CN103338788B - 贴剂 - Google Patents
贴剂 Download PDFInfo
- Publication number
- CN103338788B CN103338788B CN201280007477.1A CN201280007477A CN103338788B CN 103338788 B CN103338788 B CN 103338788B CN 201280007477 A CN201280007477 A CN 201280007477A CN 103338788 B CN103338788 B CN 103338788B
- Authority
- CN
- China
- Prior art keywords
- adhesive
- layer
- medicine
- patch
- weight
- 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.)
- Active
Links
- 239000012790 adhesive layer Substances 0.000 claims abstract description 104
- 239000003814 drug Substances 0.000 claims abstract description 70
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 56
- 229920000642 polymer Polymers 0.000 claims abstract description 47
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical class OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 43
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 26
- 239000011777 magnesium Substances 0.000 claims abstract description 26
- 239000004310 lactic acid Substances 0.000 claims abstract description 25
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 25
- 229910000323 aluminium silicate Inorganic materials 0.000 claims abstract description 23
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 230000035479 physiological effects, processes and functions Effects 0.000 claims abstract description 9
- PAADHXDWLFDAON-UHFFFAOYSA-N cycloocta[b]pyridine Chemical class C1=CC=CC=CC2=CC=CN=C21 PAADHXDWLFDAON-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002131 composite material Substances 0.000 claims description 5
- 229910052782 aluminium Inorganic materials 0.000 claims description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 3
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 238000006116 polymerization reaction Methods 0.000 claims description 3
- 229910052710 silicon Inorganic materials 0.000 claims description 3
- 230000035699 permeability Effects 0.000 abstract description 4
- -1 antihypertensive Substances 0.000 description 74
- 239000000203 mixture Substances 0.000 description 41
- 239000000178 monomer Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000003431 cross linking reagent Substances 0.000 description 25
- 229960000448 lactic acid Drugs 0.000 description 24
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 20
- 239000007788 liquid Substances 0.000 description 18
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 17
- 239000011230 binding agent Substances 0.000 description 17
- 239000010408 film Substances 0.000 description 17
- 238000000034 method Methods 0.000 description 16
- 238000004132 cross linking Methods 0.000 description 15
- 239000002585 base Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000004744 fabric Substances 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 125000005250 alkyl acrylate group Chemical group 0.000 description 10
- 239000011248 coating agent Substances 0.000 description 10
- 239000012948 isocyanate Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 238000000576 coating method Methods 0.000 description 9
- 229920001577 copolymer Polymers 0.000 description 9
- 239000000194 fatty acid Substances 0.000 description 9
- 239000000123 paper Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 9
- 235000014113 dietary fatty acids Nutrition 0.000 description 8
- 229930195729 fatty acid Natural products 0.000 description 8
- 229920000139 polyethylene terephthalate Polymers 0.000 description 8
- 239000005020 polyethylene terephthalate Substances 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- 239000000853 adhesive Substances 0.000 description 7
- 230000001070 adhesive effect Effects 0.000 description 7
- CERQOIWHTDAKMF-UHFFFAOYSA-N alpha-methacrylic acid Natural products CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 238000012545 processing Methods 0.000 description 7
- 229920002554 vinyl polymer Polymers 0.000 description 7
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 238000004873 anchoring Methods 0.000 description 5
- 229920000728 polyester Polymers 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical group COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
- 239000004698 Polyethylene Substances 0.000 description 4
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 238000010382 chemical cross-linking Methods 0.000 description 4
- 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 4
- 125000002704 decyl 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])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 229920000573 polyethylene Polymers 0.000 description 4
- 229920001296 polysiloxane Polymers 0.000 description 4
- IIYFAKIEWZDVMP-UHFFFAOYSA-N tridecane Chemical compound CCCCCCCCCCCCC IIYFAKIEWZDVMP-UHFFFAOYSA-N 0.000 description 4
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 3
- 239000004342 Benzoyl peroxide Substances 0.000 description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- 229920002799 BoPET Polymers 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000005639 Lauric acid Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000011888 foil Substances 0.000 description 3
- 230000009477 glass transition Effects 0.000 description 3
- 125000005456 glyceride group Chemical group 0.000 description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 150000002513 isocyanates Chemical class 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 238000003475 lamination Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 3
- 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 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 229920001568 phenolic resin Polymers 0.000 description 3
- 239000005011 phenolic resin Substances 0.000 description 3
- 229920000058 polyacrylate Polymers 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 230000000638 stimulation Effects 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000010409 thin film Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 229920001567 vinyl ester resin Polymers 0.000 description 3
- 239000002759 woven fabric Substances 0.000 description 3
- KBPLFHHGFOOTCA-UHFFFAOYSA-N 1-Octanol Chemical compound CCCCCCCCO KBPLFHHGFOOTCA-UHFFFAOYSA-N 0.000 description 2
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- 229920001342 Bakelite® Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 2
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 206010040880 Skin irritation Diseases 0.000 description 2
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 2
- 229920006243 acrylic copolymer Polymers 0.000 description 2
- 239000012675 alcoholic extract Substances 0.000 description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 2
- 230000001166 anti-perspirative effect Effects 0.000 description 2
- 239000003213 antiperspirant Substances 0.000 description 2
- 239000004637 bakelite Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000007334 copolymerization reaction Methods 0.000 description 2
- 238000000113 differential scanning calorimetry Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 125000003438 dodecyl 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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000003193 general anesthetic agent Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229960004194 lidocaine Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- OQILCOQZDHPEAZ-UHFFFAOYSA-N octyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OCCCCCCCC OQILCOQZDHPEAZ-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002985 plastic film Substances 0.000 description 2
- 229920006255 plastic film Polymers 0.000 description 2
- 229950000845 politef Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000036556 skin irritation Effects 0.000 description 2
- 231100000475 skin irritation Toxicity 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- QMGSCCRUAVAONE-UHFFFAOYSA-N zinc zirconium Chemical compound [Zn].[Zn].[Zn].[Zr] QMGSCCRUAVAONE-UHFFFAOYSA-N 0.000 description 2
- 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
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- XVOUMQNXTGKGMA-OWOJBTEDSA-N (E)-glutaconic acid Chemical compound OC(=O)C\C=C\C(O)=O XVOUMQNXTGKGMA-OWOJBTEDSA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- QGLWBTPVKHMVHM-KTKRTIGZSA-N (z)-octadec-9-en-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCN QGLWBTPVKHMVHM-KTKRTIGZSA-N 0.000 description 1
- FKTHNVSLHLHISI-UHFFFAOYSA-N 1,2-bis(isocyanatomethyl)benzene Chemical compound O=C=NCC1=CC=CC=C1CN=C=O FKTHNVSLHLHISI-UHFFFAOYSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- OVBFMUAFNIIQAL-UHFFFAOYSA-N 1,4-diisocyanatobutane Chemical compound O=C=NCCCCN=C=O OVBFMUAFNIIQAL-UHFFFAOYSA-N 0.000 description 1
- NJPQAIBZIHNJDO-UHFFFAOYSA-N 1-dodecylpyrrolidin-2-one Chemical compound CCCCCCCCCCCCN1CCCC1=O NJPQAIBZIHNJDO-UHFFFAOYSA-N 0.000 description 1
- OSSNTDFYBPYIEC-UHFFFAOYSA-N 1-ethenylimidazole Chemical compound C=CN1C=CN=C1 OSSNTDFYBPYIEC-UHFFFAOYSA-N 0.000 description 1
- DCRYNQTXGUTACA-UHFFFAOYSA-N 1-ethenylpiperazine Chemical compound C=CN1CCNCC1 DCRYNQTXGUTACA-UHFFFAOYSA-N 0.000 description 1
- PBGPBHYPCGDFEZ-UHFFFAOYSA-N 1-ethenylpiperidin-2-one Chemical compound C=CN1CCCCC1=O PBGPBHYPCGDFEZ-UHFFFAOYSA-N 0.000 description 1
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical compound FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 1
- RWLALWYNXFYRGW-UHFFFAOYSA-N 2-Ethyl-1,3-hexanediol Chemical compound CCCC(O)C(CC)CO RWLALWYNXFYRGW-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
- MZNSQRLUUXWLSB-UHFFFAOYSA-N 2-ethenyl-1h-pyrrole Chemical compound C=CC1=CC=CN1 MZNSQRLUUXWLSB-UHFFFAOYSA-N 0.000 description 1
- ZDHWTWWXCXEGIC-UHFFFAOYSA-N 2-ethenylpyrimidine Chemical compound C=CC1=NC=CC=N1 ZDHWTWWXCXEGIC-UHFFFAOYSA-N 0.000 description 1
- WDQMWEYDKDCEHT-UHFFFAOYSA-N 2-ethylhexyl 2-methylprop-2-enoate Chemical compound CCCCC(CC)COC(=O)C(C)=C WDQMWEYDKDCEHT-UHFFFAOYSA-N 0.000 description 1
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-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
- GWZMWHWAWHPNHN-UHFFFAOYSA-N 2-hydroxypropyl prop-2-enoate Chemical compound CC(O)COC(=O)C=C GWZMWHWAWHPNHN-UHFFFAOYSA-N 0.000 description 1
- AGBXYHCHUYARJY-UHFFFAOYSA-N 2-phenylethenesulfonic acid Chemical compound OS(=O)(=O)C=CC1=CC=CC=C1 AGBXYHCHUYARJY-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- JAUFWPNLLLUYNV-UHFFFAOYSA-N 3-(16-methylheptadecoxy)propane-1,2-diol Chemical compound CC(C)CCCCCCCCCCCCCCCOCC(O)CO JAUFWPNLLLUYNV-UHFFFAOYSA-N 0.000 description 1
- 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 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- ZVZFHCZCIBYFMZ-UHFFFAOYSA-N 6-methylheptoxybenzene Chemical compound CC(C)CCCCCOC1=CC=CC=C1 ZVZFHCZCIBYFMZ-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- XVGOZDAJGBALKS-UHFFFAOYSA-N Blonanserin Chemical compound C1CN(CC)CCN1C1=CC(C=2C=CC(F)=CC=2)=C(CCCCCC2)C2=N1 XVGOZDAJGBALKS-UHFFFAOYSA-N 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
- UDKCHVLMFQVBAA-UHFFFAOYSA-M Choline salicylate Chemical compound C[N+](C)(C)CCO.OC1=CC=CC=C1C([O-])=O UDKCHVLMFQVBAA-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 229920000089 Cyclic olefin copolymer Polymers 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
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ONKUXPIBXRRIDU-UHFFFAOYSA-N Diethyl decanedioate Chemical compound CCOC(=O)CCCCCCCCC(=O)OCC ONKUXPIBXRRIDU-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 206010016322 Feeling abnormal Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 239000005057 Hexamethylene diisocyanate Substances 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 239000005058 Isophorone diisocyanate Substances 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 229920010126 Linear Low Density Polyethylene (LLDPE) Polymers 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GYCMBHHDWRMZGG-UHFFFAOYSA-N Methylacrylonitrile Chemical compound CC(=C)C#N GYCMBHHDWRMZGG-UHFFFAOYSA-N 0.000 description 1
- 235000021360 Myristic acid Nutrition 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000005643 Pelargonic acid Substances 0.000 description 1
- 229920001363 Polidocanol Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® 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
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical class C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- ASGSROHYBOETMM-UHFFFAOYSA-N alpha-monoisostearyl glycerylether Natural products CC(C)CCCCCCCCCCCCCCCCC(=O)OCC(O)CO ASGSROHYBOETMM-UHFFFAOYSA-N 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- MQPPCKJJFDNPHJ-UHFFFAOYSA-K aluminum;3-oxohexanoate Chemical compound [Al+3].CCCC(=O)CC([O-])=O.CCCC(=O)CC([O-])=O.CCCC(=O)CC([O-])=O MQPPCKJJFDNPHJ-UHFFFAOYSA-K 0.000 description 1
- 229940035674 anesthetics Drugs 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940035678 anti-parkinson drug Drugs 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 239000003920 antivertigo agent Substances 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000002567 autonomic effect Effects 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 229910014307 bSiO Inorganic materials 0.000 description 1
- HIFVAOIJYDXIJG-UHFFFAOYSA-N benzylbenzene;isocyanic acid Chemical class N=C=O.N=C=O.C=1C=CC=CC=1CC1=CC=CC=C1 HIFVAOIJYDXIJG-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- YSXKPIUOCJLQIE-UHFFFAOYSA-N biperiden Chemical compound C1C(C=C2)CC2C1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 YSXKPIUOCJLQIE-UHFFFAOYSA-N 0.000 description 1
- 229960003003 biperiden Drugs 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 229950002871 blonanserin Drugs 0.000 description 1
- BRXCDHOLJPJLLT-UHFFFAOYSA-N butane-2-sulfonic acid Chemical compound CCC(C)S(O)(=O)=O BRXCDHOLJPJLLT-UHFFFAOYSA-N 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- HNEGQIOMVPPMNR-IHWYPQMZSA-N citraconic acid Chemical compound OC(=O)C(/C)=C\C(O)=O HNEGQIOMVPPMNR-IHWYPQMZSA-N 0.000 description 1
- 229940018557 citraconic acid Drugs 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- OIWOHHBRDFKZNC-UHFFFAOYSA-N cyclohexyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OC1CCCCC1 OIWOHHBRDFKZNC-UHFFFAOYSA-N 0.000 description 1
- KBLWLMPSVYBVDK-UHFFFAOYSA-N cyclohexyl prop-2-enoate Chemical compound C=CC(=O)OC1CCCCC1 KBLWLMPSVYBVDK-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 125000005442 diisocyanate group Chemical group 0.000 description 1
- 229940031578 diisopropyl adipate Drugs 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 229920006244 ethylene-ethyl acrylate Polymers 0.000 description 1
- 229960005082 etohexadiol Drugs 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000002657 fibrous material Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 150000002221 fluorine Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229920002313 fluoropolymer Polymers 0.000 description 1
- 239000004811 fluoropolymer Substances 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- RRAMGCGOFNQTLD-UHFFFAOYSA-N hexamethylene diisocyanate Chemical compound O=C=NCCCCCCN=C=O RRAMGCGOFNQTLD-UHFFFAOYSA-N 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229920000554 ionomer Polymers 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- NIMLQBUJDJZYEJ-UHFFFAOYSA-N isophorone diisocyanate Chemical compound CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1 NIMLQBUJDJZYEJ-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- XUGNVMKQXJXZCD-UHFFFAOYSA-N isopropyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(C)C XUGNVMKQXJXZCD-UHFFFAOYSA-N 0.000 description 1
- 229940075495 isopropyl palmitate Drugs 0.000 description 1
- 239000002655 kraft paper Substances 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 229940116335 lauramide Drugs 0.000 description 1
- ILRSCQWREDREME-UHFFFAOYSA-N lauric acid amide propyl betaine Natural products CCCCCCCCCCCC(N)=O ILRSCQWREDREME-UHFFFAOYSA-N 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 229950007687 macrogol ester Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HNEGQIOMVPPMNR-NSCUHMNNSA-N mesaconic acid Chemical compound OC(=O)C(/C)=C/C(O)=O HNEGQIOMVPPMNR-NSCUHMNNSA-N 0.000 description 1
- 229910001510 metal chloride Inorganic materials 0.000 description 1
- 238000001883 metal evaporation Methods 0.000 description 1
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 1
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
- HNEGQIOMVPPMNR-UHFFFAOYSA-N methylfumaric acid Natural products OC(=O)C(C)=CC(O)=O HNEGQIOMVPPMNR-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- AUCNMQYOQYTGPE-UHFFFAOYSA-N n-(hydroxymethyl)-n-methylprop-2-enamide Chemical compound OCN(C)C(=O)C=C AUCNMQYOQYTGPE-UHFFFAOYSA-N 0.000 description 1
- OWVWGCVNBQLTDH-UHFFFAOYSA-N n-butyl-n-methylprop-2-enamide Chemical compound CCCCN(C)C(=O)C=C OWVWGCVNBQLTDH-UHFFFAOYSA-N 0.000 description 1
- YPHQUSNPXDGUHL-UHFFFAOYSA-N n-methylprop-2-enamide Chemical compound CNC(=O)C=C YPHQUSNPXDGUHL-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-N o-dicarboxybenzene Natural products OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical class CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 229940049964 oleate Drugs 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
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 229920001558 organosilicon polymer Polymers 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 239000000810 peripheral vasodilating agent Substances 0.000 description 1
- 229960002116 peripheral vasodilator Drugs 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 1
- 229960002226 polidocanol Drugs 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 239000003505 polymerization initiator Substances 0.000 description 1
- 229920000098 polyolefin Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- UIIIBRHUICCMAI-UHFFFAOYSA-N prop-2-ene-1-sulfonic acid Chemical compound OS(=O)(=O)CC=C UIIIBRHUICCMAI-UHFFFAOYSA-N 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 239000013464 silicone adhesive Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- 229940057950 sodium laureth sulfate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- SXHLENDCVBIJFO-UHFFFAOYSA-M sodium;2-[2-(2-dodecoxyethoxy)ethoxy]ethyl sulfate Chemical compound [Na+].CCCCCCCCCCCCOCCOCCOCCOS([O-])(=O)=O SXHLENDCVBIJFO-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 150000003609 titanium compounds Chemical class 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- DVKJHBMWWAPEIU-UHFFFAOYSA-N toluene 2,4-diisocyanate Chemical class CC1=CC=C(N=C=O)C=C1N=C=O DVKJHBMWWAPEIU-UHFFFAOYSA-N 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 125000006839 xylylene group Chemical group 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 229940071566 zinc glycinate Drugs 0.000 description 1
- 239000004711 α-olefin Substances 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明的问题是提供一种含有药物(排除2-(4-乙基-1-哌嗪基)-4-(4-氟苯基)-5,6,7,8,9,10-六氢环辛四烯并[b]吡啶及其生理学上可接受的酸加成盐)的贴剂,其在药物的皮肤渗透性和在水的存在下的粘合性方面均优异。含有载体和在该载体一个表面上的粘胶层的贴剂,其中该粘胶层含有排除2-(4-乙基-1-哌嗪基)-4-(4-氟苯基)-5,6,7,8,9,10-六氢环辛四烯并[b]吡啶及其生理学上可接受的酸加成盐的药物、丙烯酸系聚合物、乳酸和硅铝酸镁。
Description
技术领域
本发明涉及通过粘附在皮肤表面或粘膜表面上而使用的贴剂。
背景技术
为了减轻粘合剂导致的皮肤刺激,具有添加了与该粘合剂相容的液体成分的粘胶层的贴剂常规上是已知的。但是,含有添加了此类液体成分的粘合剂的贴剂容易引起诸如根据使用目的,液体成分转移到被粘物(作为粘合目标的皮肤和粘膜)或载体上等的问题。由此,例如,作为解决此类问题的粘合剂,专利文献1描述了通过交联使40-80重量%的粘合剂不溶化的粘胶层,并教导了所述粘胶层表现出改进的粘结力,同时具有适当的粘合力。但是,即使此类粘胶层也伴随着由于出汗而存在汗成分的情况下粘胶层的粘合性降低的问题。专利文献2描述了通过向该粘胶层添加金属氯化物以避免上述问题并且甚至在由于出汗而存在汗成分的情况下也能防止粘胶层的粘结力降低的粘合剂。但是,其并未考虑向粘胶层赋予足够的粘合力,此类粘合剂具有进一步改进的余地。
[现有技术文献]
[专利文献]
专利文献1:JP-A-H6-319793
专利文献2:JP-A-2007-16019。
发明内容
鉴于上述情况,想要通过本发明解决的问题是提供不仅充分提高粘胶层的粘结力和药物的皮肤渗透性,还充分提高在水的存在下的粘合性的贴剂。
为了解决上述问题,本发明人等进行了深入的研究,并发现可以通过将乳酸和硅铝酸镁添加到粘胶层中来解决前述问题,由此完成本发明。
因此,本发明提供如下:
[1]贴剂,其包含载体和在该载体的一个表面上的粘胶层,其中该粘胶层含有除2-(4-乙基-1-哌嗪基)-4-(4-氟苯基)-5,6,7,8,9,10-六氢环辛四烯并[b]吡啶及其生理学上可接受的酸加成盐之外的药物、丙烯酸系聚合物、乳酸和硅铝酸镁。
[2]上述[1]的贴剂,其中粘胶层中乳酸的含量为该粘胶层总重量的0.1-10重量%。
[3]前述[1]或[2]的贴剂,其中该粘胶层含有每1重量份乳酸为0.03-7重量份的硅铝酸镁。
[4]前述[1]-[3]中任一项的贴剂,其中该硅铝酸镁是非晶质复合氧化物,其中铝、镁和硅原子经由氧原子进行了体型聚合。
[5]前述[1]-[4]中任一项的贴剂,其中除2-(4-乙基-1-哌嗪基)-4-(4-氟苯基)-5,6,7,8,9,10-六氢环辛四烯并[b]吡啶及其生理学上可接受的酸加成盐之外的药物为碱性药物。
本发明的贴剂可以提高药物的皮肤渗透效果,因为该粘胶层含有药物和乳酸。虽然含有乳酸的这类常规制剂由于在水的存在下粘合性降低而倾向于易于脱离,但本发明的贴剂由于粘胶层进一步含有硅铝酸镁,从而可以抑制该贴剂在水的存在下粘合性的降低,并可以抑制从皮肤等上的剥离。因此,本发明可以提供在药物的皮肤渗透性和在水的存在下的粘合性方面优异的贴剂。
具体实施方式
在下文中通过参照其优选实施方案说明本发明。
本发明的贴剂在粘胶层中含有药物、丙烯酸系聚合物、乳酸和硅铝酸镁。
想要包含在本发明的贴剂中的药物没有特别限制,只要排除2-(4-乙基-1-哌嗪基)-4-(4-氟苯基)-5,6,7,8,9,10-六氢环辛四烯并[b]吡啶(通用名“布南色林”)及其生理学上可接受的酸加成盐即可,并且可以经皮肤给药于哺乳动物如人类等的可透皮吸收药物是优选的。此类药物的具体实例包括全身***、催眠镇静药、抗颠痫药、解热镇痛消炎药、抗眩晕药、精神病药物、中枢神经***药物、抗痴呆药、局部***、骨骼肌松弛药、植物神经药、解痉药、抗帕金森病药、抗组胺药、强心剂、心律失常药物、利尿剂、抗高血压药、血管收缩药、冠状血管扩张药、外周血管扩张药、动脉硬化药、循环器官药物、呼吸促进药、止咳化痰药、激素药、化脓性疾病的外用药、镇痛-止痒-止血-消炎药、寄生性皮肤疾病的药物、止血药、痛风治疗药、糖尿病药物、抗恶性肿瘤药、抗生素、化疗药物、***、戒烟助剂等。
该药物不仅包括游离碱形式的药物,还包括其生理学上可接受的盐。虽然对此类盐没有特别限制,其实例包括但不限于甲酸盐、乙酸盐、乳酸盐、己二酸盐、柠檬酸盐、酒石酸盐、甲磺酸盐、富马酸盐、马来酸盐等,并且与无机酸的酸加成盐的实例包括盐酸盐、硫酸盐、硝酸盐、磷酸盐等。在本发明中,该药物可以是溶剂化物、水合物或非水合物。
当在粘胶层的交联处理过程中该药物与高度反应***联剂(例如异氰酸酯系、金属盐系、环氧化物系等)反应以引起交联剂和药物本身的变性时,本发明是特别有利的。此类药物的实例包括具有选自由醇羟基、硫醇、酚羟基和氨基(例如伯(-NH2)、仲(-NRH)、叔(-NRR’))构成的组中的一个或多个官能团的药物。
当该药物是具有碱性基团的碱性药物时本发明是特别有利的。此类药物的实例包括具有选自由醇羟基、硫醇、酚羟基和氨基(例如伯(-NH2)、仲(-NRH)、叔(-NRR’))构成的组中的一个或多个官能团的药物。在本发明中,将作为酸性添加剂的乳酸添加到粘胶层中。当碱性药物与酸性添加剂共存于粘胶层中时,由碱性药物和酸性添加剂产生的盐可以转移到该粘胶层与皮肤之间的界面处并充当表面活性剂,由此该贴剂可以在水中脱离。但是,当将硅铝酸镁添加到该粘胶层中时,该盐被硅铝酸镁保持,并可以防止其向粘胶层与皮肤之间的界面的转移。
在本发明的贴剂中,该药物优选是固体药物。固体药物在这里指的是在室温(25℃)下为固体的药物,即熔点不低于25℃的药物。这里的熔点是根据差示扫描量热法(DSC)得到的值。与由于吸附在硅铝酸镁上而倾向于阻止从粘胶层释放的液体药物相比,固体药物在本发明中特别有利,因为固体药物不会表现出此类倾向。此外,固体药物在贴剂保存过程中不容易从粘胶层中渗出。
药物以足以提供疾病、病症或失调的治疗中所需的结果,例如所需治疗效果的量存在于粘胶层中,这在本说明书中称为有效量。药物有效量指的是例如提供低于有毒水平并足以在预定时间内获得所选效果的该药物在血液中的浓度的药物量。本领域普通技术人员可以容易地确定此类量。虽然有效量随贴剂面积而改变,其优选相对于粘胶层总重量不小于0.1重量%,更优选不小于0.5重量%,特别优选不小于0.8重量%。由于过量会对粘胶层性质产生不利影响,优选不大于大约50重量%,更优选不大于大约40重量%,特别优选不大于大约30重量%。
粘胶层中所含的乳酸可以是任何乳酸,只要其通常用于本技术领域即可。其可以是作为外消旋体的DL-乳酸,或作为光学活性物质的L-乳酸或D-乳酸。由容易获得的方面来看,DL-乳酸是优选的。特别是从流动性方面来看,DL-乳酸是优选的。虽然乳酸在粘胶层中的含量可以适当地确定并且没有特别限制,其优选为粘胶层总重量的0.1-10重量%。当其小于0.1重量%时,不能将有效量的药物转移到血液中。当其超过10重量%时,粘胶层的粘结力会降低。考虑到对皮肤刺激的影响,乳酸更优选以不大于6重量%,进一步优选不大于5重量%的量使用。
硅铝酸镁可以以例如商品名Neusilin获自Fuji Chemical Industry。此外,硅铝酸镁优选是铝、镁和硅原子的非晶质复合氧化物,它们经由氧原子进行体型聚合。此类复合氧化物更具体为下式表示的硅铝酸镁:Al2O3/aMgO/bSiO2・nH2O,其中a=0.3-3且b=0.3-5。因其多孔结构,当改进在水的存在下的粘合性时,此类硅铝酸镁被认为更有利地起作用。
虽然粘胶层中硅铝酸镁的含量可以适当地设定并且没有特别限制,其优选相对于粘胶层中1重量份的乳酸为0.03-7重量份。当其小于0.03重量份时,该贴剂会在水中脱离。当其超过7重量份时,不能提供充足的粘合性。考虑到对皮肤的粘合力的充分保持,硅铝酸镁的含量更优选为0.03-5重量份。
本发明含有丙烯酸系聚合物作为粘胶层中的粘合剂。优选地,该粘合剂优选仅由丙烯酸系聚合物构成。当含有除丙烯酸系聚合物之外的粘合性聚合物作为粘合剂时,以相对于粘胶层中粘合剂的总重量为不大于10重量%的量(丙烯酸系聚合物为90重量%或更多)含有除丙烯酸系聚合物之外的该粘合性聚合物。除丙烯酸系聚合物之外的该粘合性聚合物的实例包括橡胶粘合性聚合物、有机硅粘合性聚合物等。
本发明中的丙烯酸系聚合物优选是含有(甲基)丙烯酸烷基酯单元作为主要成分(主要构成单元)的丙烯酸系聚合物。含有(甲基)丙烯酸烷基酯单元作为主要成分(主要构成单元)的丙烯酸系聚合物优选是作为主要成分的(甲基)丙烯酸烷基酯(第一单体成分)和具有能够参与交联反应的官能团的乙烯基单体(第二单体成分)的共聚物,考虑到对人皮肤的粘合性和制剂制造过程中药物的溶解性质,其中进一步聚合了其它单体(第三单体成分)的共聚物是特别优选的。
上述(甲基)丙烯酸烷基酯(第一单体成分)的实例包括其中烷基为碳原子数为1至18的直链、支链或环状烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、异戊基、新戊基、正己基、异己基、环己基、3-甲基戊基、正庚基、环庚基、正辛基、2-乙基己基、环辛基、正壬基、环壬基、正癸基、环癸基, 正十一烷基, 正十二烷基, 正十三烷基等)等的(甲基)丙烯酸烷基酯,优选其中烷基为碳原子数为4至18的直链、支链或环状烷基(例如正丁基、异丁基、叔丁基、仲丁基、正戊基、异戊基、新戊基、正己基、异己基、环己基、3-甲基戊基、正庚基、环庚基、正辛基、2-乙基己基、环辛基、正壬基、环壬基、正癸基、环癸基、正十一烷基、正十二烷基、正十三烷基等)的(甲基)丙烯酸烷基酯。为了特别在环境温度下赋予粘合性,优选使用降低该聚合物的玻璃化转变温度的单体成分。由此,烷基为碳原子数为4至8的直链、支链或环状烷基(例如正丁基、异丁基、叔丁基、仲丁基、正戊基、异戊基、新戊基、正己基、异己基、环己基、3-甲基戊基、正庚基、环庚基、正辛基、2-乙基己基、环辛基等)的(甲基)丙烯酸烷基酯是更优选的,烷基为正丁基、2-乙基己基或环己基的(甲基)丙烯酸烷基酯是特别优选的。
(甲基)丙烯酸烷基酯(第一单体成分)的特别优选的具体实例包括丙烯酸丁酯、丙烯酸2-乙基己酯、甲基丙烯酸2-乙基己酯、丙烯酸环己酯、甲基丙烯酸环己酯,且丙烯酸2-乙基己酯是最优选的。这些(甲基)丙烯酸烷基酯(第一单体成分)可以单独使用或者以其两种或多种的组合使用。
在上述具有能够参与交联反应的官能团的乙烯基单体(第二单体成分)中,能够参与交联反应的官能团的实例包括羟基、羧基、乙烯基等,优选羟基和羧基。所述单体(第二单体成分)的具体实例包括(甲基)丙烯酸羟乙酯、(甲基)丙烯酸羟丙酯、(甲基)丙烯酸、衣康酸、马来酸、马来酸酐、中康酸(methaconic acid)、柠康酸、戊烯二酸等。其中,丙烯酸、甲基丙烯酸和丙烯酸羟乙酯是优选的,并且丙烯酸是最优选的,因为它们容易获得。这些单体(第二单体成分)的一种或多种可以组合使用。
此外,上述其它单体(第三单体成分)主要用于调节粘胶层的粘结力、调节药物(化合物A或其生理学上可接受的酸加成盐)的溶解度和可释放性等。该单体(第三单体成分)的实例包括乙烯基酯如乙酸乙烯酯、丙酸乙烯酯等;乙烯基醚如甲基乙烯基醚、乙基乙烯基醚等;乙烯基酰胺如N-乙烯基-2-吡咯烷酮、N-乙烯基己内酰胺等;烷氧基(甲基)丙烯酸酯,如(甲基)丙烯酸甲氧基乙酯、(甲基)丙烯酸乙氧基乙酯、(甲基)丙烯酸四氢化糠酯等;含羟基的单体如(甲基)丙烯酸羟丙酯、丙烯酸α-羟甲酯等;具有酰胺基团的(甲基)丙烯酸衍生物如(甲基)丙烯酰胺、二甲基(甲基)丙烯酰胺、N-丁基(甲基)丙烯酰胺、N-羟甲基(甲基)丙烯酰胺等;(甲基)丙烯酸氨基烷基酯如(甲基)丙烯酸氨基乙酯、(甲基)丙烯酸二甲氨基乙酯、(甲基)丙烯酸叔丁基氨基乙酯等;(甲基)丙烯酸烷氧基烷撑二醇酯如(甲基)丙烯酸甲氧基乙二醇酯、(甲基)丙烯酸甲氧基二乙二醇酯、(甲基)丙烯酸甲氧基聚乙二醇酯、(甲基)丙烯酸甲氧基聚丙二醇酯等;(甲基)丙烯腈;含磺基的单体如苯乙烯磺酸、烯丙基磺酸、(甲基)丙烯酸磺基丙酯、(甲基)丙烯酰氧基萘磺酸、丙烯酰胺甲基磺酸等;含乙烯基的单体如乙烯基哌啶酮、乙烯基嘧啶、乙烯基哌嗪、乙烯基吡咯、乙烯基咪唑、乙烯基噁唑、乙烯基吗啉等。其中,乙烯基酯和乙烯基酰胺是优选的,乙烯基酯优选为乙酸乙烯酯,乙烯基酰胺优选为N-乙烯基-2-吡咯烷酮。这些单体(第三单体成分)的一种或多种可以组合使用。
当该丙烯酸系聚合物是(甲基)丙烯酸烷基酯(第一单体成分)和具有能够参与交联反应的官能团的乙烯基单体 (第二单体成分)的共聚物时,共聚比(第一单体成分/第二单体成分)为优选85-99重量%/1-15重量%,更优选90-99重量%/1-10重量%。
当该丙烯酸系聚合物是(甲基)丙烯酸烷基酯(第一单体成分)、具有能够参与交联反应的官能团的乙烯基单体 (第二单体成分)以及除这些之外的单体(第三单体成分)的共聚物时,共聚比(第一单体成分/第二单体成分/第三单体成分)优选为40-94重量%/1-15重量%/5-50重量%,更优选50-89重量%/1-10重量%/10-40重量%。
虽然丙烯酸系聚合物的聚合反应可以通过本身已知的方法进行并且没有特别限制,但例如可以提及包括在50-70℃下、在聚合引发剂(例如过氧化苯甲酰、偶氮二异丁腈等)的存在下、在溶剂(例如乙酸乙酯等)中使上述单体反应5-48小时的方法。
本发明中的丙烯酸系聚合物特别优选为丙烯酸2-乙基己酯/丙烯酸/N-乙烯基-2-吡咯烷酮共聚物、丙烯酸2-乙基己酯/丙烯酸2-羟乙酯/乙酸乙烯酯共聚物、丙烯酸2-乙基己酯/丙烯酸共聚物等,更优选丙烯酸2-乙基己酯/丙烯酸/N-乙烯基-2-吡咯烷酮共聚物。
虽然本发明中的丙烯酸系聚合物的玻璃化转变温度还随共聚物组成而改变,由贴剂的粘合性方面来看,其通常优选为-100至-10℃,更优选-90至-20℃。该玻璃化转变温度是通过差示扫描量热仪测得的值。
在本发明的贴剂中,粘胶层中该粘合剂(粘合性聚合物)的含量优选为粘胶层总重量的20-90重量%,更优选30-80重量%。
在本发明的贴剂中,在粘胶层中可以含有有机液态成分以赋予该粘胶层柔软感,减少由于从皮肤上剥去粘性贴剂时的粘合力导致的疼痛与刺激(物理刺激)等。
可以在没有任何特别限制的情况下使用此类有机液态成分,只要该成分本身在室温(25℃)下是液体,表现出增塑作用,并与前述丙烯酸系聚合物相容。该有机液态成分软化该粘胶层,并减轻贴剂导致的对皮肤的物理刺激。该有机液态成分的具体实例包括脂肪酸酯(下文中也简写为“C8-18(12-16)-C1-18脂肪酸酯”)如肉豆蔻酸异丙酯、月桂酸乙酯、棕榈酸异丙酯、油酸乙酯、月桂酸异硬脂酯、肉豆蔻酸异十三烷基酯、棕榈酸辛酯等,其由碳原子数为8至18(优选12-16)的脂肪酸和碳原子数为1至18的一元醇形成;碳原子数为8至9的脂肪酸[例如,羊脂酸(辛酸,C8),正壬酸(壬酸,C9)等];甘油脂肪酸酯(优选地,由碳原子数为8至12的脂肪酸形成的甘油酯(可以是单甘油酯、二甘油酯和三甘油酯的任一种));二醇,如乙二醇、二乙二醇、三乙二醇、聚乙二醇、丙二醇、1,3-丙二醇、聚丙二醇等;脂肪和油,如橄榄油、蓖麻油、角鲨烯等;有机溶剂如二甲亚砜、二甲基甲酰胺、二甲基乙酰胺、二甲基月桂酰胺、十二烷基吡咯烷酮、异山梨糖醇、油醇、N-甲基-2-吡咯烷酮等;液体表面活性剂如聚氧乙烯氢化蓖麻油、辛醇、聚乙二醇单对异辛基苯基醚、α-单异硬脂基甘油基醚、聚桂醇、月桂醇、脱水山梨糖醇倍半油酸酯、聚氧乙烯烷基醚硫酸钠、聚氧乙烯月桂基醚硫酸钠、烷基萘磺酸钠、聚氧乙烯油胺、聚氧乙烯油基醚磷酸钠、聚氧乙烯硬脂酸酯、月桂酸十甘油酯、聚氧乙烯脱水山梨糖醇单月桂酸酯、聚氧乙烯脱水山梨糖醇单硬脂酸酯、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇三油酸酯、聚氧乙烯山梨糖醇四油酸酯、甘油单油酸酯、脂肪酸的蔗糖酯、生育酚等;烃类如液体石蜡等;常规已知的增塑剂如己二酸二异丙酯、邻苯二甲酸酯、癸二酸二乙酯等;月桂酸;油酸;乙氧基化硬脂醇;甘油等。单独使用这些有机液态成分的一种,或者组合使用这些有机液态成分的两种或多种。其中,C8-18(12-16)-C1-18脂肪酸酯是优选的,肉豆蔻酸异丙酯是特别优选的。
在本发明中,有机液态成分的含量优选为粘胶层总重量的5-60重量%,更优选10-50重量%。当该含量小于5重量%时,不能充分地使该粘胶层塑化,不能获得良好的柔软感觉,或者不能充分减轻皮肤刺激。相反,当其超过60重量%时,该有机液态成分即使通过粘合剂所具有的粘结力也不能保持在该粘合剂中,这导致在粘胶层表面上的起霜(blooming),由此导致过弱的粘合力,这接下来极有可能导致使用过程中制剂从皮肤表面上脱落。
在本发明的贴剂中,粘胶层可以通过公知的化学交联处理(例如使用交联剂的交联处理)或物理交联处理(例如通过电子束如γ射线照射或紫外光照射的交联处理)进行交联。所述交联处理可以通过本领域中通常实施的手段进行。使用交联剂的化学交联处理是优选的,因为交联处理不容易导致对药物的不利影响。
当对粘胶层施以使用交联剂的化学交联处理时,该交联剂没有特别限制,只要交联结构的形成不被药物抑制即可,并且该交联剂包括过氧化物(例如过氧化苯甲酰(BPO)等)、异氰酸酯化合物(例如多官能异氰酸酯化合物)、有机金属化合物(例如锌锆(zinc zirconium)、丙氨酸锌、乙酸锌、甘氨酸锌铵化合物、钛化合物等)、金属醇化物(例如钛酸四乙酯、钛酸四异丙酯、异丙醇铝、仲丁酸铝等)、金属螯合物(例如二丙氧基双(乙酰丙酮)钛、四辛二醇钛、异丙醇铝、乙酰乙酸乙酯二异丙醇铝、三(乙酰乙酸乙酯)铝、三(乙酰丙酮)铝等)等。在含有粘合剂和有机液态成分的粘胶层中的粘合性聚合物交联了的、所谓凝胶状粘胶层是优选的,因为其赋予皮肤柔软感觉,并具有适当的粘合性和粘结力。一种或多种的上述交联剂可以组合用于交联处理。特别地,当该粘胶层含有异氰酸酯化合物时,可以减少贴剂粘合到人皮肤上的过程中粘胶层的粘结力降低,并在剥离该粘胶层时不容易发生粘结破坏。由此,异氰酸酯化合物是优选的。虽然交联剂的含量随交联剂和粘合剂的种类而改变,但其通常相对于100重量份待交联的粘合剂(丙烯酸系聚合物)为0.03-0.6重量份,优选0.05-0.4重量份(即通常为丙烯酸系聚合物总量的3-60重量%,优选5-40重量%)。
异氰酸酯化合物的实例包括脂肪族二异氰酸酯如四亚甲基二异氰酸酯、六亚甲基二异氰酸酯等,脂环族二异氰酸酯如异佛尔酮二异氰酸酯、氢化苯二甲基二异氰酸酯、氢化甲苯二异氰酸酯、氢化二苯甲烷二异氰酸酯等,芳香脂肪族二异氰酸酯如苯二甲基二异氰酸酯等,芳族二异氰酸酯如甲苯二异氰酸酯、4,4’-二苯甲烷二异氰酸酯等。上述异氰酸酯化合物可以单独使用,或者可以混合使用相同或类似的粘合剂(聚合物成分)。
化学交联处理可以通过以下方式进行:例如添加交联剂,接着在交联反应温度或更高温度下加热该粘胶层并将其保存(即老化步骤)。可以根据交联剂类型选择的加热温度优选为60-90℃,更优选60-80℃。加热时间为优选12-96小时,更优选24-72小时。
本发明的贴剂的粘胶层的厚度优选为20-300微米,更优选30-300微米,最优选50-300微米。当厚度小于20微米时,难以提供充足的粘合性和难以含有有效量的药物。当厚度高于300微米时,粘胶层的形成困难(难以涂布)。
在本发明的贴剂中,考虑到皮肤粘合性,该粘胶层优选是非水粘胶层。该非水粘胶层在这里不必限于完全不含水,而是包括含有来自于空气中的湿气、皮肤等的微量水(例如小于粘胶层总重量的1重量%)的那些。
本发明的贴剂包含载体和粘胶层,并优选具有剥离衬垫(release liner)。也就是说,本发明的贴剂具有前述粘胶层层压在载体的至少一个表面上的结构,并且优选通过用剥离衬垫覆盖来保护该粘胶层的粘合面(与层压在载体上的面相反的面)直至刚要使用前。此外,还可以在载体上施加有机硅类、氟类、蜡等的背面涂层剂并形成卷形物,而不采用剥离衬垫。
虽然对载体没有特别限制,优选的是不会使粘胶层中的药物和有机液态成分穿过并从背面损失(这减少了它们的含量)的载体(即对于该有机液态成分和药物为不可渗透的材料)。
具体实例包括聚酯(例如聚对苯二甲酸乙二醇酯等)、尼龙、聚氯乙烯、聚乙烯、聚丙烯、乙烯-乙酸乙酯共聚物、聚四氟乙烯、离聚物树脂等的单一薄膜、金属箔、以及其中层压了选自其中的两种或多种薄膜的层压薄膜,等。其中,为了改进载体对粘胶层的粘合性(锚定性质),优选使用由前述材料制成的无孔膜与下述多孔膜的层压膜作为载体,并在多孔膜一侧形成粘胶层。无孔膜的厚度优选为2-100微米,更优选2-50微米。
该多孔膜没有特别限制,只要能改善对粘胶层的锚定性即可,并且可以提及例如纸张、机织织物、无纺织物(例如聚酯无纺织物等)、机械穿孔的上述膜的单一膜(例如聚酯(例如聚对苯二甲酸乙二醇酯等)、尼龙、Saran(商品名)、聚乙烯、聚丙烯、乙烯-乙酸乙酯共聚物、聚氯乙烯、乙烯-丙烯酸乙酯共聚物、聚四氟乙烯、金属箔等,以及层压了选自其中的两种或多种薄膜的层压薄膜等)等。特别地,从载体的柔性方面来看,纸张、机织织物和无纺织物(例如聚酯(例如聚对苯二甲酸乙二醇酯等)、无纺织物等)是优选的。例如,当多孔膜是纸张、机织织物、无纺织物等的时候,该织物重量优选为5-30
g/m2,以改善锚定性。
作为载体的层压膜通过已知的层压膜制造方法制得,如干层压法、湿层压法、挤出层压法、热熔层压法、共挤出层压法等。
该载体的厚度没有特别限制,但是优选为2-200微米,更优选10-50微米。当其小于2微米时,处理性能如自身支持性可能变差。当厚度超过200微米时,依从性(followability)可能变差,导致皮肤不适。
该剥离衬垫没有特别限制,可以使用已知的剥离衬垫。其具体实例包括在剥离衬垫基材的表面上形成了包含剥离处理剂(release
treating agent)的剥离处理剂层的剥离衬垫、本身具有高剥离能力的塑料膜、具有在剥离衬垫基材的表面上形成了包含具有高剥离能力的前述塑料膜材料的剥离层的构造的剥离衬垫等。该剥离衬垫的剥离表面可以是该基材的仅仅一个表面,或是该基材的两个表面。
在此类剥离衬垫中,剥离处理剂没有特别限制,例如,可以提及剥离剂如含有长链烷基的聚合物、有机硅聚合物(有机硅剥离剂)、氟聚合物(氟剥离剂)等。剥离衬垫用的基材的实例包括塑料膜如PET膜、聚酰亚胺膜、聚丙烯膜、聚乙烯膜、聚碳酸酯膜、聚酯(排除PET)膜等,以及金属化塑料膜,其中金属蒸镀在这些膜上;纸张如日本纸、西方纸、牛皮纸、玻璃纸、高级纸等;由纤维材料制成的基材如无纺织物、布料等;金属箔等。
作为本身具有高剥离能力的塑料膜,可以使用聚乙烯(低密度聚乙烯、线型低密度聚乙烯等)、聚丙烯、乙烯-α-烯烃共聚物(嵌段共聚物或无规共聚物)如乙烯-丙烯共聚物等、由包含这些的混合物的聚烯烃树脂制成的聚烯烃膜;Teflon(注册商标)膜等。
在前述剥离衬垫用的基材的表面上形成的剥离层可以通过将前述具有高剥离能力的塑料膜材料层压或涂布在前述剥离衬垫用的基材上来形成。
该剥离衬垫的厚度没有特别限制,但是通常为200微米或更少,优选25-100微米。
虽然本发明的贴剂的制造方法没有特别限制,但其可以通过例如下述制造方法制得。
首先,将粘合性聚合物、药物和填料与根据需要的有机液态成分和其它添加剂一起加入到合适的溶剂中,将该混合物充分混合直到其变得均匀。溶剂的实例包括乙酸乙酯、甲苯、己烷、2-丙醇、甲醇、乙醇等。当添加交联剂时,将其添加到混合物中,并将该混合物充分混合。当必要的时候,可以将溶剂与交联剂一起加入,并将它们混合。
随后,将获得的混合物施加到载体的一个表面或剥离衬垫的剥离处理表面上,并干燥以形成粘胶层。前述施加可以通过例如浇铸、印刷和本身为本领域普通技术人员已知的其它技术进行。随后,将剥离衬垫或载体粘附到该粘胶层上以形成层压体。当进行交联处理时,将剥离衬垫或载体粘附到该粘胶层上,并令它们在60-90℃、优选60-70℃下静置24-48小时以促进交联反应,由此形成交联的粘胶层。
随后,将剥离衬垫剥离,将粘胶层的暴露表面浸在乳酸溶解在溶剂中的乳酸溶液中,并在大约40-100℃下干燥。在干燥后,将与上述不同的剥离衬垫的剥离处理过的表面粘附在该粘胶层上。
实施例
参照实施例在下文中更详细地解释本发明,这些实施例不被解释为是限制性的。在下文中,除非特殊规定,“份”和“%”分别指的是“重量份”和“重量%”。
[制备丙烯酸系聚合物A]
在惰性气氛下,对丙烯酸2-乙基己基酯(75份)、N-乙烯基-2-吡咯烷酮(22份)、丙烯酸(3份)和偶氮二异丁腈(0.2份)在乙酸乙酯中、在60℃下施以溶液聚合,以获得丙烯酸共聚物(丙烯酸系聚合物A)溶液。
[实施例1]
向丙烯酸系聚合物A(58.01份)、利多卡因(下文中称为“LDC”)(5.82份)、肉豆蔻酸异丙酯(下文中称为“IPM”)(32.98份)和硅铝酸镁(Neusilin(商品名),类型:UFL2,由Fuji Chemical Industry制造)(0.1份)中添加适量的乙酸乙酯并充分混合溶液,直到其变得均匀。作为交联剂,加入三官能异氰酸酯(CORONATE HL(由Japan Polyurethane Industry制造),0.09份)。用乙酸乙酯将碱的浓度调节至30重量%,将混合物充分混合并搅拌直到其变得均匀,以获得涂布溶液。将获得的涂布溶液施加到剥离衬垫(其是用有机硅剥离剂施以剥离处理的75微米厚的聚对苯二甲酸乙二醇酯(下文“PET”)膜)的剥离处理过的表面上,以使得干燥后的粘胶层的厚度为大约60微米,并干燥以形成粘胶层。将由此形成的粘胶层的粘合面粘附到3.5微米厚的PET膜与织物重量为12 g/m2的PET无纺织物的层压载体的无纺织物一侧上,以获得层压体。令该层压体在70℃下静置48小时,以制备具有交联的粘胶层的层压体。在静置后,将具有交联的粘胶层的层压体的剥离衬垫剥去,将交联的粘胶层浸在乳酸中,使得乳酸的最终含量相对于交联的粘胶层(97份)为3份。随后,单独制备与上述剥离衬垫相同的剥离衬垫,并将其粘附到交联的粘胶层的粘合面上,以获得实施例1的贴剂。利多卡因的熔点为66-69℃。该熔点通过DSC设备(由Seiko Instruments Inc. (SII)制造,型号DSC6220)测得。上述碱浓度是指通过从涂布溶液的重量(克)中减去乙酸乙酯的重量,用获得的值除以涂布溶液的重量(克)并将所得值乘以100而获得的值(重量%)。
[实施例2]
除了替代使用丙烯酸系聚合物A(56.61份)和Neusilin(1.5份)以外,以与实施例1相同的方式获得实施例2的贴剂。
[实施例3]
除了替代使用丙烯酸系聚合物A(55.22份)、Neusilin(2.9份)和交联剂(0.08份)以外,以与实施例1相同的方式获得实施例3的贴剂。
[实施例4]
除了替代使用丙烯酸系聚合物A(53.72份)、Neusilin(4.4份)和交联剂(0.08份)以外,以与实施例1相同的方式获得实施例4的贴剂。
[实施例5]
除了替代使用丙烯酸系聚合物A(47.93份)、Neusilin(10.2份)和交联剂(0.07份)以外,以与实施例1相同的方式获得实施例5的贴剂。
[实施例6]
除了替代使用丙烯酸系聚合物A(43.53份)、Neusilin(14.6份)和交联剂(0.07份)以外,以与实施例1相同的方式获得实施例6的贴剂。
[实施例7]
除了替代使用丙烯酸系聚合物A(38.74份)、Neusilin(19.4份)和交联剂(0.06份)以外,以与实施例1相同的方式获得实施例7的贴剂。
[比较例1]
除了替代使用丙烯酸系聚合物A(58.11份)和Neusilin(0.0份)以外,以与实施例1相同的方式获得比较例1的贴剂。
[实施例8]
向丙烯酸系聚合物A(58.01份)、比哌立登(下文中称为“BPD”)(5.82份)、IPM(32.98份)和硅铝酸镁(Neusilin(商品名))(0.1份)中添加适量的乙酸乙酯并充分混合溶液,直到其变得均匀。作为交联剂,加入三官能异氰酸酯(CORONATE
HL(由Japan Polyurethane Industry制造),0.09份)。用乙酸乙酯将碱的浓度调节至30重量%,将混合物充分混合并搅拌直到其变得均匀,以获得涂布溶液。将获得的涂布溶液施加到剥离衬垫(其是用有机硅剥离剂施以剥离处理的75微米厚的聚对苯二甲酸乙二醇酯(下文“PET”)膜)的剥离处理过的一个表面上,以使得干燥后的粘胶层的厚度为大约60微米,并干燥以形成粘胶层。将由此形成的粘胶层的粘合面粘附到3.5微米厚的PET膜与12 g/m2的PET无纺织物的层压膜的无纺织物一侧上,以获得层压体。令该层压体在70℃下静置48小时,以制备具有交联的粘胶层的层压体。在静置后,将具有交联的粘胶层的层压体的剥离衬垫剥去,将交联的粘胶层浸在乳酸中,使得乳酸的最终含量相对于交联的粘胶层(97份)为3份。随后,单独制备与上述剥离衬垫相同的剥离衬垫,并将其粘附到交联的粘胶层的粘合面上,以获得实施例8的贴剂。上述碱浓度是指通过从涂布溶液的重量(克)中减去乙酸乙酯的重量,用获得的值除以涂布溶液的重量(克)并将所得值乘以100而获得的值(重量%)。
[实施例9]
除了替代使用丙烯酸系聚合物A(56.61份)和Neusilin(1.5份)以外,以与实施例8相同的方式获得实施例9的贴剂。
[实施例10]
除了替代使用丙烯酸系聚合物A(55.22份)、Neusilin(2.9份)和交联剂(0.08份)以外,以与实施例8相同的方式获得实施例10的贴剂。
[实施例11]
除了替代使用丙烯酸系聚合物A(53.72份)、Neusilin(4.4份)和交联剂(0.08份)以外,以与实施例8相同的方式获得实施例11的贴剂。
[实施例12]
除了替代使用丙烯酸系聚合物A(47.93份)、Neusilin(10.2份)和交联剂(0.07份)以外,以与实施例8相同的方式获得实施例12的贴剂。
[实施例13]
除了替代使用丙烯酸系聚合物A(43.53份)、Neusilin(14.6份)和交联剂(0.07份)以外,以与实施例8相同的方式获得实施例13的贴剂。
[实施例14]
除了替代使用丙烯酸系聚合物A(38.74份)、Neusilin(19.4份)和交联剂(0.06份)以外,以与实施例8相同的方式获得实施例14的贴剂。
[比较例2]
除了替代使用丙烯酸系聚合物A(58.11份)和Neusilin(0.0份)以外,以与实施例8相同的方式获得比较例2的贴剂。
[粘合力测量试验]
通过2千克辊的一次往复运动将切成24毫米宽、50毫米长的样品加压粘附在不锈钢板上,在30分钟后,以180º的剥离角、300毫米/分钟的速度将该样品剥离,并测量此时的剥离力。以n=3进行该试验,对每次试验测量在3个点处的负载,并对总计9个点取平均。试验点为距剥离起始位置20、40、60毫米。结果显示在表1和表2中。
[保持力测量试验]
将样品切成10毫米、50毫米长,并通过辊(重量850克)的一次往复运动将其一端(大约25毫米)压向电木(酚醛树脂)板。另一端用辅助片加强。将其固定在稳定在40±2℃的温度下的设备中的吊钩上,保持30分钟后,附上负载(300克)并保持直到发生自然坠落。随后测量保持时间。以n=3进行该试验,并对总计3个测得值取平均。其结果显示在表1和表2中。
[恒定负载剥离试验]
将样品切成12毫米、50毫米长,并将一端(大约5毫米)剥离并用辅助片加强。通过辊(重量850克)的一次往复运动将试样压向电木(酚醛树脂)板。30分钟后,将试样从该板上剥离,直到试样的粘接部分的长度为30毫米。将试样水平放置在40±2℃的水浴中的测试台上,在辅助片上固定30克负载,并测量试样从测试板上自然坠落所需的时间,测定在水的存在下该制剂的剥离速度(毫米/分钟)。当试样经30分钟后并未坠落时,用尺子测量30分钟时的剥离长度,并除以30以获得该剥离速度。以n=3进行该试验,并对总计3个点取平均。其结果显示在表1和表2中。
[锚定性]
通过肉眼观察评价当衬垫从贴剂上剥离(衬垫剥离操作)时该粘胶层是否锚定在载体侧上。此外,将该贴剂粘附在酚醛树脂板上,并通过肉眼观察评价当贴剂剥落时,该粘胶层是否锚定在该载体侧上(粘合性试验)。根据下列标准评价锚定性。评价结果显示在表1和表2中。
○:在衬垫剥离操作和粘合性试验中粘胶层均锚定在载体上。
△:在衬垫剥离操作中粘胶层锚定在载体上,但是在粘合性试验中并未锚定在载体上。
×:在衬垫剥离操作中粘胶层未锚定在载体上。
[粘性]
将衬垫剥离,并在用手指触摸暴露的粘胶层时根据下列标准进行粘性的感官评价。评价结果显示在表1和表2中。
○:粘性充分。
△:粘性有些弱。
×:粘性弱。
[表1]
[表2]
与比较例1和比较例2相比,在实施例1-7和实施例8-14中在水中的剥离速度慢,这证实了含有硅铝酸镁的制剂具有优异的在水中的粘合性。
工业实用性
本发明的贴剂可以提高药物的皮肤渗透效果,因为该粘胶层含有药物和乳酸。虽然含有乳酸的此类常规制剂因为在水的存在下粘合性降低而倾向于容易剥落,但本发明的贴剂由于粘胶层进一步含有硅铝酸镁,从而可以抑制在水的存在下该贴剂的粘合性的降低,并可以抑制从皮肤等上的脱落。因此,本发明可以提供在药物的皮肤渗透性和在水的存在下的粘合性方面优异的贴剂。
本申请以在日本申请的专利申请号2011-021201为基础,其内容在这里全部引用而并入本文。
Claims (5)
1.贴剂,其含有载体和在该载体的一个表面上形成的非水粘胶层,其中,该非水粘胶层含有除2-(4-乙基-1-哌嗪基)-4-(4-氟苯基)-5,6,7,8,9,10-六氢环辛四烯并[b]吡啶及其生理学上可接受的酸加成盐之外的药物、丙烯酸系聚合物、乳酸和硅铝酸镁。
2.根据权利要求1所述的贴剂,其中,非水粘胶层中乳酸的含量为非水粘胶层的总重量的0.1-10重量%。
3.根据权利要求1或2所述的贴剂,其中,非水粘胶层含有相对于每1重量份乳酸为0.03-7重量份的硅铝酸镁。
4.根据权利要求1或2所述的贴剂,其中,硅铝酸镁是非晶质复合氧化物,在该非晶质复合氧化物中铝、镁和硅原子经由氧原子进行了体型聚合。
5.根据权利要求1或2所述的贴剂,其中,除2-(4-乙基-1-哌嗪基)-4-(4-氟苯基)-5,6,7,8,9,10-六氢环辛四烯并[b]吡啶及其生理学上可接受的酸加成盐之外的药物为碱性药物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011-021201 | 2011-02-02 | ||
JP2011021201 | 2011-02-02 | ||
PCT/JP2012/052306 WO2012105618A1 (ja) | 2011-02-02 | 2012-02-01 | 貼付製剤 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103338788A CN103338788A (zh) | 2013-10-02 |
CN103338788B true CN103338788B (zh) | 2016-03-02 |
Family
ID=46602824
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201280007477.1A Active CN103338788B (zh) | 2011-02-02 | 2012-02-01 | 贴剂 |
Country Status (8)
Country | Link |
---|---|
US (1) | US9138419B2 (zh) |
EP (1) | EP2671593B1 (zh) |
JP (1) | JP5818709B2 (zh) |
KR (1) | KR101855549B1 (zh) |
CN (1) | CN103338788B (zh) |
CA (1) | CA2825798C (zh) |
ES (1) | ES2629063T3 (zh) |
WO (1) | WO2012105618A1 (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2826003C (en) * | 2011-02-02 | 2019-01-08 | Yasuaki Okada | Blonanserin-containing patch preparation |
WO2014174564A1 (ja) * | 2013-04-22 | 2014-10-30 | 祐徳薬品工業株式会社 | メマンチン含有経皮吸収型貼付製剤 |
KR102094586B1 (ko) * | 2014-12-22 | 2020-03-27 | 히사미쓰 세이야꾸 가부시키가이샤 | 파프제 |
EP3861998B1 (en) | 2018-10-01 | 2024-02-07 | Hisamitsu Pharmaceutical Co., Inc. | Asenapine-containing adhesive patch |
JP6853594B2 (ja) * | 2019-02-08 | 2021-03-31 | 株式会社メディカルフロント | シコニン類を含有する貼付剤、及びその製造方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1568365A1 (en) * | 2002-11-27 | 2005-08-31 | Hisamitsu Pharmaceutical Co. Inc. | Warm poultice |
EP1757309A1 (en) * | 2004-04-28 | 2007-02-28 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive material |
EP2036559A1 (en) * | 2006-06-09 | 2009-03-18 | Dainippon Sumitomo Pharma Co., Ltd. | Novel tape preparation |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5843365B2 (ja) * | 1978-07-26 | 1983-09-27 | 株式会社堀内伊太郎商店 | 親水性パップ剤 |
JPS63290819A (ja) * | 1987-05-21 | 1988-11-28 | Saitama Daiichi Seiyaku Kk | パップ剤 |
JP2539330B2 (ja) | 1993-05-11 | 1996-10-02 | 日東電工株式会社 | 医療用粘着剤及びこれを用いて形成された医療用外用材 |
JP2001348329A (ja) * | 2000-06-05 | 2001-12-18 | Oda Shinsou Kk | 外用貼付剤 |
JP2003116908A (ja) * | 2001-08-06 | 2003-04-22 | Lion Corp | 貼付剤 |
JP2004123662A (ja) * | 2002-10-07 | 2004-04-22 | Lion Corp | 角質除去シート |
US7988990B2 (en) * | 2003-01-28 | 2011-08-02 | Teikoku Seiyaku Co., Ltd. | Thin aqueous cataplasm |
EP1685837A4 (en) * | 2003-11-12 | 2009-03-25 | Lead Chem Co Ltd | BRAIN PROTECTIVE AGENT OF THE TYPE ADMINISTERED BY PERCUTANEOUS ABSORPTION |
TWI412570B (zh) * | 2004-04-27 | 2013-10-21 | Showa Denko Kk | Adhesive for patch and method for producing the same |
JP4744439B2 (ja) * | 2004-04-28 | 2011-08-10 | 久光製薬株式会社 | 貼付剤 |
JP4999366B2 (ja) | 2005-06-06 | 2012-08-15 | 日東電工株式会社 | 経皮吸収製剤 |
CN101510570A (zh) | 2009-03-30 | 2009-08-19 | 苏州富能技术有限公司 | 串并联结构的薄膜太阳电池模块组及其加工方法 |
-
2012
- 2012-02-01 CA CA2825798A patent/CA2825798C/en active Active
- 2012-02-01 CN CN201280007477.1A patent/CN103338788B/zh active Active
- 2012-02-01 JP JP2012020281A patent/JP5818709B2/ja active Active
- 2012-02-01 US US13/983,134 patent/US9138419B2/en active Active
- 2012-02-01 KR KR1020137022086A patent/KR101855549B1/ko active IP Right Grant
- 2012-02-01 EP EP12742140.2A patent/EP2671593B1/en active Active
- 2012-02-01 ES ES12742140.2T patent/ES2629063T3/es active Active
- 2012-02-01 WO PCT/JP2012/052306 patent/WO2012105618A1/ja active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1568365A1 (en) * | 2002-11-27 | 2005-08-31 | Hisamitsu Pharmaceutical Co. Inc. | Warm poultice |
EP1757309A1 (en) * | 2004-04-28 | 2007-02-28 | Hisamitsu Pharmaceutical Co., Inc. | Adhesive material |
EP2036559A1 (en) * | 2006-06-09 | 2009-03-18 | Dainippon Sumitomo Pharma Co., Ltd. | Novel tape preparation |
Also Published As
Publication number | Publication date |
---|---|
CA2825798A1 (en) | 2012-08-09 |
US20130315976A1 (en) | 2013-11-28 |
JP2012176942A (ja) | 2012-09-13 |
KR101855549B1 (ko) | 2018-05-04 |
EP2671593A4 (en) | 2014-07-09 |
WO2012105618A1 (ja) | 2012-08-09 |
ES2629063T3 (es) | 2017-08-07 |
EP2671593A1 (en) | 2013-12-11 |
US9138419B2 (en) | 2015-09-22 |
KR20140014141A (ko) | 2014-02-05 |
JP5818709B2 (ja) | 2015-11-18 |
CN103338788A (zh) | 2013-10-02 |
EP2671593B1 (en) | 2017-06-07 |
CA2825798C (en) | 2018-12-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11427666B2 (en) | Silicone-containing acrylic polymers for transdermal drug delivery compositions | |
EP0651984B1 (en) | Medical adhesive sheet | |
CN103338788B (zh) | 贴剂 | |
KR20120107153A (ko) | 펜타닐 경피 패치제 | |
JPH05309128A (ja) | 貼付剤および貼付製剤 | |
US20170112781A1 (en) | Transdermal drug delivery systems with polyisobutylene face adhesive | |
TW201603835A (zh) | 里曼提明(rivastigmine)經皮組成物及使用其之方法 | |
JP4430120B2 (ja) | 抗真菌症用貼付剤 | |
RU2432179C2 (ru) | Фармацевтический препарат абсорбционного типа для чрезкожного введения | |
CN104043127A (zh) | 用于增强药物的经皮吸收的组合物和贴片制剂 | |
CN103338771B (zh) | 贴剂 | |
JP3014188B2 (ja) | アクリル系ゲル材およびアクリル系ゲル製剤 | |
US20130287823A1 (en) | Patch | |
CN102343111A (zh) | 胶粘贴片和贴片制剂 | |
JPH0565224A (ja) | ゲル材およびこれを用いた治療用ゲル製剤 | |
WO2016190002A1 (ja) | 貼付剤 | |
DE102010048788A1 (de) | Transdermales System mit Immunmodulator | |
CN103347541A (zh) | 贴片制剂的制造方法 | |
KR101566817B1 (ko) | 케토티펜 또는 그 염을 함유하는 경피흡수제제 | |
JP2009242424A (ja) | 抗真菌症用貼付剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |