JP2013067584A - Plaster - Google Patents
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- Publication number
- JP2013067584A JP2013067584A JP2011207241A JP2011207241A JP2013067584A JP 2013067584 A JP2013067584 A JP 2013067584A JP 2011207241 A JP2011207241 A JP 2011207241A JP 2011207241 A JP2011207241 A JP 2011207241A JP 2013067584 A JP2013067584 A JP 2013067584A
- Authority
- JP
- Japan
- Prior art keywords
- adhesive layer
- pressure
- patch
- sensitive adhesive
- beraprost
- 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.)
- Granted
Links
- 239000011505 plaster Substances 0.000 title abstract 3
- 239000010410 layer Substances 0.000 claims abstract description 68
- 229960002890 beraprost Drugs 0.000 claims abstract description 41
- CTPOHARTNNSRSR-APJZLKAGSA-N beraprost Chemical compound O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC(O)=O CTPOHARTNNSRSR-APJZLKAGSA-N 0.000 claims abstract description 40
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims abstract description 21
- 239000012790 adhesive layer Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000004480 active ingredient Substances 0.000 claims abstract description 7
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims description 47
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 28
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000853 adhesive Substances 0.000 claims description 16
- 230000001070 adhesive effect Effects 0.000 claims description 15
- 235000019270 ammonium chloride Nutrition 0.000 claims description 14
- 229940043348 myristyl alcohol Drugs 0.000 claims description 12
- 229920000346 polystyrene-polyisoprene block-polystyrene Polymers 0.000 claims description 11
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 claims description 10
- 229940055577 oleyl alcohol Drugs 0.000 claims description 10
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 claims description 10
- 238000010521 absorption reaction Methods 0.000 claims description 7
- 239000004014 plasticizer Substances 0.000 claims description 6
- 239000003623 enhancer Substances 0.000 claims description 5
- 231100000245 skin permeability Toxicity 0.000 abstract description 19
- 229940124532 absorption promoter Drugs 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 description 26
- 239000003814 drug Substances 0.000 description 26
- 210000003491 skin Anatomy 0.000 description 26
- -1 salt compound Chemical class 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 230000007423 decrease Effects 0.000 description 11
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 206010040880 Skin irritation Diseases 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 230000036556 skin irritation Effects 0.000 description 7
- 231100000475 skin irritation Toxicity 0.000 description 7
- 229940057995 liquid paraffin Drugs 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical compound CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 3
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 3
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 3
- 238000005520 cutting process Methods 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 229920000058 polyacrylate Polymers 0.000 description 3
- 239000010734 process oil Substances 0.000 description 3
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 3
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 3
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FWKQNCXZGNBPFD-UHFFFAOYSA-N Guaiazulene Chemical compound CC(C)C1=CC=C(C)C2=CC=C(C)C2=C1 FWKQNCXZGNBPFD-UHFFFAOYSA-N 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- 239000004952 Polyamide Substances 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 229920002367 Polyisobutene Polymers 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- BTFJIXJJCSYFAL-UHFFFAOYSA-N arachidyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 description 2
- FUWUEFKEXZQKKA-UHFFFAOYSA-N beta-thujaplicin Chemical compound CC(C)C=1C=CC=C(O)C(=O)C=1 FUWUEFKEXZQKKA-UHFFFAOYSA-N 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 239000005038 ethylene vinyl acetate Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229920003049 isoprene rubber Polymers 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- HCZKYJDFEPMADG-TXEJJXNPSA-N masoprocol Chemical compound C([C@H](C)[C@H](C)CC=1C=C(O)C(O)=CC=1)C1=CC=C(O)C(O)=C1 HCZKYJDFEPMADG-TXEJJXNPSA-N 0.000 description 2
- 230000007721 medicinal effect Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 2
- 239000004745 nonwoven fabric Substances 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 229920002239 polyacrylonitrile Polymers 0.000 description 2
- 229920002647 polyamide Polymers 0.000 description 2
- 229920001083 polybutene Polymers 0.000 description 2
- 229920001707 polybutylene terephthalate Polymers 0.000 description 2
- 229920000728 polyester Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920000139 polyethylene terephthalate Polymers 0.000 description 2
- 239000005020 polyethylene terephthalate Substances 0.000 description 2
- 229920002635 polyurethane Polymers 0.000 description 2
- 239000004814 polyurethane Substances 0.000 description 2
- 229920000915 polyvinyl chloride Polymers 0.000 description 2
- 239000004800 polyvinyl chloride Substances 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 2
- 239000002759 woven fabric Substances 0.000 description 2
- AJZJIYUOOJLBAU-CEAXSRTFSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;n,n,2-trimethyl-3-phenothiazin-10-ylpropan-1-amine Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1=CC=C2N(CC(CN(C)C)C)C3=CC=CC=C3SC2=C1.C1=CC=C2N(CC(CN(C)C)C)C3=CC=CC=C3SC2=C1 AJZJIYUOOJLBAU-CEAXSRTFSA-N 0.000 description 1
- FBZQBGYPONNWCG-UHFFFAOYSA-N (4,5-dihydroxy-2,3-dimethoxyphenyl)-phenylmethanone Chemical compound COC1=C(O)C(O)=CC(C(=O)C=2C=CC=CC=2)=C1OC FBZQBGYPONNWCG-UHFFFAOYSA-N 0.000 description 1
- SWFHGTMLYIBPPA-UHFFFAOYSA-N (4-methoxyphenyl)-phenylmethanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1 SWFHGTMLYIBPPA-UHFFFAOYSA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- JXNPEDYJTDQORS-HZJYTTRNSA-N (9Z,12Z)-octadecadien-1-ol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCO JXNPEDYJTDQORS-HZJYTTRNSA-N 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 1
- PMGQWSIVQFOFOQ-BDUVBVHRSA-N (e)-but-2-enedioic acid;(2r)-2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound OC(=O)\C=C\C(O)=O.CN1CCC[C@@H]1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PMGQWSIVQFOFOQ-BDUVBVHRSA-N 0.000 description 1
- CZHLPWNZCJEPJB-UHFFFAOYSA-N 1-chloro-3-methylbutane Chemical compound CC(C)CCCl CZHLPWNZCJEPJB-UHFFFAOYSA-N 0.000 description 1
- MEZZCSHVIGVWFI-UHFFFAOYSA-N 2,2'-Dihydroxy-4-methoxybenzophenone Chemical compound OC1=CC(OC)=CC=C1C(=O)C1=CC=CC=C1O MEZZCSHVIGVWFI-UHFFFAOYSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- HBKBEZURJSNABK-MWJPAGEPSA-N 2,3-dihydroxypropyl (1r,4ar,4br,10ar)-1,4a-dimethyl-7-propan-2-yl-2,3,4,4b,5,6,10,10a-octahydrophenanthrene-1-carboxylate Chemical compound C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(=O)OCC(O)CO HBKBEZURJSNABK-MWJPAGEPSA-N 0.000 description 1
- CIVCELMLGDGMKZ-UHFFFAOYSA-N 2,4-dichloro-6-methylpyridine-3-carboxylic acid Chemical compound CC1=CC(Cl)=C(C(O)=O)C(Cl)=N1 CIVCELMLGDGMKZ-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- WYUYEJNGHIOFOC-VVTVMFAVSA-N 2-[(z)-1-(4-methylphenyl)-3-pyrrolidin-1-ylprop-1-enyl]pyridine;hydrochloride Chemical compound Cl.C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C\CN1CCCC1 WYUYEJNGHIOFOC-VVTVMFAVSA-N 0.000 description 1
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- OMIGHNLMNHATMP-UHFFFAOYSA-N 2-hydroxyethyl prop-2-enoate Chemical compound OCCOC(=O)C=C OMIGHNLMNHATMP-UHFFFAOYSA-N 0.000 description 1
- HFCUBKYHMMPGBY-UHFFFAOYSA-N 2-methoxyethyl prop-2-enoate Chemical compound COCCOC(=O)C=C HFCUBKYHMMPGBY-UHFFFAOYSA-N 0.000 description 1
- ROGIWVXWXZRRMZ-UHFFFAOYSA-N 2-methylbuta-1,3-diene;styrene Chemical compound CC(=C)C=C.C=CC1=CC=CC=C1 ROGIWVXWXZRRMZ-UHFFFAOYSA-N 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- IJALWSVNUBBQRA-UHFFFAOYSA-N 4-Isopropyl-3-methylphenol Chemical compound CC(C)C1=CC=C(O)C=C1C IJALWSVNUBBQRA-UHFFFAOYSA-N 0.000 description 1
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 description 1
- PLXMOAALOJOTIY-FPTXNFDTSA-N Aesculin Natural products OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)[C@H]1Oc2cc3C=CC(=O)Oc3cc2O PLXMOAALOJOTIY-FPTXNFDTSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
- WNBCMONIPIJTSB-BGNCJLHMSA-N Cichoriin Natural products O([C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1)c1c(O)cc2c(OC(=O)C=C2)c1 WNBCMONIPIJTSB-BGNCJLHMSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- MQIUGAXCHLFZKX-UHFFFAOYSA-N Di-n-octyl phthalate Natural products CCCCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCCC MQIUGAXCHLFZKX-UHFFFAOYSA-N 0.000 description 1
- SWECWXGUJQLXJF-BTJKTKAUSA-N Dimetindene maleate Chemical compound OC(=O)\C=C/C(O)=O.CN(C)CCC=1CC2=CC=CC=C2C=1C(C)C1=CC=CC=N1 SWECWXGUJQLXJF-BTJKTKAUSA-N 0.000 description 1
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- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 108700042658 GAP-43 Proteins 0.000 description 1
- 244000043261 Hevea brasiliensis Species 0.000 description 1
- 239000013032 Hydrocarbon resin Substances 0.000 description 1
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
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- 235000019483 Peanut oil Nutrition 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920000297 Rayon Polymers 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 241000705989 Tetrax Species 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
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- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- TUFYVOCKVJOUIR-UHFFFAOYSA-N alpha-Thujaplicin Natural products CC(C)C=1C=CC=CC(=O)C=1O TUFYVOCKVJOUIR-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 239000001518 benzyl (E)-3-phenylprop-2-enoate Substances 0.000 description 1
- NGHOLYJTSCBCGC-QXMHVHEDSA-N benzyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OCC1=CC=CC=C1 NGHOLYJTSCBCGC-QXMHVHEDSA-N 0.000 description 1
- YTCZZXIRLARSET-VJRSQJMHSA-M beraprost sodium Chemical compound [Na+].O([C@H]1C[C@@H](O)[C@@H]([C@@H]21)/C=C/[C@@H](O)C(C)CC#CC)C1=C2C=CC=C1CCCC([O-])=O YTCZZXIRLARSET-VJRSQJMHSA-M 0.000 description 1
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Abstract
Description
本発明は、貼付剤に関する。 The present invention relates to a patch.
薬物の投与方法としては、従来から経口投与、直腸投与、皮内投与、静脈投与等の種々の方法が知られており、吸収後肝臓において一次代謝を受けにくいことや、副作用が少なく、安全かつ持続的に薬物を吸収させることが期待できる方法として、貼付剤等により経皮投与をする方法が注目されている。しかしながら、異物の体内への進入を防ぐバリヤー機能を持っている皮膚は薬物に対して強力なバリヤー機能を発揮するため、経皮投与においては、薬物の透過性が低く、十分な薬効が期待できないという問題を有していた。そのため、経皮投与における薬物の皮膚透過性を高めるための様々な検討がなされており、例えば、国際公開第０１／００５３８１号（特許文献１）には、塩形態を有する酸性薬物と塩化アンモニウムのような塩基性物質の付加塩化合物とを含有する経皮吸収製剤が記載されている。 Various methods such as oral administration, rectal administration, intradermal administration, intravenous administration and the like have been conventionally known as drug administration methods, and are less susceptible to primary metabolism in the liver after absorption, and have fewer side effects and are safe and safe. As a method that can be expected to absorb the drug continuously, a method of transdermal administration using a patch or the like has attracted attention. However, skin that has a barrier function to prevent foreign substances from entering the body exerts a strong barrier function against the drug. Therefore, in the case of transdermal administration, drug permeability is low and sufficient medicinal effects cannot be expected. Had the problem. Therefore, various studies for enhancing the skin permeability of drugs in transdermal administration have been made. For example, International Publication No. 01/005381 (Patent Document 1) describes acidic drugs having a salt form and ammonium chloride. A transdermally absorbable preparation containing an addition salt compound of such a basic substance is described.
また、ベラプロストは強力な血小板凝集抑制作用及び血管拡張作用を有する薬物であり、血管障害の治療薬として期待されている。しかしながら、ベラプロストは化学的にきわめて不安定であるため、従来、その投与方法としては静脈内投与や経口投与等の限られた方法しかなかった。現在ではベラプロストの経皮投与に関する開発が行われており、例えば、国際公開第１９９６／０１５７９３号（特許文献２）にはベラプロストと飽和脂肪酸や不飽和脂肪酸とを含有する経皮吸収製剤として、貼付剤が記載されている。しかしながら、特許文献２に記載の貼付剤においては、ベラプロストの皮膚透過性は未だ十分なものではなかった。 Beraprost is a drug having a strong platelet aggregation inhibitory action and vasodilatory action, and is expected as a therapeutic drug for vascular disorders. However, since beraprost is chemically extremely unstable, conventionally, there have been only limited methods such as intravenous administration and oral administration. At present, development related to transdermal administration of beraprost has been carried out. For example, International Publication No. 1996/015793 (Patent Document 2) is applied as a transdermal absorption preparation containing beraprost and saturated fatty acid or unsaturated fatty acid. Agents are described. However, in the patch described in Patent Document 2, the skin permeability of beraprost has not been sufficient yet.
本発明は、上記従来技術の有する課題に鑑みてなされたものであり、ベラプロストの皮膚透過性に優れた貼付剤を提供することを目的とする。 This invention is made | formed in view of the subject which the said prior art has, and aims at providing the patch excellent in the skin permeability of beraprost.
本発明者らは、上記目的を達成すべく鋭意研究を重ねた結果、支持体と粘着剤層とを備える貼付剤において、前記粘着剤層中に、有効成分としてベラプロスト又はその薬理学的に許容される塩と、経皮吸収促進剤として炭素数１４〜２０の脂肪族アルコールとを組み合わせて含有せしめることにより、ベラプロストの皮膚透過性が向上することを見出し、本発明を完成するに至った。なお、特許文献１〜２においては、貼付剤においてベラプロストと炭素数１４〜２０の脂肪族アルコールとを組み合わせることについて何ら言及されていない。 As a result of intensive studies to achieve the above object, the present inventors have found that in a patch comprising a support and an adhesive layer, belaprost or its pharmacologically acceptable as an active ingredient in the adhesive layer. It was found that the permeation of beraprost was improved by containing a combination of a salt to be added and an aliphatic alcohol having 14 to 20 carbon atoms as a transdermal absorption enhancer, and the present invention was completed. In Patent Documents 1 and 2, there is no mention of combining beraprost and an aliphatic alcohol having 14 to 20 carbon atoms in the patch.
すなわち、本発明の貼付剤は、
粘着剤層と支持体層とを備えており、有効成分としてのベラプロスト又はその薬理学的に許容される塩と、経皮吸収促進剤としての炭素数１４〜２０の脂肪族アルコールと、を前記粘着剤層中に含有することを特徴とするものである。
That is, the patch of the present invention is
A pressure-sensitive adhesive layer and a support layer, wherein the beraprost as an active ingredient or a pharmacologically acceptable salt thereof, and a C14-20 aliphatic alcohol as a transdermal absorption enhancer, It contains in an adhesive layer.
本発明の貼付剤としては、前記脂肪族アルコールがミリスチルアルコール又はオレイルアルコールであることが好ましい。また、前記脂肪族アルコールがミリスチルアルコールである場合には、その含有量が前記粘着剤層中において５〜１０質量％であることが好ましく、前記脂肪族アルコールがオレイルアルコールである場合には、その含有量が前記粘着剤層中において２．５〜１０質量％であることがより好ましい。 In the patch of the present invention, the aliphatic alcohol is preferably myristyl alcohol or oleyl alcohol. Further, when the aliphatic alcohol is myristyl alcohol, the content thereof is preferably 5 to 10% by mass in the pressure-sensitive adhesive layer, and when the aliphatic alcohol is oleyl alcohol, The content is more preferably 2.5 to 10% by mass in the pressure-sensitive adhesive layer.
さらに、本発明の貼付剤としては、前記粘着剤層中に塩化アンモニウムをさらに含有することがより好ましい。また、本発明の貼付剤としては、前記粘着剤層中にスチレン−イソプレン−スチレンブロック共重合体をさらに含有することが好ましく、さらに、前記粘着剤層中に粘着付与剤及び可塑剤をさらに含有することが好ましい。 Furthermore, as the patch of the present invention, it is more preferable that the pressure-sensitive adhesive layer further contains ammonium chloride. Further, the adhesive patch of the present invention preferably further contains a styrene-isoprene-styrene block copolymer in the pressure-sensitive adhesive layer, and further contains a tackifier and a plasticizer in the pressure-sensitive adhesive layer. It is preferable to do.
本発明によれば、ベラプロストの皮膚透過性に優れた貼付剤を提供することが可能となる。 ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the patch excellent in the skin permeability of beraprost.
以下、本発明をその好適な実施形態に即して詳細に説明する。 Hereinafter, the present invention will be described in detail with reference to preferred embodiments thereof.
本発明の貼付剤は、粘着剤層と支持体層とを備えている。前記粘着剤層は、前記支持体層の面上（通常は一方の面上）に形成された層であり、有効成分、経皮吸収促進剤及び粘着基剤を含有している層である。本発明に係る粘着剤層は、前記有効成分としてベラプロスト又はその薬理学的に許容される塩を含有しており、前記経皮吸収促進剤として炭素数１４〜２０の脂肪族アルコールを含有している。また、このような粘着剤層の厚さとしては特に制限されないが、通常１０〜３００μｍ程度であることが好ましい。 The patch of the present invention includes an adhesive layer and a support layer. The pressure-sensitive adhesive layer is a layer formed on the surface of the support layer (usually on one surface), and is a layer containing an active ingredient, a percutaneous absorption promoter, and a pressure-sensitive adhesive base. The pressure-sensitive adhesive layer according to the present invention contains beraprost or a pharmacologically acceptable salt thereof as the active ingredient, and contains an aliphatic alcohol having 14 to 20 carbon atoms as the transdermal absorption promoter. Yes. Further, the thickness of the pressure-sensitive adhesive layer is not particularly limited, but is usually preferably about 10 to 300 μm.
前記ベラプロストとは、分子式Ｃ２４Ｈ３０Ｏ５で表わされる２，３，３ａ，８ｂ−テトラヒドロ−２−ヒドロキシ−１−（３−ヒドロキシ−４−メチル−１−オクテン−６−イン−１−イル）−１Ｈ−シクロペンタ（ｂ）ベンゾフラン−５−ブタン酸［２，３，３ａ，８ｂ−ｔｅｔｒａｈｙｄｒｏ−２−ｈｙｄｒｏｘｙ−１−（３−ｈｙｄｒｏｘｙ−４−ｍｅｔｈｙｌ−１−ｏｃｔｅｎ−６−ｙｎ−１−ｙｌ）−１Ｈ−ｃｙｃｌｏｐｅｎｔａ（ｂ）ｂｅｎｚｏｆｕｒａｎ−５−ｂｕｔａｎｏｉｃ ａｃｉｄ］を指す。前記ベラプロストはプロスタグランジンＩ２誘導体の１種であり、血小板凝集抑制作用及び血管拡張作用を有する薬物である。 The beraprost is 2,3,3a, 8b-tetrahydro-2-hydroxy-1- (3-hydroxy-4-methyl-1-octene-6-in-1-- represented by the molecular formula C 24 H 30 O 5 Yl) -1H-cyclopenta (b) benzofuran-5-butanoic acid [2,3,3a, 8b-tetrahydro-2-hydroxy-1- (3-hydroxy-4-methyl-1-octen-6-yn-1 -Yl) -1H-cyclopenta (b) benzofuran-5-butanoic acid]. The beraprost is one of prostaglandin I 2 derivatives and is a drug having a platelet aggregation inhibitory action and a vasodilator action.
本発明において有効成分として含有されるベラプロストの形態としては、遊離体であってもその薬理学的に許容される塩であってもよく、製造中及び／又は製造された製剤中においてベラプロストの塩が脱塩されて遊離体となったものであってもよく、これらのうちの１種であっても２種以上が混合されていてもよい。これらの中でも、本発明に係るベラプロストの形態としては、薬物の安定性が向上し、酸によりひきおこされる皮膚への刺激や製剤物性の低下を抑制できる傾向にあるという観点から、ベラプロストの薬理学的に許容される塩であることが好ましい。 The form of beraprost contained as an active ingredient in the present invention may be a free form or a pharmacologically acceptable salt thereof, and the salt of beraprost during production and / or in the produced preparation. May be desalted to form a free form, and one of these may be used, or two or more may be mixed. Among these, the form of beraprost according to the present invention includes beraprost pharmacology from the viewpoint that the stability of the drug is improved and the skin irritation caused by acid and the decrease in physical properties of the preparation tend to be suppressed. Preferably, the salt is acceptable.
前記ベラプロストの薬理学的に許容される塩としては、例えば、アルカリ金属、アルカリ土類金属、アルミニウム等の金属塩；トロメタミン等のアミン塩が挙げられ、これらの中でもナトリウム塩であることが好ましい。 Examples of the pharmacologically acceptable salt of beraprost include metal salts such as alkali metals, alkaline earth metals, and aluminum; amine salts such as tromethamine, among which sodium salts are preferable.
本発明の貼付剤において、このようなベラプロスト及びその薬理学的に許容される塩の合計含有量としては、前記粘着剤層中において０．２〜１０質量％であることが好ましく、０．５〜５質量％であることがより好ましい。前記含有量が前記下限未満である場合には、ベラプロストの皮膚透過性が不十分となる傾向にあり、他方、前記上限を超える場合には、ベラプロストの結晶が析出して粘着剤層の粘着力が低下する傾向にある。 In the patch of the present invention, the total content of such beraprost and a pharmacologically acceptable salt thereof is preferably 0.2 to 10% by mass in the pressure-sensitive adhesive layer. More preferably, it is -5 mass%. When the content is less than the lower limit, the skin permeability of beraprost tends to be insufficient. On the other hand, when the content exceeds the upper limit, the beraprost crystals precipitate and the adhesive strength of the adhesive layer is increased. Tend to decrease.
本発明に係る炭素数１４〜２０の脂肪族アルコールとしては、直鎖状であっても分岐鎖状であってもよく、飽和であっても不飽和であってもよい。このような炭素数１４〜２０の脂肪族アルコールとしては、ミリスチルアルコール、オレイルアルコール、オクチルドデカノール、イソステアリルアルコール、ステアリルアルコール、セチルアルコール、リノリルアルコールが挙げられ、これらの中でも、ベラプロストの皮膚透過性がより向上する傾向にあるという観点から、炭素数１４〜２０の直鎖状の脂肪族アルコールであることが好ましく、ミリスチルアルコール、オレイルアルコールであることがより好ましい。また、本発明に係る炭素数１４〜２０の脂肪族アルコールとしては、１種を単独で用いても２種以上を組み合わせて用いてもよい。 The aliphatic alcohol having 14 to 20 carbon atoms according to the present invention may be linear or branched, and may be saturated or unsaturated. Examples of the aliphatic alcohol having 14 to 20 carbon atoms include myristyl alcohol, oleyl alcohol, octyldodecanol, isostearyl alcohol, stearyl alcohol, cetyl alcohol, and linoleyl alcohol. Among these, beraprost penetrates the skin. From the viewpoint that the property tends to be further improved, it is preferably a linear aliphatic alcohol having 14 to 20 carbon atoms, more preferably myristyl alcohol or oleyl alcohol. Moreover, as a C14-C20 aliphatic alcohol based on this invention, you may use individually by 1 type, or may be used in combination of 2 or more type.
本発明の貼付剤において、このような炭素数１４〜２０の脂肪族アルコールの含有量としては、前記粘着剤層中において１〜２０質量％であることが好ましく、２．５〜１０質量％であることがより好ましい。前記含有量が前記下限未満である場合には、ベラプロストの皮膚透過性が不十分となる傾向にあり、他方、前記上限を超える場合には、粘着剤層の粘着力や凝集力が低下する傾向にある。特に、本発明に係る炭素数１４〜２０の脂肪族アルコールがミリスチルアルコールである場合には、その含有量は前記粘着剤層中において１〜２０質量％であることが好ましく、５〜１０質量％であることがより好ましい。また、本発明に係る炭素数１４〜２０の脂肪族アルコールがオレイルアルコールである場合には、その含有量は前記粘着剤層中において１〜２０質量％であることが好ましく、２．５〜１０質量％であることがより好ましい。前記ミリスチルアルコール又はオレイルアルコールの含有量が前記下限未満である場合には、ベラプロストの皮膚透過性が不十分となる傾向にあり、他方、前記上限を超える場合には、粘着剤層の粘着力や凝集力が低下する傾向にある。 In the patch of the present invention, the content of the aliphatic alcohol having 14 to 20 carbon atoms is preferably 1 to 20% by mass in the pressure-sensitive adhesive layer, and preferably 2.5 to 10% by mass. More preferably. When the content is less than the lower limit, the skin permeability of beraprost tends to be insufficient. On the other hand, when the content exceeds the upper limit, the adhesive strength and cohesive strength of the pressure-sensitive adhesive layer tend to decrease. It is in. In particular, when the aliphatic alcohol having 14 to 20 carbon atoms according to the present invention is myristyl alcohol, the content is preferably 1 to 20% by mass in the pressure-sensitive adhesive layer, and 5 to 10% by mass. It is more preferable that Moreover, when C14-20 aliphatic alcohol which concerns on this invention is oleyl alcohol, it is preferable that the content is 1-20 mass% in the said adhesive layer, and is 2.5-10. More preferably, it is mass%. When the content of the myristyl alcohol or oleyl alcohol is less than the lower limit, the skin permeability of beraprost tends to be insufficient, whereas when the content exceeds the upper limit, The cohesive force tends to decrease.
本発明の貼付剤としては、前記粘着剤層中に塩化アンモニウムをさらに含有することが好ましい。塩化アンモニウムをさらに含有せしめることにより、ベラプロストの皮膚透過性をより向上させることができる傾向にある。特に、通常、薬物が塩の形態である場合には、皮膚における異物の体内への進入を防ぐバリヤー機能がより強力に発揮されるため、薬物の透過性が低くなり、十分な薬効が期待できない傾向にあるが、前記塩化アンモニウムをさらに含有せしめることにより、ベラプロストが塩の形態であってもその皮膚透過性をより向上させることができる傾向にある。 The patch of the present invention preferably further contains ammonium chloride in the pressure-sensitive adhesive layer. By further containing ammonium chloride, the skin permeability of beraprost tends to be further improved. In particular, when the drug is in the form of a salt, the barrier function for preventing the entry of foreign substances in the skin into the body is exerted more strongly, so the drug permeability is low and sufficient drug efficacy cannot be expected. There is a tendency, but by further containing the ammonium chloride, the skin permeability tends to be further improved even if beraprost is in the form of a salt.
前記塩化アンモニウムを本発明の貼付剤に含有せしめる場合、その含有量としては、前記粘着剤層中において０．１３〜２．５質量％であることが好ましく、０．１３〜１．３質量％であることがより好ましい。前記塩化アンモニウムの含有量が前記下限未満である場合には、ベラプロストの皮膚透過性が低下する傾向にあり、他方、前記上限を超える場合には、塩化アンモニウムの溶解性が低下し、製剤物性が低下する傾向にある。 When the ammonium chloride is contained in the patch of the present invention, the content thereof is preferably 0.13 to 2.5% by mass in the pressure-sensitive adhesive layer, and 0.13 to 1.3% by mass. It is more preferable that When the content of the ammonium chloride is less than the lower limit, the skin permeability of beraprost tends to decrease. On the other hand, when the content exceeds the upper limit, the solubility of ammonium chloride decreases and the physical properties of the preparation are reduced. It tends to decrease.
また、前記粘着剤層中における前記塩化アンモニウムの含有量としては、前記ベラプロスト及びその薬理学的に許容される塩の合計含有量に対して０．５〜１０倍モル、より好ましくは０．５〜７倍モルとなるような含有量であることが好ましい。前記含有量が前記下限未満である場合には、ベラプロストの皮膚透過性が不十分となり、十分な薬効が得られない傾向にある。他方、前記上限を超える場合には、ベラプロストの皮膚透過性は向上するものの、塩化アンモニウムの溶解性が低下し、製剤物性の低下が起こりやすくなる傾向にある。 Moreover, as content of the said ammonium chloride in the said adhesive layer, it is 0.5-10 times mole with respect to the total content of the said beraprost and its pharmacologically acceptable salt, More preferably, it is 0.5. The content is preferably ˜7 times mol. When the content is less than the lower limit, the skin permeability of beraprost is insufficient and sufficient medicinal effects tend not to be obtained. On the other hand, when the upper limit is exceeded, although the skin permeability of beraprost is improved, the solubility of ammonium chloride is lowered and the physical properties of the preparation tend to be lowered.
また、本発明に係る粘着剤層における粘着基剤としては、スチレン−イソプレン−スチレンブロック共重合体、スチレン−ブタジエン−スチレンブロック共重合体、スチレン−イソプレンゴム、スチレン−ブタジエンゴム、ポリイソプレン、ポリイソブチレン、ポリブタジエンゴム、シリコーンゴム、アクリル系ポリマー、天然ゴム、ポリウレタン系ゴム等が挙げられ、これらのうちの１種を単独で用いても２種以上を組み合わせて用いてもよい。 Further, as the adhesive base in the adhesive layer according to the present invention, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-isoprene rubber, styrene-butadiene rubber, polyisoprene, poly Examples include isobutylene, polybutadiene rubber, silicone rubber, acrylic polymer, natural rubber, polyurethane rubber, and the like. One of these may be used alone, or two or more may be used in combination.
本発明において、前記粘着基剤としては、ベラプロストの皮膚透過性をより向上させることができる傾向にあるという観点から、スチレン−イソプレン−スチレンブロック共重合体であることが好ましい。前記スチレン−イソプレン−スチレンブロック共重合体としては、具体的には、カリフレックスＴＲ−１１０７、ＴＲ−１１１１、ＴＲ−１１１２又はＴＲ−１１１７（商品名、シェル化学（株）製）、クインタック３５３０、３５７０Ｃ又は３４２１（商品名、日本ゼオン（株）製）、ＪＳＲ ＳＩＳ−５０００又は５００２（商品名、日本合成ゴム（株）製）、ソルプレン４２８（商品名、フィリップペトロリアム（株）製）等が挙げられ、これらのうちの１種を単独で用いても２種以上を組み合わせて用いてもよい。 In the present invention, the adhesive base is preferably a styrene-isoprene-styrene block copolymer from the viewpoint that the skin permeability of beraprost tends to be further improved. Specific examples of the styrene-isoprene-styrene block copolymer include Califlex TR-1107, TR-1111, TR-1112, or TR-1117 (trade name, manufactured by Shell Chemical Co., Ltd.), QUINTAC 3530. 3570C or 3421 (trade name, manufactured by Nippon Zeon Co., Ltd.), JSR SIS-5000 or 5002 (trade name, manufactured by Nippon Synthetic Rubber Co., Ltd.), Sorprene 428 (trade name, manufactured by Philippe Petroleum Co., Ltd.), etc. One of these may be used alone, or two or more may be used in combination.
前記スチレン−イソプレン−スチレンブロック共重合体を前記貼付剤に含有せしめる場合、その含有量としては、前記粘着剤層中において５〜５０質量％であることが好ましく、１０〜４０質量％であることがより好ましい。前記含有量をこのような範囲内にすることにより、粘着性や長時間の皮膚への付着性、薬物の経皮吸収性・分散性、剥離時の痛み、皮膚のかぶれ等が大きく改善される傾向にある。また、前記含有量が前記下限未満である場合には、粘着剤層の凝集力や保型性等が低下する傾向にあり、他方、前記上限を超える場合には、粘着剤層の凝集力が増加して粘着力の低下や、粘着剤層の不均一化を招く傾向にある。 When the styrene-isoprene-styrene block copolymer is contained in the patch, the content thereof is preferably 5 to 50% by mass in the pressure-sensitive adhesive layer, and 10 to 40% by mass. Is more preferable. By making the content within such a range, the adhesiveness, adhesion to the skin for a long time, transdermal absorbability / dispersibility of the drug, pain at the time of peeling, skin irritation, etc. are greatly improved. There is a tendency. Moreover, when the content is less than the lower limit, the cohesive force and shape retention of the pressure-sensitive adhesive layer tend to be reduced. On the other hand, when the content exceeds the upper limit, the cohesive force of the pressure-sensitive adhesive layer is low. It tends to increase and cause a decrease in adhesive strength and non-uniformity of the adhesive layer.
前記ポリイソブチレンとしては、具体的には、オパノールＢ−３、Ｂ−１０、Ｂ−１５、Ｂ−５０、Ｂ−１００、Ｂ−２００（商品名、ＢＡＳＦ製）、ビスタネックスＬＭ−ＭＳ、ＬＭ−ＭＨ、ＭＭＬ−８０、ＬＬＭ−１００、ＬＬＭ−１２０、ＬＬＭ−１４０（商品名、エクソン化学（株）製）、テトラックス３Ｔ、４Ｔ、５Ｔ、６Ｔ（商品名、日本石油化学（株）製）等が挙げられ、これらのうちの１種を単独で用いても２種以上を組み合わせて用いてもよい。前記ポリイソブチレンを前記貼付剤に含有せしめる場合、その含有量としては、前記粘着剤層中において２〜３０質量％であることが好ましく、４〜２０質量％であることがより好ましい。前記含有量をこのような範囲内にすることにより、粘着性や長時間の皮膚への付着性、薬物の経皮吸収性・分散性、剥離時の痛み、皮膚のかぶれ等が大きく改善される傾向にある。また、前記含有量が前記下限未満である場合には、粘着力や長時間の皮膚への付着性が低下し、剥離時の痛みや皮膚のかぶれ等が増加する傾向にある。他方、前記上限を超える場合には、粘着剤層の保型性等が低下しべたつきが増加する傾向にある。 Specific examples of the polyisobutylene include Opanol B-3, B-10, B-15, B-50, B-100, B-200 (trade name, manufactured by BASF), Vistanex LM-MS, LM. -MH, MML-80, LLM-100, LLM-120, LLM-140 (trade name, manufactured by Exxon Chemical Co., Ltd.), Tetrax 3T, 4T, 5T, 6T (trade name, manufactured by Nippon Petrochemical Co., Ltd.) ) And the like, and one of these may be used alone, or two or more may be used in combination. When the polyisobutylene is contained in the patch, the content thereof is preferably 2 to 30% by mass in the pressure-sensitive adhesive layer, and more preferably 4 to 20% by mass. By making the content within such a range, the adhesiveness, adhesion to the skin for a long time, transdermal absorbability / dispersibility of the drug, pain at the time of peeling, skin irritation, etc. are greatly improved. There is a tendency. Moreover, when the said content is less than the said minimum, adhesive force and the adhesiveness to the skin for a long time will fall, and there exists a tendency for the pain at the time of peeling, skin irritation, etc. to increase. On the other hand, when it exceeds the upper limit, the shape retention of the pressure-sensitive adhesive layer and the like tend to decrease and the stickiness tends to increase.
前記アクリル系ポリマーとしては、ブチルアクリレート、２−エチルヘキシルアクリレート、酢酸ビニル、メタクリレート、ヒドロキシエチルアクリレート、グリシジルメタクリレート、メトキシエチルアクリレート、アクリル酸からなる群から選択される少なくとも２種類の化合物の共重合体が挙げられ、具体的には、ＤＵＲＯ−ＴＡＫ ８７−２０９７、８７−２１９４、８７−２１９６、８７−２２８７、８７−２５１６、８７−２８５２、８７−２３５Ａ（商品名、ヘンケル・ジャパン製）、ニッセツＫＰ−７７、ＡＳ−３７０（商品名、日本カーバイト工業（株）製）等が挙げられ、これらのうちの１種を単独で用いても２種以上を組み合わせて用いてもよい。前記アクリル系ポリマーを前記貼付剤に含有せしめる場合、その含有量としては、ベラプロストの皮膚透過性をより向上させることができる傾向にあるという観点から、前記粘着剤層中において９３質量％以下であることが好ましい。 Examples of the acrylic polymer include a copolymer of at least two compounds selected from the group consisting of butyl acrylate, 2-ethylhexyl acrylate, vinyl acetate, methacrylate, hydroxyethyl acrylate, glycidyl methacrylate, methoxyethyl acrylate, and acrylic acid. Specifically, DURO-TAK 87-2097, 87-2194, 87-2196, 87-2287, 87-2516, 87-2852, 87-235A (trade name, manufactured by Henkel Japan), Nissetsu KP -77, AS-370 (trade name, manufactured by Nippon Carbide Industry Co., Ltd.), etc., may be used alone or in combination of two or more. In the case where the acrylic polymer is contained in the patch, the content is 93% by mass or less in the pressure-sensitive adhesive layer from the viewpoint that the skin permeability of beraprost tends to be further improved. It is preferable.
また、前記貼付剤としては、前記粘着剤層中に粘着付与剤及び可塑剤をさらに含有することが好ましい。前記粘着付与剤としては、例えば、ロジンエステル、水添ロジンエステル、マレイン化ロジン、脂環族飽和炭化水素樹脂、テルペンフェノール等が挙げられ、具体的には、エステルガムＡ、ＡＡ−Ｇ、Ｈ又はＨＰ（商品名、荒川化学工業（株）製）、ハリエスターＬ、Ｓ又はＰ（商品名、荒川化学工業（株）製）、パインクリスタルＫＥ−１００（商品名、荒川化学工業（株）製）、ＫＥ−３１１（商品名、荒川化学工業（株）製）、ハーコリンＤ（商品名、理化ハーキュレス（株）製）、フォーラル８５又は１０５（商品名、理化ハーキュレス（株）製）、ステベライトエステル７又は１０（商品名、理化ハーキュレス（株）製）、ペンタリン４８２０又は４７４０（商品名、理化ハーキュレス（株）製）、アルコンＰ−８５又はＰ−１００（商品名、荒川化学工業（株）製）等が挙げられ、これらのうちの１種を単独で用いても２種以上を組み合わせて用いてもよい。 Moreover, as said patch, it is preferable to further contain a tackifier and a plasticizer in the said adhesive layer. Examples of the tackifier include rosin ester, hydrogenated rosin ester, maleated rosin, alicyclic saturated hydrocarbon resin, terpene phenol, and the like. Specifically, ester gum A, AA-G, H Or HP (trade name, manufactured by Arakawa Chemical Industries, Ltd.), Harrier Star L, S or P (trade name, manufactured by Arakawa Chemical Industries, Ltd.), Pine Crystal KE-100 (trade name, Arakawa Chemical Industries, Ltd.) ), KE-311 (trade name, manufactured by Arakawa Chemical Co., Ltd.), Hercolin D (trade name, manufactured by Rika Hercules Co., Ltd.), Foral 85 or 105 (trade name, manufactured by Rika Hercules Co., Ltd.), Steve Light ester 7 or 10 (trade name, manufactured by Rika Hercules Co., Ltd.), pentalin 4820 or 4740 (trade name, manufactured by Rika Hercules Co., Ltd.), Alcon P-85 or P-10 (Trade name, manufactured by Arakawa Chemical Industries, Ltd.) and the like, may be used in combination of two or more be used one of these singly.
前記粘着付与剤を前記貼付剤に含有せしめる場合、その含有量としては、前記粘着剤層中において５〜６０質量％であることが好ましく、１０〜５０質量％であることがより好ましい。前記含有量をこのような範囲内にすることにより、粘着性や長時間の皮膚への付着性、薬物の経皮吸収性・分散性、剥離時の痛み、皮膚のかぶれ等が大きく改善される傾向にある。また、前記含有量が前記下限未満である場合には、粘着力や長時間の皮膚への付着性が低下する傾向にあり、他方、前記上限を超える場合には、薬物の経皮吸収性、粘着剤層の保型性等が低下し、剥離時の痛み、皮膚のかぶれ、べたつき等が増加する傾向にある。 When the adhesive agent is included in the patch, the content thereof is preferably 5 to 60% by mass and more preferably 10 to 50% by mass in the adhesive layer. By making the content within such a range, the adhesiveness, adhesion to the skin for a long time, transdermal absorbability / dispersibility of the drug, pain at the time of peeling, skin irritation, etc. are greatly improved. There is a tendency. Further, when the content is less than the lower limit, the adhesive force and long-term skin adhesion tend to decrease, while when the content exceeds the upper limit, the drug transdermal absorbability, The shape retention of the pressure-sensitive adhesive layer is lowered, and there is a tendency that pain at the time of peeling, skin irritation, stickiness and the like increase.
前記可塑剤としては、石油系オイル（例えば、流動パラフィン等のパラフィン系プロセスオイル、ナフテン系プロセスオイル、芳香族系プロセスオイル等）、スクワラン、スクワレン、植物系オイル（例えば、オリーブ油、ツバキ油、ひまし油、トール油、ラッカセイ油）、二塩基酸エステル（例えば、ジブチルフタレート、ジオクチルフタレート等）、液状ゴム（例えば、液状ポリブテン、液状イソプレンゴム等）等が挙げられ、これらのうちの１種を単独で用いても２種以上を組み合わせて用いてもよい。このような可塑剤としては、粘着剤層の皮膚への付着性がより向上し、皮膚への刺激が低減される傾向にあるという観点から、流動パラフィン、液状ポリブテンが好ましい。 Examples of the plasticizer include petroleum oils (for example, paraffinic process oils such as liquid paraffin, naphthenic process oils, aromatic process oils, etc.), squalane, squalene, vegetable oils (for example, olive oil, camellia oil, castor oil). , Tall oil, peanut oil), dibasic acid esters (for example, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubbers (for example, liquid polybutene, liquid isoprene rubber, etc.), etc. You may use it, or may use it in combination of 2 or more types. As such a plasticizer, liquid paraffin and liquid polybutene are preferable from the viewpoint that the adhesiveness of the pressure-sensitive adhesive layer to the skin is further improved and irritation to the skin tends to be reduced.
前記可塑剤を前記貼付剤に含有せしめる場合、その含有量としては、前記粘着剤層中において７〜７０質量％であることが好ましく、１０〜６０質量％であることがより好ましい。前記含有量をこのような範囲内にすることにより、粘着性や長時間の皮膚への付着性、薬物の経皮吸収性・分散性、剥離時の痛み、皮膚のかぶれ等が大きく改善される傾向にある。また、前記含有量が前記下限未満である場合には、粘着力や薬物の経皮吸収性・分散性が低下する傾向にあり、他方、前記上限を超える場合には、粘着剤層の凝集力や保型性が低下し、剥離時の痛み、べたつき等が増加する傾向にある。 When the plasticizer is contained in the patch, the content thereof is preferably 7 to 70% by mass and more preferably 10 to 60% by mass in the pressure-sensitive adhesive layer. By making the content within such a range, the adhesiveness, adhesion to the skin for a long time, transdermal absorbability / dispersibility of the drug, pain at the time of peeling, skin irritation, etc. are greatly improved. There is a tendency. In addition, when the content is less than the lower limit, the adhesive strength and the transdermal absorbability / dispersibility of the drug tend to be reduced. On the other hand, when the content exceeds the upper limit, the cohesive strength of the adhesive layer In addition, the shape retention tends to decrease, and the pain and stickiness at the time of peeling tend to increase.
さらに、前記貼付剤としては、本発明の効果を損なわない範囲において、酸化防止剤（例えばアスコルビン酸、没食子酸プロピル、ブチルヒドロキシアニソール、ジブチルヒドロキシトルエン（ＢＨＴ）、ノルジヒドログアヤレチン酸、トコフェロール、酢酸トコフェロール等）、紫外線吸収剤（例えばパラアミノ安息香酸、パラアミノ安息香酸エステル、パラジメチルアミノ安息香酸アミル、サリチル酸エステル、アントラニル酸メチル、ウンベリフェロン、エスクリン、ケイヒ酸ベンジル、シノキサート、グアイアズレン、ウロカニン酸、２−（２−ヒドロキシ−５−メチルフェニル）ベンゾトリアゾール、４−メトキシベンゾフェノン、２−ヒドロキシ−４−メトキシベンゾフェノン、オクタペンゾン、ジオキシベンゾン、ジヒドロキシジメトキシベンゾフェノン、スリンペンゾン、ベンゾレルシノール、オクチルジメチルパラアミノベンゾエート、エチルヘキシルパラメトキシサイナメート等）、抗菌剤（例えばパラオキシ安息香酸エステル、安息香酸、安息香酸塩、ソルビン酸、ソルビン酸塩、デヒドロ酢酸塩、４−イソプロピル−３−メチルフェノール、２−イソプロピル−５−メチルフェノール、ヒノキチオール、クレゾール、２，４，４−トリクロロ−２‘−ヒドロキシジフェニルエーテル、３，４，４’−トリクロロカルバニド、クロロブタノール等）、充填剤（例えば水酸化アルミニウム、含水ケイ酸アルミニウム、カオリン、酸化チタン、タルク、酸化亜鉛、含水シリカ、炭酸マグネシウム、リン酸水素カルシウム、ケイ酸マグネシウム、ケイソウ土、無水ケイ酸、ベントナイト、ステアリン酸ナトリウム、ステアリン酸カルシウム、ステアリン酸カリウム、ステアリン酸マグネシウム、ステアリン酸亜鉛等）、抗ヒスタミン剤（例えば塩化イソペンチル、塩酸ジフェンヒドラミン、塩酸イプロヘプチン、塩酸ジフェニルピラリン、塩酸シプロヘプタジン、塩酸トリプロリジン、塩酸プロメタジン、塩酸ホモクロルシクリジン、酒石酸アリメマジン、タンニン酸ジフェンヒドラミン、テオクル酸ジフェニルピラリン、フマル酸クレマスチン、マレイン酸クロルフェニラミン、マレイン酸ジメチンデン、メキタジン等）、清涼剤、香料等を前記粘着剤層中に含有していてもよい。 Further, as the patch, an antioxidant (for example, ascorbic acid, propyl gallate, butylhydroxyanisole, dibutylhydroxytoluene (BHT), nordihydroguaiaretic acid, tocopherol, Tocopherol acetate, etc.), UV absorbers (e.g. paraaminobenzoic acid, paraaminobenzoic acid ester, amyl paradimethylaminobenzoic acid, salicylic acid ester, methyl anthranilate, umbelliferone, esculin, benzyl cinnamate, cinoxalate, guaiazulene, urocanic acid, 2- (2-hydroxy-5-methylphenyl) benzotriazole, 4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone, octapentone, dioxybenzone, dihydroxy Dimethoxybenzophenone, slumpenzone, benzolercinol, octyldimethylparaaminobenzoate, ethylhexylparamethoxycynamate, etc.), antibacterial agents (eg paraoxybenzoate, benzoic acid, benzoate, sorbic acid, sorbate, dehydroacetate, 4 -Isopropyl-3-methylphenol, 2-isopropyl-5-methylphenol, hinokitiol, cresol, 2,4,4-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorocarbanide, chlorobutanol, etc.) , Fillers (eg aluminum hydroxide, hydrous aluminum silicate, kaolin, titanium oxide, talc, zinc oxide, hydrous silica, magnesium carbonate, calcium hydrogen phosphate, magnesium silicate, diatomaceous earth, anhydrous Iic acid, bentonite, sodium stearate, calcium stearate, potassium stearate, magnesium stearate, zinc stearate, etc.), antihistamines (eg isopentyl chloride, diphenhydramine hydrochloride, iproheptin hydrochloride, diphenylpyralin hydrochloride, cyproheptadine hydrochloride, triprolidine hydrochloride, hydrochloric acid Promethazine, homochlorcyclidine hydrochloride, alimemazine tartrate, diphenhydramine tannate, diphenylpyraline teocrate, clemastine fumarate, chlorpheniramine maleate, dimethindene maleate, mequitazine, etc.), cooling agents, perfumes, etc. in the adhesive layer You may contain.
本発明に係る支持体層としては、前記粘着剤層を支持可能なものであればよく、特に制限されないが、貼付剤の皮膚に対する粘着性を高める観点から、適度な柔軟性を有していることが好ましい。また、前記支持体層の厚さとしては特に制限されないが、通常２〜３０００μｍ程度であることが好ましい。 The support layer according to the present invention is not particularly limited as long as it can support the pressure-sensitive adhesive layer, but has moderate flexibility from the viewpoint of increasing the adhesiveness of the patch to the skin. It is preferable. Further, the thickness of the support layer is not particularly limited, but is usually preferably about 2 to 3000 μm.
このような支持体層の形態としては、フィルム、織布及び不織布を挙げることができる。前記フィルム、織布及び不織布の材質としては、特に制限されず、通常貼付剤の支持体層の材質として使用できるものを適宜用いることができる。このような材質としては、例えば、ポリエチレン、ポリプロピレン、エチレン−酢酸ビニル共重合体、ポリ塩化ビニル、ポリウレタン、ポリエチレンテレフタレ−ト、ポリブチレンテレフタレート等のポリエステル；ナイロン等のポリアミド；レーヨン、パルプ、綿等のセルロース又はその誘導体；ポリアクリロニトリル等が挙げられ、これらのうちの１種を単独で用いても２種以上を組み合わせて用いてもよい。 Examples of such a support layer include a film, a woven fabric, and a non-woven fabric. The material for the film, woven fabric, and nonwoven fabric is not particularly limited, and any material that can be used as a material for the support layer of a patch can be used as appropriate. Examples of such materials include polyethylene, polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, polyurethane, polyethylene terephthalate, polybutylene terephthalate, and other polyesters; polyamides such as nylon; rayon, pulp, cotton And the like; polyacrylonitrile and the like, and one of these may be used alone, or two or more thereof may be used in combination.
また、本発明の貼付剤としては、貼付剤を使用する時まで前記粘着剤層の表面を被覆して保護するために、剥離ライナー層をさらに備えていてもよい。前記剥離ライナー層の材質としては、特に制限されず、通常貼付剤の剥離ライナー層の材質として使用できるものを適宜用いることができる。このような材質としては、例えば、ポリエチレン、ポリプロピレン、エチレン−酢酸ビニル共重合体、エチレン−ビニルアルコール共重合体、ポリ塩化ビニル、ポリウレタン、ポリエチレンテレフタレ−ト、ポリブチレンテレフタレート、ポリエチレンナフタレート等のポリエステル；ナイロン等のポリアミド；ポリアクリロニトリル；セルロース又はその誘導体；アルミニウム等の金属箔等が挙げられ、これらのうちの１種を単独で用いても２種以上を組み合わせて用いてもよい。前記剥離ライナー層としては、前記材質からなるフィルム及びシートが挙げられ、このようなフィルム及びシートとしては、その離型性を増すために、前記粘着剤層に接する面にあらかじめシリコーン処理やフッ素樹脂処理等が施されたものであってもよい。 The patch of the present invention may further include a release liner layer for covering and protecting the surface of the pressure-sensitive adhesive layer until the patch is used. The material of the release liner layer is not particularly limited, and a material that can be used as a material of a release liner layer of a normal patch can be appropriately used. Examples of such materials include polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polyurethane, polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate. Polyesters; polyamides such as nylon; polyacrylonitrile; cellulose or derivatives thereof; metal foils such as aluminum, and the like. One of these may be used alone, or two or more may be used in combination. Examples of the release liner layer include films and sheets made of the above-described materials. In order to increase the releasability of such films and sheets, the surface in contact with the pressure-sensitive adhesive layer is preliminarily treated with silicone or fluororesin. It may be processed.
本発明に係る貼付剤は、特に制限されず、公知の貼付剤の製造方法を適宜採用することにより製造することができ、例えば、以下の方法により製造することができる。先ず、前記ベラプロスト又はその薬理学的に許容される塩と、前記脂肪族アルコールと、必要に応じて前記塩化アンモニウムと、前記粘着基剤とを常法に従って練合して均一な粘着剤層組成物を得る。次いで、この粘着剤層組成物を前記支持体層の面上（通常は一方の面上）に所定の厚みで塗布して粘着剤層を形成する。次いで、前記粘着剤層の前記支持体層と反対の面上に前記剥離ライナー層を貼り合わせ、所定の形状に裁断することにより本発明の貼付剤を得ることができる。あるいは、前記粘着剤層組成物を先ず前記剥離ライナー層の一方の面上に所定の厚みで塗布して粘着剤層を形成した後に、前記粘着剤層の前記剥離ライナー層と反対の面上に前記支持体層を貼り合わせ、所定の形状に裁断することにより本発明の貼付剤を得てもよい。 The patch according to the present invention is not particularly limited and can be produced by appropriately adopting a known method for producing a patch. For example, it can be produced by the following method. First, a uniform pressure-sensitive adhesive layer composition obtained by kneading the beraprost or a pharmacologically acceptable salt thereof, the aliphatic alcohol, and if necessary, the ammonium chloride and the pressure-sensitive adhesive base according to a conventional method. Get things. Next, this pressure-sensitive adhesive layer composition is applied on the surface of the support layer (usually on one surface) with a predetermined thickness to form a pressure-sensitive adhesive layer. Next, the adhesive liner of the present invention can be obtained by laminating the release liner layer on the surface of the pressure-sensitive adhesive layer opposite to the support layer and cutting it into a predetermined shape. Alternatively, the pressure-sensitive adhesive layer composition is first applied on one surface of the release liner layer with a predetermined thickness to form a pressure-sensitive adhesive layer, and then the pressure-sensitive adhesive layer is formed on the surface opposite to the release liner layer. You may obtain the patch of this invention by bonding the said support body layer and cut | judging to a predetermined shape.
以下、実施例及び比較例に基づいて本発明をより具体的に説明するが、本発明は以下の実施例に限定されるものではない。なお、各実施例及び比較例において得られた貼付剤において、皮膚透過試験は以下に示す方法により行った。 EXAMPLES Hereinafter, although this invention is demonstrated more concretely based on an Example and a comparative example, this invention is not limited to a following example. In the patches obtained in each of the examples and comparative examples, the skin permeation test was performed by the method shown below.
（皮膚透過試験）
先ず、ヘアレスマウスの背部皮膚を剥離し、その真皮側がレセプター槽側となるようにして、３２℃の温水を外周部に循環させたフランツ型フロースルーセルに装着した。次いで、この皮膚の角質層側に５ｃｍ２の大きさに切断して剥離ライナー層を除去した貼付剤を貼付した。前記フロースルーセルのレセプター槽にはリン酸緩衝溶液（ｐＨ７．４）を５ｍＬ／ｈｒの流量でフローして、レセプター槽から４時間毎に２４時間まで試料液を採取し、採取したそれぞれの試料液について高速液体クロマトグラフ法により薬物（ベラプロスト）の濃度を測定し、得られた測定値から、１時間あたりの薬物の皮膚透過速度最大値（Ｊｍａｘ：μｇ／ｃｍ２／ｈｒ）を、以下の式：
Ｊｍａｘ（μｇ／ｃｍ２／ｈｒ）＝［薬物濃度（μｇ／ｍｌ）×流量（ｍｌ）］／貼付剤面積（ｃｍ２）／時間（ｈｒ）
により算出した。また、測定開始から２４時間経過後まで、２４時間分の薬物の累積皮膚透過量（μｇ／ｃｍ２／２４ｈｒ）を、上記により得られた薬物透過量を２４時間分積算することにより求めた。さらに、薬物の利用率（％）を、以下の式：
利用率（％）＝｛（２４時間分の薬物の累積皮膚透過量）／（貼付剤１ｃｍ２あたりの薬物の含有量）｝×１００
により算出した。皮膚透過速度最大値及び／又は累積皮膚透過量の値が大きい製剤は、薬物の皮膚透過性に優れたものと認められる。
(Skin penetration test)
First, the dorsal skin of a hairless mouse was peeled off, and the dermis side was placed on the receptor tank side, and attached to a Franz-type flow-through cell in which hot water of 32 ° C. was circulated around the outer periphery. Then, a patch obtained by cutting the release liner layer by cutting to a size of 5 cm 2 was applied to the skin stratum corneum side. A phosphate buffer solution (pH 7.4) is flowed into the receptor tank of the flow-through cell at a flow rate of 5 mL / hr, and a sample solution is collected from the receptor tank every 24 hours for up to 24 hours. The concentration of the drug (beraprost) was measured for the liquid by high performance liquid chromatography, and the maximum value of the skin permeation rate of the drug per hour (Jmax: μg / cm 2 / hr) was determined from the obtained measured value as follows: formula:
Jmax (μg / cm 2 / hr) = [drug concentration (μg / ml) × flow rate (ml)] / patch area (cm 2 ) / hour (hr)
Calculated by Furthermore, from the start of the measurement until after 24 hours, the cumulative skin permeation amount of 24 hours of drug (μg / cm 2 / 24hr) , the drug permeation amount obtained by the above was determined by integrating 24 hours. In addition, the drug utilization rate (%) is calculated using the following formula:
Utilization rate (%) = {(cumulative skin permeation amount of drug for 24 hours) / (content of drug per 1 cm 2 of patch)} × 100
Calculated by A preparation having a maximum value of skin permeation rate and / or a large cumulative skin permeation value is recognized as having excellent drug skin permeability.
（実施例１）
先ず、ベラプロストナトリウムが２．００質量％、ミリスチルアルコールが５．００質量％、塩化アンモニウムが０．２５質量％、スチレン−イソプレン−スチレンブロック共重合体（ＳＩＳ）が２４．４１質量％、粘着付与剤（「アルコンＰ−１００」、荒川化学工業（株）製）が４３．９３質量％、流動パラフィンが２４．４１質量％となるようにそれぞれ秤取して混合し、粘着剤層組成物を得た。次いで、得られた粘着剤層組成物を１００ｇ／ｍ２となるようにポリエステルフィルムの一方の面上に展延した後、前記粘着剤層組成物の塗布面をポリプロピレン製の剥離ライナー層で覆い、所定の大きさ（１０ｃｍ×１４ｃｍ）に裁断して貼付剤（粘着剤）を得た。得られた貼付剤について皮膚透過試験を行った結果を粘着剤層組成物の組成と共に表１に示す。
Example 1
First, 2.00% by mass of beraprost sodium, 5.00% by mass of myristyl alcohol, 0.25% by mass of ammonium chloride, 24.41% by mass of styrene-isoprene-styrene block copolymer (SIS), tackifying The adhesive (“Arcon P-100”, manufactured by Arakawa Chemical Industries, Ltd.) was weighed and mixed so that the amount was 43.93% by mass and liquid paraffin was 24.41% by mass. Obtained. Next, after the obtained pressure-sensitive adhesive layer composition was spread on one surface of the polyester film so as to be 100 g / m 2 , the coated surface of the pressure-sensitive adhesive layer composition was covered with a polypropylene release liner layer Then, it was cut into a predetermined size (10 cm × 14 cm) to obtain a patch (adhesive). Table 1 shows the results of skin permeation tests on the obtained patches together with the composition of the pressure-sensitive adhesive layer composition.
（実施例２〜４）
ミリスチルアルコールに代えてオレイルアルコール、オクチルドデカノール、イソステアリルアルコールをそれぞれ用いたこと以外は実施例１と同様にして貼付剤を得た。得られた貼付剤について皮膚透過試験を行った結果を各粘着剤層組成物の組成と共に表１に示す。
(Examples 2 to 4)
A patch was obtained in the same manner as in Example 1 except that oleyl alcohol, octyldodecanol and isostearyl alcohol were used in place of myristyl alcohol. The results of skin permeation tests on the obtained patches are shown in Table 1 together with the composition of each adhesive layer composition.
（比較例１〜１３）
ミリスチルアルコールに代えてそれぞれ表１に示す経皮吸収促進剤を用いたこと以外は実施例１と同様にして貼付剤を得た。得られた貼付剤について皮膚透過試験を行った結果を各粘着剤層組成物の組成と共に表１に示す。なお、表１中、「オイドラギット（＊１）」とは、ローム・ファーマ社製の「オイドラギッドＬ−１００」を指す。
(Comparative Examples 1 to 13)
A patch was obtained in the same manner as in Example 1 except that the percutaneous absorption enhancer shown in Table 1 was used instead of myristyl alcohol. The results of skin permeation tests on the obtained patches are shown in Table 1 together with the composition of each adhesive layer composition. In Table 1, “Eudragit (* 1)” refers to “Eudragid L-100” manufactured by Rohm Pharma.
（実施例５〜６）
塩化アンモニウム、ＳＩＳ、粘着付与剤、流動パラフィンの含有量をそれぞれ表２に示す含有量としたこと以外は実施例１と同様にして貼付剤を得た。得られた貼付剤について皮膚透過試験を行った結果を各粘着剤層組成物の組成と共に表２に示す。また、実施例１において得られた貼付剤についても併せて示す。
(Examples 5-6)
A patch was obtained in the same manner as in Example 1 except that the contents of ammonium chloride, SIS, tackifier and liquid paraffin were changed to the contents shown in Table 2, respectively. Table 2 shows the results of skin permeation tests on the obtained patches together with the composition of each pressure-sensitive adhesive layer composition. In addition, the patch obtained in Example 1 is also shown.
（実施例７〜９）
ミリスチルアルコール、ＳＩＳ、粘着付与剤、流動パラフィンの含有量をそれぞれ表３に示す含有量としたこと以外は実施例１と同様にして貼付剤を得た。得られた貼付剤について皮膚透過試験を行った結果を各粘着剤層組成物の組成と共に表３に示す。また、実施例１において得られた貼付剤についても併せて示す。
(Examples 7 to 9)
A patch was obtained in the same manner as in Example 1 except that the contents of myristyl alcohol, SIS, tackifier, and liquid paraffin were changed to the contents shown in Table 3, respectively. Table 3 shows the results of skin permeation tests performed on the obtained patches together with the composition of each pressure-sensitive adhesive layer composition. In addition, the patch obtained in Example 1 is also shown.
（実施例１０〜１２）
オレイルアルコール、ＳＩＳ、粘着付与剤、流動パラフィンの含有量をそれぞれ表４に示す含有量としたこと以外は実施例２と同様にして貼付剤を得た。得られた貼付剤について皮膚透過試験を行った結果を各粘着剤層組成物の組成と共に表４に示す。また、実施例２において得られた貼付剤についても併せて示す。
(Examples 10 to 12)
A patch was obtained in the same manner as in Example 2 except that the contents of oleyl alcohol, SIS, tackifier and liquid paraffin were changed to the contents shown in Table 4, respectively. Table 4 shows the results of skin permeation tests on the obtained patches together with the composition of each pressure-sensitive adhesive layer composition. In addition, the patch obtained in Example 2 is also shown.
表１〜４に示した結果から明らかなように、本発明の貼付剤は、ベラプロストの皮膚透過性が優れることが確認された。これに対して、炭素数１４〜２０の脂肪族アルコールを含有しない貼付剤は、従来の経皮吸収促進剤が含有されていてもベラプロストの皮膚透過性が劣ることが確認された。 As is clear from the results shown in Tables 1 to 4, it was confirmed that the patch of the present invention was excellent in the skin permeability of beraprost. On the other hand, it was confirmed that a patch containing no aliphatic alcohol having 14 to 20 carbon atoms is inferior in skin permeability of beraprost even when a conventional transdermal absorption enhancer is contained.
以上説明したように、本発明によれば、ベラプロストの皮膚透過性に優れた貼付剤を提供することが可能となる。 As described above, according to the present invention, it is possible to provide a patch excellent in skin permeability of beraprost.
Claims (7)
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| WO2015020153A1 (en) | 2013-08-09 | 2015-02-12 | 帝國製薬株式会社 | Beraprost-containing patch |
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| WO2002098396A1 (en) * | 2001-05-31 | 2002-12-12 | Hisamitsu Pharmaceutical Co., Inc. | Percutaneously absorbable patches |
| WO2008050673A1 (en) * | 2006-10-27 | 2008-05-02 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive skin patch |
| JP2011507904A (en) * | 2007-12-21 | 2011-03-10 | ザーズ ファーマ， インコーポレイテッド | Patches, formulations and related methods for transdermal delivery of alprazolam and other drugs |
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| WO1996015793A1 (en) * | 1994-11-17 | 1996-05-30 | Toray Industries, Inc. | Percutaneously absorbable preparation |
| JPH09169635A (en) * | 1995-12-20 | 1997-06-30 | Sekisui Chem Co Ltd | Percutaneous absorption preparation |
| WO2001005381A1 (en) * | 1999-07-15 | 2001-01-25 | Hisamitsu Pharmaceutical Co., Inc. | Percutaneously absorbable preparations |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015020153A1 (en) | 2013-08-09 | 2015-02-12 | 帝國製薬株式会社 | Beraprost-containing patch |
| JPWO2015020153A1 (en) * | 2013-08-09 | 2017-03-02 | 帝國製薬株式会社 | A patch containing beraprost |
| US10335389B2 (en) | 2013-08-09 | 2019-07-02 | Teikoku Seiyaku Co., Ltd. | Beraprost-containing patch |
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