JPH0251403B2 - - Google Patents
Info
- Publication number
- JPH0251403B2 JPH0251403B2 JP58001043A JP104383A JPH0251403B2 JP H0251403 B2 JPH0251403 B2 JP H0251403B2 JP 58001043 A JP58001043 A JP 58001043A JP 104383 A JP104383 A JP 104383A JP H0251403 B2 JPH0251403 B2 JP H0251403B2
- Authority
- JP
- Japan
- Prior art keywords
- thiaprostaglandin
- drug
- pentanol
- cyclohexyl
- transdermal administration
- 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 - Lifetime
Links
- 239000003814 drug Substances 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 239000002674 ointment Substances 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000006210 lotion Substances 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000006071 cream Substances 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 150000001768 cations Chemical class 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- 230000000144 pharmacologic effect Effects 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 230000009471 action Effects 0.000 description 6
- -1 ammonium cations Chemical class 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 150000004702 methyl esters Chemical class 0.000 description 6
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 6
- 229920000858 Cyclodextrin Polymers 0.000 description 5
- 230000036772 blood pressure Effects 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
- 235000019271 petrolatum Nutrition 0.000 description 5
- FGOJCPKOOGIRPA-UHFFFAOYSA-N 1-o-tert-butyl 4-o-ethyl 5-oxoazepane-1,4-dicarboxylate Chemical compound CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O FGOJCPKOOGIRPA-UHFFFAOYSA-N 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000003871 white petrolatum Substances 0.000 description 4
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 229940031578 diisopropyl adipate Drugs 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000024883 vasodilation Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 206010015150 Erythema Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000000702 anti-platelet effect Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 231100000321 erythema Toxicity 0.000 description 2
- SHZIWNPUGXLXDT-UHFFFAOYSA-N ethyl hexanoate Chemical compound CCCCCC(=O)OCC SHZIWNPUGXLXDT-UHFFFAOYSA-N 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-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
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 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
- 239000004166 Lanolin Substances 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-O Methylammonium ion Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 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 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-O benzylaminium Chemical compound [NH3+]CC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-O 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229960002645 boric acid Drugs 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- OJYGBLRPYBAHRT-IPQSZEQASA-N chloralose Chemical compound O1[C@H](C(Cl)(Cl)Cl)O[C@@H]2[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]21 OJYGBLRPYBAHRT-IPQSZEQASA-N 0.000 description 1
- 239000000460 chlorine Chemical group 0.000 description 1
- 229910052801 chlorine Chemical group 0.000 description 1
- 239000008294 cold cream Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940105990 diglycerin Drugs 0.000 description 1
- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- SFFVATKALSIZGN-UHFFFAOYSA-N hexadecan-7-ol Chemical compound CCCCCCCCCC(O)CCCCCC SFFVATKALSIZGN-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HOMQOIVYFSPUGZ-YHPDFFPYSA-N methyl 6-[(1r,2s,3r)-2-[(e)-5-cyclohexyl-3-hydroxypent-1-enyl]-3-hydroxy-5-oxocyclopentyl]sulfanylhexanoate Chemical compound O[C@@H]1CC(=O)[C@H](SCCCCCC(=O)OC)[C@H]1\C=C\C(O)CCC1CCCCC1 HOMQOIVYFSPUGZ-YHPDFFPYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000015927 pasta Nutrition 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Description
本発明は７−チアプロスタグランジンE1類を
有効成分とする経皮投与用薬剤に関する。更に詳
細には、血管拡張、降血圧、抗血小板凝集作用等
の優れた薬理作用を有する７−チアプロスタグラ
ンジンE1類を有効成分とし、局所投与に適した
経皮投与用薬剤に関する。
７−チアプロスタグランジンE1類、例えば７
−チアプロスタグランジンE1，16，17，18，19，
20−ペンタノル−15−シクロヘキシル−７−チア
プロスタグランジンE1，16，17，18，19，20−
ペンタノル−15−シクロペンチル−７−チアプロ
スタグランジンE1，16，17，18，19，20−ペン
タノル−15−シクロヘキシル−Δ2−チアプロス
タグランジンE1、およびそれらのエステル類な
どは優れた血管拡張、降血圧、抗血小板凝集作用
等の薬理作用を有し、また経口投与可能なプロス
タグランジンとして知られている（欧州特許公開
公報No.51284）。また該公報には、７−チアプロス
タグランジンE1類の投与方法として経口的にあ
るいは直腸内、皮下、筋肉内、静脈内等の非経口
的投与が記載されている。
しかしながらかかる投与による場合には、全身
にその薬理作用、例えば血管拡張作用が及び、局
所的にその薬理作用を限定せしめて投与すること
が困難である。また皮内投与の場合には、皮膚の
苦痛などを伴うという欠点がある。
そこで本発明者らは、７−チアプロスタグラン
ジンE1類の経口投与の場合に生ずる副作用を解
消し、簡便な投与形態を開発することを目的とし
て鋭意研究したところ、７−チアプロスタグラン
ジンE1類は経皮吸収が優れ、かつ好ましい薬理
作用を表わすことを見出し本発明に到達したもの
である。
すなわち本発明は下記式〔〕
〔式中、記号〓は一重結合又は二重結合を示
し、R1は水素原子、低級アルキル基または薬理
学的に許容しうる陽イオンを表わし、R2は水素
原子またはメチル基を表わし、R3は置換もしく
は非置換の炭素数５〜８のアルキル基または置換
もしくは非置換の炭素数５〜８のシクロアルキル
基を表わす。〕
で表わされる７−チアプロスタグランジンE1類
を有効成分とする経皮投与用薬剤である。
本発明の薬剤で有効成分として用いられる化合
物は、上記式〔〕の７−チアプロスタグランジ
ンE1類である。
上記式〔〕において、R1は水素原子、低級
アルキル基または薬理学的に許容しうる陽イオン
を表わす。かかる低級アルキル基としては、メチ
ル、エチル、プチル、イソプロピル、ペンチル、
ヘキシル基などが挙げられる。なかでもメチル
基、エチル基が好ましい。薬理学的に許容しうる
陽イオンとしては、例えば、ナトリウム、カリウ
ムなどのアルカリ金属イオン；NH4 +、テトラメ
チルアンモニウム、モノメチルアンモニウム、ベ
ンジルアンモニウムなどのアンモニウムカチオン
などが挙げられ、なかでもナトリウムイオンが好
ましい。
R2は水素原子またはメチル基を表わす。特に
水素原子が好ましい。
R3は置換もしくは非置換の炭素数５〜８のア
ルキル基または置換もしくは非置換の炭素数５〜
８のシクロアルキル基を表わす。非置換の炭素数
５〜８のアルキル基としては、例えばｎ−ペンチ
ル、ｎ−ヘキシル、２−メチルヘキシル、ｎ−ヘ
プチル、ｎ−オクチル等が挙げられる。非置換の
炭素数５〜８のシクロアルキル基としては、例え
ばシクロペンチル、シクロヘキシルなどが挙げら
れる。かかる非置換のアルキル基もしくはシクロ
アルキル基の置換基としては、フツ素、塩素など
のハロゲン原子；ヒドロキシ基；アセトキシ基、
プロピオニルオキシ基などのアシロキシ基；メト
キシ、エトキシ、ブトキシなどのアルコキシ基等
が挙げられる。
かかる７−チアプロスタグランジンE1類の好
ましい具体例は次のものがある。
(1) ７−チアプロスタグランジンE1、
(2) 17，20−ジメチル−７−チアプロスタグラン
ジンE1、
(3) 16，16−ジメチル−７−チアプロスタグラン
ジンE1、
(4) 16，17，18，19，20−ペンタノル−15−シク
ロヘキシル−７−チアプロスタグランジンE1、
(5) 16，17，18，19，20−ペンタノル−15−シク
ロペンチル−７−チアプロスタグランジンE1、
(6) 16，17，18，19，20−ペンタノル−15−シク
ロヘキシル−Δ2−７−チアプロスタグランジ
ンE1、
(7) (1)のナトリウム塩、
(8) (1)のメチルエステル、
(9) (4)のナトリウム塩、
(10) (4)のメチルエステル、
(11) (5)のナトリウム塩、
(12) (5)のメチルエステル、
(13) (2)のメチルエステル、
(14) (3)のメチルエステル、
(15) (6)のメチルエステル、
７−チアプロスタグランジンE1類は、欧州特
許公開公報No.51284に記載されているように、対
応する２−オルガノチオ−２−シクロペンテノン
と有機銅リチウム化合物とを共役付加反応に付す
ことにより製造される。
７−チアプロスタグランジンE1類を経皮投与
する場合、好ましい薬理作用を示す。すなわち７
−チアプロスタグランジンE1類を経皮投与する
とき、経口投与と同等あるいはそれ以上の降圧作
用等の薬理作用を発現し、その持続時間が長いと
いう利点を有する。また局所的にその薬理作用を
限定せしめて投与することが可能であるため、７
−チアプロスタグランジンE1類の経皮投与は特
に、末梢血管疾患、例えばバージヤー病、レイノ
ー病などに有効である。
７−チアプロスタグランジンE1類を有効成分
とする経皮投与用薬剤の剤形としては、軟膏、ク
リーム、ローシヨン、液剤等が挙げられる。
軟膏の基剤としては、例えばヒマシ油、オリー
ブ油、ゴマ油、サフラワー油などの脂肪油；ラノ
リン；白色、黄色もしくは親水ワセリン；ロウオ
レイルアルコール、イソステアリルアルコール、
オクチルドデカノール、ヘキシルデカノールなど
の高級アルコール類；グリセリン、ジグリセリ
ン、エチレングリコール、プロピレングリコー
ル、ソルビトール、１，３−ブタンジオールなど
のグリコール類などが挙げられる。また７−チア
プロスタグランジンE1類の可溶化剤としてエタ
ノール、ジメチルスルホキシド、ポリエチレング
リコールなどを用いてもよい。また必要に応じ
て、パラオキシ安息香酸エステル、安息香酸ナト
リウム、サリチル酸、ソルビン酸、ホウ酸などの
保存剤；プチルヒドロキシアニソール、ジプチル
ヒドロキシトルエンなどの酸化防止剤などを用い
てもよい。
７−チアプロスタグランジンE1類の経皮吸収
促進を図るため、ジイソプロピルアジペート、ジ
エチルセバケート、エチルカプロエート、エチル
ラウレートなどの吸収促進剤を加えてもよい。ま
た７−チアプロスタグランジンE1類の安定化を
図るため、７−チアプロスタグランジンE1類を
α−シクロデキストリン、β−シクロデキストリ
ン、γ−シクロデキストリンなどのシクロデキス
トリン；α−メチル化シクロデキストリン、β−
メチル化シクロデキストリンなどのメチル化シク
ロデキストリンなどの包接化合物として用いるこ
ともできる。
軟膏は通常の方法によつて製造することができ
る。
クリーム剤としては水中油型クリーム剤のクリ
ーム剤が７−チアプロスタグランジンE1類の安
定化を図るうえで好ましい。またその基剤として
は、前述した如き、脂肪油、高級アルコール類、
グリコール類などが用いられ、またジエチレング
リコール、プロピレングリコール、ソルビタンモ
ノ脂肪酸エステル、ポリソルベート80、ラウリル
硫酸ナトリウムなどの乳化剤が用いられる。更に
必要に応じて前述した如き保存剤、酸化防止剤な
どを添加してもよい。また軟膏剤の場合と同様
に、７−チアプロスタグランジンE1類をシクロ
デキストリン、メチル化シクロデキストリンの包
接化合物として用いることもできる。クリーム剤
は通常の方法によつて製造することができる。
ローシヨン剤としては、懸濁型、乳剤型、溶液
型ローシヨン剤が挙げられる。懸濁型ローシヨン
剤は、アルギン酸ナトリウム、トラガント、カル
ボキシメチルセルロースナトリウムなどの懸濁化
剤を用い、必要に応じて酸化防止剤、保存剤など
を加えて得られる。
乳剤型ローシヨン剤は、ソルビタンモノ脂肪酸
エステル、ポリソルベート80、ラウリル硫酸ナト
リウムなどの乳化剤を用い、通常の方法で得られ
る。
溶液型ローシヨン剤は、アルコール型ローシヨ
ン剤が好ましくエタノールなどのアルコールを用
いて通常の方法で得られる。
液剤としては、７−チアプロスタグランジン
E1類をエタノールなどのアルコール溶液に溶解
し、必要に応じて酸化防止剤、保存剤などを添加
したものが挙げられる。
これらの剤形以外でも、パスタ剤、パツプ剤、
エアゾール剤等の剤形が挙げられる。かかる製剤
は通常の方法によつて製造することができる。７
−チアプロスタグランジンE1類の投与量は、化
合物の種類、病態等によつて異なるが通常約１mg
〜約10mg／Kg−体重の量で投与される。従つて経
皮投与用薬剤に含有せしめる７−チアプロスタグ
ランジンE1類の量は、かかる投与量によつて決
定される。
本発明の７−チアプロスタグランジンE1類を
有効成分とする経皮投与用薬剤は前述した如く皮
膚に局所的に薬物を投与するため、その作用部位
が限定され、特定の部位にのみ血管拡張作用等の
薬理作用を発現せしめることが可能である。ま
た、経皮投与した場合、薬理作用の持続時間が長
く、強力な薬理作用を発現するという利点もあ
る。
以下本発明を実施例により更に詳細に説明す
る。
実施例 １
アジピン酸ジイソプロピル13mgに16，17，18，
19，20−ペンタノル−15−シクロヘキシル−７−
チアプロスタグランジンE1メチルエステル１mg
を溶解し、そこへ白色ワセリン40mgを加えてよく
練合して均一な軟膏とした。
かかる軟膏剤中における薬物の安定性を調べた
ところ40日経過後においても薬物は分解されなか
つた。
実施例 ２
16，17，18，19，20−ペンタノル−15−シクロ
ペンチル−７−チアプロスタグランジンE1メチ
ルエステル２mgを取り、これを親水軟膏（白色ワ
セリン、ステアリルアルコール、プロピレングリ
コール、ラウリル硫酸ナトリウム、パラオキシ安
息香酸エチル、パラオキシ安息香酸プロピル）
100mgとよく練合して均一な軟膏とした。
実施例 ３
17，20−ジメチル−７−チアプロスタグランジ
ンE1メチルエステル１mgを取り、これをコール
ドクリーム（ミツロウ、流動パラフイン、精製
水、ホウ砂）50mgに加えて、練合し均一なクリー
ム剤を得た。
実施例 ４〜11
薬物のエタノール溶液Ca0.2重量％を調製し、
この溶液を健常成人男子の下腕内側の皮膚上に面
積約４〜６cm2の円型内に溶媒を蒸発させながら指
定用量を塗布した。塗布後塗布局所周辺部に現わ
れる紅斑を末梢血管拡張及び／または血管透過性
増大の指標として観察し、その出現時間及び消失
時間を測定した。結果を下記表１にまとめた。
The present invention relates to a drug for transdermal administration containing 7-thiaprostaglandin E 1 as an active ingredient. More specifically, the present invention relates to a transdermal drug suitable for local administration, which contains 7-thiaprostaglandin E 1 class as an active ingredient, which has excellent pharmacological effects such as vasodilation, blood pressure reduction, and antiplatelet aggregation effects. 7-thiaprostaglandin E class 1 , e.g. 7
-Thiaprostaglandin E 1 , 16, 17, 18, 19,
20-Pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 , 16, 17, 18, 19, 20-
Pentanol-15-cyclopentyl-7-thiaprostaglandin E 1 , 16, 17, 18, 19, 20-pentanol-15-cyclohexyl-Δ 2 -thiaprostaglandin E 1 and their esters are excellent. It has pharmacological effects such as vasodilation, blood pressure lowering, and antiplatelet aggregation, and is also known as an orally administrable prostaglandin (European Patent Publication No. 51284). The publication also describes oral administration or parenteral administration such as intrarectal, subcutaneous, intramuscular, and intravenous administration of 7-thiaprostaglandin E 1 . However, when such administration is performed, its pharmacological action, such as vasodilatory action, extends throughout the body, and it is difficult to limit the pharmacological action locally and administer the drug. In addition, intradermal administration has the disadvantage of causing pain to the skin. Therefore, the present inventors conducted intensive research with the aim of eliminating the side effects that occur when 7-thiaprostaglandin E type 1 is orally administered and developing a simple administration form, and found that 7-thiaprostaglandin The present invention was achieved based on the discovery that class E 1 has excellent transdermal absorption and exhibits favorable pharmacological effects. That is, the present invention is based on the following formula [] [In the formula, the symbol 〓 represents a single bond or a double bond, R 1 represents a hydrogen atom, a lower alkyl group, or a pharmacologically acceptable cation, R 2 represents a hydrogen atom or a methyl group, and R 3 represents a substituted or unsubstituted alkyl group having 5 to 8 carbon atoms or a substituted or unsubstituted cycloalkyl group having 5 to 8 carbon atoms. ] This is a drug for transdermal administration containing 7-thiaprostaglandin E 1 represented by the following as an active ingredient. The compound used as an active ingredient in the drug of the present invention is 7-thiaprostaglandin E 1 of the above formula []. In the above formula [], R 1 represents a hydrogen atom, a lower alkyl group, or a pharmacologically acceptable cation. Such lower alkyl groups include methyl, ethyl, butyl, isopropyl, pentyl,
Examples include hexyl group. Among these, methyl group and ethyl group are preferred. Examples of pharmacologically acceptable cations include alkali metal ions such as sodium and potassium; ammonium cations such as NH 4 + , tetramethylammonium, monomethylammonium, and benzyl ammonium; among them, sodium ions are preferable. R 2 represents a hydrogen atom or a methyl group. Particularly preferred is a hydrogen atom. R 3 is a substituted or unsubstituted alkyl group having 5 to 8 carbon atoms, or a substituted or unsubstituted alkyl group having 5 to 8 carbon atoms;
8 represents a cycloalkyl group. Examples of the unsubstituted alkyl group having 5 to 8 carbon atoms include n-pentyl, n-hexyl, 2-methylhexyl, n-heptyl, n-octyl, and the like. Examples of the unsubstituted cycloalkyl group having 5 to 8 carbon atoms include cyclopentyl and cyclohexyl. Substituents for such unsubstituted alkyl groups or cycloalkyl groups include halogen atoms such as fluorine and chlorine; hydroxy groups; acetoxy groups;
Examples include acyloxy groups such as propionyloxy groups; alkoxy groups such as methoxy, ethoxy, and butoxy. Preferred specific examples of such 7-thiaprostaglandin E 1 are as follows. (1) 7-thiaprostaglandin E 1 , (2) 17,20-dimethyl-7-thiaprostaglandin E 1 , (3) 16,16-dimethyl-7-thiaprostaglandin E 1 , (4 ) 16,17,18,19,20-pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 , (5) 16,17,18,19,20-pentanol-15-cyclopentyl-7-thiaprostaglandin Sodium salt of thiaprostaglandin E 1 , (6) 16,17,18,19,20-pentanol-15-cyclohexyl-Δ 2 -7-thiaprostaglandin E 1 , (7) (1), (8) (1 ) methyl ester, (9) sodium salt of (4), (10) methyl ester of (4), (11) sodium salt of (5), (12) methyl ester of (5), (13) (2 ) methyl ester, (14) methyl ester of (3), (15) methyl ester of (6), 7-thiaprostaglandin E class 1 , as described in European Patent Publication No. 51284. , is produced by subjecting the corresponding 2-organothio-2-cyclopentenone and an organocopper lithium compound to a conjugate addition reaction. When 7-thiaprostaglandin E type 1 is administered transdermally, it exhibits favorable pharmacological effects. i.e. 7
- When thiaprostaglandin E type 1 is administered transdermally, it has the advantage that it exhibits pharmacological effects such as antihypertensive effects that are equivalent to or greater than oral administration, and that these effects last for a long time. In addition, since it is possible to administer locally with its pharmacological action limited,
- Transdermal administration of thiaprostaglandin E class 1 is particularly effective for peripheral vascular diseases such as Burgeer's disease and Raynaud's disease. Dosage forms of drugs for transdermal administration containing 7-thiaprostaglandin E type 1 as an active ingredient include ointments, creams, lotions, liquids, and the like. Bases for ointments include fatty oils such as castor oil, olive oil, sesame oil, safflower oil; lanolin; white, yellow or hydrophilic petrolatum; wax oleyl alcohol, isostearyl alcohol,
Examples include higher alcohols such as octyldodecanol and hexyldecanol; glycols such as glycerin, diglycerin, ethylene glycol, propylene glycol, sorbitol, and 1,3-butanediol. Further, ethanol, dimethyl sulfoxide, polyethylene glycol, etc. may be used as a solubilizing agent for 7-thiaprostaglandin E 1 class. If necessary, preservatives such as paraoxybenzoic acid ester, sodium benzoate, salicylic acid, sorbic acid, and boric acid; antioxidants such as butylated hydroxyanisole and diptylated hydroxytoluene may be used. In order to promote transdermal absorption of 7-thiaprostaglandin E 1 , an absorption enhancer such as diisopropyl adipate, diethyl sebacate, ethyl caproate, ethyl laurate, etc. may be added. In addition, in order to stabilize 7-thiaprostaglandin E 1 , 7-thiaprostaglandin E 1 was converted to cyclodextrin such as α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin; α-methylated. Cyclodextrin, β-
It can also be used as an inclusion compound of methylated cyclodextrin, such as methylated cyclodextrin. Ointments can be manufactured by conventional methods. As the cream, an oil-in-water cream is preferred in order to stabilize 7-thiaprostaglandin E 1 . In addition, as the base, fatty oils, higher alcohols,
Glycols and the like are used, and emulsifiers such as diethylene glycol, propylene glycol, sorbitan monofatty acid ester, polysorbate 80, and sodium lauryl sulfate are used. Furthermore, the above-mentioned preservatives, antioxidants, etc. may be added as necessary. Further, as in the case of ointments, 7-thiaprostaglandin E 1 type can also be used as an inclusion compound of cyclodextrin or methylated cyclodextrin. Creams can be manufactured by conventional methods. Examples of lotions include suspension-type, emulsion-type, and solution-type lotions. Suspension type lotions are obtained using a suspending agent such as sodium alginate, tragacanth, or sodium carboxymethyl cellulose, and optionally adding an antioxidant, preservative, etc. Emulsion-type lotions can be obtained by conventional methods using emulsifiers such as sorbitan monofatty acid ester, polysorbate 80, and sodium lauryl sulfate. The solution-type lotion agent is preferably an alcohol-type lotion agent, which can be obtained by a conventional method using alcohol such as ethanol. As a liquid, 7-thiaprostaglandin
Examples include those in which Type E 1 is dissolved in an alcoholic solution such as ethanol, and antioxidants, preservatives, etc. are added as necessary. In addition to these dosage forms, there are also pasta preparations, poultice preparations,
Examples include dosage forms such as aerosols. Such formulations can be manufactured by conventional methods. 7
-The dosage of thiaprostaglandin E class 1 varies depending on the type of compound, pathological condition, etc., but is usually about 1 mg.
Administered in an amount of ~10 mg/Kg - body weight. Therefore, the amount of 7-thiaprostaglandin E 1 to be included in a drug for transdermal administration is determined by the dosage. The drug for transdermal administration of the present invention containing 7-thiaprostaglandin E type 1 as an active ingredient is administered locally to the skin as described above, so the site of action is limited and only blood vessels in specific areas are affected. It is possible to produce pharmacological effects such as dilation. Further, when administered transdermally, there is an advantage that the pharmacological action lasts for a long time and exhibits a strong pharmacological action. The present invention will be explained in more detail below with reference to Examples. Example 1 13 mg of diisopropyl adipate 16, 17, 18,
19,20-pentanol-15-cyclohexyl-7-
Thiaprostaglandin E 1 methyl ester 1mg
was dissolved, 40 mg of white petrolatum was added thereto, and the mixture was thoroughly kneaded to form a uniform ointment. When the stability of the drug in such an ointment was investigated, it was found that the drug did not degrade even after 40 days. Example 2 Take 2 mg of 16,17,18,19,20-pentanol-15-cyclopentyl-7-thiaprostaglandin E 1 methyl ester and add it to a hydrophilic ointment (white petrolatum, stearyl alcohol, propylene glycol, sodium lauryl sulfate). , ethyl paraoxybenzoate, propyl paraoxybenzoate)
Mix well with 100 mg to make a uniform ointment. Example 3 Take 1 mg of 17,20-dimethyl-7-thiaprostaglandin E 1 methyl ester, add it to 50 mg of cold cream (beeswax, liquid paraffin, purified water, borax), and knead to form a uniform cream. obtained the drug. Examples 4 to 11 Prepare a 0.2% by weight ethanol solution of the drug,
The specified dose of this solution was applied to the skin of the inner side of the lower arm of a healthy adult male in a circular shape with an area of about 4 to 6 cm 2 while the solvent was allowed to evaporate. After application, erythema that appeared around the application site was observed as an indicator of peripheral vasodilation and/or increased vascular permeability, and the time of appearance and disappearance of the erythema was measured. The results are summarized in Table 1 below.
【表】
実施例 12
〔経皮投与によるラツトの血圧に対する効果の
測定〕体重約250ｇのウイスター系雄性ラツトで
前日腹部を除毛したものを実験に用いた。ウレタ
ンとα−クロラロースを腹腔内投与し、麻酔した
ラツトを仰けに固定し、総頚動脈にカニユーレを
挿入、圧トランスジユーサーを介して血圧を測定
した。
被検化合物（化合物Ａ：16，17，18，19，20−
ペンタノル−15−シクロヘキシル−７−チアプロ
スタグランジンE1メチルエステル）の２％軟膏
（基剤、白色ワセリン：アジピン酸ジイソプロピ
ル＝約４：１（重量比））は除毛した腹部に0.15
ｇ／Kg（被検化合物３mg／Kg）を塗布した。結果
は表２の示したとおりである。[Table] Example 12 [Measurement of the effect of transdermal administration on blood pressure in rats] Male Wistar rats weighing approximately 250 g whose abdominal hair had been removed the previous day were used in the experiment. Urethane and α-chloralose were administered intraperitoneally, the anesthetized rat was fixed supine, a cannula was inserted into the common carotid artery, and blood pressure was measured via a pressure transducer. Test compound (compound A: 16, 17, 18, 19, 20-
A 2% ointment of pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 methyl ester (base, white petrolatum: diisopropyl adipate = approximately 4:1 (weight ratio)) was applied to the abdomen from which hair was removed.
g/Kg (3 mg/Kg of test compound). The results are shown in Table 2.
【表】
表２に示すように被検化合物Ａは塗布10分後す
でに血圧下降を示し、30分後にプラトーに達し、
４時間以上持続した。また塗布部は、５〜10分で
潮紅し、４〜５時間持続した。
実施例 13
16，17，18，19，20−ペンタノル−15−シクロ
ヘキシル−７−チアプロスタグランジンE1メチ
ルエステル１mgと白色ワセリン40mgとをよく練合
して均一に分散せしめ、軟膏を得た。[Table] As shown in Table 2, test compound A already showed a decrease in blood pressure 10 minutes after application, reached a plateau after 30 minutes, and
Lasted over 4 hours. The applied area became flushed within 5 to 10 minutes and lasted for 4 to 5 hours. Example 13 1 mg of 16, 17, 18, 19, 20-pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 methyl ester and 40 mg of white petrolatum were thoroughly kneaded and uniformly dispersed to obtain an ointment. .
Claims (1)
し、R1は水素原子、低級アルキル基または薬理
学的に許容しうる陽イオンを表わし、R2は水素
原子またはメチル基を表わし、R3は置換もしく
は非置換の炭素数５〜８のアルキル基または置換
もしくは非置換の炭素数５〜８のシクロアルキル
基を表わす。〕 で表わされる７−チアプロスタグランジンE1類
を有効成分とする経皮投与用薬剤。 ２ ７−チアプロスタグランジンE1類が、７−
チアプロスタグランジンE1，16，17，18，19，
20−ペンタノル−15−シクロヘキシル−７−チア
プロスタグランジンE1，16，17，18，19，20−
ペンタノル−15−シクロペンチル−７−チアプロ
スタグランジンE1、または17，20−ジメチル−
７−チアプロスタグランジンE1，16，17，18，
19，20−ペンタノル−15−シクロヘキシル−Δ2
−７−チアプロスタグランジンE1およびそれら
のエステル類である特許請求の範囲第１項記載の
経皮投与用薬剤。 ３ 剤形が軟膏、クリーム、ローシヨンまたは液
剤である特許請求の範囲第１項又は第２項記載の
経皮投与用薬剤。[Claims] 1. The following formula [] [In the formula, the symbol 〓 represents a single bond or a double bond, R 1 represents a hydrogen atom, a lower alkyl group, or a pharmacologically acceptable cation, R 2 represents a hydrogen atom or a methyl group, and R 3 represents a substituted or unsubstituted alkyl group having 5 to 8 carbon atoms or a substituted or unsubstituted cycloalkyl group having 5 to 8 carbon atoms. ] A drug for transdermal administration containing 7-thiaprostaglandin E type 1 represented by the following as an active ingredient. 2 7-Thiaprostaglandin E class 1 is 7-
Thiaprostaglandin E 1 , 16, 17, 18, 19,
20-Pentanol-15-cyclohexyl-7-thiaprostaglandin E 1 , 16, 17, 18, 19, 20-
Pentanol-15-cyclopentyl-7-thiaprostaglandin E 1 or 17,20-dimethyl-
7-thiaprostaglandin E 1 , 16, 17, 18,
19,20-pentanol-15-cyclohexyl-Δ 2
The drug for transdermal administration according to claim 1, which is -7-thiaprostaglandin E 1 and esters thereof. 3. The drug for transdermal administration according to claim 1 or 2, which is in the form of an ointment, cream, lotion, or liquid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP104383A JPS59128327A (en) | 1983-01-10 | 1983-01-10 | Drug for transcutaneous administration containing 7-thiaprostaglandin e1 compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP104383A JPS59128327A (en) | 1983-01-10 | 1983-01-10 | Drug for transcutaneous administration containing 7-thiaprostaglandin e1 compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59128327A JPS59128327A (en) | 1984-07-24 |
| JPH0251403B2 true JPH0251403B2 (en) | 1990-11-07 |
Family
ID=11490527
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP104383A Granted JPS59128327A (en) | 1983-01-10 | 1983-01-10 | Drug for transcutaneous administration containing 7-thiaprostaglandin e1 compound |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59128327A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU677073B2 (en) * | 1993-06-18 | 1997-04-10 | Teijin Limited | Blood vessel thickening inhibitor and smooth muscle fiber migration inhibitor each containing 7-thiaprostaglandin e1 compound as active ingredient |
| AU1467295A (en) * | 1994-01-28 | 1995-08-15 | Teijin Limited | Prostacyclin-containing oleaginous ointment |
| US7888392B2 (en) | 2005-02-14 | 2011-02-15 | Taisho Pharmaceutical Co., Ltd. | Ointment |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5536494A (en) * | 1978-08-16 | 1980-03-14 | American Cyanamid Co | Prostaglandin vasodilator and hypotensive drug by local application or infusion |
| JPS55111417A (en) * | 1979-02-12 | 1980-08-28 | American Cyanamid Co | Drug for locally creating skin vasodilatation for treatment of vessel spasmus or ischemia condition |
-
1983
- 1983-01-10 JP JP104383A patent/JPS59128327A/en active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5536494A (en) * | 1978-08-16 | 1980-03-14 | American Cyanamid Co | Prostaglandin vasodilator and hypotensive drug by local application or infusion |
| JPS55111417A (en) * | 1979-02-12 | 1980-08-28 | American Cyanamid Co | Drug for locally creating skin vasodilatation for treatment of vessel spasmus or ischemia condition |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59128327A (en) | 1984-07-24 |
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