CN108495654A - 外用液剂 - Google Patents
外用液剂 Download PDFInfo
- Publication number
- CN108495654A CN108495654A CN201680079721.3A CN201680079721A CN108495654A CN 108495654 A CN108495654 A CN 108495654A CN 201680079721 A CN201680079721 A CN 201680079721A CN 108495654 A CN108495654 A CN 108495654A
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- Prior art keywords
- liquid
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- effect medicine
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- 239000007788 liquid Substances 0.000 title claims abstract description 54
- 239000003814 drug Substances 0.000 claims abstract description 44
- 230000003153 cholinolytic effect Effects 0.000 claims abstract description 42
- 150000002148 esters Chemical class 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000006210 lotion Substances 0.000 claims description 43
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical group C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 claims description 32
- 229960005434 oxybutynin Drugs 0.000 claims description 27
- 150000003839 salts Chemical class 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 13
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical group C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims description 6
- 229940031569 diisopropyl sebacate Drugs 0.000 claims description 6
- XFKBBSZEQRFVSL-UHFFFAOYSA-N dipropan-2-yl decanedioate Chemical compound CC(C)OC(=O)CCCCCCCCC(=O)OC(C)C XFKBBSZEQRFVSL-UHFFFAOYSA-N 0.000 claims description 6
- 239000001540 sodium lactate Substances 0.000 claims description 6
- 229940005581 sodium lactate Drugs 0.000 claims description 6
- 235000011088 sodium lactate Nutrition 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 229940001447 lactate Drugs 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- MUXOBHXGJLMRAB-UHFFFAOYSA-N Dimethyl succinate Chemical compound COC(=O)CCC(=O)OC MUXOBHXGJLMRAB-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims 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 claims description 4
- 229940095064 tartrate Drugs 0.000 claims description 4
- RDOFJDLLWVCMRU-UHFFFAOYSA-N Diisobutyl adipate Chemical compound CC(C)COC(=O)CCCCC(=O)OCC(C)C RDOFJDLLWVCMRU-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 229940031769 diisobutyl adipate Drugs 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- ZDQWESQEGGJUCH-UHFFFAOYSA-N Diisopropyl adipate Chemical compound CC(C)OC(=O)CCCCC(=O)OC(C)C ZDQWESQEGGJUCH-UHFFFAOYSA-N 0.000 claims 1
- 229960000583 acetic acid Drugs 0.000 claims 1
- 238000012360 testing method Methods 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 210000003491 skin Anatomy 0.000 description 14
- 235000019441 ethanol Nutrition 0.000 description 10
- 238000000034 method Methods 0.000 description 8
- 230000035900 sweating Effects 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 7
- 210000003780 hair follicle Anatomy 0.000 description 7
- 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 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229940031578 diisopropyl adipate Drugs 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- -1 quinindium Chemical compound 0.000 description 6
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 5
- QCHFTSOMWOSFHM-UHFFFAOYSA-N SJ000285536 Natural products C1OC(=O)C(CC)C1CC1=CN=CN1C QCHFTSOMWOSFHM-UHFFFAOYSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 229960001416 pilocarpine Drugs 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940022663 acetate Drugs 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 150000001991 dicarboxylic acids Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000004744 fabric Substances 0.000 description 3
- 210000004209 hair Anatomy 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- AXOIZCJOOAYSMI-UHFFFAOYSA-N succinylcholine Chemical compound C[N+](C)(C)CCOC(=O)CCC(=O)OCC[N+](C)(C)C AXOIZCJOOAYSMI-UHFFFAOYSA-N 0.000 description 3
- WYDUSKDSKCASEF-LJQANCHMSA-N (1s)-1-cyclohexyl-1-phenyl-3-pyrrolidin-1-ylpropan-1-ol Chemical compound C([C@](O)(C1CCCCC1)C=1C=CC=CC=1)CN1CCCC1 WYDUSKDSKCASEF-LJQANCHMSA-N 0.000 description 2
- IVQOFBKHQCTVQV-UHFFFAOYSA-N 2-hydroxy-2,2-diphenylacetic acid 2-(diethylamino)ethyl ester Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCCN(CC)CC)C1=CC=CC=C1 IVQOFBKHQCTVQV-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229930003347 Atropine Natural products 0.000 description 2
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WMSYWJSZGVOIJW-ONUALHDOSA-L Mivacurium chloride Chemical compound [Cl-].[Cl-].C([C@@H]1C2=CC(OC)=C(OC)C=C2CC[N+]1(C)CCCOC(=O)CC/C=C/CCC(=O)OCCC[N+]1(CCC=2C=C(C(=CC=2[C@H]1CC=1C=C(OC)C(OC)=C(OC)C=1)OC)OC)C)C1=CC(OC)=C(OC)C(OC)=C1 WMSYWJSZGVOIJW-ONUALHDOSA-L 0.000 description 2
- 239000004909 Moisturizer Substances 0.000 description 2
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- HWHLPVGTWGOCJO-UHFFFAOYSA-N Trihexyphenidyl Chemical compound C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 HWHLPVGTWGOCJO-UHFFFAOYSA-N 0.000 description 2
- 229960000396 atropine Drugs 0.000 description 2
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 2
- 229960001498 benactyzine Drugs 0.000 description 2
- GIJXKZJWITVLHI-PMOLBWCYSA-N benzatropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(C=1C=CC=CC=1)C1=CC=CC=C1 GIJXKZJWITVLHI-PMOLBWCYSA-N 0.000 description 2
- 229960001081 benzatropine Drugs 0.000 description 2
- 229960003003 biperiden Drugs 0.000 description 2
- YSXKPIUOCJLQIE-UHFFFAOYSA-N biperiden Chemical compound C1C(C=C2)CC2C1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 YSXKPIUOCJLQIE-UHFFFAOYSA-N 0.000 description 2
- HOZOZZFCZRXYEK-GSWUYBTGSA-M butylscopolamine bromide Chemical compound [Br-].C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3[N+]([C@H](C2)[C@@H]2[C@H]3O2)(C)CCCC)=CC=CC=C1 HOZOZZFCZRXYEK-GSWUYBTGSA-M 0.000 description 2
- 229960002677 darifenacin Drugs 0.000 description 2
- HXGBXQDTNZMWGS-RUZDIDTESA-N darifenacin Chemical compound C=1C=CC=CC=1C([C@H]1CN(CCC=2C=C3CCOC3=CC=2)CC1)(C(=O)N)C1=CC=CC=C1 HXGBXQDTNZMWGS-RUZDIDTESA-N 0.000 description 2
- 229960001908 dexetimide Drugs 0.000 description 2
- LQQIVYSCPWCSSD-HSZRJFAPSA-N dexetimide Chemical compound O=C1NC(=O)CC[C@@]1(C=1C=CC=CC=1)C1CCN(CC=2C=CC=CC=2)CC1 LQQIVYSCPWCSSD-HSZRJFAPSA-N 0.000 description 2
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 229960004428 doxacurium Drugs 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 210000002683 foot Anatomy 0.000 description 2
- SQKXYSGRELMAAU-UHFFFAOYSA-N imidafenacin Chemical compound CC1=NC=CN1CCC(C(N)=O)(C=1C=CC=CC=1)C1=CC=CC=C1 SQKXYSGRELMAAU-UHFFFAOYSA-N 0.000 description 2
- 229950005396 imidafenacin Drugs 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
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- OEXHQOGQTVQTAT-JRNQLAHRSA-N ipratropium Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 OEXHQOGQTVQTAT-JRNQLAHRSA-N 0.000 description 2
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- RMHMFHUVIITRHF-UHFFFAOYSA-N pirenzepine Chemical compound C1CN(C)CCN1CC(=O)N1C2=NC=CC=C2NC(=O)C2=CC=CC=C21 RMHMFHUVIITRHF-UHFFFAOYSA-N 0.000 description 2
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- YXRDKMPIGHSVRX-OOJCLDBCSA-N rocuronium Chemical compound N1([C@@H]2[C@@H](O)C[C@@H]3CC[C@H]4[C@@H]5C[C@@H]([C@@H]([C@]5(CC[C@@H]4[C@@]3(C)C2)C)OC(=O)C)[N+]2(CC=C)CCCC2)CCOCC1 YXRDKMPIGHSVRX-OOJCLDBCSA-N 0.000 description 2
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- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 description 2
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- XTJFFFGAUHQWII-UHFFFAOYSA-N Dibutyl adipate Chemical compound CCCCOC(=O)CCCCC(=O)OCCCC XTJFFFGAUHQWII-UHFFFAOYSA-N 0.000 description 1
- VIZORQUEIQEFRT-UHFFFAOYSA-N Diethyl adipate Chemical compound CCOC(=O)CCCCC(=O)OCC VIZORQUEIQEFRT-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明提供一种即便含有高浓度的抗胆碱作用药但“粘腻感”仍然小的外用液剂。外用液剂包含水、抗胆碱作用药及二羧酸酯，且抗胆碱作用药的含量以外用液剂的总质量为基准计为10质量％～20质量％。
Description
【技术领域】
本发明涉及一种外用液剂。
【现有技术】
作为多汗症的治疗方法，提出有给药包含奥昔布宁(Oxybutynin)等抗胆碱作用药的外用组合物的方法(专利文献1及2)。
[现有技术文献]
[专利文献]
专利文献1：美国专利申请公开第2014/0037713号说明书
专利文献2：国际公开第2007/046102号
【发明内容】
[发明所要解决的问题]
本发明人等人新发现了如下问题：如果增加外用液剂中的抗胆碱作用药的含量，则存在产生由抗胆碱作用药引起的“粘腻感”，外用液剂的使用感降低的倾向。因此，本发明的目的在于提供一种即便含有高浓度的抗胆碱作用药但“粘腻感”也较小的外用液剂。
[解决问题的技术手段]
本发明人等人发现通过在含有高浓度的抗胆碱作用药的外用液剂中含有二羧酸酯而抑制由抗胆碱作用药引起的“粘腻感”，从而完成本发明。
即，本发明提供一种外用液剂，其包含水、抗胆碱作用药及二羧酸酯，且抗胆碱作用药的含量以上述外用液剂的总质量为基准计为10质量％～20质量％。上述抗胆碱作用药可以为奥昔布宁或其药学上可接受的盐。上述抗胆碱作用药的含量以上述外用液剂的总质量为基准计可为15质量％～20质量％。上述二羧酸酯可为选自由己二酸二异丙酯、癸二酸二乙酯、癸二酸二异丙酯、己二酸二异丁酯、琥珀酸二甲酯及苯二甲酸二丁酯所组成的群中的1种以上的化合物。上述抗胆碱作用药与上述二羧酸酯的质量比可为1：0.25～1：0.75。上述二羧酸酯的含量以上述外用液剂的总质量为基准计可为2.5质量％～15质量％。上述外用液剂可进一步包含选自由乳酸盐、酒石酸盐、乙酸盐及磷酸盐所组成的群中的1种以上的盐。上述盐可为乳酸钠。上述外用液剂可为洗液剂形。上述外用液剂可为多汗症治疗用。
[发明的效果]
本发明的外用液剂通过包含二羧酸酯而抑制由抗胆碱作用药引起的“粘腻感”。
【图式简单说明】
图1是表示考察洗剂中的盐对奥昔布宁在猪毛囊中的蓄积性产生的影响的试验的结果的图。
图2是表示考察洗剂中的奥昔布宁的浓度对发汗抑制作用产生的影响的试验的结果的图。
图3是表示考察洗剂中的奥昔布宁的浓度对发汗抑制作用产生的影响的试验的结果的图。
图4是表示考察洗剂中的奥昔布宁的浓度对奥昔布宁在猪毛囊中的蓄积性产生的影响的试验的结果的图。
【实施方式】
以下揭示一种实施方式而详细说明本发明。
本发明的一种实施方式为一种外用液剂，其包含水、抗胆碱作用药及二羧酸酯，且抗胆碱作用药的含量，以上述外用液剂的总质量为基准计为10质量％～20质量％。上述外用液剂可用于多汗症治疗。
抗胆碱作用药为具有抗胆碱作用的任意药物即可，并无特别限定，例如可列举：奥昔布宁、咪达那新(Imidafenacin)、妥斯平(Trospium)、托特罗定(Tolterodine)、格隆溴铵(glycopyrrolate)、丙胺太林(Propantheline)、苯扎托品(benztropine)、阿托品(atropine)、后马托品(homatropine)、托品卡胺、贝那替秦(benactyzine)、比哌立登(Biperiden)、莨菪碱(scopolamine)、丁溴东莨菪碱(scopolamine butylbromide)、环戊通(cyclopentolate)、达非那新(Darifenacin)、右苄替米特(dexetimide)、双环维林、依美铵(emepronium)、六氢硅地芬尼多(hexahydro-sila-difenidol)、奥替铵(octilonium)、邻甲苯海那明(orphenadrine)、奥芬铵(oxyphenonium)、哌仑西平(pirenzepine)、普环啶(procyclidine)、格罗铵(darotropium)、异丙托铵(ipratropium)、噻托铵(tiotropium)、氧托铵(oxitropium)、奎尼丁、苯海索(trihexyphenidyl)、美维库铵(mivacurium)、阿曲库铵(atracurium)、多沙氯铵(doxacurium)、顺式阿曲库铵(Cisatracurium)、维库铵(vecuronium)、罗库铵(rocuronium)、泮库铵(pancuronium)、筒箭毒碱(tubocurarine)、加拉明(gallamine)、哌库铵(pipecuronium)、咪噻芬(trimetaphan)、琥珀酰胆碱(succinylcholine)、丁二酰胆碱(suxamethonium)、十烃季铵及六羟季铵。抗胆碱作用药优选为奥昔布宁或其药学上可接受的盐。作为奥昔布宁药学上可接受的盐，可列举盐酸奥昔布宁等。
抗胆碱作用药的含量，以外用液剂的总质量为基准计为10质量％～20质量％。抗胆碱作用药的含量，以上述外用液剂的总质量为基准计可为15质量％～20质量％。抗胆碱作用药的含量的下限值以上述外用液剂的总质量为基准计可为10、12、15或18质量％。
二羧酸酯降低上述外用液剂的粘性而抑制“粘腻感”。作为二羧酸酯的具体例，可列举：己二酸二异丙酯、癸二酸二乙酯、癸二酸二异丙酯、琥珀酸二甲酯、己二酸二丁酯、己二酸二异丁酯、己二酸二辛酯、癸二酸二辛酯、苯二甲酸二乙酯及苯二甲酸二丁酯。二羧酸酯的含量，以上述外用液剂的总质量为基准计可为2.5质量％～15质量％或5质量％～15质量％。二羧酸酯的含量的下限值以上述外用液剂的总质量为基准计可为1、2.5、3、3.75、5或8质量％。二羧酸酯的含量的上限值以上述外用液剂的总质量为基准计可为10、11.25、12或15质量％。通过二羧酸酯的含量的上述下限值与上述上限值的任意组合，可进一步减轻由抗胆碱作用药引起的“粘腻感”。
抗胆碱作用药与二羧酸酯的质量比可为1：0.25～1：0.75。抗胆碱作用药与二羧酸酯的质量比的下限值即相对于每单位质量的二羧酸酯的抗胆碱作用药的质量的下限值可为1：0.75、1：0.70、1：0.65、1：0.6、1：0.55或1：0.5。抗胆碱作用药与二羧酸酯的质量比的上限值即相对于每单位质量的二羧酸酯的抗胆碱作用药的质量的上限值可为1：0.05、1：0.15、1：0.25、1：0.3、1：0.33、1：0.35或1：0.4。通过抗胆碱作用药与二羧酸酯的质量比的上述下限值与上述上限值的任意组合，可进一步减轻由抗胆碱作用药引起的“粘腻感”。
外用液剂中的水是用以使抗胆碱药及二羧酸酯以及其他成分溶解或分散的介质。水的含量，以外用液剂的总质量为基准计例如可为10质量％～99质量％。
通过使外用液剂进一步包含选自由乳酸盐、酒石酸盐、乙酸盐及磷酸盐所组成的群中的1种以上的盐，抗胆碱作用药于皮肤的附属器官中的蓄积性提高。通过提高上述蓄积性，可于抑制由给药抗胆碱作用药所引发的口渴等副作用的同时治疗多汗症。盐可为无水物或水合物。乳酸可为L体及D体的任一者，也可为这些的任意的混合物。酒石酸可为L体、D体及内消旋体的任一者，也可为这些的任意的混合物。作为盐，例如可列举：与钠、钾及锂等一价金属的盐，与钙及镁等二价金属的盐，与铝等三价金属的盐，以及与氨、乙二胺、三乙基胺、二乙醇胺、三乙醇胺及葡甲胺等胺化合物的盐。就提高抗胆碱作用药于皮肤的附属器官中的蓄积性的观点而言，盐优选为乳酸盐，更优选为乳酸钠。
上述盐的含量，以外用液剂的总质量为基准计例如可为0.1质量％～10质量％。外用液剂中的抗胆碱作用药与上述盐的摩尔比例如可为1：0.5～1：2的范围。
外用液剂中除了上述成分以外还可以包含低级醇、表面活性剂、保存稳定剂、油脂、溶解剂、填充剂、保湿剂、pH调节剂、浸透压调节剂、增粘剂、清凉剂、收敛药及血管收缩药等。
低级醇提高抗胆碱作用药的溶解性及分散性，提高抗胆碱作用药于皮肤上的分布性。作为低级醇的具体例，可列举：甲醇、乙醇及异丙醇。低级醇的含量，以外用液剂的总质量为基准计例如可为0质量％～90质量％。
表面活性剂有助于使抗胆碱作用药乳化于水等介质中。作为表面活性剂的具体例，可列举：非离子性表面活性剂(聚山梨醇酯20、聚山梨醇酯80、聚山梨醇酯60、聚氧乙烯氢化蓖麻油20、聚氧乙烯氢化蓖麻油40及聚氧乙烯氢化蓖麻油60等)、离子性表面活性剂及两性表面活性剂。表面活性剂的含量，以外用液剂的总质量为基准计例如可为0质量％～10质量％。
作为保存稳定剂的具体例，可列举：对羟苯甲酸酯、异丙基甲基苯酚、苯氧基乙醇及瑞香草酚。
作为油脂及溶解剂的具体例，可列举：脂肪酸及脂肪族醇。
作为填充剂的具体例，可列举：无机粉体(滑石、蒙脱石、膨润石及高岭土等)及有机粉体。
作为保湿剂的具体例，可列举：多元醇、糖类、脲、凡士林及石蜡。
外用液剂的pH值可设为4.5～7.5的范围内。pH值的测定是依据日本药典第十六修订版的一般试验法的“2.54pH值测定法”使用复合玻璃电极进行。
外用液剂可为洗剂及擦剂等形态，另外，也可为收容于适宜容器(例如用以喷雾液剂的喷雾容器、用以涂抹液剂的容器及气溶胶剂容器等)内的涂抹剂及喷雾剂等形态。
外用液剂可通过将上述各成分进行混合、混和而制造。
外用液剂视需要摇晃容器而使各成分均质地混和后，涂抹、散布或喷洒至欲抑制发汗的皮肤部位，视需要涂开。
[实施例]
试验例1
依据表1的组成而制备洗剂，于被试验者(4名)的手掌涂抹500μL。双手相互搓擦而使洗剂于双手手掌上均匀地扩散开，以下述3个等级作为基准，对3分钟后的“粘腻感”的程度进行打分。
0：不感到粘腻
1：感到粘腻
2：感到非常粘腻
根据上述分数的平均值，以下述3个等级作为基准而评价粘腻程度。
○：平均值未达0.5
△：平均值为0.5以上且未达1.0
×：平均值为1.0以上
[表1]
| 参考例 | 1 | 2 | 3 | 4 |
| 盐酸奥昔布宁 | 8 | 10 | 15 | 20 |
| 乳酸钠 | 2.3 | 2.8 | 4.3 | 5.7 |
| 乙醇 | 40 | 40 | 40 | 40 |
| 纯化水 | 49.7 | 47.2 | 40.7 | 34.3 |
| 合计 | 100 | 100 | 100 | 100 |
将结果示于表2。若盐酸奥昔布宁的含量为10质量％以上则感到粘腻，若为15质量％以上则感到强的粘腻。
[表2]
| 参考例 | 1 | 2 | 3 | 4 |
| 平均值 | 0.25 | 0.75 | 1.75 | 2 |
| 评价 | 〇 | △ | × | × |
试验例2
依据表3的组成而制备洗剂，利用下述方法测定各洗剂的冲量值。冲量值越小则表示粘性越低。
1)将洗剂50μL注入至96孔盘内，于32℃下静置一晚使之干燥。
2)使质构分析仪的SUS制探针(直径5mm)抵接于已干燥的洗剂。
3)测定使探针以2mm/s的速度上升而离开洗剂时受到的力，算出该曲线下面积作为冲量值(g·s)。
[表3]
将结果示于表4。各洗剂的冲量值为经过3次测定所获得的平均值。可确认与其他洗剂相比，添加有月桂醇、油醇、聚桂醇、己二酸二异丙酯、癸二酸二乙酯、癸二酸二异丙酯、己二酸二异丁酯、琥珀酸二甲酯或苯二甲酸二丁酯的洗剂在经干燥时的冲量值较小，粘性降低。
[表4]
试验例3
依据表5的组成而制备洗剂，在被试验者(3名)的手掌涂抹300μL。比较例1、4、5及9以及实施例1～3中使用与试验例2相同的洗剂。双手相互搓擦而使洗剂于双手手掌上均匀地扩散开，以下述4个等级作为基准，对3分钟后的“粘腻感”的程度进行打分。
0：不感到粘腻
1：稍感粘腻
2：感到粘腻
3：感到非常粘腻
根据上述分数的平均值，以下述5个等级作为基准而评价粘腻程度。
◎：平均值未达0.1
○：平均值为0.1以上且未达1.0
△：平均值为1.0以上且未达2.0
×：平均值为2.0以上且未达3.0
××：平均值为3.0以上
[表5]
将结果示于表6。可确认与不含二羧酸酯的洗剂相比，添加有己二酸二异丙酯、癸二酸二乙酯或癸二酸二异丙酯的洗剂其粘腻感得到减轻。
[表6]
试验例4
使用试验例2及3的实施例1～9及比较例1的洗剂，利用下述方法评价奥昔布宁的保存稳定性。
1)量取100μL的洗剂，测定重量。
2)添加50mL的流动相并混合，利用高效液相色谱法(HPLC)测定各洗剂的奥昔布宁浓度。HPLC的条件如下所述。
流动相：0.1w/w％磷酸水溶液(包含0.5w/v％的十二烷基硫酸钠)：乙腈＝45：55(v/v)
流速：1.5mL/min
柱：TSKgel ODS-80Ts(Tosoh股份有限公司)
保留时间：10分钟
3)将洗剂于60℃下静置2周后的每单位重量的液体中的奥昔布宁含量相对于理论值的值(％)与初期的相对于理论值的值(％)进行比较。相对于初期的值为97.5％以上的情形时，将奥昔布宁的保存稳定性评价为良好。
将结果示于表7。添加有己二酸二异丙酯、癸二酸二乙酯或癸二酸二异丙酯的洗剂于60℃的环境下静置2周后，盐酸奥昔布宁的保存情况仍良好。另外，未添加二羧酸酯的比较例1中的盐酸奥昔布宁的保存情况也良好。
[表7]
试验例5
使用试验例3的比较例1及实施例4的洗剂，利用下述方法测定奥昔布宁的皮肤渗透性。
1)于使用皮刀采集的人皮肤表面的面积3cm2区域涂抹5μL的洗剂。
2)干燥数秒后，以皮肤的真皮侧成为受体层侧的方式将皮肤设置于Franz池。使用生理食盐水作为受体层。于设置皮肤后经过4、8、12、16、20及24小时的时间点对受体溶液进行采样。向所采集的溶液0.5mL中添加乙腈0.5mL并搅拌，进而进行离心分离而去除蛋白质，制成试验溶液。
3)在与试验例4相同的条件下利用HPLC测定试验溶液的奥昔布宁浓度。
4)根据所得的测定值而算出奥昔布宁每小时的皮肤渗透速度，取其最大值作为Jmax(μg/cm2/h)。另外，求出24小时的累积渗透量(μg/cm2)。
将结果示于表8。添加有己二酸二异丙酯的洗剂表现出与不含二羧酸酯的洗剂为相同程度的皮肤渗透性。
[表8]
试验例6
依据表9的组成而制备洗剂，以目视确认溶解状态。进而，在猪皮肤上涂抹洗剂，利用下述方法测定奥昔布宁于毛囊中的蓄积量。
1)对5cm2的轻轻刮除毛发后的猪皮肤涂抹20μL洗剂。个体数n＝3。
2)6小时后，使用消毒用酒精擦拭皮肤表面并使用磷酸缓冲液进行冲洗而去除皮肤表面所附着的奥昔布宁。
3)从皮肤采集对应于20根毛发的毛囊部分。
4)使用1mL萃取液从毛囊萃取奥昔布宁。使用试验例4的流动相作为萃取液。
5)利用HPLC测定奥昔布宁的浓度。HPLC的条件与试验例4相同。
[表9]
| 组合物 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| 奥昔布宁 | 4.54 | - | ||||||||
| 盐酸奥昔布宁 | - | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
| 氢氧化钠 | 0.51 | |||||||||
| 磷酸氢二钠 | 0.9 | |||||||||
| 乳酸钠 | 1.42 | |||||||||
| 乙酸钠 | 1.04 | |||||||||
| 反丁烯二酸二钠 | 1.02 | |||||||||
| 柠檬酸三钠 | 1.09 | |||||||||
| 苯甲酸钠 | 1.83 | |||||||||
| 酒石酸二钠-二水合物 | 2.92 | |||||||||
| 乙醇 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 | 40 |
| 其他 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
| 纯化水 | 55.26 | 54.8 | 52.49 | 53.9 | 53.38 | 58.76 | 53.78 | 53.71 | 52.97 | 51.88 |
| 合计 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
将结果示于表10及图1。包含磷酸盐、乳酸盐、乙酸盐或酒石酸盐的洗剂与不含这些盐的洗剂相比奥昔布宁在毛囊中的蓄积性提高。
[表10]
| 组合物 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| 溶解状态 | × | × | × | 〇 | 〇 | 〇 | 〇 | 〇 | 〇 | 〇 |
试验例7
依据表11的组成而制备洗剂。利用匹鲁卡品诱发发汗试验而测定洗剂的发汗抑制作用。另外，利用与试验例6相同的方法，对猪皮肤涂抹洗剂，测定奥昔布宁的浓度。
匹鲁卡品诱发发汗试验利用下述方法进行。
1)利用40质量％乙醇水溶液将洗剂稀释12倍。
2)于小鼠的足跖部约0.5cm2区域涂抹洗剂10μL或15μL。个体数n＝5～6。
3)4小时后在麻醉下于足跖涂抹碘及淀粉溶液。
4)皮内给药匹鲁卡品5μg/只。
5)5分钟后计数因碘淀粉反应而产生的黑点的个数。
[表11]
| 组合物 | 11 | 12 | 13 | 14 | 15 |
| 盐酸奥昔布宁 | 0 | 1 | 2.5 | 5 | 10 |
| 乳酸 | 2.29 | ||||
| 氯化钠 | 1.48 | ||||
| 乳酸钠 | 0.28 | 0.71 | 1.42 | 2.84 | |
| 乙醇 | 40 | 40 | 40 | 40 | 40 |
| 其他 | 2 | 2 | 2 | 2 | 2 |
| 纯化水 | 54.23 | 56.72 | 54.79 | 51.58 | 45.16 |
| 合计 | 100 | 100 | 100 | 100 | 100 |
将结果示于图2～图4。图2表示洗剂的涂抹量为10μL时的匹鲁卡品诱发发汗试验的结果，图3表示洗剂的涂抹量为15μL时的匹鲁卡品诱发发汗试验的结果。可确认洗剂的发汗抑制作用取决于奥昔布宁的浓度。另外，可确认奥昔布宁于毛囊中的蓄积量取决于奥昔布宁的浓度。
Claims (10)
1.一种外用液剂，其包含水、抗胆碱作用药及二羧酸酯，且抗胆碱作用药的含量，以上述外用液剂的总质量为基准计为10质量％～20质量％。
2.如权利要求1的外用液剂，其中上述抗胆碱作用药为奥昔布宁或其药学上可接受的盐。
3.如权利要求1或2的外用液剂，其中上述抗胆碱作用药的含量，以上述外用液剂的总质量为基准计为15质量％～20质量％。
4.如权利要求1至3中任一项的外用液剂，其中上述二羧酸酯为选自由己二酸二异丙酯、癸二酸二乙酯、癸二酸二异丙酯、己二酸二异丁酯、琥珀酸二甲酯及苯二甲酸二丁酯所组成的群中的1种以上的化合物。
5.如权利要求1至4中任一项的外用液剂，其中上述抗胆碱作用药与上述二羧酸酯的质量比为1：0.25～1：0.75。
6.如权利要求1至5中任一项的外用液剂，其中上述二羧酸酯的含量，以上述外用液剂的总质量为基准计为2.5质量％～15质量％。
7.如权利要求1至6中任一项的外用液剂，其进一步包含选自由乳酸盐、酒石酸盐、乙酸盐及磷酸盐所组成的群中的1种以上的盐。
8.如权利要求7的外用液剂，其中上述盐为乳酸钠。
9.如权利要求1至8中任一项的外用液剂，其为洗液剂形。
10.如权利要求1至9中任一项的外用液剂，其为多汗症治疗用。
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| EP1174132A1 (en) * | 1999-04-26 | 2002-01-23 | Lead Chemical Co. Ltd. | Percutaneous absorption preparations containing oxybutynin |
| CN101904812A (zh) * | 2002-11-01 | 2010-12-08 | 华生实验室公司 | 用于奥昔布宁经皮治疗的组合物和方法 |
| US20140037713A1 (en) * | 2012-08-03 | 2014-02-06 | Antares Pharma Ipl, Ag | Transdermal compositions for anti-cholinergic agents |
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| WO2000061120A1 (fr) * | 1999-04-13 | 2000-10-19 | Hisamitsu Pharmaceutical Co., Inc. | Préparations destinées à être absorbées par voie percutanée |
| KR100333956B1 (ko) * | 1999-07-02 | 2002-04-24 | 서경배 | 라우릴디에탄올아미드를 함유하는 옥시부티닌의 투과증진제 조성물 |
| GB0109143D0 (en) * | 2001-04-11 | 2001-05-30 | Unilever Plc | Antiperspirant compositions comprising microemulsions |
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| JP4873871B2 (ja) * | 2005-02-28 | 2012-02-08 | 久光製薬株式会社 | 粘着剤及び貼付剤 |
| CN101340884A (zh) | 2005-10-19 | 2009-01-07 | 曼尼·马纳舍·辛格尔 | 用于治疗多汗症的方法 |
| BR112015015421A2 (pt) * | 2012-12-27 | 2017-07-11 | Microdose Therapeutx Inc | métodos e composições para a administração de oxibutinina |
| CN105213350B (zh) * | 2015-11-11 | 2018-11-30 | 上海爱的发制药有限公司 | 盐酸奥昔布宁缓释胶囊及其制备方法 |
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