JPH0331217A - Percutaneous absorption promoting composition and external preparation containing same composition - Google Patents
Percutaneous absorption promoting composition and external preparation containing same compositionInfo
- Publication number
- JPH0331217A JPH0331217A JP16460189A JP16460189A JPH0331217A JP H0331217 A JPH0331217 A JP H0331217A JP 16460189 A JP16460189 A JP 16460189A JP 16460189 A JP16460189 A JP 16460189A JP H0331217 A JPH0331217 A JP H0331217A
- Authority
- JP
- Japan
- Prior art keywords
- parts
- propylene glycol
- composition
- drug
- acid ester
- 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.)
- Pending
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 65
- 238000010521 absorption reaction Methods 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 230000001737 promoting effect Effects 0.000 title claims abstract description 30
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 118
- 239000003814 drug Substances 0.000 claims abstract description 49
- -1 sebacic acid diester Chemical class 0.000 claims abstract description 34
- CXMXRPHRNRROMY-UHFFFAOYSA-N n-Decanedioic acid Natural products OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims abstract description 7
- AXTGDCSMTYGJND-UHFFFAOYSA-N 1-dodecylazepan-2-one Chemical compound CCCCCCCCCCCCN1CCCCCC1=O AXTGDCSMTYGJND-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims description 44
- MMOXZBCLCQITDF-UHFFFAOYSA-N N,N-diethyl-m-toluamide Chemical compound CCN(CC)C(=O)C1=CC=CC(C)=C1 MMOXZBCLCQITDF-UHFFFAOYSA-N 0.000 claims description 10
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Natural products OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 claims description 10
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 8
- 229960003512 nicotinic acid Drugs 0.000 claims description 6
- 235000001968 nicotinic acid Nutrition 0.000 claims description 6
- 239000011664 nicotinic acid Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 18
- 150000002148 esters Chemical class 0.000 abstract description 12
- 239000002253 acid Substances 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 239000004615 ingredient Substances 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 abstract description 2
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 229960003710 dantrolene sodium Drugs 0.000 description 28
- LTWQNYPDAUSXBC-CDJGKPBYSA-L dantrolene sodium hemiheptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N\N1C(=O)[N-]C(=O)C1.C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N\N1C(=O)[N-]C(=O)C1 LTWQNYPDAUSXBC-CDJGKPBYSA-L 0.000 description 28
- 230000000694 effects Effects 0.000 description 22
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 239000000499 gel Substances 0.000 description 13
- 150000003839 salts Chemical class 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000003623 enhancer Substances 0.000 description 8
- MCRPKBUFXAKDKI-UHFFFAOYSA-N ethyl pyridine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC=C1 MCRPKBUFXAKDKI-UHFFFAOYSA-N 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 239000012488 sample solution Substances 0.000 description 8
- 210000003491 skin Anatomy 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 229960001673 diethyltoluamide Drugs 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 210000003205 muscle Anatomy 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 6
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 6
- UMQFMEMKBWWILL-UHFFFAOYSA-N butyl pyridine-4-carboxylate Chemical compound CCCCOC(=O)C1=CC=NC=C1 UMQFMEMKBWWILL-UHFFFAOYSA-N 0.000 description 6
- 239000002131 composite material Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 230000001070 adhesive effect Effects 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 229920001971 elastomer Polymers 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000005060 rubber Substances 0.000 description 5
- 231100000245 skin permeability Toxicity 0.000 description 5
- 229940058015 1,3-butylene glycol Drugs 0.000 description 4
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 235000019437 butane-1,3-diol Nutrition 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 229960003511 macrogol Drugs 0.000 description 4
- 239000003158 myorelaxant agent Substances 0.000 description 4
- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- 150000005846 sugar alcohols Polymers 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 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
- 241000700159 Rattus Species 0.000 description 3
- 229920002125 Sokalan® Polymers 0.000 description 3
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 238000004898 kneading Methods 0.000 description 3
- 230000003020 moisturizing effect Effects 0.000 description 3
- 239000002985 plastic film Substances 0.000 description 3
- 229920006255 plastic film Polymers 0.000 description 3
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 239000011787 zinc oxide Substances 0.000 description 3
- OZOMQRBLCMDCEG-CHHVJCJISA-N 1-[(z)-[5-(4-nitrophenyl)furan-2-yl]methylideneamino]imidazolidine-2,4-dione Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(O1)=CC=C1\C=N/N1C(=O)NC(=O)C1 OZOMQRBLCMDCEG-CHHVJCJISA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 2
- LVYLCBNXHHHPSB-UHFFFAOYSA-N 2-hydroxyethyl salicylate Chemical compound OCCOC(=O)C1=CC=CC=C1O LVYLCBNXHHHPSB-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 208000014644 Brain disease Diseases 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- 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 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- DIZPMCHEQGEION-UHFFFAOYSA-H aluminium sulfate (anhydrous) Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000002921 anti-spasmodic effect Effects 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 229940125715 antihistaminic agent Drugs 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 229940124575 antispasmodic agent Drugs 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- KVYGGMBOZFWZBQ-UHFFFAOYSA-N benzyl nicotinate Chemical compound C=1C=CN=CC=1C(=O)OCC1=CC=CC=C1 KVYGGMBOZFWZBQ-UHFFFAOYSA-N 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
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- GPLRAVKSCUXZTP-UHFFFAOYSA-N diglycerol Chemical compound OCC(O)COCC(O)CO GPLRAVKSCUXZTP-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000004945 emulsification Methods 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
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- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
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- 238000004519 manufacturing process Methods 0.000 description 2
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 229940035363 muscle relaxants Drugs 0.000 description 2
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
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- LPLVUJXQOOQHMX-MOGLOQIBSA-N (2s,3s,4s,5r,6r)-6-[(2r,3r,4s,5s,6s)-2-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-6-carboxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-c Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-MOGLOQIBSA-N 0.000 description 1
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- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 1
- PJJGZPJJTHBVMX-UHFFFAOYSA-N 5,7-Dihydroxyisoflavone Chemical compound C=1C(O)=CC(O)=C(C2=O)C=1OC=C2C1=CC=CC=C1 PJJGZPJJTHBVMX-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000298 Cellophane Polymers 0.000 description 1
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- 229960004535 oxazepam Drugs 0.000 description 1
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 229960000292 pectin Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229960003893 phenacetin Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920001083 polybutene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001195 polyisoprene Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 229940125706 skeletal muscle relaxant agent Drugs 0.000 description 1
- 231100000274 skin absorption Toxicity 0.000 description 1
- 230000037384 skin absorption Effects 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229920006132 styrene block copolymer Polymers 0.000 description 1
- 229920003048 styrene butadiene rubber Polymers 0.000 description 1
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- IMCGHZIGRANKHV-AJNGGQMLSA-N tert-butyl (3s,5s)-2-oxo-5-[(2s,4s)-5-oxo-4-propan-2-yloxolan-2-yl]-3-propan-2-ylpyrrolidine-1-carboxylate Chemical compound O1C(=O)[C@H](C(C)C)C[C@H]1[C@H]1N(C(=O)OC(C)(C)C)C(=O)[C@H](C(C)C)C1 IMCGHZIGRANKHV-AJNGGQMLSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- 229960002784 thioridazine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 1
- 229960004880 tolnaftate Drugs 0.000 description 1
- 229940100640 transdermal system Drugs 0.000 description 1
- 229960000363 trapidil Drugs 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、経皮吸収促進組成物及びこれを含有する外用
剤に関する。更に詳しくは。DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a transdermal absorption promoting composition and an external preparation containing the same. For more details.
■ １−）’ｆジルアザシクロへブタン−２−オンと。■ 1-)'f with dilazacyclohebutan-2-one.
■ プロピレングリコールド。■ Propylene glycol.
■ ニコチン酸エステル、イソニコチン酸エステル、セ
バシン酸ジエステル及びＮ、Ｎ−ジエチル−ｍ−）ルア
ミドからなる群より選択された一種又は二種以上とを。(2) One or more selected from the group consisting of nicotinic acid ester, isonicotinic acid ester, sebacic acid diester, and N,N-diethyl-m-)ylamide.
含有することを特徴とする経皮吸収促進組成物と、これ
を含有する外用剤に関する。The present invention relates to a transdermal absorption promoting composition characterized by containing the same, and an external preparation containing the same.
（従来の技術）
経皮吸収促進剤は２表皮組織、とくに角質層が備えてい
る薬物吸収に対するバリアー機能を低減させ、薬物の皮
膚透過性を増大させる物質である。(Prior Art) A transdermal absorption enhancer is a substance that reduces the barrier function of two epidermal tissues, particularly the stratum corneum, against drug absorption and increases the skin permeability of drugs.
経皮治療システム（Ｔｒａｎａｄｅｒｍａｌ Ｔｈｅｒ
ａｐｅｕｔｉｃＳｙｓｔｅｍ：ＴＴＳ）の新しい概念が
導入されて以来。Transdermal Thermal System
Since the new concept of apeutic System (TTS) was introduced.
優れた経皮吸収促進剤の開発の必要性も更に高まってお
り、その研究も盛んである。There is an increasing need to develop excellent percutaneous absorption enhancers, and research on this topic is also active.
すなわち、経皮吸収性に劣る薬物は勿論、経皮吸収性が
比較的良好であると考えられている薬物であっても、ま
た全身的治療目的の薬物に限らず２局所的治療目的の薬
物であっても、その経皮吸収過程における律速段階と考
えられている角質層透過過程の透過速度を上昇させるこ
とが、的確な投与コントロール下で的確な薬効を発現さ
せようとするＴＴＳの製剤を設計する上で、肝要だから
である。In other words, not only drugs with poor transdermal absorption, but also drugs that are considered to have relatively good transdermal absorption, and not only drugs for systemic treatment but also drugs for local treatment. However, increasing the permeation rate of the stratum corneum permeation process, which is considered to be the rate-limiting step in the transdermal absorption process, is the key to developing TTS formulations that aim to achieve accurate medicinal efficacy under precise administration control. This is because it is essential when designing.
近時２種々の経皮吸収促進剤の報告がなされている中で
、とりわけ優れた経皮透過性を示す物質として１−ドデ
シルアザシクロへブタン−２−オン［商品名：エイシン
（Ａｚｏｎｅ■）、米国ネルソン社。以下本明細書にお
いて本化合物をエイシンと称す］が注目されている（特
公昭６０−３７０９２号、特開昭６１−２７９６６号）
。Recently, two kinds of transdermal absorption enhancers have been reported, and 1-dodecyl azacyclohebutan-2-one [trade name: Eishin (Azone)] is a substance that shows particularly excellent transdermal permeability. , Nelson Company, USA. This compound is hereinafter referred to as Eishin] has attracted attention (Japanese Patent Publication No. 60-37092, JP-A No. 61-27966).
.
このエイシンに関する特許文献には、薬剤にエイシンと
、「不活性担体としてのプロピレングリコール」とを配
合することが記載されており、−１゜た特開昭６０−３
６４２２号公報には、このエイシンとプロピレングリコ
ール等との二成分系混合物が薬物の浸透を増大させうる
ビヒクルであると開示されている。従って、エイシンの
経皮吸収促進効果を高めるためにプロピレングリコール
を配合することは既に公知である。This patent document regarding Eishin describes the combination of Eishin and "propylene glycol as an inert carrier" in a drug, and JP-A-60-3 which was -1°
Publication No. 6422 discloses that this binary mixture of eisin and propylene glycol is a vehicle that can increase the penetration of drugs. Therefore, it is already known to incorporate propylene glycol in order to enhance the effect of promoting transdermal absorption of Eishin.
このような複合系の経皮吸収促進組成物については、
Ａｒｃｈ、 Ｄｅｒｍ、、 １１８．４７４〜４７７（
１９８２）や特開昭６１−３３１２８号公報などにも認
められる。Regarding such a complex transdermal absorption promoting composition,
Arch, Derm, 118.474-477 (
1982) and Japanese Unexamined Patent Publication No. 61-33128.
の皮膚透過速度を顕著に高めるばかりでなく。As well as significantly increasing the skin permeation rate of.
水溶性、脂溶性薬物の双方に効果を示すこと。Showing effects on both water-soluble and fat-soluble drugs.
毒性が低いことなどから経皮吸収促進剤として優れてい
る。しかしながら、エイシン単独系は勿論、エイシンと
プロピレングリコールに代表される複合系においても、
実用的な薬物経皮吸収促進効果を示すまでには至ってい
ない。It is excellent as a transdermal absorption enhancer due to its low toxicity. However, not only in the single system of Eishin, but also in the complex system represented by Eishin and propylene glycol,
It has not yet been shown to have a practical effect on promoting transdermal absorption of drugs.
本発明の目的は、エイシン−プロピレングリコール複合
系に認められる効果に比し、相乗的経皮吸収促進効果を
示す組成物を提供することにある。また本発明の他の目
的はかかる組成物を含有する外用剤を提供することにあ
る。An object of the present invention is to provide a composition that exhibits a synergistic transdermal absorption promoting effect compared to the effect observed in the eisin-propylene glycol complex system. Another object of the present invention is to provide an external preparation containing such a composition.
（課題を解決するための手段）
そこで２本発明者らは前記目的にかなう経皮吸収促進組
成物につき、鋭意研究したところ貼付剤の分野で汎用さ
れているグリコール類の中で最も一般的な１，３−プチ
レングリコールトエイゾンとの複合系ではエイシンの有
する経皮吸収促進効果を高めることはできず、またエイ
シンとアジピン酸イソプロピルとの複合系などあるいは
エイシンとサリチル酸エチレングリコールとの複合系に
おいてもエイシンの吸収促進作用をむしろ減弱させるこ
とを確認した。後者の知見はエイシンの経皮吸収促進作
用がジエチルセバケートなどの親油性物質の存在下では
効果が減殺されるとの報告［Ｓ、 Ｋｏｎｄｏ ｅｔ
ａｌ、、、Ｊ、 Ｐｈａｒｍａｃｏｂｉｏ−Ｄｙｎ、、
１１．８８−９４（１９８８）＋特にその第９２頁
左欄第１２−１５行］を裏付けていると認められた。(Means for Solving the Problems) Therefore, the present inventors conducted intensive research on a composition for promoting transdermal absorption that meets the above-mentioned purpose. A composite system of 1,3-butylene glycol and Eisone cannot enhance the transdermal absorption promoting effect of Eisin, and a composite system of Eisin and isopropyl adipate, or a composite system of Eisin and ethylene glycol salicylate, etc. It was also confirmed that the absorption-promoting effect of Eishin was actually weakened. The latter finding is based on a report that the percutaneous absorption promoting effect of Eishin is diminished in the presence of lipophilic substances such as diethyl sebacate [S, Kondo et al.
al,,,J,Pharmacobio-Dyn,,
11.88-94 (1988) + especially page 92, left column, lines 12-15].
このような状況下で更に鋭意研究の結果、エイシンと、
特定のプロピレングリコールと、エイシンの促進効果を
低下させると記載されていたジエチルセバケートそのも
のや同じ親油性物質であるニコチン酸エステル、イソニ
コチン酸エステル、Ｎ、Ｎ−ジエチル−ｍ −）ルアミ
ドとの特定の配合によるときは、全く意外にも逆にエイ
シンの吸収促進効果を相乗的に高めることを知見して本
発蓋に至−た。Under these circumstances, as a result of further intensive research, Eishin and
The combination of specific propylene glycol with diethyl sebacate itself and the same lipophilic substances nicotinic acid ester, isonicotinic acid ester, N,N-diethyl-m-)ylamide, which have been described as reducing the promoting effect of eicin. We have discovered that, quite unexpectedly, when using a specific formulation, the absorption promoting effect of Eishin is synergistically enhanced.
すなわち９本発明は ■ エイシンと。In other words, the present invention is ■ With Eishin.
■ プロピレングリコールド。■ Propylene glycol.
■ ニコチン酸エステル、イソニコチン酸エステル、セ
バシン酸ジエステル、及びＮ、Ｎ−ジエチル−ｍ −）
ルアミドからなる群より選択された一種又は二種以上と
を
含有することを特徴とする経皮吸収促進組成物及び該組
成物と薬物とを含有することを特徴とする外用剤をその
構成とするものである。■ Nicotinic acid ester, isonicotinic acid ester, sebacic acid diester, and N,N-diethyl-m-)
The composition comprises a transdermal absorption promoting composition characterized by containing one or more kinds selected from the group consisting of polyamides, and an external preparation characterized by containing the composition and a drug. It is something.
なお１本発明の経皮吸収促進効果は骨格筋弛緩剤である
ダントロレンナトリウム及び脳血管障害２頭部外傷治療
剤であるインデロキサジン塩酸塩などによって確認され
た。Note that the percutaneous absorption promoting effect of the present invention was confirmed with dantrolene sodium, a skeletal muscle relaxant, and inderoxazine hydrochloride, a therapeutic agent for cerebrovascular disorders and head trauma.
ダントロレンナトリウムは、他の多くの末梢性筋弛緩剤
と異なり、神経系を介さずに直接骨格の興奮収縮連開期
のカルシウム遊離を阻害することにより筋弛緩作用を発
現する薬剤であり。Dantrolene sodium, unlike many other peripheral muscle relaxants, is a drug that exerts muscle relaxing effects by directly inhibiting calcium release during the excitation-contraction phase of the skeleton, without going through the nervous system.
既に使用に供されている。しかし、現在の投与経路は経
口あるいは注射であり、薬剤の作用が患部以外の全身に
及ぶことから９種々の副作用が報告されている。従って
１局所性筋緊張疾患に対しては全身的投与は好ましくな
く、主として薬剤が疾患部位である筋肉内に移行するよ
うにしたＴＴＳの製剤開発が要望されていた。しかしな
がらダントロレンナトリウムは極めて皮膚吸収が悪く。Already in use. However, the current administration route is oral or injection, and nine different side effects have been reported because the drug's effects extend to the whole body other than the affected area. Therefore, systemic administration is not preferable for localized muscle tension diseases, and there has been a demand for the development of a TTS formulation that allows the drug to primarily migrate into the muscle, which is the diseased area. However, dantrolene sodium has extremely poor skin absorption.
ＴＴＳの製剤開発に当って、ダントロレンナトリウムの
皮膚透過性を大巾に改善するため強力な経皮吸収促進剤
を開発する必要があった。When developing the TTS formulation, it was necessary to develop a strong transdermal absorption enhancer to significantly improve the skin permeability of dantrolene sodium.
しかして、最近に至り、このダントロレンナトリウムに
ついて外用剤とする発明が公開された（特開平１−１２
８９２８号）。Recently, however, an invention has been published that uses dantrolene sodium as an external preparation (Japanese Patent Application Laid-Open No. 1-12
No. 8928).
該公報には、ダントロレンナトリウムを外用剤とするに
当り吸収調節剤としてエイシンやアジピン酸イソプロピ
ルやセバシン酸ジエチルをも包括する特定ジカルボン酸
の特定アルコールついて記載されている。This publication describes specific alcohols of specific dicarboxylic acids, including eishin, isopropyl adipate, and diethyl sebacate, as absorption modifiers for preparing dantrolene sodium as an external preparation.
しかしながら、該公報には本発明に必須のニコチン酸エ
ステル、イソニコチン酸エステル。However, the publication describes nicotinic acid esters and isonicotinic acid esters that are essential to the present invention.
Ｎ、Ｎ−ジエチル−ｍ−）ルアミドについては全く開示
されておらず、また本発明に必須のセバシン酸ジエステ
ルについては具体的記載がないばかりでなく、促進効果
を減弱するあるいは高めないアジピン酸イソプロピルや
１，３−ブチレングリコールをも包括する特定されない
開示に止まるだけであり、前記Ｊ、 Ｐｈａｒｍａｃｏ
ｂｉｏ−Ｄｙｎ、に基づく当業者の認識をも勘案すれば
セパシン酸ジエステルトフロビレングリコールとエイシ
ンとの複合系を示唆するものではない。N,N-diethyl-m-)ylamide is not disclosed at all, and sebacic acid diester, which is essential to the present invention, is not specifically described, and isopropyl adipate does not attenuate or enhance the promoting effect. and 1,3-butylene glycol.
Considering the knowledge of those skilled in the art based on bio-Dyn, this does not suggest a composite system of sepacic acid diester toflobylene glycol and eisin.
また、実施例６など、ダントロレンナトリウムの経皮吸
収がほとんど認められない製剤例を開示しており、果し
てダントロレンナトリウム外用剤特に貼付剤の発明が実
用的であるかどうかが疑問であるばかりでなく、効果が
確認されているのは単にエイシン−プロピレングリコー
ル複合系のみであり、その奏したとする効果も本発明が
奏した効果と顕著な差異が認められる。In addition, Example 6 and other formulations in which almost no transdermal absorption of dantrolene sodium is observed are disclosed, which not only raises questions as to whether the invention of a topical dantrolene sodium preparation, especially a patch, is practical. However, only the Eisin-propylene glycol composite system has been confirmed to be effective, and the effects that it is said to have achieved are significantly different from those achieved by the present invention.
一方、全身的適用目的のインデロキサジン又はその塩の
経皮吸収外用剤については２本出願人の出願に係る特開
平１−６８３２３号で公知である。On the other hand, a percutaneous absorption topical preparation of inderoxazine or its salt for systemic application is known from Japanese Patent Laid-Open No. 1-68323 filed by the present applicant.
誠
→発明は、特定の吸収促進効果をもたらす外用製剤の処
方について開示しているものの、エイシンの使用を開示
するものではなく、かつその吸収促進効果も本発明の効
果と比較すれば相違することが認められた。Makoto: Although the invention discloses the formulation of an external preparation that brings about a specific absorption-promoting effect, it does not disclose the use of Eishin, and its absorption-promoting effect is also different when compared to the effect of the present invention. was recognized.
本発明の特定されたエイシン−プロピレングリコール併
用系に更に配合されるニコチン酸エステル、イソニコチ
ン酸エステル及ヒセバシン酸ジエステルのエステルとし
ては低級アルキル基やアラルキル基等によって構成され
るエステルであり、低級アルキル基の具体例としてはメ
チル基、エチル基、プロピル基、イソプロピル基、ブチ
ル基、ペンチル基など炭素数が１乃至６個の直鎖又は分
岐状のアルキル基が、アラルキル基としてはベンジル基
、フェネチル基などが好適なものとして例示される。The esters of nicotinic acid ester, isonicotinic acid ester, and hisebacic acid diester that are further blended into the eisin-propylene glycol combination system specified in the present invention are esters composed of lower alkyl groups, aralkyl groups, etc. Specific examples of groups include linear or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, and pentyl groups; examples of aralkyl groups include benzyl and phenethyl groups. Preferred examples include groups.
これらニコチン酸エステル、イソニコチン酸エステル、
セバシン酸ジエステル（以下エステル類という）及びＮ
、Ｎ−ジエチル−ｍ−トルアミド（以下ＤＥＥＴという
）は、これらを単独であるいはその二種以上を適宜組合
せて使用することができる。These nicotinic acid esters, isonicotinic acid esters,
Sebacic acid diester (hereinafter referred to as esters) and N
, N-diethyl-m-toluamide (hereinafter referred to as DEET) can be used alone or in an appropriate combination of two or more thereof.
本発明組成物の各構成成分の使用量は、該組成物全量に
対し、エイシンが約５乃至３５重量％、好ましくは約１
０乃至２５重量％、プロピレングリコールが約３０乃至
９０重量％、好ましくは約４０乃至８０重量％、エステ
ル類又はＤＥＥＴが約５乃至３５重量％、好ましくは約
１０乃至２５重量％である。The amount of each component used in the composition of the present invention is approximately 5 to 35% by weight, preferably approximately 1% by weight, based on the total amount of the composition.
0 to 25% by weight, propylene glycol about 30 to 90%, preferably about 40 to 80%, and esters or DEET about 5 to 35%, preferably about 10 to 25%.
本発明は、上記組成物と、薬物とを含有する外用剤をも
包含するものであり、外用剤としては、貼付剤、ゲル軟
膏などを含む軟膏、乳剤など皮膚適用製剤のいずれであ
ってもよいが、投与が簡便かつ制御可能で的確な薬効を
期待できるＴＴＳの製剤形態としての貼付剤が好適であ
る。The present invention also includes external preparations containing the above-mentioned composition and a drug, and examples of the external preparation include any of skin-applied preparations such as patches, ointments including gel ointments, and emulsions. However, it is preferable to use a patch as a formulation of TTS, which is easy to administer, can be controlled, and can be expected to have accurate medicinal efficacy.
本発明外用剤に用いられる薬剤は２本発明の経皮吸収促
進組成物によってその経皮吸収が著しく高められる薬剤
であればいずれでもよく。The drug used in the external preparation of the present invention may be any drug whose transdermal absorption is significantly enhanced by the transdermal absorption promoting composition of the present invention.
就中副作用の軽減、薬効の持続化、肝臓初回通過による
不活化回避などを目的としてＴＴＳの製剤化が適切な投
与形態として望まれており。Among other things, preparation of TTS as an appropriate dosage form is desired for the purpose of reducing side effects, sustaining drug efficacy, and avoiding inactivation due to first passage through the liver.
かつ本来経皮吸収に劣る薬物であればなお好ましい。It is even more preferable if the drug is inherently inferior in transdermal absorption.
従って、薬物は治療目的が局所的であると。Therefore, the drug is local in its therapeutic purpose.
全身的であるとを問わない。また、水溶性薬剤。It doesn't matter if it's systemic. Also, water-soluble drugs.
脂溶性薬剤あるいは難溶性の薬物でありてもよい。It may be a fat-soluble drug or a poorly soluble drug.
このような薬剤としては２例えば
（１）抗炎症剤
：’ −ｆ ソン、ハイドロコーチシン、ペタメタシン
、デキサメタシン、プレドニゾロン。Such drugs include (1) anti-inflammatory agents: '-fson, hydrocortiscin, petamethacin, dexamethacin, prednisolone;
トリアムシノロン、フルオロジノロンやその塩、その誘
導体などのステロイド系抗炎症剤や、アセトアミノフェ
ン、フェナセチン、インドメタシン、フルフェナム酸、
メフェナム酸。Steroid anti-inflammatory drugs such as triamcinolone, fluorodinolone, its salts, and its derivatives, acetaminophen, phenacetin, indomethacin, flufenamic acid,
Mefenamic acid.
ジクロフェナック、アルクロフェナック、クリダナク、
イブプロフェン、フェノプロフェン、フルルビプロフェ
ン、ケトプロフェン。Diclofenac, Arclofenac, Clidanac,
Ibuprofen, fenoprofen, flurbiprofen, ketoprofen.
フエンブフエン、チアラミド、ナプロキセる２タ フェニルブ一ゾン、オキシフェンプダゾン。Fuenbufuen, thiaramide, naproxel 2ta Phenylbuzone, oxyphenpudazone.
ピロキシカムやその塩、その誘導体などの非ステロイド
系抗炎症剤、グリチルリチン、グリチルレチン酸などそ
の他の抗炎症剤。Nonsteroidal anti-inflammatory agents such as piroxicam, its salts, and its derivatives, and other anti-inflammatory agents such as glycyrrhizin and glycyrrhetinic acid.
（２）抗生物質
クロラムフェニコール、テトラサイクリン系抗生物質、
ペニシリン系抗生物質、セファロスポリン系抗生物質、
マクロライド系抗生物質、リンコマイシン系抗生物質、
アミノグリコシド系抗生物質などの抗生物質。(2) Antibiotics chloramphenicol, tetracycline antibiotics,
penicillin antibiotics, cephalosporin antibiotics,
macrolide antibiotics, lincomycin antibiotics,
Antibiotics such as aminoglycoside antibiotics.
（３）抗真菌剤
トルナフテート、クロトリマゾール、グリセオフルビン
、ナイスタチン、アンホテリシンーＢなどの抗真菌剤。(3) Antifungal agents Antifungal agents such as tolnaftate, clotrimazole, griseofulvin, nystatin, amphotericin-B.
（４）循環器用剤
ニトログリセリン、インソルビドニトレート、トラピジ
ル、ニコランジルなどの血管拡張剤やニフェジピン、ニ
カルジピン、ニモジピン、ニトレンジピンやその塩など
のカルシウム抗拮剤などの循環器用剤。(4) Cardiovascular agents Circulatory agents such as vasodilators such as nitroglycerin, insorbide nitrate, trapidil, and nicorandil, and calcium antagonists such as nifedipine, nicardipine, nimodipine, nitrendipine and its salts.
（５） 抗ヒスタミン剤 ジフェンヒドラミン、クロルフェニラミン。(5) Antihistamines diphenhydramine, chlorpheniramine.
フレマスチンやその塩などの抗ヒスタミン剤。Antihistamines such as flemastine and its salts.
（６）精神神経用剤
ジアゼパム、クロルジアゼポキシド、ニトラゼパム、オ
キサゼパム、フルジアゼパム。(6) Neuropsychiatric agents diazepam, chlordiazepoxide, nitrazepam, oxazepam, fludiazepam.
メタゼバム、クロルプロマジン、ハロペリドール、フル
フェナジン、チオリダジン、ベルフェナジンやその塩な
どの精神神経用剤。Neuropsychiatric drugs such as metazebam, chlorpromazine, haloperidol, fluphenazine, thioridazine, belphenazine and its salts.
（７）筋弛緩剤
ダントロレン、ブリシノールやその塩などの骨格筋弛緩
剤など。(7) Muscle relaxants such as skeletal muscle relaxants such as dantrolene, bricinol and its salts.
（８）鎮痙剤
アトロピン、スコポラミンやその塩、その誘導体などの
鎮痙剤。(8) Antispasmodics Antispasmodics such as atropine, scopolamine, its salts, and its derivatives.
（９）脳障害改善剤 インデロキサジンやその塩などの脳障害改善剤。(9) Brain disorder improving agent Brain disorder improving agents such as inderoxazine and its salts.
などが挙げられる。Examples include.
これらの薬剤その低木発明外用剤に用いられる薬剤は、
適応症など治療目的に応じて適宜合剤とすることができ
る。These drugs are used in external preparations for shrub inventions.
It can be used as a combination drug as appropriate depending on the therapeutic purpose such as indication.
薬剤の配合量は、用いられる基剤１本発明吸収促進組成
物の種類や使用量に応じて若干具なるものの、製剤全体
に対して約０．１乃至５重量％。The amount of the drug to be blended varies depending on the type and amount of the absorption-promoting composition of the present invention used, but it is approximately 0.1 to 5% by weight based on the total formulation.
好ましくは約０゜５乃至３重量％であり、ダントロレン
テ） ＩＪウムの場合は、約１．５重量％以上となると
２本発明吸収促組成物による薬物の経皮吸収が更に高ま
ることが確認されており、約１．５乃至３重量％がなお
好適である。It is preferably about 0.5 to 3% by weight, and in the case of IJum, it has been confirmed that when it is about 1.5% by weight or more, the transdermal absorption of the drug by the absorption-promoting composition of the present invention is further enhanced. approximately 1.5 to 3% by weight is still preferred.
本発明の外用剤に加えられるエイシン、プロピレングリ
コール及びエステル類またはＤＥＥＴからなる経皮吸収
促進組成物は、その構成及び配合割合など前記のとおり
のものが使用され。The transdermal absorption promoting composition consisting of eishin, propylene glycol, and esters or DEET to be added to the external preparation of the present invention has the composition and blending ratio as described above.
外用剤に占める該組成物の使用割合は、外用剤の形態、
薬物や基剤の種類や使用量に応じて若干具なるものの製
剤全体に対し、約０．５乃至５０重量％、とくに約５乃
至４０重量％が好適である。The proportion of the composition used in the external preparation depends on the form of the external preparation,
It is preferably about 0.5 to 50% by weight, particularly about 5 to 40% by weight, based on the total amount of the drug, depending on the type and amount of the drug and base used.
なお１本発明外用剤には、上記吸収促進組成物の他に、
従来公知の経皮吸収促進剤を２本発明経皮吸収促進効果
を損なわない範囲内で更に加えることが可能である。こ
のような経皮吸収促進剤としては、ジメチルスルホキシ
ド、ジメチルアセトアミド、ジメチルホルムアミド、乳
酸、尿素類などが例示として挙げられる。In addition to the above-mentioned absorption-promoting composition, the external preparation of the present invention also contains:
It is possible to further add two conventionally known percutaneous absorption enhancers within a range that does not impair the percutaneous absorption promoting effect of the present invention. Examples of such percutaneous absorption enhancers include dimethyl sulfoxide, dimethylacetamide, dimethylformamide, lactic acid, and ureas.
また９本発明の経皮吸収促進組成物の各構成成分は、外
用剤製剤化に当り、同時に加えることを意味せず、外用
剤中にその組成物の成分が含有されていればよい。Furthermore, each component of the transdermal absorption promoting composition of the present invention does not have to be added at the same time when preparing an external preparation, but it is sufficient that the components of the composition are contained in the external preparation.
外用剤中例えば貼付剤は２通常支持体と、薬物を放出し
うる態様の感圧接着剤層（薬物を感圧接着剤層に混和す
る場合９層を分ける場合。Among external preparations, for example, patches usually have two layers: a support and a pressure-sensitive adhesive layer capable of releasing the drug (in the case where the drug is mixed into the pressure-sensitive adhesive layer, there are nine separate layers).
特殊な形態の薬剤放出部を含む場合などがある）。(e.g., they may contain special forms of drug release).
及びこの感圧接着剤層を保護する剥離フィルムからなっ
ている。and a release film that protects this pressure-sensitive adhesive layer.
簡略化のために、薬剤混和型感圧接着剤層の貼付剤につ
いて説明すれば、感圧接着剤層には。For the sake of simplicity, if a patch with a drug-incorporated pressure-sensitive adhesive layer is described, the pressure-sensitive adhesive layer will be described as follows.
治療目的とする薬剤、貼付基剤及び本発明経皮吸収促進
組成物を混和し、膏体とする。A therapeutic drug, a patch base, and the percutaneous absorption promoting composition of the present invention are mixed to form a plaster.
貼付基剤は、薬剤を均質に混和可能で、常温で感圧接着
性があり、貼着した際薬物が放出され、かつ本発明吸収
促進組成物により促進される薬物の経皮吸収を損なわな
い基剤であればよく、エイシン−プロピレングリコール
−エステル類またはＤＥＥＴの作用を減殺する基剤以外
の全ての一般用貼付基剤が挙げられる。The patch base can homogeneously mix the drug, has pressure-sensitive adhesive properties at room temperature, releases the drug when applied, and does not impair the transdermal absorption of the drug promoted by the absorption-promoting composition of the present invention. Any base may be used, including all general adhesive bases other than bases that reduce the effect of eisin-propylene glycol esters or DEET.
粘着成分としては、具体的には天然ゴム、スチレン−ブ
タジェンゴム（ＳＢＲ）、ポリイソプレンゴム、ポリイ
ソブチレンゴム、スチレン−インプレン−スチレン−ブ
ロック共重合体（ＳＩＳ）。Specific examples of adhesive components include natural rubber, styrene-butadiene rubber (SBR), polyisoprene rubber, polyisobutylene rubber, and styrene-inprene-styrene block copolymer (SIS).
スチレン−ブタジェン−スチレンブロック共重合体（Ｓ
ＢＳ）、シリコンゴム（オルガノポリシロキサンゴム）
ｙ （メタ）アクリル酸−（メタ）アクリル酸エステ
ル共重合体などのアクリル系共重合体、親水性高分子と
してはポリアクリル酸ナトリウム、カルボキシメチルセ
ルロース（ＣＭＣ）、 カルボキシメチルセルロースナ
トリウム（ＣＭＣＮａ）、ポリビニルアルコール（ＰＶ
Ａ）、ポリビニルピロリジン（ｐｖｐ）、メチルビニル
エーテル無水マレイン酸共重合体、アルギン酸ナトリウ
ム、アルギン酸プロピレンクリコールエステル、ペクチ
ン、ザンタンガム、キサンタンガム、ローカストピーン
ガム、グアーガム、アラピアノガラクタン、ヒアルロン
酸ナトリウムなどが挙げられる。Styrene-butadiene-styrene block copolymer (S
BS), silicone rubber (organopolysiloxane rubber)
y Acrylic copolymers such as (meth)acrylic acid-(meth)acrylic ester copolymers, hydrophilic polymers such as sodium polyacrylate, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMCNa), and polyvinyl alcohol. (PV
A), polyvinylpyrrolidine (pvp), methyl vinyl ether maleic anhydride copolymer, sodium alginate, alginate propylene glycol ester, pectin, xanthan gum, xanthan gum, locust pea gum, guar gum, alapiano galactan, sodium hyaluronate, etc. .
ゴムなどは、ラテックスエマルジョンとして使用しうる
。また、これらの粘着成分や親水性高分子は適宜組合せ
て用いることができる。Rubber and the like can be used as latex emulsions. Moreover, these adhesive components and hydrophilic polymers can be used in appropriate combinations.
これらに必要により加えられる成分としては。Ingredients that can be added to these as needed are:
ゼラチンなどの泥状化剤】カオリン、ベントナイト、酸
化亜鉛、酸化チタンなどの粉末賦形剤；フィントンＯ（
商品名９日本ゼオン社製脂肪族系）、アルコン■（商品
名、荒用化学社製、脂環族系）などの石油樹脂、ロジン
、水添ロジン。Sludge agent such as gelatin] Powder excipients such as kaolin, bentonite, zinc oxide, titanium oxide; Finton O (
Petroleum resins, rosin, hydrogenated rosin, such as product name 9 (aliphatic type, manufactured by Nippon Zeon Co., Ltd.), Alcon ■ (product name, manufactured by Arayo Kagaku Co., Ltd., alicyclic type).
エステルガムなどの樹脂等の粘着付与成分；ポリブテン
、流動パラフィン、インプロピルミリステートの如き高
級脂肪酸エステル類、シリコンオイルや各種植物油等の
軟化剤；グリセリルモノステアレートなどのグリセリル
脂肪酸エステル、ポリオキシエチレンソルビタンモノラ
ウレート（例えば日光ケミカルズ社：ＴＬ−１０）。Tackifier components such as resins such as ester gum; higher fatty acid esters such as polybutene, liquid paraffin, and inpropyl myristate; softeners such as silicone oil and various vegetable oils; glyceryl fatty acid esters such as glyceryl monostearate, polyoxyethylene Sorbitan monolaurate (for example, Nikko Chemicals: TL-10).
ポリオキシエチレンソルビタンモノステアレート（例え
ば日光ケミカルズ社： ＴＳ−１０） ナトノポリオキ
シエチレンンルピタン脂肪酸エステル。Polyoxyethylene sorbitan monostearate (for example, Nikko Chemicals: TS-10) Natonopolyoxyethylene lupitan fatty acid ester.
ソルビタンモノステアレート（日光ケミカルズ社： ５
Ｓ−１０）などのソルビタン脂肪酸エステル等ノ界面活
性剤；メチルパラベン、エチルパラペン、プロピルパラ
ベン、フチルハラヘン、ソルビン酸、ソルビン酸の塩類
、ブチルヒドロキシアニソール（ＢＨＡ）、ジブチルヒ
ドロキシトルエン（ＢＩＴ）、ノルジヒドログアイアレ
チン酸。Sorbitan monostearate (Nikko Chemicals: 5
Surfactants such as sorbitan fatty acid esters such as S-10); methylparaben, ethylparapen, propylparaben, phthylhalachen, sorbic acid, salts of sorbic acid, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BIT), nordihydroguay Aretic acid.
グアヤコールエステル類等の防腐乃至酸化（老化）防止
剤；酢酸、コハク酸、クエン酸、リンゴ酸、フマール酸
、マレイン酸、酒石酸などの有機酸等のｐＨ調整剤（そ
れ自身貼付基剤として有用な特性もある）；塩化アルミ
ニウム、硫酸アルミニウム、ミョウバン、アルミニウム
アラントイネート等の三価金属イオンを生成する塩など
の収斂剤；アルカリ土類金属塩などの保湿剤；メントー
ルなどの着香料；薬剤の溶剤；水などが挙げられる。Preservatives and oxidation (aging) inhibitors such as guaiacol esters; pH adjusters such as organic acids such as acetic acid, succinic acid, citric acid, malic acid, fumaric acid, maleic acid, and tartaric acid (themselves useful as patch bases) astringents such as salts that produce trivalent metal ions such as aluminum chloride, aluminum sulfate, alum, and aluminum allantoinate; humectants such as alkaline earth metal salts; flavoring agents such as menthol; Solvent; water etc. are mentioned.
なお、保湿剤としては、マンニット、ソルビット、グリ
セリン、ジグリセリン、トリグリセリン、プロピレング
リコールなどの多価アルコールも挙げられるが、多価ア
ルコール中当該貼付剤の分野において汎用されている１
、３−ブチレングリコールは９本発明吸収促進組成物の
プロピレングリコールに代えて使用すると、逆に経皮吸
収促進効果を低下させる。従って、多価アルコールは保
湿剤として用いられるが、多価アルコール中１，３−ブ
チレングリコールは２本発明の吸収促進効果を損わない
範囲で保湿剤として使用することを妨げるものではない
が、むしろ使用しないのが好適である。また、多価アル
コールは、薬剤の溶媒となるものも含まれている。In addition, examples of moisturizing agents include polyhydric alcohols such as mannitol, sorbitol, glycerin, diglycerin, triglycerin, and propylene glycol.
When 3-butylene glycol is used in place of propylene glycol in the absorption-promoting composition of the present invention, the percutaneous absorption-promoting effect is conversely reduced. Therefore, polyhydric alcohol is used as a moisturizing agent, and 1,3-butylene glycol in polyhydric alcohol does not preclude its use as a moisturizing agent as long as it does not impair the absorption promoting effect of the present invention. Rather, it is preferable not to use it. Polyhydric alcohols also include those that serve as solvents for drugs.
これらの基剤は、薬剤及び経皮吸収促進組成物の使用量
及び経皮吸収促進効果を考慮して適宜定められる。具体
的には、これら基剤の使用量は、パップ剤と、テープ剤
などの貼付剤とでは相違するが、製剤（膏体）全体に対
し、約４５乃至９９．４重量％（プロピレングリコール
を除いて）、好ましくは約５７乃至９４．５重量％用い
るのが好適である。These bases are appropriately determined in consideration of the amount of the drug and the percutaneous absorption promoting composition to be used and the percutaneous absorption promoting effect. Specifically, the amount of these bases used differs between poultices and patches such as tapes, but the amount of these bases used is approximately 45 to 99.4% by weight (propylene glycol) based on the entire preparation (paste). ), preferably about 57 to 94.5% by weight.
なお、ダントロレンナトリウムの溶剤としては、マクロ
ゴール（ＰＥＧ）４００．Ｎ−メチル−２−ピロリドン
、エチレングリコール、ＰＥＧとの共存系におけるプロ
ピレングリコ−／Ｉ／、 りＩＪ セ゛リン、ジグリセ
リン、トリグリセリン、水（常水及び精製水）が挙げら
れる。In addition, as a solvent for dantrolene sodium, macrogol (PEG) 400. N-methyl-2-pyrrolidone, ethylene glycol, propylene glycol/I/ in a coexistence system with PEG, serine, diglycerin, triglycerin, and water (normal water and purified water).
溶剤は薬物に特有であって、特に限定されるものではな
いが２通常上記マクロゴール（ＰＥＧ）。The solvent is drug specific and is typically, but not limited to, the macrogol (PEG) mentioned above.
Ｎ−メチル−２−ピロリドン、プロピレングリコール、
グリセリン類の他、エタノール、イソプロパツール、ベ
ンジンアルコール、フェネチルアルコールナトのアルコ
ール類、クロタミトンなどの有機溶媒又は水あるいはこ
れらの混合溶媒が挙げられる。N-methyl-2-pyrrolidone, propylene glycol,
In addition to glycerin, organic solvents such as ethanol, isopropanol, benzine alcohol, phenethyl alcohol, crotamiton, water, or a mixed solvent thereof may be used.
本発明貼付剤を製造するには、薬物、基剤。In order to manufacture the patch of the present invention, a drug and a base are required.
経皮吸収促進組成物の各成分を均一に練合し。Each component of the composition for promoting transdermal absorption is kneaded uniformly.
練合物を支持体に展延し、必要により乾燥し。The mixture is spread on a support and dried if necessary.
剥離フィルムを貼合し、適宜の大きさに裁断し。Attach release film and cut to appropriate size.
包装する。Pack it.
均一な膏体を練合して製造する際には１機械的な練合操
作を容易にするため用いられる薬剤。When kneading and manufacturing a uniform paste, 1) A chemical used to facilitate the mechanical kneading operation.
基剤、経皮吸収促進組成物の各成分の物理化学的性状を
考慮して、その添加練合順序を適宜設定し、あるいは加
温、超音波処理することは自由である。Taking into consideration the physicochemical properties of the base and each component of the transdermal absorption promoting composition, it is free to appropriately set the order of addition and kneading, or to perform heating and ultrasonic treatment.
バッグ剤あるいはテープ製剤をエマルジョン法で製造す
るに際して、粘着成分のゴム類などは予めラテックスエ
マルジョンとして調製し。When producing bag or tape formulations using the emulsion method, adhesive components such as rubber are prepared in advance as a latex emulsion.
添加練合することができる。It can be added and kneaded.
展延は、製造された膏体を支持体あるいは剥離フィルム
に適宜の温度を保持するかあるいは加熱して膏体を所定
の厚さに均一に塗布するなど常法に従って行なわれる。Spreading is carried out according to a conventional method, such as by maintaining the prepared paste on a support or a release film at an appropriate temperature or by heating it to uniformly apply the paste to a predetermined thickness.
乾燥は、溶媒法、あるいはエマルジョン法によって含水
量の少ないテープ製剤などを製造する際に行なわれ、溶
媒あるいは水を揮散させる。Drying is performed when producing tape formulations with low water content by a solvent method or an emulsion method, and the solvent or water is volatilized.
次いで膏体を支持体に展延したときはその膏体上に剥離
フィルムを貼合し、膏体を剥離フィルム上に展延したと
きは、展延膏体上に支持体を貼合する。Next, when the paste is spread on a support, a release film is laminated onto the paste, and when the paste is spread on the release film, a support is laminated onto the spread plaster.
支持体は布、不織布、プラスチックフィルムなどが用い
られ、殊にネルや不織布が好ましい。As the support, cloth, nonwoven fabric, plastic film, etc. are used, and flannelette and nonwoven fabric are particularly preferred.
また、剥離フィルムは剥離処理を施したセロファンやポ
リエチレンフィルムなどが好適に用いられる。Further, as the release film, cellophane or polyethylene film that has been subjected to release treatment is preferably used.
他の外用剤９例えばマクロゴール等を基剤とする軟膏、
カルボキシビニルポリマーを基剤トするゲル剤（ヒドロ
ゲルあるいは親水性ゲル軟膏）、水、油性成分、乳化剤
を基剤とする乳剤も、常法に従って製剤化することがで
きる。Other external preparations 9 For example, ointments based on macrogol, etc.
Gels (hydrogel or hydrophilic gel ointment) based on carboxyvinyl polymers, emulsions based on water, oily components, and emulsifiers can also be formulated according to conventional methods.
（発明の効果）
本発明組成物は、従来公知のエイシン−プロピレングリ
コール複合系促進剤と比較して、薬物の皮膚透過速度を
相乗的に高める。従って。(Effects of the Invention) The composition of the present invention synergistically increases the skin permeation rate of drugs compared to conventionally known eisin-propylene glycol complex promoters. Therefore.
該組成物を用いて貼付剤とすることにより実用的ＴＴＳ
の製剤化が可能となる。Practical TTS can be achieved by making a patch using this composition.
It becomes possible to formulate a formulation of
殊に１本発明の経皮吸収促進の相乗効果は。In particular, one aspect of the present invention is the synergistic effect of promoting percutaneous absorption.
プロピレングリコールに代えて１．３−ブチレングリコ
ールを用いても、あるいはエステル類としてアジピン酸
イソプロピルやサリチル酸エチレングリコールな用いて
も達成できず、むしろ低下させる場合があり、前記文献
による当業者の認識に反して全く予想外の効果である。Even if 1,3-butylene glycol is used in place of propylene glycol, or isopropyl adipate or ethylene glycol salicylate is used as an ester, this cannot be achieved, and in fact, it may be reduced. On the contrary, this is a completely unexpected effect.
かかる相乗効果は以下の試験法によって確認された。Such synergistic effect was confirmed by the following test method.
実験１． ダントロレンナトリウムの皮膚透過性試験
（ｉｎ Ｖｉｔｒｏ）
（試料溶液の調製）
比較例 １゜
ダントロレンナトリウム２部をマクロゴール４００４８
部に、６０℃で加温溶解し１次いで室温に戻してこれに
プロピレングリコール５０部を添加して良く混合して試
料溶液を得た。Experiment 1. Skin permeability test of dantrolene sodium (in vitro) (Preparation of sample solution) Comparative example 1゜Two parts of dantrolene sodium was added to Macrogol 40048
The sample solution was dissolved by heating at 60° C., then returned to room temperature, 50 parts of propylene glycol was added thereto, and mixed well to obtain a sample solution.
比較例 ２゜
マクロゴール４００を３８部とし、プロピレングリコー
ルな４０部とし、プロピレングリコールを添加混合した
後、イソニコチン酸ｎ−ブチル２０部を添加混合した他
比較例１と同様にして試料溶液を得た。Comparative Example 2 A sample solution was prepared in the same manner as in Comparative Example 1 except that 38 parts of macrogol 400 and 40 parts of propylene glycol were added and mixed, and then 20 parts of n-butyl isonicotinate was added and mixed. Obtained.
比較例 ３゜
イソニコチン酸ｎ−ブチル２０部に代えて、エイシン２
０部とした他、比較例２と同様にして試料溶液を得た。Comparative Example 3 In place of 20 parts of n-butyl isonicotinate, Eishin 2
A sample solution was obtained in the same manner as in Comparative Example 2 except that the sample solution was 0 parts.
実験方法
前日に剪毛処理したハートレイ（Ｈａｒｔｌｅｙ）系雄
性モルモットの腹部皮膚を摘出し、フランツ（Ｆｒａｎ
ｚ）型拡散セルに装着後、ダントロレンナトリウムの試
料溶液、同様にして調製した本発明のダントロレンナト
リウム溶液をそれぞれ、ドナー側に加えた。レセプター
側には等張化した１０ｍＭリン酸二水素カリウム溶液を
用い、セル温度は３７°Ｃで行った。経時的にレセプタ
ー溶液を採取し、試料溶液、実施例溶液のダントロレン
ナトリウムの濃度を高速液体クロマトグラフィー（ＨＰ
ＬＣ）で測定し、３２時間後のダントロレンナトリウム
（ＤＮ）累積皮膚透過量（単位＊ ｎｇ／ ｓｑ−ｃ
ｍ ）を求め、透過率（比較例３を１としたときの実施
例の倍率）を求めた。Experimental method The abdominal skin of male Hartley guinea pigs, which had been shaved the day before, was removed and
z) After mounting in the type diffusion cell, a sample solution of dantrolene sodium and a dantrolene sodium solution of the present invention prepared in the same manner were respectively added to the donor side. An isotonic 10 mM potassium dihydrogen phosphate solution was used on the receptor side, and the cell temperature was 37°C. The receptor solution was collected over time, and the concentration of dantrolene sodium in the sample solution and the example solution was measured by high performance liquid chromatography (HP
The cumulative skin permeation amount of dantrolene sodium (DN) after 32 hours (unit * ng/sq-c) was measured by LC).
m ) was determined, and the transmittance (the magnification of the example when Comparative Example 3 is set to 1) was determined.
実験結果を下表に示す。The experimental results are shown in the table below.
以上の実験からも明らかなように、エイシン及ヒエステ
ル類を加えないプロピレングリコール単独系、エイシン
を加えないプロピレングリコールエステル類複合系、エ
ステル類を加えないエイシン−プロピレングリコール複
合系（なお１表には示さなかったが、プロピレングリコ
ールな加工ないエイシン単独系もエイシン−エステル類
複合系もダロントレンナトリウム累積透過量はほとんど
ない）のうち、最も皮膚透過効果を発揮する比較例３の
エイシン−プロピレングリコール複合系に比較して２本
発明経皮吸収促進剤は全（予想外の顕著な経皮吸収促進
効果を示し、その効果は水の入って系でも顕著なのでパ
ップ剤のような含水系で使用したとしても実用的な経皮
吸収促進効果を達成できる。表には示さなかったが、イ
ソニコチン酸メチル、ニコチン酸ベンジルでも同様の結
果を示した。As is clear from the above experiments, the propylene glycol single system without the addition of Eishin and hisesters, the propylene glycol ester complex system without the addition of Eishin, and the Eisin-propylene glycol complex system without the addition of esters (Table 1) Although not shown, the Eisin-propylene glycol complex of Comparative Example 3 exhibits the most skin permeation effect among the Eishin single system without propylene glycol processing and the Eisin-ester complex system that have almost no cumulative permeation amount of Darontrene sodium. The transdermal absorption enhancer of the present invention exhibited an unexpectedly remarkable effect on promoting transdermal absorption compared to other systems, and this effect was noticeable even in water-containing systems, so it was used in water-containing systems such as poultices. Although not shown in the table, methyl isonicotinate and benzyl nicotinate also showed similar results.
実験例 ２． 塩酸インデロキサジンの皮膚透過試験（
ｉｎ Ｖｉｔｒｏ）
薬物として塩酸インデロキサジンを用い、塩酸インデロ
キサジンの溶剤としてエタノールを用いそれぞれの使用
量をこの系に好適な量に設定し。Experimental example 2. Skin permeation test of inderoxazine hydrochloride (
In Vitro) Inderoxazine hydrochloride was used as the drug, and ethanol was used as the solvent for inderoxazine hydrochloride, and the amounts of each were set to amounts suitable for this system.
皮膚透過量を累積８時間で求めた他は実験例１と同様に
調製、試験を行った。なお、比較例４〜７の調製は下表
の配合量で後記実施例７と同様にして行った。The preparation and test were conducted in the same manner as in Experimental Example 1, except that the amount of skin permeation was determined over a cumulative 8 hours. In addition, Comparative Examples 4 to 7 were prepared in the same manner as in Example 7 described later using the amounts shown in the table below.
その結果を下表に示す。The results are shown in the table below.
この表から明らかのように、グロピレングリコール単独
系、エイシン−プロピレン複合系に比較して１本発明経
皮吸収促進組成物が顕著な効果を発揮する。表には示さ
なかったが、インニコチン酸エチル、イソニコチン酸ｎ
−フチルウニコチン酸ｎ−ブチルについても同様な効
果が認められた。As is clear from this table, the transdermal absorption promoting composition of the present invention exhibits a remarkable effect compared to the glopylene glycol single system and the Eisin-propylene composite system. Although not shown in the table, ethyl innicotinate, isonicotinic acid n
Similar effects were observed for n-butyl -phthyluninicotinate.
実験 ３．ダントロレンナトリウム ゲル製剤のモルモ
ット皮膚透過性試験（ｉｎ Ｖｉｔｒｏ）コール２０ｇ
を良（混合し、これに５％濃度のダントロレンナトリウ
ムのマクロゴール４００溶１２０ｇを攪拌上少量づつ添
加する。次いでエイシン５ｇを加え良く混合して試料と
する。Experiment 3. Dantrolene sodium gel formulation guinea pig skin permeability test (in vitro) Cole 20g
Mix well and add 120 g of Macrogol 400 solution of 5% concentration dantrolene sodium little by little while stirring. Next, add 5 g of Eisin and mix well to prepare a sample.
（実験方法）
試料溶液及び実施例溶液に代えて、それぞれ試料ゲル（
比較例８）、実施例９及び１０のゲル製剤ヲ用い、２４
時間後のダントロレン累積皮膚透過量（ｎｇ／ｃｒｎ２
）から比較例８を１としたときの透過率を求めた他は、
実験１の方法と同様にした。(Experimental method) Sample gel (
Comparative Example 8), using the gel formulations of Examples 9 and 10, 24
Cumulative skin permeation amount of dantrolene after hours (ng/crn2
), except that the transmittance was determined when Comparative Example 8 was set to 1.
The method was the same as in Experiment 1.
実験結果を下表に示す。The experimental results are shown in the table below.
第３表 プロピレングリコール含有水性ゲル基剤系にお
けるダントロレンナトリウムのモルモット皮膚透過性（
ｉｎ Ｖｉｔｒｏ）この表からも明らかなように、エス
テル類またはＤＥＥＴを加えないエイゾンーグロビレン
グリコール複合系に比較して、イソニコチン酸ｎ−ブチ
ルなどのエステル類やＤＥＥＴを加えた本発明経皮吸収
促進組成物を含有するゲル製剤が、相乗的に高いダント
ロレンナトリウムの経皮吸収促進効果を奏する。Table 3 Guinea pig skin permeability of dantrolene sodium in propylene glycol-containing aqueous gel base system (
(in vitro) As is clear from this table, compared to the Azon-globylene glycol complex system that does not contain esters or DEET, the transdermal system of the present invention that contains esters such as n-butyl isonicotinate and DEET A gel preparation containing an absorption-promoting composition exhibits a synergistically high transdermal absorption-promoting effect of dantrolene sodium.
実験 ４． ラット筋肉白濃度測定
ラット筋肉的濃度測定法
前日剪毛したＷｉｓｔａｒ系雄性ラットの後肢部と６ｃ
ｍ”に裁断したパップ剤（実施例１２）を貼付し、３゜
６、１２．１８および２４時間後に直下の筋肉を摘出し
。Experiment 4. Rat muscle white density measurement Rat muscle density measurement method Hind limbs and 6c of male Wistar rats shaved the day before
A poultice (Example 12) cut into pieces of m" was applied, and the muscle immediately below was removed at 3.6, 12.18 and 24 hours later.
標本とした。It was used as a specimen.
標本はメタノールとホモジネートした後、遠心分離し、
上澄液を減圧乾固させ、含水アセトニトリルで抽出後、
ダントロレンナトリウム量を高速液体クロマトグラフィ
ー（ＨＰＬＣ）で測定した。The specimen was homogenized with methanol and then centrifuged.
After drying the supernatant under reduced pressure and extracting with aqueous acetonitrile,
The amount of dantrolene sodium was measured by high performance liquid chromatography (HPLC).
結果を下表に示す。The results are shown in the table below.
第、１表
パップ剤（実施例１２）貼付後のラット時間
筋肉内濃度（ｎｇ／ｇ筋肉）５６７
９８６
１２ ６８５
１８ ２５９
２４ ２３２
この表からも明らかなように、ゲル製剤より拡散性の劣
るパップ剤において９本発明の吸収促進組成物含有パッ
プ剤から、ダントロレンナトリウムが筋肉に送達されそ
の筋肉内濃度はきわめて高い。Table 1 Rat time after application of poultice (Example 12)
Intramuscular concentration (ng/g muscle) 567 986 12 685 18 259 24 232 As is clear from this table, in the poultices with poorer dispersibility than the gel preparations, dantrolene Sodium is delivered to the muscles and its intramuscular concentrations are extremely high.
（実施例） 以下実施例を掲記し１本発明を更に詳細に説明する。(Example) The present invention will be explained in more detail below with reference to Examples.
実施例 １゜
ダントロレンナトリウム２部を、マクロゴール４００に
６０℃で加温溶解した後、室温に戻しこれにプロピレン
グリコール５０部を添加してよ（混合し。Example 1: Dissolve 2 parts of dantrolene sodium in Macrogol 400 by heating at 60°C, return to room temperature, and add 50 parts of propylene glycol to the solution (mix).
これに更にエイシン１０部、イソニコチン酸エチル１０
部を添加後よく混合して溶液（全量１００ｇ ）を得た
。In addition to this, 10 parts of Eisin, 10 parts of ethyl isonicotinate
After addition, the mixture was thoroughly mixed to obtain a solution (total amount: 100 g).
実施例 ２゜
イソニコチン酸エチルに代えてイソニコチン酸ｎ−ブチ
ルを使用した他は実施例１と同様にして溶液を得た。Example 2 A solution was obtained in the same manner as in Example 1, except that n-butyl isonicotinate was used in place of ethyl isonicotinate.
実施例 ３
イソニコチン酸エチルに代えてニコチン酸ｎ−ブチルを
使用した他は実施例１と同様にして溶液を得た。Example 3 A solution was obtained in the same manner as in Example 1 except that n-butyl nicotinate was used instead of ethyl isonicotinate.
実施例４゜
イソニコチン酸エチルに代えジエチルセバケートを使用
した他は実施例１と同様にして溶液を得た。Example 4 A solution was obtained in the same manner as in Example 1, except that diethyl sebacate was used in place of ethyl isonicotinate.
実施例 ５゜ ダントロレンナトリウム２部、エイシン１０部。Example 5゜ 2 parts of Dantrolene Sodium, 10 parts of Eishin.
イソニコチン酸エチル１０部を混合し、これにグロビレ
ングリコール５０部、精製水２５部、及びスノ（ン６０
（Ｓｐａｎ ６０ 、商品名、花王アトラス社製）３
部を加えて均一に乳化させて乳液を得た。Mix 10 parts of ethyl isonicotinate, add 50 parts of globylene glycol, 25 parts of purified water, and 60 parts of
(Span 60, product name, manufactured by Kao Atlas) 3
of the mixture was added and uniformly emulsified to obtain a milky lotion.
実施例 ６゜
プロピレングリコールな４０部とし、ポリエチレングリ
コールを３８部とした他は実施例２と同様にして溶液を
得た。Example 6 A solution was obtained in the same manner as in Example 2, except that 40 parts of propylene glycol and 38 parts of polyethylene glycol were used.
実施例 ７゜
塩酸インデロキサジン５部をプロピレングリコール５部
に加温溶解し１次いで、エイシン５部及びジエチルセパ
ケート５０部を添加し、これにエタノール３５部を加え
てよく混合して溶液（全量１００ｇ）を得た。Example 7 5 parts of inderoxazine hydrochloride were dissolved in 5 parts of propylene glycol by heating, then 5 parts of Eisin and 50 parts of diethyl sepacate were added, and 35 parts of ethanol was added thereto and mixed well to form a solution ( A total amount of 100 g) was obtained.
実施例 ８゜
エタノールを３０部、エイシンを１０部とした他は、実
施例７と同様にして溶液を得た。Example 8 A solution was obtained in the same manner as in Example 7, except that 30 parts of ethanol and 10 parts of Eishin were used.
実施例 ９．（ゲル）
１％カーボポー／９９３４（商品名グツドリッチケミカ
ル社製カルボキシビニルポリマー）５０ｇ及びプロピレ
ングリコール２０ｇを良く混合し、これに５％濃度のダ
ントロレンナトリウムのマクロゴール４００溶液２０ｇ
を攪拌上少量づつ添加する。次いでエイシン５ｇ及びイ
ソニコチン酸ｎ−ブチル５ｇを加え良く混合してゲル製
剤を得た。Example 9. (Gel) 50 g of 1% Carbopo/9934 (trade name: carboxyvinyl polymer manufactured by Gutdrich Chemical Co.) and 20 g of propylene glycol were mixed well, and to this was added 20 g of a 5% concentration of dantrolene sodium in Macrogol 400 solution.
Add it little by little while stirring. Next, 5 g of Eisin and 5 g of n-butyl isonicotinate were added and mixed well to obtain a gel preparation.
実施例 １０．（ゲル）
イソニコチン酸ｎ−ブチルをＤＥＥＴに代えた他は実施
例１０と同様にしてゲル製剤を得た。Example 10. (Gel) A gel preparation was obtained in the same manner as in Example 10, except that n-butyl isonicotinate was replaced with DEET.
実施例 １１．（パップ剤）
ゼラチン３０部及びクエン酸５部を、精製水１７９部と
濃度グリセリン４０部の混液で溶解、練合し。Example 11. (Poultice) 30 parts of gelatin and 5 parts of citric acid were dissolved and kneaded in a mixed solution of 179 parts of purified water and 40 parts of concentrated glycerin.
これにプロピレングリコール２０部及び防腐剤２．５部
を溶解した溶液を添加する。さらにエイシン２０部、イ
ソニコチン酸エチル２０部、防腐剤３．５部。A solution of 20 parts of propylene glycol and 2.5 parts of preservative is added to this. Additionally, 20 parts of Eishin, 20 parts of ethyl isonicotinate, and 3.5 parts of preservative.
界面活性剤３０部（ツイーン ６０：１５部、ス・くン
０６０：１５部）と酸化亜鉛６部と精製水２０部の分散
物との混合物を添加してよ（練合して、ペースト状物ヲ
得た。ついで、カルボキシメチルセルロースナトリウム
１０部、ポリアクリル酸ナトリウム３０ｇをプロピレン
グリコール１３９部に分散させた混合物を添加後よく練
合する。さらにメチルビニルエーテル／無水マレイン酸
共重合体（ＧＡＦ商品商品名ガントレノンアン５部を精
製水６０部に溶解した液を添加して練合せ次いでエイシ
ン８０部、イソニコチン酸エチル８０部を添加する。ダ
ントロレンナトリウム２０部をマクロゴール４００ ２
５部とプロピレングリコール２５部に混合し、６０℃で
加温処理した液を添加して練合する。最後に天然ゴムラ
テックス１２０部及び濃グリセリン２０部の混合物を添
加し、６０℃で均一に練合した後ネルに展延し、その表
面にプラスチックフィルムを貼合して所定の大きさに裁
断する。Add a mixture of 30 parts of surfactant (Tween 60:15 parts, Su-Kun 060:15 parts) and a dispersion of 6 parts of zinc oxide and 20 parts of purified water (knead to form a paste). Then, a mixture of 10 parts of sodium carboxymethyl cellulose and 30 g of sodium polyacrylate dispersed in 139 parts of propylene glycol was added and kneaded thoroughly. Furthermore, methyl vinyl ether/maleic anhydride copolymer (GAF product) was added. A solution prepared by dissolving 5 parts of dantrolene sodium in 60 parts of purified water is added and kneaded. Then, 80 parts of Eisin and 80 parts of ethyl isonicotinate are added. 20 parts of dantrolene sodium is added to Macrogol 400 2
5 parts of propylene glycol and 25 parts of propylene glycol, a solution heated at 60° C. is added and kneaded. Finally, a mixture of 120 parts of natural rubber latex and 20 parts of concentrated glycerin is added and kneaded uniformly at 60°C, then spread on flannel, a plastic film is pasted on the surface and cut into a predetermined size. .
実施例 １２．（バッグ剤）
ゼラチン３０部、及びクエン酸５部を、精製水１３３部
と濃グリセリン５０部及びプロピレングリコール４０部
で溶解、練合し、これにプロピレングリコール２０部及
び防腐剤２．５部を溶解した溶液を添加する。さらにエ
イシン２０部、インニコチン酸エチル２０部、防腐剤３
．５部、界面活性剤６５部（ツイーン６０°１５部、ス
パン６０°５０部）と酸化亜鉛６部と精製水２０部との
分散物との混合物を添加してよく練合してペースト状物
を得た。ついで、カルボヤメンヤ。−７ナトリウ、□。Example 12. (Bag agent) 30 parts of gelatin and 5 parts of citric acid were dissolved and kneaded with 133 parts of purified water, 50 parts of concentrated glycerin, and 40 parts of propylene glycol, and 20 parts of propylene glycol and 2.5 parts of preservative were added thereto. Add dissolved solution. Additionally, 20 parts of Eishin, 20 parts of ethyl innicotinate, and 3 parts of preservative.
．． 5 parts, 65 parts of surfactant (15 parts of Tween 60°, 50 parts of Span 60°), a mixture of a dispersion of 6 parts of zinc oxide, and 20 parts of purified water were added and kneaded well to form a paste. I got it. Next, Karboyamenya. -7 Natoriu, □.
部、ポリアクリル酸ナトリウム３０ｇをプロピレングリ
コール１４０部に分散させた混合物を添加後、よ（練合
する。After adding a mixture of 30 g of sodium polyacrylate dispersed in 140 parts of propylene glycol, the mixture was kneaded.
次いでエイシン８０部、イソニコチン酸エチル８０部、
ダントロレンナトリウム２０部をプロピレングリコール
８０部に混合し、均一に練合する。Next, 80 parts of Eishin, 80 parts of ethyl isonicotinate,
20 parts of dantrolene sodium is mixed with 80 parts of propylene glycol and kneaded uniformly.
さらに、メチルビニルエーテル／無水マレイン酸共重合
体（ＧＡＦ社製社製品名ガングレッツアン５部を精製水
６０部に溶解した液を添加して練合した後、ネルに展延
し、その表面にプラスチックフィルムを貼合して、所定
の大きさに裁断する。Furthermore, a solution prepared by dissolving 5 parts of methyl vinyl ether/maleic anhydride copolymer (GAF Co., Ltd. product name: Gangretzan in 60 parts of purified water) was added and kneaded, and then spread on a flannel and coated on its surface. Laminate plastic film and cut to desired size.
Claims (1)
ンと、 （２）プロピレングリコールと、 （３）ニコチン酸エステル、イソニコチン酸エステル、
セバシン酸ジエステル及びＮ，Ｎ−ジエチル−ｍ−トル
アミドからなる群よ り選択された一種又は二種以上とを、 含有することを特徴とする経度吸収促進組成物。 ［２］薬物と、 （１）１−ドデシルアザシクロヘプタン−２−オンと、 （２）プロピレングリコールと、 （３）ニコチン酸エステル、イソニコチン酸エステル、
セバシン酸ジエステル及びＮ，Ｎ−ジエチル−ｍ−トル
アミドからなる群よ り選択された一種又は二種以上とを、 含有することを特徴とする薬物の経皮吸収性を著しく促
進させた外用剤。[Scope of Claims] [1] (1) 1-dodecyl azacycloheptan-2-one, (2) propylene glycol, (3) nicotinic acid ester, isonicotinic acid ester,
1. A longitudinal absorption promoting composition comprising one or more selected from the group consisting of sebacic acid diester and N,N-diethyl-m-toluamide. [2] Drug, (1) 1-dodecyl azacycloheptan-2-one, (2) Propylene glycol, (3) Nicotinic acid ester, isonicotinic acid ester,
1. An external preparation which significantly promotes transdermal absorption of a drug, characterized by containing one or more selected from the group consisting of sebacic acid diester and N,N-diethyl-m-toluamide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16460189A JPH0331217A (en) | 1989-06-27 | 1989-06-27 | Percutaneous absorption promoting composition and external preparation containing same composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16460189A JPH0331217A (en) | 1989-06-27 | 1989-06-27 | Percutaneous absorption promoting composition and external preparation containing same composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0331217A true JPH0331217A (en) | 1991-02-12 |
Family
ID=15796282
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16460189A Pending JPH0331217A (en) | 1989-06-27 | 1989-06-27 | Percutaneous absorption promoting composition and external preparation containing same composition |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0331217A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001523273A (en) * | 1998-02-09 | 2001-11-20 | マクロケム・コーポレーシヨン | Antifungal nail lacquer and method of using same |
-
1989
- 1989-06-27 JP JP16460189A patent/JPH0331217A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001523273A (en) * | 1998-02-09 | 2001-11-20 | マクロケム・コーポレーシヨン | Antifungal nail lacquer and method of using same |
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