CN1857239A - Coenzyme Q10 injection emulsion and its preparing process - Google Patents
Coenzyme Q10 injection emulsion and its preparing process Download PDFInfo
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- CN1857239A CN1857239A CN 200610046134 CN200610046134A CN1857239A CN 1857239 A CN1857239 A CN 1857239A CN 200610046134 CN200610046134 CN 200610046134 CN 200610046134 A CN200610046134 A CN 200610046134A CN 1857239 A CN1857239 A CN 1857239A
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- Prior art keywords
- injection
- coenzyme
- emulsion
- preheated
- water
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- 239000000839 emulsion Substances 0.000 title claims abstract description 75
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 title claims abstract description 69
- 238000002347 injection Methods 0.000 title claims abstract description 66
- 239000007924 injection Substances 0.000 title claims abstract description 66
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 235000017471 coenzyme Q10 Nutrition 0.000 title claims abstract description 42
- 229940110767 coenzyme Q10 Drugs 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000008215 water for injection Substances 0.000 claims abstract description 18
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 9
- 235000006708 antioxidants Nutrition 0.000 claims abstract description 9
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 8
- 239000007957 coemulsifier Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 8
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 8
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 8
- 239000008158 vegetable oil Substances 0.000 claims abstract description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 43
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 26
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 22
- 238000004945 emulsification Methods 0.000 claims description 18
- 239000002245 particle Substances 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 17
- 235000011187 glycerol Nutrition 0.000 claims description 15
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 13
- 229930003427 Vitamin E Natural products 0.000 claims description 13
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 13
- 229920001983 poloxamer Polymers 0.000 claims description 13
- 229960000502 poloxamer Drugs 0.000 claims description 13
- 235000019165 vitamin E Nutrition 0.000 claims description 13
- 229940046009 vitamin E Drugs 0.000 claims description 13
- 239000011709 vitamin E Substances 0.000 claims description 13
- 239000004530 micro-emulsion Substances 0.000 claims description 12
- 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 11
- 239000007788 liquid Substances 0.000 claims description 11
- 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 10
- 229930195725 Mannitol Natural products 0.000 claims description 10
- 239000000594 mannitol Substances 0.000 claims description 10
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 238000005360 mashing Methods 0.000 claims description 10
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 10
- 235000012424 soybean oil Nutrition 0.000 claims description 10
- 239000003549 soybean oil Substances 0.000 claims description 10
- 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 9
- 238000009472 formulation Methods 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 9
- 239000000787 lecithin Substances 0.000 claims description 9
- 229940067606 lecithin Drugs 0.000 claims description 9
- 235000010445 lecithin Nutrition 0.000 claims description 9
- 229940083466 soybean lecithin Drugs 0.000 claims description 9
- 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 8
- 239000008101 lactose Substances 0.000 claims description 8
- 230000001954 sterilising effect Effects 0.000 claims description 8
- 238000004659 sterilization and disinfection Methods 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000003643 water by type Substances 0.000 claims description 6
- 102000002322 Egg Proteins Human genes 0.000 claims description 5
- 108010000912 Egg Proteins Proteins 0.000 claims description 5
- 241000287828 Gallus gallus Species 0.000 claims description 5
- 235000005687 corn oil Nutrition 0.000 claims description 5
- 239000002960 lipid emulsion Substances 0.000 claims description 5
- 210000004681 ovum Anatomy 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- -1 Palmic acid diol ester Chemical class 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 238000005070 sampling Methods 0.000 claims description 4
- 210000000582 semen Anatomy 0.000 claims description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical group O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 4
- 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
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- 239000003921 oil Substances 0.000 claims description 3
- 235000019198 oils Nutrition 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound 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
- OYHQOLUKZRVURQ-HZJYTTRNSA-M 9-cis,12-cis-Octadecadienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC([O-])=O OYHQOLUKZRVURQ-HZJYTTRNSA-M 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
- 244000068988 Glycine max Species 0.000 claims description 2
- 235000010469 Glycine max Nutrition 0.000 claims description 2
- 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 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019485 Safflower oil Nutrition 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 235000012000 cholesterol Nutrition 0.000 claims description 2
- 229940107161 cholesterol Drugs 0.000 claims description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000002168 ethanoic acid esters Chemical class 0.000 claims description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 claims description 2
- XSEOYPMPHHCUBN-FGYWBSQSSA-N hydroxylated lecithin Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCC[C@@H](O)[C@H](O)CCCCCCCC XSEOYPMPHHCUBN-FGYWBSQSSA-N 0.000 claims description 2
- 229940049918 linoleate Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 229930182817 methionine Natural products 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000000473 propyl gallate Substances 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 229940075579 propyl gallate Drugs 0.000 claims description 2
- 235000005713 safflower oil Nutrition 0.000 claims description 2
- 239000003813 safflower oil Substances 0.000 claims description 2
- OARRHUQTFTUEOS-UHFFFAOYSA-N safranin Chemical compound [Cl-].C=12C=C(N)C(C)=CC2=NC2=CC(C)=C(N)C=C2[N+]=1C1=CC=CC=C1 OARRHUQTFTUEOS-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 2
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 229940001474 sodium thiosulfate Drugs 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- 235000010199 sorbic acid Nutrition 0.000 claims description 2
- 239000004334 sorbic acid Substances 0.000 claims description 2
- 229940075582 sorbic acid Drugs 0.000 claims description 2
- 239000008347 soybean phospholipid Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims 1
- 239000003925 fat Substances 0.000 claims 1
- WIBFFTLQMKKBLZ-SEYXRHQNSA-N n-butyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCCCC WIBFFTLQMKKBLZ-SEYXRHQNSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 230000008685 targeting Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 5
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 4
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 230000001804 emulsifying effect Effects 0.000 description 3
- 229920001993 poloxamer 188 Polymers 0.000 description 3
- 229940044519 poloxamer 188 Drugs 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- ACCCMOQWYVYDOT-UHFFFAOYSA-N hexane-1,1-diol Chemical compound CCCCCC(O)O ACCCMOQWYVYDOT-UHFFFAOYSA-N 0.000 description 1
- 229960001438 immunostimulant agent Drugs 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000010297 mechanical methods and process Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[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 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000010415 tropism Effects 0.000 description 1
- 229940035936 ubiquinone Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The coenzyme Q10 injection emulsion has coenzyme Q10 as the effective medicine component, and each 1000 ml emulsion contains coenzyme Q10 1-10g, vegetable oil for injection 0-200g, emulsifier 1-50g, isoosmotic regulator 5-50g, antioxidant 0.05-5g, pH regulator in the quantity of regulating pH value to 3.0-9.0, co-emulsifier 10-500g and water for injection for the rest. It provides the patient with treating medicine and essential nourishing matter. It has high physical stability and may be prepared into freeze dried preparation for further raised stability and convenient storing and transportation. The coenzyme Q10 injection emulsion has certain targeting effect, so that it has raised bioavailability and lowered toxic side effect.
Description
(1) technical field
The present invention relates to medical technical field, exactly is a kind of injectable emulsion and lyophilized formulations thereof that contains coenzyme Q10.
(2) background technology
Coenzyme Q10 is one of important member of coenzyme Q kind, and it is the chemical compound of a class quinone.Claim ubiquinone again, universal quinone, the derivant of oxidized coenzyme Q10 etc.Coenzyme Q10 extensively is present in leaf and the seed of yeast, plant, and in the heart of animal, spleen, liver and the kidney.
Clinically, coenzyme Q10 is important antioxidants and immunostimulant.Be mainly used in the disease of aspects such as the treatment heart, lung, liver.In recent years, a lot of in the research of carrying out aspect the extraction of coenzyme Q10 crude drug and the preparation, Japan was engaged in this production existing more than 30 year, had overwhelming superiority technically.About the preparation of coenzyme Q10, correlational study both domestic and external is also a lot, and the product that mainly goes on the market has tablet, capsule, injection etc.All there is Related product production in enterprises such as Wuzhong, Jiangsu Suzhou No.6 Pharmaceutical Factory of Industry Co.,Ltd, Taizhou pharmacy head factory, biochemical-pharmaceutical factory, Qingdao, Anhui BBCA Pharmaceuticals Co., Ltd..Obviously, this medicine prior dosage form is difficult to satisfy the needs of its disease for the treatment of.Tablet, capsule etc. are difficult to take for the patient of dysphagia, and all there are shortcomings such as bioavailability is low in tablet and capsule.Because coenzyme Q10 is a fat-soluble medicine, the concentration of one side in injection, promptly dissolubility is restricted, makes the clinical application kind single; Preparation is easily separated out at the process Chinese medicine that stores on the other hand, and physical stability is bad; In addition, coenzyme Q 10 injection lacks good body internal target tropism, and bioavailability is lower.Therefore this research is made injectable emulsion (comprising: lipomul, submicronized emulsion, microemulsion and freeze-dried emulsion thereof) afterwards with coenzyme Q10, can remedy the deficiency that the existing preparation of coenzyme Q10 exists.
(3) summary of the invention
The object of the present invention is to provide and to be directly used in intravenous good stability, obvious results coenzyme Q 10 injection emulsion and preparation method.
The technical scheme that adopts is:
Coenzyme Q 10 injection emulsion comprises lipomul, submicronized emulsion, microemulsion, and is included in fat emulsion for injection lyophilized formulations, submicronized emulsion lyophilized formulations and the microemulsion lyophilized formulations for preparing on the coenzyme Q 10 injection emulsion basis.
Coenzyme Q 10 injection emulsion is to be mixed with by coenzyme Q10, injection vegetable oil, emulsifying agent, isoosmotic adjusting agent, antioxidant, pH regulator agent, coemulsifier and water for injection.In every 1000ml injectable emulsion, contain:
PH to 3.0-9.0 is transferred in coenzyme Q10 1-10g, injection vegetable oil 0-200g, emulsifying agent 1-50g, isoosmotic adjusting agent 5-50g, antioxidant 0.05-5g, coemulsifier 10-500g, pH regulator agent, and surplus is a water for injection.
Above-mentioned injection vegetable oil is: the mixture of one or more in soybean oil, Oleum sesami, safranine caul-fat, Oleum Arachidis hypogaeae semen, Oleum Ricini, Oleum Camelliae, safflower oil, the Semen Maydis oil.
Soybean oil is selected from and contains: the soybean oil of one or more compositions in long chain triglyceride, medium chain triglyceride, glycerin mono-fatty acid ester, the glycerol list linoleate.
Mentioned emulsifier is: lecithin, hydroxylated lecithin, soybean phospholipid, soybean lecithin, hydrogenated soya phosphatide, Ovum Gallus domesticus Flavus lecithin, poloxamer, cholesterol, (deoxidation) sodium cholate, polyglycereol Palmic acid diol ester, acetic acid esters of mono, polyoxyethylene anhydrate sorbic acid cetylate, poly-hexanediol, 1, the mixture of one or more among 2-propylene glycol, the Drewmulse.
Above-mentioned isoosmotic adjusting agent is: the mixture of one or more in glucose, sodium chloride, sorbitol, xylitol, the mannitol.
Above-mentioned pH regulator agent is: the mixture of one or more in hydrochloric acid, phosphoric acid, citric acid (sodium), sodium hydroxide (potassium), glacial acetic acid, buffer agent such as sodium dihydrogen phosphate and the sodium hydrogen phosphate.
Above-mentioned antioxidant is: the mixture of one or more in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, ascorbic acid, propyl gallate, ascorbyl palmitate, butylated hydroxyarisol (BHA), ditertbutylparacresol (BHT), vitamin E, cysteine, the methionine.
Above-mentioned coemulsifier is: glycerol, Polyethylene Glycol, 1, the mixture of one or more in 2-propylene glycol, n-butyl alcohol, ethylene glycol, propylene glycol, the polyglycerin ester.
Above-mentioned emulsification method can be selected phase conversion emulsifying or PIT emulsion process for use, replace liquid feeding emulsion process, continuous emulsifying method, Mechanical Method (stirring and emulsifying device, dispersing emulsification machine, colloid mill, ultrasonic emulsification device), low-energy emulsification method, Micro Fluid method etc.
Fat emulsion for injection particle size of emulsion scope should be preferably less than 0.5 micron at the 0.1-0.8 micron.Submicronized emulsion emulsion particle diameter scope should be at the 0.1-0.5 micron.Microemulsion emulsion particle diameter scope should be about 0.2 micron.On the basis of above-mentioned lipomul, submicronized emulsion, microemulsion emulsion, adding mannitol, lactose are made the injection freeze-dried emulsion through lyophilization, and injection freeze-dried emulsion, every 1000ml contain coenzyme Q10 1-10g, mannitol 5-300g, lactose 10-300g.
The preparation method of coenzyme Q 10 injection emulsion, 1000ml is an example with preparation, is to get emulsifying agent 1-50g, coenzyme Q10 1-10g and injection vegetable oil 0-200g, is heated to 45-80 ℃, and its dissolving is mixed, it is standby to make medicinal liquid; Get isoosmotic adjusting agent 5-50g, antioxidant 0.05-5g and account for the water for injection of gross weight 20-50% miscible, be heated to 45-80 ℃, add the above-mentioned medicinal liquid that has made, mixing disperses through tissue mashing machine, and per minute 20000 changes, and three minutes, triplicate; Add coemulsifier 10-500g, mend to 1000ml, be adjusted to pH3.0-9.0, cross the high pressure dispersing emulsification machine, three times repeatedly with pH value with being preheated to 45-80 ℃ of water for injection, sampling, microscopically is observed particle diameter, stops when emulsion particle diameter meets the requirements, and filters, embedding, sterilization, numbering promptly gets product.
The preparation of freeze-dried emulsion may further comprise the steps: mannitol that on the basis of above-mentioned emulsion, adds and lactose, and lyophilization is collected content and is promptly got freeze-dried emulsion, and every 1000ml contains mannitol 5-300g, lactose 10-300g.
The invention has the advantages that:
Coenzyme Q10 fat-soluble seen characteristics such as photo-labile, makes the preparation of its preparation have certain difficulty, but its fat-soluble characteristics provide convenience for the preparation of Emulsion just.The patient that is prepared as of coenzyme Q10 Emulsion provides administering modes such as injection and infusion, and dosage range is wide, is convenient to the doctor and implements individual administration according to patient's concrete condition.
The lipomul of coenzyme Q10 has been not only for the patient provides Drug therapy, and provides necessary nutrient substance for weak patient.(microemulsion is transparent, and particle diameter is about 0.2 micron owing to particle in the emulsion is less for microemulsion and submicronized emulsion; Submicron emulsion is translucent, and size ratio microemulsion particle diameter is big slightly), the Emulsion physical stability is good, has solved the bad difficult problem of emulsion stability.The preparation of corresponding freeze-drying preparation for injection has further solved the stability of formulation problem, has made things convenient for the storage and the circulation of product simultaneously.Have certain target function in vivo owing to Emulsion in addition, thereby improved the bioavailability of preparation, reduced the toxic and side effects of medicine.
(4) specific embodiment
Embodiment one
Coenzyme Q 10 injection emulsion, this Emulsion is fat emulsion for injection, is example with 1000ml, is by Ovum Gallus domesticus Flavus lecithin 15.0g, refined soybean oil 100g, coenzyme Q10 4.00g, vitamin e1 .00g gets glycerol 50.0g, poloxamer F
6810.0g add the injection water after being mixed with to 1000ml, regulate pH value 3-9 and be prepared into.
Embodiment two
Coenzyme Q 10 injection emulsion, this Emulsion is the injection submicronized emulsion, is example with 1000ml, is by soybean lecithin 10.0g, coenzyme Q10 5.00g, vitamin E 0.500g gets 1,2-propylene glycol 100g, poloxamer F
68After 20g is mixed with, add the injection water, regulate pH value 3-9 and be prepared into to 1000ml.
Embodiment three
Coenzyme Q 10 injection emulsion, this Emulsion is the injection microemulsion, is example with 1000ml, is by coenzyme Q10 6.00g, vitamin E 0.100g, 1,2-propylene glycol 300g, poloxamer 30g adds the injection water to 1000ml after glycerol 15g is mixed with, regulate pH value 3-9 and be prepared into.
Embodiment four
The lyophilized preparation of coenzyme Q 10 injection emulsion is by coenzyme Q10 5g, soybean lecithin 12g, and poloxamer 15g, mannitol 30g, lactose 20g through disperseing, spares matter, and lyophilization is prepared into.
Embodiment five
Coenzyme Q 10 injection Emulsion is example with 1000ml, is by adding the injection water to 1000ml after coenzyme Q10 5g, refined soybean oil 100g, lecithin 25g, sorbitol 25g, sodium sulfite 2.5g, the glycerol 250g preparation, regulating pH value 3-9 and be prepared into.
Embodiment six
Coenzyme Q 10 injection Emulsion is example with 1000ml, is by coenzyme Q10 9.5g, refined soybean oil 195g, lecithin 48g, glucose 45g, adds the injection water after vitamin E 4g, the glycerol 480g preparation to 1000ml, regulates pH value 3-9 and is prepared into.
Embodiment seven
The preparation method of coenzyme Q 10 injection emulsion (fat emulsion for injection) is: (1) gets Ovum Gallus domesticus Flavus lecithin 15.0g, refined soybean oil 100g, and coenzyme Q10 4.00g, vitamin E 1.00g is preheated to 70 ℃, stirring and evenly mixing.(2) get glycerol 50.0g, poloxamer 188 (F
68) 10.0g and account for total amount 20-50% water for injection, be preheated to 70 ℃, stirring and evenly mixing.The solution that (2) are made joins in the solution that (1) make, and the limit edged stirs, and disperses through tissue mashing machine, and per minute 20000 changes, and three minutes, triplicate.(3) add and be preheated to 70 ℃ of waters for injection, transfer pH to 3-9, cross the high pressure dispersing emulsification machine repeatedly, examine under a microscope particle diameter, stop when emulsion particle diameter meets the requirements until sample with the pH regulator agent to full dose 1000ml.(4) filter, embedding, sterilization, numbering gets product.
Embodiment eight
The preparation method of coenzyme Q 10 injection emulsion (injection submicronized emulsion) is: (1) gets soybean lecithin 10.0g, coenzyme Q10 5.00g, and vitamin E 0.500g is preheated to 70 ℃ of stirrings, and mixing is standby.(2) get 1,2-propylene glycol 100g, poloxamer 188 (F
68) 20g and the water for injection that accounts for total amount 20-50% is preheated to 70 ℃, stirring and evenly mixing.The solution that (2) are made joins in the solution that (1) make, and the limit edged stirs, and disperses through tissue mashing machine, and per minute 20000 changes, and three minutes, triplicate.(3) add and be preheated to 70 ℃ of waters for injection, transfer pH to 3-9, cross the high pressure dispersing emulsification machine repeatedly, examine under a microscope, stop when emulsion particle diameter meets the requirements until sample with the pH regulator agent to full dose 1000ml.(4) filter, embedding, sterilization, numbering gets product.
Embodiment nine
The preparation method of coenzyme Q 10 injection emulsion (injection microemulsion) is: (1) gets coenzyme Q10 6.00g, and vitamin E 0.100g is preheated to 70 ℃, and stirring and evenly mixing is standby.(2) get 1,2-propylene glycol 300g, poloxamer 188 (F
68) 30g, glycerol 15g and the water for injection that accounts for total amount 20-50% are preheated to 70 ℃, stirring and evenly mixing.The solution that (2) are made joins in the solution that (1) make, and the limit edged stirs, and disperses through tissue mashing machine, and per minute 20000 changes, and three minutes, triplicate.(3) add and be preheated to 70 ℃ of waters for injection in right amount, transfer to 3-9, cross the high pressure dispersing emulsification machine repeatedly, examine under a microscope, stop when emulsion particle diameter meets the requirements until sample with the pH regulator agent to full dose 1000ml.(4) filter, embedding, sterilization, numbering gets product.
Embodiment ten
The preparation method of coenzyme Q 10 injection emulsion (freeze-drying preparation for injection) is: (1) gets coenzyme Q10 5g, soybean lecithin 12g, poloxamer 15g and the water for injection that accounts for gross weight 20-50% are preheated to 70 ℃, stirring and evenly mixing, disperse through tissue mashing machine, per minute 20000 changes, and three minutes, triplicate.(2) add mannitol 30g, lactose 20g is stirred to mix homogeneously.Cross the high pressure dispersing emulsification machine, three times repeatedly, content is collected in lyophilization.
Claims (10)
1, coenzyme Q 10 injection emulsion, with the coenzyme Q10 is the active drug composition, it is characterized in that: contain in every 1000ml emulsion: pH to 3.0-9.0, coemulsifier 10-500g are transferred in coenzyme Q10 1-10g, injection vegetable oil 0-200g, emulsifying agent 1-50g, isoosmotic adjusting agent 5-50g, antioxidant 0.05-5g, pH regulator agent, and surplus is a water for injection.
2, according to the described coenzyme Q 10 injection emulsion that contains of claim 1, it is characterized in that: this Emulsion is lipomul or submicronized emulsion, microemulsion and fat emulsion for injection lyophilized formulations, submicronized emulsion lyophilized formulations, microemulsion lyophilized formulations.
3, according to the described coenzyme Q 10 injection emulsion that contains of claim 1, its feature also is described emulsifying agent, is anhydrate one or more mixture among sorbic acid cetylate, the Drewmulse of lecithin, hydroxylated lecithin, soybean phospholipid, soybean lecithin, hydrogenated soya phosphatide, Ovum Gallus domesticus Flavus lecithin, poloxamer, cholesterol, NaTDC, polyglycereol Palmic acid diol ester, acetic acid esters of mono, polyoxyethylene; Isoosmotic adjusting agent is one or more the mixture in glucose, sodium chloride, sorbitol, xylitol, the mannitol; The pH regulator agent is one or more the mixture in hydrochloric acid, phosphoric acid, citric acid (sodium), sodium hydroxide (potassium), glacial acetic acid, buffer agent such as sodium dihydrogen phosphate and the sodium hydrogen phosphate; Antioxidant is one or more the mixture in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, ascorbic acid, propyl gallate, ascorbyl palmitate, butylated hydroxyarisol (BHA), ditertbutylparacresol (BHT), vitamin E, cysteine, the methionine; Coemulsifier is glycerol, Polyethylene Glycol, 1, the mixture of one or more in 2-propylene glycol, n-butyl alcohol, ethylene glycol, propylene glycol, the polyglycerin ester; Described injection vegetable oil is one or more a mixture such as soybean oil, Oleum sesami, safranine caul-fat, Oleum Ricini, Oleum Camelliae, safflower oil, Oleum Arachidis hypogaeae semen, Semen Maydis oil and artificial oil acetoacetic ester, butyl oleate, soybean oil wherein is selected from one or more the mixture in long chain triglyceride, medium chain triglyceride, glycerin mono-fatty acid ester, the glycerol list linoleate.
4, the preparation method of coenzyme Q 10 injection emulsion according to claim 1,1000ml is an example with preparation, it is characterized in that getting emulsifying agent 1-50g, coenzyme Q10 1-10g and injection vegetable oil 0-200g, is heated to 45-80 ℃, make its dissolving mixing, it is standby to make medicinal liquid; Get isoosmotic adjusting agent 5-50g, antioxidant 0.05-5g and account for the water for injection of gross weight 20-50% miscible, be heated to 45-80 ℃, add the medicinal liquid that has made, mixing, after tissue mashing machine disperseed, per minute 20000 changeed, three minutes, triplicate adds coemulsifier 10-500g again, mends to 1000ml with the water for injection that is preheated to 45-80 ℃, regulate pH value to 3-9 with the pH value regulator, be preheated to 45-80 ℃, cross the high pressure dispersing emulsification machine, emulsion particle diameter is the 0.1-0.8 micron, filter, embedding, sterilization, promptly; Add mannitol 5-300g, lactose 10-300g, stirring and dissolving, moisture is removed in lyophilization, makes freeze-drying preparation for injection.
5, coenzyme Q 10 injection emulsion according to claim 1 is characterized in that containing soybean lecithin 10.0g in this Emulsion of 1000ml, coenzyme Q10 5.00g, vitamin E 0.500g, 1,2-propylene glycol 100g, poloxamer F
6820g, surplus is a water for injection.
6, coenzyme Q 10 injection emulsion according to claim 1 is characterized in that containing coenzyme Q10 6.00g in this Emulsion of 1000ml, vitamin E 0.100g, and 1,2-propylene glycol 300g, poloxamer 30g, glycerol 15g, surplus is a water for injection.
7, the preparation method of coenzyme Q 10 injection emulsion according to claim 1 is: get Ovum Gallus domesticus Flavus lecithin 15.0g, and refined soybean oil 100g, coenzyme Q10 4.00g, vitamin E 1.00g is preheated to 70 ℃, stirring and evenly mixing, the medicinal liquid that makes is standby; Get glycerol 50.0g, poloxamer F
6810.0g and account for the water for injection of gross weight 20-50%, be preheated to 70 ℃, stirring and evenly mixing adds the medicinal liquid that has prepared, the limit edged stirs, and disperses through tissue mashing machine, and per minute 20000 changes three minutes, triplicate adds and is preheated to 70 ℃ of waters for injection to full dose 1000ml, regulates pH value to 3-9, cross the high pressure dispersing emulsification machine, three times repeatedly, sampling, microscopically is observed particle diameter, stops when emulsion particle diameter meets the requirements, and filters, embedding, sterilization gets product.
8, the preparation method of coenzyme Q 10 injection emulsion according to claim 1 is: get soybean lecithin 10.0g, and coenzyme Q10 5.00g, vitamin E 0.500g is preheated to 70 ℃ of stirrings, mixing, it is standby to make medicinal liquid; Get 1,2-propylene glycol 100g, poloxamer F
6820g and account for the water for injection of gross weight 20-50% is preheated to 70 ℃, stirring and evenly mixing, add the above-mentioned medicinal liquid that has made, the limit edged stirs, and disperses through tissue mashing machine, per minute 20000 changes, and three minutes, triplicate, add and be preheated to 70 ℃ of waters for injection, regulate pH value, cross the high pressure dispersing emulsification machine repeatedly to pH3-9 to full dose 1000ml, examine under a microscope until sampling and to stop when emulsion particle diameter meets the requirements, filter embedding, sterilization, numbering gets product.
9, the preparation method of coenzyme Q 10 injection emulsion according to claim 1 is: get coenzyme Q10 6.00g, vitamin E 0.100g is preheated to 70 ℃, stirring and evenly mixing, and it is standby to make medicinal liquid; Get 1,2-propylene glycol 300g, poloxamer 30g, glycerol 15g and the water for injection that accounts for gross weight 20-50% are preheated to 70 ℃, and stirring and evenly mixing adds the above-mentioned medicinal liquid that has made, the limit edged stirs, disperse through tissue mashing machine, per minute 20000 changes three minutes, triplicate, add and be preheated to 70 ℃ of waters for injection, regulate pH value, cross the high pressure dispersing emulsification machine to pH3-9 to full dose 1000ml, three times repeatedly, sampling, microscopically is observed particle diameter, stops when emulsion particle diameter meets the requirements, filter, embedding, sterilization gets product.
10, the preparation method of the lyophilized formulations of coenzyme Q 10 injection emulsion according to claim 1 is: coenzyme Q10 5g, soybean lecithin 12g, poloxamer 15g and account for the water for injection of gross weight 20-50%, be preheated to 70 ℃, stirring and evenly mixing disperses through tissue mashing machine, per minute 20000 changes, and three minutes, triplicate, add mannitol 30g, lactose 20g is stirred to mix homogeneously, cross the high pressure dispersing emulsification machine, three times repeatedly, content is collected in lyophilization.
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