=N/OC)\C=1N=C(SC1)N)=O)=O)C(=O)O NGFKTFCPPHBWOS-AMWHJWHASA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010014418 Electrolyte imbalance Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010016717 Fistula Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020741 Hyperpyrexia Diseases 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 208000010718 Multiple Organ Failure Diseases 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- RRJHESVQVSRQEX-SUYBPPKGSA-N O-formylcefamandole Chemical compound CN1N=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)[C@H](OC=O)C=3C=CC=CC=3)[C@H]2SC1 RRJHESVQVSRQEX-SUYBPPKGSA-N 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 206010044248 Toxic shock syndrome Diseases 0.000 description 1
- 231100000650 Toxic shock syndrome Toxicity 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 210000003489 abdominal muscle Anatomy 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000000680 avirulence Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960002440 cefamandole nafate Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 239000007957 coemulsifier Substances 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009506 drug dissolution testing Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 230000003890 fistula Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000004868 gas analysis Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 208000006750 hematuria Diseases 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- 229950005770 hyprolose Drugs 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003886 intestinal anastomosis Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 210000000867 larynx Anatomy 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 208000029744 multiple organ dysfunction syndrome Diseases 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a cefetamet pivoxil hydrochloride submicron emulsion solid preparation, which comprises the following components in part by weight: 1 part of cefetamet pivoxil hydrochloride submicron emulsion grains, 0.4 to 3 parts of diluent, 0 to 0.5 part of disintegrating agent, 0 to 0.2 part of adhesive, 0 to 6 parts of flavoring agent, 0 to 0.4 part of aromatizer and 0 to 0.2 part of lubricant. The invention also discloses application of the preparation in preparation of a medicament for treating cholangitis, particularly acute pyogenic cholangitis.
Description
Technical field
The present invention relates to a kind of cefetamet pivoxil hydrochloride submicron emulsion solid preparation and new application the thereof, be specifically related to the solid preparation and new application the thereof of the Cefetamet Pivoxil Hydrochloride of a kind of process microemulsified processing, belong to medical technical field.
Background technology
Acute pyogenic cholangitis is because of biliary tract stenosis or the inaccessible cholestasis that causes, in addition bacterial infection and the acute festering type symptom takes place.The patient can show as the shiver with cold hyperpyrexia, jaundice and right hypochondrial region, the companion feels sick, vomits simultaneously, progress along with the state of an illness, bacteriogenic toxin not cracked ends sinus hepaticus enters concurrent pyemia of blood circulation and toxic shock, and body inspires multiple inflammatory mediator and generates because of hypoxic-ischemic produces a large amount of oxygen-derived free radicals, bring out pancreatitis, cause multiple organ dysfunction syndrome such as liver, kidney, the heart, lung, blood vessel.
Cefetamet Pivoxil Hydrochloride, its chemical name is: (6R, 7R)-the 3-methyl-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetylamino]-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-formic acid pivaloyl oxygen methyl ester hydrochloride, molecular formula: C
20H
25N
5O
7S
2HCl, molecular weight: 548.04, structural formula is:
For oral third generation broad-spectrum cephalosporin class antibiotic, gram positive bacteria and gram negative bacteria all there are very strong antibacterial activity, stable to bacteriogenic beta-lactamase.Be applicable to responsive microbial lower respiratory infection, ear, nose, larynx infection and urinary system infection etc. clinically.
At present, the listing preparation of Cefetamet Pivoxil Hydrochloride has tablet, capsule, granule, dispersible tablet, dry suspension, its poor stability, and dissolution is low, and it is insoluble problem that the raw material granulation is clamminess always.
Patent documentation CN1319533C discloses a kind of hydrochloric acid cefetamet pivoxil dispersible tablet and preparation method thereof, contain active component 25-35%, filler 55-70%, disintegrating agent 2.0-4.3%, correctives 1.0-2.0%, lubricant 0.5-2.0%, binding agent 0.2-0.4%, adopt boiling granulating technology, add adjuvant simultaneously and mix compacting in flakes.Patent documentation CN100484574C discloses a kind of hydrochloric acid cefetamet pivoxil dispersible tablet and preparation method thereof equally, raw material Cefetamet Pivoxil Hydrochloride and supplementary product starch, microcrystalline Cellulose, hyprolose, acesulfame potassium and carboxymethylstach sodium are done mixed wet mixing more earlier, airpillow-dry, tabletting.
Above-mentioned patent exists long-term shelf-stability poor, the problem that dissolution is low, the prescription that can not satisfy the prescriptive period.
The inventor is through research in earnest for a long time, unexpectedly find, using emulsion technique is handled the Cefetamet Pivoxil Hydrochloride raw material, can improve the stability of Cefetamet Pivoxil Hydrochloride greatly, but also significantly improved the dissolution of preparation, and use it for preparation treatment pyogenic cholangitis medicine, obtain unforeseeable technique effect, finished the present invention thus.
Summary of the invention
The object of the present invention is to provide a kind of cefetamet pivoxil hydrochloride submicron emulsion solid preparation and new application the thereof, specifically, the solid preparation of the Cefetamet Pivoxil Hydrochloride that the process microemulsified is handled and new application the thereof, the problem that Cefetamet Pivoxil Hydrochloride solid preparation poor stability, the dissolution that has well solved present listing is low, raw material is granulated and is clamminess, and can be used for preparation treatment pyogenic cholangitis medicine, obtained the satisfied technique effect of cold people.
The technical scheme that the present invention solves is as follows:
The invention provides a kind of Cefetamet Pivoxil Hydrochloride submicron emulsion granule, it is mainly made by following parts by weight by Cefetamet Pivoxil Hydrochloride, cholesterol, poloxamer 188 and sodium deoxycholate:
1 part of Cefetamet Pivoxil Hydrochloride
Cholesterol 2.5-15 part
Poloxamer 188 1.2-13 parts
Sodium deoxycholate 0.5-6 part.
As preferably, the parts by weight of each component of Cefetamet Pivoxil Hydrochloride submicron emulsion granule of the present invention are:
1 part of Cefetamet Pivoxil Hydrochloride
Cholesterol 4-10 part
Poloxamer 188 2.6-6 parts
Sodium deoxycholate 1-3.5 part.
As preferably, the parts by weight of each component of Cefetamet Pivoxil Hydrochloride submicron emulsion granule of the present invention are:
1 part of Cefetamet Pivoxil Hydrochloride
6.6 parts in cholesterol
188 4.1 parts of poloxamers
2.3 parts of sodium deoxycholates.
The present invention also provides a kind of preparation Cefetamet Pivoxil Hydrochloride submicron emulsion particulate method, comprise the steps: cholesterol, poloxamer 188 and sodium deoxycholate are added in the proper amount of water for injection, add the Cefetamet Pivoxil Hydrochloride 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 Cefetamet Pivoxil Hydrochloride.
Wherein, the amount of water for injection be all supplementary material weight summations 4-7 doubly; Tissue mincer is a JJ-2B type high-speed tissue mashing machine, and rotating speed is 10000-15000r/min, shear agitation 10-20 minute; High pressure dispersing emulsification machine model is NS1001L, by the import of Italian GEA Niro Soavi company, maximum working pressure (MWP) 1500bar, output 10L/hr, circulating emulsion 4-5 time.Above tissue mincer and high pressure dispersing emulsification machine and operation thereof are to enumerate explanation not limit, and this area has the equipment of identical function and operation well known in the art can be made and be used for finishing the present invention.
Though prior art openly discloses the method for preparing the submicron emulsion preparation already, for example two go on foot emulsion processes.At first under slight fever medicine (also cry and comprise emulsifying agent) is dissolved or be dispersed in the oil phase, dissolving such as emulsifying agent, isoosmotic adjusting agent or be dispersed in aqueous phase is with oil, water is biphase is heated to 70 ℃ respectively, biphase then mixing.Reuse gets slightly breast with emulsify at a high speed device (blender, tissue mashing machine etc.) high speed dispersion, and thick breast is cooled to-20 ℃ rapidly, through high pressure dispersing emulsification machine or the emulsifying of microjet machine, promptly gets submicron emulsion.Regulate pH value, remove by filter macroparticle, packing, pressure sterilizing, promptly.But the present invention has adopted diverse ways with it, 1) do not adopt oil for injection; 2) direct mixture; 3) need not to use freeze drying protectant; its benefit is: adopt water miscible emulsifier combination; the emulsifying in aqueous solution with active component and emulsifying agent; avoided the use oil for injection; simplified operating procedure; and adopt lyophilization or spray drying at last, and make emulsified particles, it is better to compare the submicron emulsion stability of solution.
The technical scheme that the present invention solves also comprises:
A kind of cefetamet pivoxil hydrochloride submicron emulsion solid preparation comprises above-mentioned Cefetamet Pivoxil Hydrochloride submicron emulsion granule and pharmaceutically acceptable excipient, and described solid preparation is preferably granule, tablet, capsule, dispersible tablet or dry suspension.
Wherein, used excipient is not particularly limited, usually be selected from pharmaceutically conventional excipient, cefetamet pivoxil hydrochloride submicron emulsion solid preparation of the present invention preferably comprises the following component of weight portion: 1 part of Cefetamet Pivoxil Hydrochloride submicron emulsion granule, diluent 0.4-3 part, disintegrating agent 0-0.5 part, binding agent 0-0.2 part, correctives 0-6 part, aromatic 0-0.4 part and lubricant 0-0.2 part.
As preferably, wherein, 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.
Further, the present invention also provides the preparation method of above-mentioned described cefetamet pivoxil hydrochloride submicron emulsion solid preparation, and it comprises the steps:
(1) Cefetamet Pivoxil Hydrochloride submicron emulsion granule is pulverized, crossed 80 mesh sieves, standby;
(2) diluent, disintegrating agent, correctives are pulverized, crossed 80 mesh sieves, mix, standby;
(3) with the said components 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 cefetamet pivoxil hydrochloride submicron emulsion solid preparation.
The present invention also provides Cefetamet Pivoxil Hydrochloride submicron emulsion granule to be used for the treatment of application in the medicine of cyst type acne in preparation.
The present invention also further provides cefetamet pivoxil hydrochloride submicron emulsion solid preparation to be used for the treatment of application in the medicine of pyogenic cholangitis in preparation.
The present invention makes Cefetamet Pivoxil Hydrochloride submicron emulsion granule by specific excipient and supplementary material proportioning thereof, Cefetamet Pivoxil Hydrochloride submicron emulsion granule provided by the invention and Cefetamet Pivoxil Hydrochloride solid preparation, and compared with prior art, major advantage is as follows:
(1) active ingredient hydrochloric acid Ro-15-8075 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 Cefetamet Pivoxil Hydrochloride submicron emulsion
1650g cholesterol, 1025g poloxamer 188 and 575g sodium deoxycholate are added in the 20L water for injection, add 250g Cefetamet Pivoxil Hydrochloride mix homogeneously again, 80 ℃ 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 3248g of Cefetamet Pivoxil Hydrochloride, yield 92.8%.
The particulate preparation of Comparative Examples 1 Cefetamet Pivoxil Hydrochloride submicron emulsion (adding different component)
1650g cholesterol, 1025g Tween 80 and 575g sodium lauryl sulphate are added in the 20L water for injection, add 250g Cefetamet Pivoxil Hydrochloride mix homogeneously again, 80 ℃ 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 3160g of Cefetamet Pivoxil Hydrochloride, yield 90.3%.
The particulate preparation of embodiment 2 Cefetamet Pivoxil Hydrochloride submicron emulsion
500g cholesterol, 325g poloxamer 188 and 125g sodium deoxycholate are added in the 6000ml water for injection, add 125g Cefetamet Pivoxil Hydrochloride mix homogeneously again, 90 ℃ 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 988g of Cefetamet Pivoxil Hydrochloride, yield 91.9%.
The particulate preparation of Comparative Examples 2 Cefetamet Pivoxil Hydrochloride submicron emulsion (adding not commensurability)
300g cholesterol, 145g poloxamer 188 and 60g sodium deoxycholate are added in the 6000ml water for injection, add 125g Cefetamet Pivoxil Hydrochloride mix homogeneously again, 90 ℃ 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 570g of Cefetamet Pivoxil Hydrochloride, yield 90.5%.
The particulate preparation of embodiment 3 Cefetamet Pivoxil Hydrochloride submicron emulsion
1250g cholesterol, 750g poloxamer 188 and 437.5g sodium deoxycholate are added in the 15000ml water for injection, add 125g Cefetamet Pivoxil Hydrochloride mix homogeneously again, 70 ℃ of heating in water bath are stirred to molten condition, adopt the shear agitation 20min of tissue mincer, rotating speed 15000r/min, get colostric fluid, again through high pressure dispersing emulsification machine circulating emulsion 5 times, emulsion, spray drying then, obtain the submicron emulsion granule 2390g of Cefetamet Pivoxil Hydrochloride, yield 93.3%.
The particulate preparation of Comparative Examples 3 Cefetamet Pivoxil Hydrochloride submicron emulsion (adopting two step emulsion processes)
Under 50 ℃ the 125g Cefetamet Pivoxil Hydrochloride is dispersed in the 750g injection soybean oil, 1250g cholesterol and 437.5g Tween 80 are dispersed in the 1000ml water, with oil, water is biphase is heated to 70 ℃ respectively, biphase then mixing.Reuse tissue mashing machine high speed dispersion gets slightly breast, and thick breast is cooled to-20 ℃ rapidly, through the emulsifying of high pressure dispersing emulsification machine, gets submicron emulsion.Spray drying then obtains the submicron emulsion granule 2163g of Cefetamet Pivoxil Hydrochloride, yield 84.4%.
The preparation of embodiment 4 Cefetamet Pivoxil Hydrochloride sheets
350g Cefetamet Pivoxil Hydrochloride submicron emulsion granule, 85g pregelatinized Starch, 77g microcrystalline Cellulose, the 40g carboxymethylstach sodium of embodiment 1 preparation are crossed 80 mesh sieves respectively, and mix homogeneously adds 5% 30 POVIDONE K 30 BP/USP then
3080% alcoholic solution 100ml makes soft material, and 20 mesh sieves are granulated, 60 ℃ of oven dry, and 20 mesh sieve granulate add 6g magnesium stearate mix homogeneously again, and tabletting makes the Cefetamet Pivoxil Hydrochloride sheet.
The preparation of Comparative Examples 4 Cefetamet Pivoxil Hydrochloride sheets is made by the Cefetamet Pivoxil Hydrochloride submicron emulsion granule of Comparative Examples 1.
The preparation of embodiment 5 cefetamet pivoxil hydrochloride capsules
With 108.1g Cefetamet Pivoxil Hydrochloride submicron emulsion granule, 50g starch and the 3.5g Pulvis Talci mix homogeneously of embodiment 2 preparations, filled capsules makes cefetamet pivoxil hydrochloride capsule.
The preparation of Comparative Examples 5 cefetamet pivoxil hydrochloride capsules is made by the Cefetamet Pivoxil Hydrochloride submicron emulsion granule of Comparative Examples 2.
The preparation of embodiment 6 hydrochloric acid cefetamet pivoxil dispersible tablets
107.7g Cefetamet Pivoxil Hydrochloride submicron emulsion granule, 80g microcrystalline Cellulose, 30g lactose, 18g Aspartane, 15g low-substituted hydroxypropyl cellulose and the 10g cross-linking sodium carboxymethyl cellulose of embodiment 2 preparations are crossed 80 mesh sieves respectively, mix homogeneously adds 4% 30 POVIDONE K 30 BP/USP then
3060% alcoholic solution 80ml makes soft material, and 20 mesh sieves are granulated, 65 ℃ of oven dry, and 20 mesh sieve granulate add 2.8g magnesium stearate mix homogeneously again, and tabletting makes hydrochloric acid cefetamet pivoxil dispersible tablet.
The preparation of Comparative Examples 6 hydrochloric acid cefetamet pivoxil dispersible tablets is made by the Cefetamet Pivoxil Hydrochloride submicron emulsion granule of Comparative Examples 2.
The particulate preparation of embodiment 7 Cefetamet Pivoxil Hydrochlorides
256.6g Cefetamet Pivoxil Hydrochloride submicron emulsion granule, 1130g sucrose, 420g mannitol, 80g dextrin, 32g Fructus Citri tangerinae XIANGFEN and the 22g Aspartane of embodiment 3 preparations are crossed 80 mesh sieves respectively, and mix homogeneously adds 8% 30 POVIDONE K 30 BP/USP then
3060% alcoholic solution 350ml makes soft material, and 20 mesh sieves are granulated, 60 ℃ of oven dry, and 20 mesh sieve granulate, packing makes the Cefetamet Pivoxil Hydrochloride granule.
The preparation of embodiment 8 Cefetamet Pivoxil Hydrochloride dry suspension
256.1g Cefetamet Pivoxil Hydrochloride submicron emulsion granule, 850g sucrose, 600g mannitol, 120 lactose, 77g Fructus Fragariae Ananssae XIANGFEN, the 38g Pulvis Talci of embodiment 3 preparation are crossed 80 mesh sieves respectively, mix homogeneously then, packing makes the Cefetamet Pivoxil Hydrochloride dry suspension.
Test example 1 dissolution detects
The sample for preparing among the sample of embodiment of the invention 4-6 preparation and Comparative Examples 4-6, patent documentation CN1319533C, the patent documentation CN100484574C is carried out dissolution detection, result such as table 1.
Table 1 dissolution testing result
Can find out by The above results, the sample for preparing among the sample of embodiment of the invention 4-6 preparation and Comparative Examples 4-6, patent documentation CN1319533C, the patent documentation CN100484574C compares dissolution and is significantly improved, and proved absolutely that the present invention is at the superiority that improves aspect the dissolution.
Test example 2 study on the stability
With the sample of embodiment of the invention 4-8, Comparative Examples 4-6, patent documentation CN1319533C and patent documentation CN100484574C 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 Comparative Examples 4-6, patent documentation CN1319533C and patent documentation CN100484574C 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 4-8 preparation does not all have obvious variation.Illustrated that the present invention is at the superiority that improves aspect stable.
Test example 3 clinical preceding preparations
1, case selection is selected acute pyogenic cholangitis patient 78 examples, male 53 examples, women 25 examples, ages 25～78 example; 72 examples of wherein suffering from abdominal pain, 68 examples of generating heat, abdominal tenderness 54 examples, rebound tenderness 21 examples, yellow sclera 10 examples, 8 examples of suffering a shock, disturbance of consciousness 2 examples.The lab testing result: numeration of leukocyte increases 53 examples, and blood amylase increases 20 examples, and amylase in urine increases 17 examples, and bilirubin increases 35 examples, and the transaminase increases 26 examples, renal dysfunction 7 examples, electrolyte disturbance 27 examples, hypoxemia 13 examples; Serious symptom pyogenic cholangitis 8 examples wherein.78 routine patients are divided into cefamandole nafate internal therapy group (A organizes 27 examples) at random, matched group (B organizes 25 examples) and listing sample matched group (C organizes 26 examples), and three groups all have comparability at aspects such as age, sex, disease type and the state of an illness.
2, the conventional fasting of Therapeutic Method B group patient, gastrointestinal decompression, spasmolysis and analgesia, vein fluid infusion, correct Water-Electrolyte disorder and acid-base balance, nutritional support, anticholinergic agent, infection, support is suited the medicine to the illness and liver protecting therapy the time, actively goes operative treatment.The A group adds the Cefetamet Pivoxil Hydrochloride sheet with the embodiment of the invention 4 preparations, a 500mg, 2 times on the one on the basis of B group treatment.C group therapeutic scheme is identical with the A group, selects the Cefetamet Pivoxil Hydrochloride sheet of the Lukang Medical Co., Ltd., Shandong of having gone on the market for use, each 500mg, 2 times on the one.Three groups is a course of treatment with 10d all.
3, observation index symptom: comprise stomachache, heating, feel sick, vomiting etc.; Sign comprises tension of abdominal muscle, tenderness, rebound tenderness, yellow sclera, shock etc.; Lab index comprises routine blood test, hematuria amylase, liver function, renal function, blood electrolyte, blood gas analysis etc., recording blood pressure, pulse, body temperature.
4, therapeutic evaluation standard clinical criterion of therapeutical effect is divided recovery from illness, produce effects, progress and invalid 4 grades of evaluations.Recovery from illness: symptom, sign, lab index recover normal; Produce effects: the state of an illness is clearly better, but has 1 not recover normal fully in above-mentioned 4; Progressive: the state of an illness takes a turn for the better to some extent, but not obvious; Invalid: the state of an illness does not have and alleviates behind the medication 10d.Recovery from illness and produce effects add up to effectively.
Test example 4 clinical test results
1, a dead example (B group) in clinical efficacy 78 examples for shock appears driving in the wrong direction when being admitted to hospital in morbidity 5d, loses operation opportunity, and it is dead that all rescue measures proved ineffectual, remembers that curative effect is invalid.2 examples (A group and each 1 example of B group) refusal is performed the operation and is left hospital, and does not count object of study.2 customary expectant treatments, the equal early operation treatment of other cases.The art formula comprises: exploration of common bile duct, T Tube Drain art; Common bile duct and intestinal anastomosis art etc., bile leakage after operation 1 example (C group), conservative healing, no fistula of operative incision.
Clinical efficacy after three groups of treatments of table 3
Annotate: compare with matched group:
★P＜0.05; Compare with the listing sample:
△P＜0.05.
The A group has 16 examples to cure, 7 routine produce effects, and total effective rate is 88.46%; B group 10 examples are cured, 5 routine produce effects, and total effective rate is 62.5%; C group 13 examples are cured, 5 routine produce effects, and total effective rate is 69.23%.The A group is compared with B group, C group, and the total effective rate diversity is (P＜0.05) significantly.
2, there are 2 routine patients symptoms such as headache to occur in the untoward reaction therapeutic process in the observation group, do not influence treatment; There are 3 routine patients to occur feeling sick, vomitting phenomenon in the listing sample sets, after taking metoclopramide, improve.Family numbers of patients all has good reflection, gives Cefetamet Pivoxil Hydrochloride sheet of the present invention higher evaluation.As seen the Cefetamet Pivoxil Hydrochloride sheet is efficient, a safety, the novel therapeutic acute pyogenic cholangitis medicine that patient tolerability is good.
Claims (11)
1. a Cefetamet Pivoxil Hydrochloride submicron emulsion granule is characterized in that mainly being made by Cefetamet Pivoxil Hydrochloride, cholesterol, poloxamer 188 and sodium deoxycholate, by following parts by weight:
1 part of Cefetamet Pivoxil Hydrochloride
Cholesterol 2.5-15 part
Poloxamer 188 1.2-13 parts
Sodium deoxycholate 0.5-6 part.
2. Cefetamet Pivoxil Hydrochloride submicron emulsion granule according to claim 1 is characterized in that each composition weight umber is:
1 part of Cefetamet Pivoxil Hydrochloride
Cholesterol 4-10 part
Poloxamer 188 2.6-6 parts
Sodium deoxycholate 1-3.5 part.
3. Cefetamet Pivoxil Hydrochloride submicron emulsion granule according to claim 1 is characterized in that each composition weight umber is:
1 part of Cefetamet Pivoxil Hydrochloride
6.6 parts in cholesterol
188 4.1 parts of poloxamers
2.3 parts of sodium deoxycholates.
4. one kind prepares as the particulate method of each described Cefetamet Pivoxil Hydrochloride submicron emulsion of claim 1-3, it is characterized in that comprising the steps: cholesterol, poloxamer 188 and sodium deoxycholate are added in an amount of water for injection, add the Cefetamet Pivoxil Hydrochloride mix homogeneously again, 70-90 ℃ of heating in water bath is stirred to molten condition, adopt tissue mincer's shear agitation, get colostric fluid, again through high pressure dispersing emulsification machine circulating emulsion, get emulsion, lyophilization or spray drying then obtain the submicron emulsion granule of Cefetamet Pivoxil Hydrochloride.
5. cefetamet pivoxil hydrochloride submicron emulsion solid preparation, it is characterized in that comprising each described Cefetamet Pivoxil Hydrochloride submicron emulsion granule of claim 1-4 and pharmaceutically acceptable other excipient, described solid preparation is selected from granule, tablet, capsule or dry suspension.
6. cefetamet pivoxil hydrochloride submicron emulsion solid preparation according to claim 5 is characterized in that described solid preparation is the following component that comprises by weight: 1 part of Cefetamet Pivoxil Hydrochloride submicron emulsion granule, diluent 0.4-3 part, disintegrating agent 0-0.5 part, binding agent 0-0.2 part, correctives 0-6 part, aromatic 0-0.4 part and lubricant 0-0.2 part.
7. cefetamet pivoxil hydrochloride submicron emulsion solid preparation according to claim 6 is characterized in that described diluent is selected from one or more in microcrystalline Cellulose, lactose, starch, pregelatinized Starch, sorbitol, mannitol, dextrin, calcium sulfate, the calcium hydrogen phosphate; Perhaps 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; Perhaps 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; Perhaps described correctives is selected from one or more in sucrose, Aspartane, saccharin sodium, the steviosin; Perhaps 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; Perhaps described lubricant is selected from one or more in magnesium stearate, Pulvis Talci, colloidality silicon dioxide, PEG6000, the sodium lauryl sulphate.
8. method for preparing each described cefetamet pivoxil hydrochloride submicron emulsion solid preparation of claim 5-7, it comprises the steps:
(1) Cefetamet Pivoxil Hydrochloride submicron emulsion granule is pulverized, crossed 80 mesh sieves, 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 cefetamet pivoxil hydrochloride submicron emulsion solid preparation.
9. Cefetamet Pivoxil Hydrochloride submicron emulsion granule according to claim 1 is used for the treatment of application in the medicine of pyogenic cholangitis in preparation.
10. cefetamet pivoxil hydrochloride submicron emulsion solid preparation according to claim 5 is used for the treatment of application in the medicine of pyogenic cholangitis in preparation.
11. a cefetamet pivoxil hydrochloride submicron emulsion solid preparation is characterized in that comprising each described Cefetamet Pivoxil Hydrochloride submicron emulsion granule of claim 1-4 and pharmaceutically acceptable other excipient, described solid preparation is selected from dispersible tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102299661A CN101721371B (en) | 2009-11-12 | 2009-11-12 | Cefetamet pivoxil hydrochloride submicron emulsion solid preparation and new application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102299661A CN101721371B (en) | 2009-11-12 | 2009-11-12 | Cefetamet pivoxil hydrochloride submicron emulsion solid preparation and new application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101721371A CN101721371A (en) | 2010-06-09 |
| CN101721371B true CN101721371B (en) | 2011-07-06 |
Family
ID=42443327
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009102299661A Expired - Fee Related CN101721371B (en) | 2009-11-12 | 2009-11-12 | Cefetamet pivoxil hydrochloride submicron emulsion solid preparation and new application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101721371B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102397249B (en) * | 2011-07-14 | 2013-01-23 | 海南美大制药有限公司 | Cefetamet pivoxil hydrochloride liposome solid preparation |
| 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 |
-
2009
- 2009-11-12 CN CN2009102299661A patent/CN101721371B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN101721371A (en) | 2010-06-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2001289699B2 (en) | New pharmaceutical composition | |
| CN112891546A (en) | Site-specific enteral delivery of adsorbents alone or in combination with degrading molecules | |
| CN101623259B (en) | Amoxicillin lipidosome solid preparation | |
| RU2201272C2 (en) | Application of inhibitors of gastro- intestinal lipase | |
| CN101069675A (en) | A method of alleviating signs and symptons of spasticity | |
| EP1663187A2 (en) | Antiflatulents in combination with histamine h1-receptor antagonists for treating gastrointestinal disorders | |
| EP2117550A1 (en) | Use of ranolazine for the treatment of non-coronary microvascular diseases | |
| US20160354387A1 (en) | Pharmaceutical composition based on a hepatoprotector and a prebiotic, and production and application thereof | |
| CN101103960A (en) | Dry mixed suspension containing racecadotril and preparation method thereof | |
| CN101721371B (en) | Cefetamet pivoxil hydrochloride submicron emulsion solid preparation and new application thereof | |
| CN101632677A (en) | Suspension powder injection of cefoperazone sodium and tazobactam sodium pharmaceutical composition and new application thereof | |
| CN101708166B (en) | Cefpodoxime proxetil submicron emulsion solid preparation and novel application thereof | |
| CN101612159A (en) | The application of chemical compound 20 (S)-ginsenoside Rh2 in the preparation anti-fatigue medicament | |
| CN101721373B (en) | Solid cefdinir sub-microemulsion and application thereof | |
| CN101757627A (en) | Combined drug and drug combination for treating diabetes | |
| CN101982174A (en) | Formula of compound medicine preparation for relieving cough and preventing asthma and preparation method thereof | |
| CN101700232B (en) | Cefprozil submicron emulsion solid preparation and new application thereof | |
| CN101780075B (en) | Combined drug for treating insomnia | |
| CN101524353B (en) | Oral anti-allergy compound pharmaceutical composition | |
| CN102716128A (en) | Pharmaceutical composition for treating asthma | |
| WO2005105109A1 (en) | Oral modified-release lozenges and their preparation method | |
| CN102228457A (en) | Pharmaceutical composition for treating diabetes and complication thereof | |
| EP1957090A1 (en) | Use of adsorbent carbon microspheres for the treatment of irritable bowel syndrome | |
| CN102218062B (en) | Medicine composition for treating diabetes mellitus | |
| CN1736386A (en) | Pharmaceutical formulation for treating skin allergy and preparation process thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: HAINAN MEIDA PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: WANG MING Effective date: 20130723 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 570125 HAIKOU, HAINAN PROVINCE TO: 570216 HAIKOU, HAINAN PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20130723 Address after: 570216 C03, Haikou Free Trade Zone, Hainan, China Patentee after: Hainan Meida Pharmaceutical Co., Ltd. Address before: The new business building No. 48 570125 Hainan city of Haikou province China World Trade Center Road, room 2601 Patentee before: Wang Ming |
|
| DD01 | Delivery of document by public notice |
Addressee: Hainan Meida Pharmaceutical Co., Ltd. Document name: Notification to Pay the Fees |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110706 Termination date: 20161112 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |