IL93721A - Mixed micelles compositions and their use as carriers for the parenteral application of low molecular weight drugs - Google Patents
Mixed micelles compositions and their use as carriers for the parenteral application of low molecular weight drugsInfo
- Publication number
- IL93721A IL93721A IL9372190A IL9372190A IL93721A IL 93721 A IL93721 A IL 93721A IL 9372190 A IL9372190 A IL 9372190A IL 9372190 A IL9372190 A IL 9372190A IL 93721 A IL93721 A IL 93721A
- Authority
- IL
- Israel
- Prior art keywords
- mixed micelles
- carriers
- active substances
- molecular weight
- mixed
- Prior art date
Links
- 239000000693 micelle Substances 0.000 title claims abstract description 42
- 239000000969 carrier Substances 0.000 title claims abstract description 7
- 239000000203 mixture Substances 0.000 title description 6
- 239000003814 drug Substances 0.000 title description 3
- 229940079593 drug Drugs 0.000 title description 2
- 239000013543 active substance Substances 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 claims description 14
- 238000009826 distribution Methods 0.000 claims description 7
- 239000011782 vitamin Substances 0.000 claims description 5
- 229930003231 vitamin Natural products 0.000 claims description 5
- 235000013343 vitamin Nutrition 0.000 claims description 5
- 229940088594 vitamin Drugs 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 230000002924 anti-infective effect Effects 0.000 claims description 2
- 239000002872 contrast media Substances 0.000 claims description 2
- 239000000824 cytostatic agent Substances 0.000 claims description 2
- 230000001085 cytostatic effect Effects 0.000 claims description 2
- 239000002955 immunomodulating agent Substances 0.000 claims description 2
- 229940121354 immunomodulator Drugs 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 230000002584 immunomodulator Effects 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 21
- 239000004615 ingredient Substances 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000012876 carrier material Substances 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 210000002751 lymph Anatomy 0.000 description 3
- 210000004324 lymphatic system Anatomy 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 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 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000001830 cholanoic acids Chemical class 0.000 description 2
- 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 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- -1 fatty acid esters Chemical class 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 230000001926 lymphatic effect Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 150000003905 phosphatidylinositols Chemical class 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 239000012460 protein solution Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- OABYVIYXWMZFFJ-ZUHYDKSRSA-M sodium glycocholate 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)NCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 OABYVIYXWMZFFJ-ZUHYDKSRSA-M 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000008347 soybean phospholipid Substances 0.000 description 2
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 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 description 1
- 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 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 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 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 108010007979 Glycocholic Acid Proteins 0.000 description 1
- 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 description 1
- 235000000072 L-ascorbyl-6-palmitate Nutrition 0.000 description 1
- 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 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N Octadecylamine Chemical group CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 1
- 229960003942 amphotericin b Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 229960005475 antiinfective agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 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 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229940009025 chenodeoxycholate Drugs 0.000 description 1
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound 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)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 239000003763 cholanic acid derivative Substances 0.000 description 1
- 229940099352 cholate Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound 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 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 229940009976 deoxycholate Drugs 0.000 description 1
- 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 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 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 description 1
- 239000008103 glucose Substances 0.000 description 1
- RBNPOMFGQQGHHO-UHFFFAOYSA-N glyceric acid Chemical compound OCC(O)C(O)=O RBNPOMFGQQGHHO-UHFFFAOYSA-N 0.000 description 1
- GHCZAUBVMUEKKP-GYPHWSFCSA-N glycochenodeoxycholic acid Chemical compound 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)NCC(O)=O)C)[C@@]2(C)CC1 GHCZAUBVMUEKKP-GYPHWSFCSA-N 0.000 description 1
- RFDAIACWWDREDC-FRVQLJSFSA-N glycocholic acid Chemical compound 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)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 RFDAIACWWDREDC-FRVQLJSFSA-N 0.000 description 1
- WVULKSPCQVQLCU-BUXLTGKBSA-N glycodeoxycholic 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)NCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 WVULKSPCQVQLCU-BUXLTGKBSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 210000000987 immune system Anatomy 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
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
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- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
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- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 238000002602 scintillography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- BHTRKEVKTKCXOH-BJLOMENOSA-N taurochenodeoxycholic acid Chemical compound 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)NCCS(O)(=O)=O)C)[C@@]2(C)CC1 BHTRKEVKTKCXOH-BJLOMENOSA-N 0.000 description 1
- WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound 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)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 description 1
- AWDRATDZQPNJFN-VAYUFCLWSA-N taurodeoxycholic 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)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 AWDRATDZQPNJFN-VAYUFCLWSA-N 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Dispersion Chemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Plant Substances (AREA)
- Steroid Compounds (AREA)
- Seal Device For Vehicle (AREA)
- Cosmetics (AREA)
Abstract
Mixed micelles can be used as carriers for the parenteral administration of low molecular weight active substances.
Description
93721/2 ηιοιηη i na> Ο>ΝΥΟΟ ora vnn>¾>m mniyo ni^>o v C - UDD o>>yan pin H^V ^i inn i?p\ya noioj Mixed micelles compositions and their use as carriers for the parenteral application of low molecular drugs H. HOFFMANN-LA ROCHE A.G.
C: 79993/2 RAN 4602/25 The present invention is concerned with the use of mixed micelles as carriers for the parenteral administration of pharmaceutically active eubstances as well as mixed micelle solutions which contain certain pharmaceutically active substances.
It is known to use mixed micelles as a vehicle for pharmaceutically active substances. DE-PS 27 30 570 describes mixed micelle solutions for the parenteral administration of fat-soluble active substances, i.e. active substances which are not soluble in water or which are difficultly soluble in water, especially benzodiazepines and vitamin K. EP-A2-133 258 describes mixed micelle solutions for the parenteral administration of vitamin E. Furthermore, mixed micelles have been proposed for the production of aqueous protein solutions (EP-A1-252004 ) . In the use of mixed micelles for the solubilization of non-steroidal antiinflammatories in accordance with EP-Al-280 887 the problem lay in improving the tolerance of the active substances in the case of injections .
In the case of parenteral, especially interstitial, e.g. intramuscular, subcutaneous or intradermal, administration of pharmaceutically active substances, those having a molecular weight <1000 can be taken up lymphatically . while active substances whose molecular weight amounts to about 16000 or above are taken up to substantial extent from the lymphatic system. 35 can. however, be desirable also to introduce Grn/29.1.90 low-molecular active substances, which are normally not transported to a substantial extent by the lymphatic system, into this and thus to transport them to the destination. This is especially true in the case of active substances which influence the immune system, such as immunosupressants and imraunost imulants . It has surprisingly been found that mixed micelles are transformed in the case of interstitial applications into liposomes which are taken up and transported by the lymphatic system. In the case of certain hypotheses which have been put forward, active substances contained in mixed micelles are taken up by the liposomes formed in the organism. Whether in each case such hypotheses are proved can be ascertained experimentally by determining the distribution coefficient of the active substance in octanol/water . Active substances whose distribution coefficient in the system octanol/water is greater than 4 about 10 , preferably greater than about 106 , fulfil the hypothesis, i.e. are taken up by the liposomes which are formed.
Fat-soluble vitamins, e.g. vitamins A. E and K. have a distribution coefficient of >106 in octanol/water. As mentioned above, mixed micelle solutions of such vitamins have become known. However, it has not become known that these vitamins, after parenteral, especially interstitial, administration as mixed micelle solutions, pass into the lymphatic vessels in the form of liposomes.
The object of the invention is accordingly the use of mixed micelles as carriers for the parenteral, especially interstitial, therapeutic administration of low-molecular active substances having a distribution coefficient in 4 octanol/ water of greater than about 10 . with fat-soluble vitamins being excluded.
As low-molecular active substances there are to be understood in the present connection active substances having a molecular weight below 20000. The low-molecular active substances preferably have a molecular weight below 5000.
Examples of active substances in the case of whose parenteral, especially interstitial, therapeutic administration the use in accordance with the invention of mixed micelles as carriers comes into consideration are immunomodulators , e.g. immunosuppressants such as (all-E)--3.7-dimethyl-9- (2-trif luoromethyl)-6-(nonyloxy)phenyl--2. .6.8-nonatetraenoic acid and related compounds which are described in EP-A1-169 571; cyclosporin or FK 506 (Immunology Today 10. 6-9 (1989)); as well as lipophilic derivatives thereof, e.g. 20-alkanoyloxy derivatives; immunostimulants such as N-acetylmuramyl-L-alanyl-D--isoglutamyl-L-alanyl-2- ( 1 ' .2 ' -dipalmitoyl) phosphatidyl--ethanolaraine (Cancer Immunol. Iramunother. (1986) 22: 191-196); peptide antigens and oligosaccharide antigens or lipophilic derivatives thereof, e.g. peptide-fatty acid conjugates (EP-A2-290 246); contrast agents for lymphatic scintillography; cytostatics, e.g. cis-Pt complexes such as cis-bis-N-decylarainodiacetato-l.2-diaminocyclohexane--platinum; or anthra- cyclines such as doxorubicin or methotrexate or lipophilic derivatives thereof such as the fatty acid esters mentioned above, or lipophilic derivatives of 5-f luoro-2 ' -deoxyuridine. e.g. palmitoate (Microencapsulation 1988. Vol. 5. No. 1. p. 1-11) and phosphate (Japan. Kokai 1091 195); lipophilic derivatives of 1-fl-D-arabinofuranosyl-cytosine (Ara-C) such as oleate and palmitate (Int. J. Cancer 37. 149-154 [1986]) and cholesteryloxycarbonylglycyl-Ara-C (Chem. Pharm. Bull Vol. 36 (1988) 4060 et seq.); phosphatidylinositol and lysophospholipids (DE-OS 3008082); and anti- infectives such as amphotericin B. nystatin, gentamycin. chloroquin. penicillins such as ampicillin: and tetracyclines or lipophilic derivatives thereof such as the fatty acid esters mentioned above.
The previously named active substances can be incorporated in mixed micelles using technologies known per se. for example as described in DE-PS 27 30 570. In comparison to liposomal solutions, mixed micelle solutions are simpler to manufacture and have an improved stability. The mixed micelle solutions manufacturable in accordance with the invention therefore combine the advantage of the stability of mixed micelle solutions with the improved efficacy of lymphatically- and/or liposomally-applied active substance.
In the scope of the present invention there are to be understood under mixed micelles or mixed micelle solutions aqueous, homogeneous solutions of cholanic acid derivatives, especially alkali salts thereof and lipids.
Examples of cholanic acid salts are Na cholate, glycocho-late, taurocholate , deoxycholate, glyco- and taurodeoxy-cholate, chenodeoxycholate; and glyco- and taurocheno-deoxycholate. Examples of lipids are natural, semi--synthetic and wholly-synthetic lipids, especially phosphatidylcholines, glycerol ether phosphatides, phosphatidylethanolamine, phosphatidyl inositol , phosphatidylser ine, sphingomyelin, plasmalogens . cardio-lipin. sulphatides and monoglycer ides . The mixed micelles can contain as additional components cholesterol (up to about 30 mol% based on the amount of lipid) and lipids having negatively- or positively-loaded groups such as phosphatidic acids or stearylamine (up to about 10 mol% based on the amount of lipid).
The mixed micelle solutions can be manufactured by simply mixing together the individual ingredients. It is. however, advantageous to dissolve the lipoid ingredient, the micelle former and the active substance(s) . which is/are difficultly soluble in water or insoluble in water. in an organic solvent, then to evaporate the organic solvent and thereupon to add the water, the isotonizing additives and. if desired, the additional ingredients, whereby as a rule the isotonizing additives and for the most part also the optional additional ingredients are mixed with the water prior to the addition to the mentioned evaporation residue. As organic solvents there come into consideration those in which the components to be solubilized are sufficiently soluble, such as e.g. lower alkanols. especially ethanol.
An especially preferred procedure comprises stirring intensively approximately one molar part of micelle former, approximately one molar part of lipoid ingredient and approximately 0.3 to one molar part of water. optionally in the presence of up to 2% of an organic solvent such as ethanol. as well as the active substance(s) which is/are difficultly soluble in water or insoluble in water until the mixture appears homogeneous, whereupon the water, the isotonizing additives and. if desired, the additional ingredients are added until the desired dilution or concentration has been achieved. It is. how- ever, also possible to carry out the above procedure with- out the active substance and only at the end to solubilize the active substance(s) in the micelle solution.
The ratio between the lipoid ingredient and the micelle former lies in the order of 0.1:1 to 2:1. Mixture ratios of 0.1:1 to 0.8:1 and 1.5:1 to 2:1 are preferred. The mixture ratio 0.8:1 to 1.5:1 is quite especially preferred .
The amount of lipoid ingredient plus micelle former in the injection solution can vary over vide limits and can amount to e.g. 50-200 mg/ml of injection solution.
The amount of the pharmacon in the mixed micelle solution can also vary over wide limits and can amount to e.g. 0.1-20 mg/ml of injection solution.
Antioxidants such as tocopherols, ascorbic palmitate. sodium ascrobate. sodium hydrogen sulphite, eodium pyrosulphite or sodium sulphite can be added to prevent oxidation reactions of the active substance and of the carrier materials.
Additional active substances for pH-ad justment , e.g. phosphate, citrate or Tris buffer; for isotonization. e.g. sodium chloride, mannitol. sorbitol or glucose, and for preservation, e.g. methyl and propyl p-hydroxybenzoate. benzyl alcohol or phenol, can also be added.
Where desired, the mixed micelle-protein solutions can be converted into dry preparations with the aid of conventional lyophilization procedures.
The following Examples are intended to illustrate the invention further.
Example 1 Manufacture of mixed micelle solutions: Active substance (all-E)-3.7-dimethyl-9-(2-trif luoro-methyl )-6- (nonyloxy) phenyl-2.4 , 6 , 8-nonatetraenoic acid (A) 30.8 mg of soya lecithin (Epikuron 200. Lucas Meyer. Hamburg, Germany). 21.40 mg of sodium glycocholate and 0.4 mg of (all-E)-3.7-dimethyl-9-(2-trif luoromethyl ) -6- -(nonyloxy)phenyl-2.4.6.8-nonatetraenoic acid are dissolved in 5 ml of chloroform/methanol (1:1. vol/vol%) in a round flask. The film which results after evaporation of the organic solvent (rotary evaporator. 40°C) is dispersed in 1 ml of 3.8% mannitol solution (wt/vol%). The micelles obtained are adjusted to pH 6.0 ± 0.1 with IN HC1, sterilized, filled into vials and lyophilized. The mixed micelles are manufactured with the exclusion of light and in an inert gas atmosphere, e.g. under nitrogen, in order to prevent isomer ization reactions of the active substance as well as oxidation reactions of the active substance and of the carrier materials, especially of the phospholipids .
Example 2 Active substance 31.5 ' -di-O-palmitoyl-5-f luoro-2 ' --deoxuridine (B) 30.8 g of soya lecithin (Epikuron 200. Lucas Meyer. Hamburg. Germany). 21.67 mg of sodium glycocholate and 1.0 rag of 3 ' .5 ' -di-O-palmitoyl-5-f luoro-2 * -deoxyur idine are dissolved in 5 ml of chloroform/methanol (1:1. vol/vol%) in a round flask. The film which results after evaporation of the organic solvent (rotary evaporator, 40°C) is dispersed in 1 ml of 3.8% mannitol solution. The micelles obtained are adjusted to pH 6.0 ± 0.1 with IN HC1, sterilized and filled into ampoules. The manufacture of the micelles is carried out in an inert gas atmosphere, e.g. under nitrogen, in order to prevent oxidation reactions of the active substance and of the carrier materials, especially of the phospholipids.
The mixed micelle solutions were administered intra-dermally to the right hind leg of experimental animals (sheep) by means of a device described in EP-A-272530.
Blood was removed through a jugular vein catheter and lymphatic fluid was removed through a cannula in the branching lymph vessel at the right popliteal lymph node (Pharm. Res. Vol. 5. 472-476 (1988)).
Figure 1 shows the amount of the administered dosage found in the lymph. For comparison there are quoted the values which were obtained with two low-molecular active substances whose distribution coefficient in octanol/water is <10 Figure 2 shows the amounts of active substance A found in the lymph after administration in mixed micelles and as an oily formulation.
Claims (4)
1. Mixed micelles for use as carriers for the parenteral therapeutic administration of low-molecular active substances having a distribution coefficient in octanol/ water of greater than about 104, with fat-soluble vitamins being excluded.
2. Mixed micelles according to claim 1 for active substances having a distribution coefficient in octanol/ water of greater than about 106 and a molecular weight below 5000.
3. Mixed micelles according to claim 1 or 2, in which the active substance is an immunomodulator, a cytostatic, an antiinfective or a contrast agent.
4. Mixed micelles according to claims 1-3 for interstitial application. 20 Mixed micelles according to claim 4 for intramus subcutaneous or intradermal application. For the Applicants, DR. REINHOLD COHN AND PARTNERS 79993-2/Claims/TG/be/18.10.1993
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH104189 | 1989-03-21 | ||
| CH10390 | 1990-01-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL93721A0 IL93721A0 (en) | 1990-12-23 |
| IL93721A true IL93721A (en) | 1994-04-12 |
Family
ID=25683528
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL9372190A IL93721A (en) | 1989-03-21 | 1990-03-13 | Mixed micelles compositions and their use as carriers for the parenteral application of low molecular weight drugs |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0388817B1 (en) |
| JP (1) | JP3007111B2 (en) |
| KR (1) | KR900013942A (en) |
| AT (1) | ATE102479T1 (en) |
| AU (1) | AU635248B2 (en) |
| CA (1) | CA2011262C (en) |
| DE (1) | DE59004845D1 (en) |
| DK (1) | DK0388817T3 (en) |
| ES (1) | ES2062140T3 (en) |
| HU (1) | HUT53799A (en) |
| IE (1) | IE64191B1 (en) |
| IL (1) | IL93721A (en) |
| MC (1) | MC2102A1 (en) |
| NZ (1) | NZ232865A (en) |
| PT (1) | PT93522B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU6461090A (en) * | 1989-10-30 | 1991-05-02 | Abbott Laboratories | Injectable formulation for lipophilic drugs |
| CA2033725C (en) * | 1990-01-24 | 2001-05-29 | Folker Pittrof | Pharmaceutical and cosmetic compositions containing a salt of cholanic acid |
| JP2740153B2 (en) * | 1995-03-07 | 1998-04-15 | エフ・ホフマン−ラ ロシユ アーゲー | Mixed micelle |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1202370B (en) * | 1976-07-12 | 1989-02-09 | Hoffmann La Roche | INJECTABLE SOLUTIONS IN WHICH THE EMOLITHIC LIFE OF NATURAL MICELLES TRAINING AGENTS IS AVOIDED BY THE ADDITION OF LIPOIDS AND RELATED PRODUCTS |
| DE3221579A1 (en) * | 1982-06-08 | 1983-12-22 | Eckert, Theodor, Prof. Dr., 4400 Münster | Solubilisation of active substances, which are sparingly soluble in water, in aqueous solution using a mixture of cholinephosphoric acid glycerol diester (choline-lecithin) and sodium deoxycholate as solubiliser, and the therapeutic use of the aqueous solutions obtained thereby |
| ZA854828B (en) * | 1984-07-27 | 1986-03-26 | Hoffmann La Roche | Phenyl nonatetraenoic acid derivatives |
| EP0252004A1 (en) * | 1986-06-26 | 1988-01-07 | Ciba-Geigy Ag | Pharmaceutical compositions for parenteral application |
| DE3726099A1 (en) | 1986-08-07 | 1988-07-14 | Puetter Medice Chem Pharm | Pharmaceutical preparations |
| CA1319886C (en) * | 1987-02-03 | 1993-07-06 | Alberto Ferro | Mixed micelle solutions |
-
1990
- 1990-03-09 NZ NZ232865A patent/NZ232865A/en unknown
- 1990-03-13 IL IL9372190A patent/IL93721A/en not_active IP Right Cessation
- 1990-03-14 HU HU901555A patent/HUT53799A/en unknown
- 1990-03-15 JP JP2062830A patent/JP3007111B2/en not_active Expired - Lifetime
- 1990-03-15 MC MC902119A patent/MC2102A1/en unknown
- 1990-03-16 ES ES90105026T patent/ES2062140T3/en not_active Expired - Lifetime
- 1990-03-16 EP EP90105026A patent/EP0388817B1/en not_active Expired - Lifetime
- 1990-03-16 AU AU51404/90A patent/AU635248B2/en not_active Ceased
- 1990-03-16 DE DE90105026T patent/DE59004845D1/en not_active Expired - Fee Related
- 1990-03-16 DK DK90105026.0T patent/DK0388817T3/en not_active Application Discontinuation
- 1990-03-16 AT AT90105026T patent/ATE102479T1/en not_active IP Right Cessation
- 1990-03-19 KR KR1019900003626A patent/KR900013942A/en not_active Ceased
- 1990-03-20 IE IE101790A patent/IE64191B1/en not_active IP Right Cessation
- 1990-03-20 CA CA002011262A patent/CA2011262C/en not_active Expired - Fee Related
- 1990-03-20 PT PT93522A patent/PT93522B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU5140490A (en) | 1990-09-27 |
| IL93721A0 (en) | 1990-12-23 |
| EP0388817A3 (en) | 1991-07-03 |
| PT93522B (en) | 1996-03-29 |
| NZ232865A (en) | 1992-07-28 |
| ES2062140T3 (en) | 1994-12-16 |
| JP3007111B2 (en) | 2000-02-07 |
| HUT53799A (en) | 1990-12-28 |
| HU901555D0 (en) | 1990-06-28 |
| DK0388817T3 (en) | 1994-05-02 |
| CA2011262C (en) | 2000-06-20 |
| IE64191B1 (en) | 1995-07-12 |
| PT93522A (en) | 1990-11-07 |
| CA2011262A1 (en) | 1990-09-21 |
| EP0388817A2 (en) | 1990-09-26 |
| AU635248B2 (en) | 1993-03-18 |
| KR900013942A (en) | 1990-10-22 |
| DE59004845D1 (en) | 1994-04-14 |
| EP0388817B1 (en) | 1994-03-09 |
| IE901017L (en) | 1990-09-21 |
| JPH02289511A (en) | 1990-11-29 |
| ATE102479T1 (en) | 1994-03-15 |
| MC2102A1 (en) | 1991-03-11 |
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