TWI666016B - 外用液劑 - Google Patents
外用液劑 Download PDFInfo
- Publication number
- TWI666016B TWI666016B TW105135108A TW105135108A TWI666016B TW I666016 B TWI666016 B TW I666016B TW 105135108 A TW105135108 A TW 105135108A TW 105135108 A TW105135108 A TW 105135108A TW I666016 B TWI666016 B TW I666016B
- Authority
- TW
- Taiwan
- Prior art keywords
- anticholinergic
- agent
- external
- lotion
- dicarboxylic acid
- Prior art date
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- 239000007788 liquid Substances 0.000 title claims abstract description 47
- 239000000812 cholinergic antagonist Substances 0.000 claims abstract description 41
- -1 dicarboxylic acid ester Chemical class 0.000 claims abstract description 34
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims abstract description 22
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000006210 lotion Substances 0.000 claims description 45
- 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 31
- 229960005434 oxybutynin Drugs 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 21
- HBTAOSGHCXUEKI-UHFFFAOYSA-N 4-chloro-n,n-dimethyl-3-nitrobenzenesulfonamide Chemical group CN(C)S(=O)(=O)C1=CC=C(Cl)C([N+]([O-])=O)=C1 HBTAOSGHCXUEKI-UHFFFAOYSA-N 0.000 claims description 7
- 229940031578 diisopropyl adipate Drugs 0.000 claims description 7
- 208000008454 Hyperhidrosis Diseases 0.000 claims description 6
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-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
- 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 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
- 230000037315 hyperhidrosis Effects 0.000 claims description 5
- 229940001447 lactate Drugs 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 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
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 229940022663 acetate Drugs 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- 229940095064 tartrate Drugs 0.000 claims description 4
- 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 3
- RDOFJDLLWVCMRU-UHFFFAOYSA-N Diisobutyl adipate Chemical compound CC(C)COC(=O)CCCCC(=O)OCC(C)C RDOFJDLLWVCMRU-UHFFFAOYSA-N 0.000 claims description 3
- 229940031769 diisobutyl adipate Drugs 0.000 claims description 3
- 239000001540 sodium lactate Substances 0.000 claims description 3
- 229940005581 sodium lactate Drugs 0.000 claims description 3
- 235000011088 sodium lactate Nutrition 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 2
- 238000012360 testing method Methods 0.000 description 24
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- 230000000694 effects Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 10
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- 238000009825 accumulation Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 210000003780 hair follicle Anatomy 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
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- 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
- 230000001078 anti-cholinergic effect Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 229960001416 pilocarpine Drugs 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 230000001166 anti-perspirative effect Effects 0.000 description 3
- 239000003213 antiperspirant Substances 0.000 description 3
- 239000004359 castor oil Substances 0.000 description 3
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- UWNADWZGEHDQAB-UHFFFAOYSA-N 2,5-dimethylhexane Chemical group CC(C)CCC(C)C UWNADWZGEHDQAB-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 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
- 238000000605 extraction Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229940015042 glycopyrrolate Drugs 0.000 description 2
- 210000004209 hair Anatomy 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000001139 pH measurement Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 2
- 231100000245 skin permeability Toxicity 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 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 2
- 239000012085 test solution Substances 0.000 description 2
- 229960004045 tolterodine Drugs 0.000 description 2
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 2
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 2
- 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 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- GFRUPHOKLBPHTQ-UHFFFAOYSA-N 2-(2-cyclohexyl-2-hydroxy-1-oxo-2-phenylethoxy)ethyl-diethyl-methylammonium Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC[N+](C)(CC)CC)C1CCCCC1 GFRUPHOKLBPHTQ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 1
- BKLAJZNVMHLXAP-VKGMXUHCSA-N 3-[(1r,5s)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octan-3-yl]-2,2-diphenylpropanenitrile Chemical compound C([C@H]1CC[C@@H](C2)[N+]1(C)C)C2CC(C#N)(C=1C=CC=CC=1)C1=CC=CC=C1 BKLAJZNVMHLXAP-VKGMXUHCSA-N 0.000 description 1
- IJALWSVNUBBQRA-UHFFFAOYSA-N 4-Isopropyl-3-methylphenol Chemical compound CC(C)C1=CC=C(O)C=C1C IJALWSVNUBBQRA-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- YXSLJKQTIDHPOT-UHFFFAOYSA-N Atracurium Dibesylate Chemical compound C1=C(OC)C(OC)=CC=C1CC1[N+](CCC(=O)OCCCCCOC(=O)CC[N+]2(C)C(C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 YXSLJKQTIDHPOT-UHFFFAOYSA-N 0.000 description 1
- 229930003347 Atropine Natural products 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- XTJFFFGAUHQWII-UHFFFAOYSA-N Dibutyl adipate Chemical compound CCCCOC(=O)CCCCC(=O)OCCCC XTJFFFGAUHQWII-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- ZTVIKZXZYLEVOL-MCOXGKPRSA-N Homatropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(O)C1=CC=CC=C1 ZTVIKZXZYLEVOL-MCOXGKPRSA-N 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 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 1
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- OWWLUIWOFHMHOQ-XGHATYIMSA-N Pipecuronium Chemical compound N1([C@@H]2[C@@H](OC(C)=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)N2CC[N+](C)(C)CC2)CC[N+](C)(C)CC1 OWWLUIWOFHMHOQ-XGHATYIMSA-N 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
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- 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 1
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- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
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- QTBCATBNRIYMPB-UHFFFAOYSA-N cyclohexyl-hydroxy-phenyl-(3-piperidin-1-ylpropyl)silane Chemical compound C1CCCCC1[Si](C=1C=CC=CC=1)(O)CCCN1CCCCC1 QTBCATBNRIYMPB-UHFFFAOYSA-N 0.000 description 1
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Abstract
本發明提供一種即便高濃度含有抗膽鹼作用藥但「黏膩感」仍小之外用液劑。外用液劑包含水、抗膽鹼作用藥及二羧酸酯，且抗膽鹼作用藥之含量，以外用液劑之總質量為基準計為10質量%～20質量%。
Description
本發明係關於一種外用液劑。
作為多汗症之治療方法，提出有投予包含奧昔布寧(Oxybutynin)等抗膽鹼作用藥之外用組合物之方法(專利文獻1及2)。 [先前技術文獻] [專利文獻] 專利文獻1：美國專利申請公開第2014/0037713號說明書 專利文獻2：國際公開第2007/046102號
[發明所欲解決之問題] 本發明者等人新發現了若增加外用液劑中之抗膽鹼作用藥之含量，則存在產生由抗膽鹼作用藥引起之「黏膩感」而外用液劑之使用感降低之傾向的問題。因此，本發明之目的在於提供一種即便高濃度含有抗膽鹼作用藥但「黏膩感」亦較小之外用液劑。 [解決問題之技術手段] 本發明者等人發現藉由使含有高濃度之抗膽鹼作用藥之外用液劑含有二羧酸酯而抑制由抗膽鹼作用藥引起之「黏膩感」，從而完成本發明。 即，本發明提供一種外用液劑，其係包含水、抗膽鹼作用藥及二羧酸酯者，且抗膽鹼作用藥之含量，以上述外用液劑之總質量為基準計為10質量%～20質量%。上述抗膽鹼作用藥可為奧昔布寧或其於藥學上容許之鹽。上述抗膽鹼作用藥之含量，以上述外用液劑之總質量為基準計可為15質量%～20質量%。上述二羧酸酯可為選自由己二酸二異丙酯、癸二酸二乙酯、癸二酸二異丙酯、己二酸二異丁酯、琥珀酸二甲酯及苯二甲酸二丁酯所組成之群中之1種以上之化合物。上述抗膽鹼作用藥與上述二羧酸酯之質量比可為1：0.25～1：0.75。上述二羧酸酯之含量，以上述外用液劑之總質量為基準計可為2.5質量%～15質量%。上述外用液劑可進而包含選自由乳酸鹽、酒石酸鹽、乙酸鹽及磷酸鹽所組成之群中之1種以上之鹽。上述鹽可為乳酸鈉。上述外用液劑可為洗液劑形。上述外用液劑可為多汗症治療用。 [發明之效果] 本發明之外用液劑藉由包含二羧酸酯而抑制由抗膽鹼作用藥引起之「黏膩感」。
以下揭示一實施形態而詳細說明本發明。 本發明之一實施形態係一種外用液劑，其係包含水、抗膽鹼作用藥及二羧酸酯者，且抗膽鹼作用藥之含量，以上述外用液劑之總質量為基準計為10質量%～20質量%。上述外用液劑可用於多汗症治療。 抗膽鹼作用藥為具有抗膽鹼作用之任意藥物即可，並無特別限定，例如可列舉：奧昔布寧、咪達那新(Imidafenacin)、妥斯平(Trospium)、托特羅定(Tolterodine)、格隆溴銨(glycopyrrolate)、丙胺太林(Propantheline)、苯紮托品(benztropine)、阿托品(atropine)、後馬托品(homatropine)、托品卡胺、貝那替秦(benactyzine)、比哌立登(Biperiden)、莨菪鹼(scopolamine)、丁溴東莨菪鹼(scopolamine butylbromide)、環戊通(cyclopentolate)、達非那新(Darifenacin)、右苄替米特(dexetimide)、雙環維林、依美銨(emepronium)、六氫矽地芬尼多(hexahydro-sila-difenidol)、奧替銨(octilonium)、鄰甲苯海那明(orphenadrine)、奧芬銨(oxyphenonium)、哌侖西平(pirenzepine)、普環啶(procyclidine)、格羅銨(darotropium)、異丙托銨(ipratropium)、噻托銨(tiotropium)、氧托銨(oxitropium)、奎尼丁、苯海索(trihexyphenidyl)、美維庫銨(mivacurium)、阿曲庫銨(atracurium)、多沙氯銨(doxacurium)、順式阿曲庫銨(Cisatracurium)、維庫銨(vecuronium)、羅庫銨(rocuronium)、泮庫銨(pancuronium)、筒箭毒鹼(tubocurarine)、加拉明(gallamine)、哌庫銨(pipecuronium)、咪噻芬(trimetaphan)、琥珀醯膽鹼(succinylcholine)、丁二醯膽鹼(suxamethonium)、十烴季銨及六羥季銨。抗膽鹼作用藥較佳為奧昔布寧或其於藥學上容許之鹽。作為奧昔布寧於藥學上容許之鹽，可列舉鹽酸奧昔布寧等。 抗膽鹼作用藥之含量，以外用液劑之總質量為基準計為10質量%～20質量%。抗膽鹼作用藥之含量，以上述外用液劑之總質量為基準計可為15質量%～20質量%。抗膽鹼作用藥之含量之下限值以上述外用液劑之總質量為基準計可為10、12、15或18質量%。 二羧酸酯降低上述外用液劑之黏性而抑制「黏膩感」。作為二羧酸酯之具體例，可列舉：己二酸二異丙酯、癸二酸二乙酯、癸二酸二異丙酯、琥珀酸二甲酯、己二酸二丁酯、己二酸二異丁酯、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。二羧酸酯之含量，以上述外用液劑之總質量為基準計可為2.5質量%～15質量%或5質量%～15質量%。二羧酸酯之含量之下限值以上述外用液劑之總質量為基準計可為1、2.5、3、3.75、5或8質量%。二羧酸酯之含量之上限值以上述外用液劑之總質量為基準計可為10、11.25、12或15質量%。藉由二羧酸酯之含量之上述下限值與上述上限值之任意組合，可進一步減輕由抗膽鹼作用藥引起之「黏膩感」。 抗膽鹼作用藥與二羧酸酯之質量比可為1：0.25～1：0.75。抗膽鹼作用藥與二羧酸酯之質量比之下限值即相對於每單位質量之二羧酸酯的抗膽鹼作用藥之質量之下限值可為1：0.75、1：0.70、1：0.65、1：0.6、1：0.55或1：0.5。抗膽鹼作用藥與二羧酸酯之質量比之上限值即相對於每單位質量之二羧酸酯的抗膽鹼作用藥之質量之上限值可為1：0.05、1：0.15、1：0.25、1：0.3、1：0.33、1：0.35或1：0.4。藉由抗膽鹼作用藥與二羧酸酯之質量比之上述下限值與上述上限值之任意組合，可進一步減輕由抗膽鹼作用藥引起之「黏膩感」。 外用液劑中之水係用以使抗膽鹼藥及二羧酸酯以及其他成分溶解或分散之介質。水之含量，以外用液劑之總質量為基準計例如可為10質量%～99質量%。 藉由使外用液劑進而包含選自由乳酸鹽、酒石酸鹽、乙酸鹽及磷酸鹽所組成之群中之1種以上之鹽，抗膽鹼作用藥於皮膚之附屬器官中之蓄積性提高。藉由提高上述蓄積性，可於抑制由投予抗膽鹼作用藥所引發之口渴等副作用之同時治療多汗症。鹽可為無水物或水合物。乳酸可為L體及D體之任一者，亦可為該等之任意之混合物。酒石酸可為L體、D體及內消旋體之任一者，亦可為該等之任意之混合物。作為鹽，例如可列舉：與鈉、鉀及鋰等一價金屬之鹽，與鈣及鎂等二價金屬之鹽，與鋁等三價金屬之鹽，以及與氨、乙二胺、三乙基胺、二乙醇胺、三乙醇胺及葡甲胺等胺化合物之鹽。就提高抗膽鹼作用藥於皮膚之附屬器官中之蓄積性之觀點而言，鹽較佳為乳酸鹽，更佳為乳酸鈉。 上述鹽之含量，以外用液劑之總質量為基準計例如可為0.1質量%～10質量%。外用液劑中之抗膽鹼作用藥與上述鹽之莫耳比例如可為1：0.5～1：2之範圍。 外用液劑中除了上述成分以外亦可包含低級醇、界面活性劑、保存穩定劑、油脂、溶解劑、填充劑、保濕劑、pH調節劑、浸透壓調節劑、增黏劑、清涼劑、收斂藥及血管收縮藥等。 低級醇提高抗膽鹼作用藥之溶解性及分散性，提高抗膽鹼作用藥於皮膚上之分佈性。作為低級醇之具體例，可列舉：甲醇、乙醇及異丙醇。低級醇之含量，以外用液劑之總質量為基準計例如可為0質量%～90質量%。 界面活性劑有助於使抗膽鹼作用藥乳化於水等介質中。作為界面活性劑之具體例，可列舉：非離子性界面活性劑(聚山梨醇酯20、聚山梨醇酯80、聚山梨醇酯60、聚氧乙烯氫化蓖麻油20、聚氧乙烯氫化蓖麻油40及聚氧乙烯氫化蓖麻油60等)、離子性界面活性劑及兩性界面活性劑。界面活性劑之含量，以外用液劑之總質量為基準計例如可為0質量%～10質量%。 作為保存穩定劑之具體例，可列舉：對羥苯甲酸酯、異丙基甲基苯酚、苯氧基乙醇及瑞香草酚。 作為油脂及溶解劑之具體例，可列舉：脂肪酸及脂肪族醇。 作為填充劑之具體例，可列舉：無機粉體(滑石、蒙脫石、膨潤石及高嶺土等)及有機粉體。 作為保濕劑之具體例，可列舉：多元醇、糖類、脲、凡士林及石蠟。 外用液劑之pH值可設為4.5～7.5之範圍內。pH值之測定係依據日本藥典第十六修訂版之一般試驗法之「2.54 pH值測定法」使用複合玻璃電極進行。 外用液劑可為洗劑及擦劑等形態，又，亦可為收容於適宜容器(例如用以噴灑液劑之噴霧容器、用以塗抹液劑之容器及氣溶膠劑容器等)內之塗抹劑及噴霧劑等形態。 外用液劑可藉由將上述各成分進行混合、混和而製造。 外用液劑係視需要搖晃容器而使各成分均質地混和後，塗抹、散佈或噴灑至欲抑制發汗之皮膚部位，視需要塗開。 [實施例] 試驗例1 依據表1之組成而製備洗劑，於被試驗者(4名)之手掌塗抹500 μL。雙手相互搓擦而使洗劑於雙手手掌上均勻地擴散開，以下述3個等級作為基準，對3分鐘後之「黏膩感」之程度進行打分。 0：不感到黏膩 1：感到黏膩 2：感到非常黏膩 根據上述分數之平均值，以下述3個等級作為基準而評價黏膩程度。 ○：平均值未達0.5 △：平均值為0.5以上且未達1.0 ×：平均值為1.0以上 [表1]
將結果示於表2。若鹽酸奧昔布寧之含量為10質量%以上則感到黏膩，若為15質量%以上則感到非常黏膩。 [表2]
試驗例2 依據表3之組成而製備洗劑，利用下述方法測定各洗劑之力積值。力積值越小則表示黏性越低。 1)將洗劑50 μL注入至96孔盤內，於32℃下靜置一晩使之乾燥。 2)使質構分析儀之SUS製探針(直徑5 mm)抵接於已乾燥之洗劑。 3)測定使探針以2 mm/s之速度上升而離開洗劑時受到之力，算出該曲線下面積作為力積值(g・s)。 [表3]
將結果示於表4。各洗劑之力積值為經過3次測定所獲得之平均值。可確認與其他洗劑相比，添加有月桂醇、油醇、聚桂醇、己二酸二異丙酯、癸二酸二乙酯、癸二酸二異丙酯、己二酸二異丁酯、琥珀酸二甲酯或苯二甲酸二丁酯之洗劑於經乾燥時之力積值較小，黏性降低。 [表4]
試驗例3 依據表5之組成而製備洗劑，於被試驗者(3名)之手掌塗抹300 μL。比較例1、4、5及9以及實施例1～3中使用與試驗例2相同之洗劑。雙手相互搓擦而使洗劑於雙手手掌上均勻地擴散開，以下述4個等級作為基準，對3分鐘後之「黏膩感」之程度進行打分。 0：不感到黏膩 1：稍感黏膩 2：感到黏膩 3：感到非常黏膩 根據上述分數之平均值，以下述5個等級作為基準而評價黏膩程度。 ◎：平均值未達0.1 ○：平均值為0.1以上且未達1.0 △：平均值為1.0以上且未達2.0 ×：平均值為2.0以上且未達3.0 ××：平均值為3.0以上 [表5]
將結果示於表6。可確認與不含二羧酸酯之洗劑相比，添加有己二酸二異丙酯、癸二酸二乙酯或癸二酸二異丙酯之洗劑其黏膩感得到減輕。 [表6]
試驗例4 使用試驗例2及3之實施例1～9及比較例1之洗劑，利用下述方法評價奧昔布寧之保存穩定性。 1)量取100 μL之洗劑，測定重量。 2)添加50 mL之流動相並混合，利用高效液相層析法(HPLC)測定各洗劑之奧昔布寧濃度。HPLC之條件如下所述。 流動相：0.1 w/w%磷酸水溶液(包含0.5 w/v%之十二烷基硫酸鈉)：乙腈＝45：55(v/v) 流速：1.5 mL/min 管柱：TSKgel ODS-80Ts(Tosoh股份有限公司) 保持時間：10分鐘 3)將洗劑於60℃下靜置2週後之每單位重量之液體中之奧昔布寧含量相對於理論值之比值(%)與初期之相對於理論值之比值(%)進行比較。於靜置後之比值相對於初期之比值為97.5%以上之情形時，將奧昔布寧之保存穩定性評價為良好。 將結果示於表7。添加有己二酸二異丙酯、癸二酸二乙酯或癸二酸二異丙酯之洗劑於60℃之環境下靜置2週後，鹽酸奧昔布寧之保存情況仍良好。又，未添加二羧酸酯之比較例1中之鹽酸奧昔布寧之保存情況亦良好。 [表7]
試驗例5 使用試驗例3之比較例1及實施例4之洗劑，利用下述方法測定奧昔布寧之皮膚滲透性。 1)於使用皮刀採集之人皮膚表面之面積3 cm2
區域塗抹5 μL之洗劑。 2)乾燥數秒後，以皮膚之真皮側成為受體層側之方式將皮膚設置於Franz池。使用生理食鹽水作為受體層。於設置皮膚後經過4、8、12、16、20及24小時之時間點對受體溶液進行採樣。於所採集之溶液0.5 mL中添加乙腈0.5 mL並攪拌，進而進行離心分離而去除蛋白質，製成試驗溶液。 3)於與試驗例4相同之條件下利用HPLC測定試驗溶液之奧昔布寧濃度。 4)根據所得之測定值而算出奧昔布寧每小時之皮膚滲透速度，取其最大值作為Jmax
(μg/cm2
/h)。又，求出24小時之累積滲透量(μg/cm2
)。 將結果示於表8。添加有己二酸二異丙酯之洗劑表現出與不含二羧酸酯之洗劑為相同程度之皮膚滲透性。 [表8]
試驗例6 依據表9之組成而製備洗劑，以目視確認溶解狀態。進而，於豬皮膚塗抹洗劑，利用下述方法測定奧昔布寧於毛囊中之蓄積量。 1)於5 cm2
之輕輕刮除毛髮後之豬皮膚塗抹20 μL洗劑。個體數n＝3。 2)6小時後，使用消毒用酒精擦拭皮膚表面並使用磷酸緩衝液進行沖洗而去除皮膚表面所附著之奧昔布寧。 3)自皮膚採集對應於20根毛髮之毛囊部分。 4)使用1 mL萃取液自毛囊萃取奧昔布寧。使用試驗例4之流動相作為萃取液。 5)利用HPLC測定奧昔布寧之濃度。HPLC之條件與試驗例4相同。 [表9]
將結果示於表10及圖1。包含磷酸鹽、乳酸鹽、乙酸鹽或酒石酸鹽之洗劑與不含該等鹽之洗劑相比奧昔布寧於毛囊中之蓄積性提高。 [表10]
試驗例7 依據表11之組成而製備洗劑。利用匹魯卡品誘發發汗試驗而測定洗劑之發汗抑制作用。又，利用與試驗例6相同之方法，於豬皮膚塗抹洗劑，測定奧昔布寧之濃度。 匹魯卡品誘發發汗試驗係利用下述方法進行。 1)利用40質量%乙醇水溶液將洗劑稀釋12倍。 2)於小鼠之足蹠部約0.5 cm2
區域塗抹洗劑10 μL或15 μL。個體數n＝5～6。 3)4小時後於麻醉下於足蹠塗抹碘及澱粉溶液。 4)皮內投予匹魯卡品5 μg/隻。 5)5分鐘後計數因碘澱粉反應而產生之黑點之個數。 [表11]
將結果示於圖2～圖4。圖2表示洗劑之塗抹量為10 μL時之匹魯卡品誘發發汗試驗之結果，圖3表示洗劑之塗抹量為15 μL時之匹魯卡品誘發發汗試驗之結果。可確認洗劑之發汗抑制作用取決於奧昔布寧之濃度。又，可確認奧昔布寧於毛囊中之蓄積量取決於奧昔布寧之濃度。
圖1係表示調查洗劑中之鹽對奧昔布寧於豬毛囊中之蓄積性產生之影響之試驗之結果的圖表。 圖2係表示調查洗劑中之奧昔布寧之濃度對發汗抑制作用產生之影響之試驗之結果的圖表。 圖3係表示調查洗劑中之奧昔布寧之濃度對發汗抑制作用產生之影響之試驗之結果的圖表。 圖4係表示調查洗劑中之奧昔布寧之濃度對奧昔布寧於豬毛囊中之蓄積性產生之影響之試驗之結果的圖表。
Claims (10)
- 一種外用液劑，其係包含水、抗膽鹼作用藥及二羧酸酯者，且抗膽鹼作用藥之含量，以上述外用液劑之總質量為基準計為10質量%~20質量%。
- 如請求項1之外用液劑，其中上述抗膽鹼作用藥為奧昔布寧或其於藥學上容許之鹽。
- 如請求項1或2之外用液劑，其中上述抗膽鹼作用藥之含量，以上述外用液劑之總質量為基準計為15質量%~20質量%。
- 如請求項1或2之外用液劑，其中上述二羧酸酯為選自由己二酸二異丙酯、癸二酸二乙酯、癸二酸二異丙酯、己二酸二異丁酯、琥珀酸二甲酯及苯二甲酸二丁酯所組成之群中之1種以上之化合物。
- 如請求項1或2之外用液劑，其中上述抗膽鹼作用藥與上述二羧酸酯之質量比為1：0.25~1：0.75。
- 如請求項1或2之外用液劑，其中上述二羧酸酯之含量，以上述外用液劑之總質量為基準計為2.5質量%~15質量%。
- 如請求項1或2之外用液劑，其進而包含選自由乳酸鹽、酒石酸鹽、乙酸鹽及磷酸鹽所組成之群中之1種以上之鹽。
- 如請求項7之外用液劑，其中上述鹽為乳酸鈉。
- 如請求項1或2之外用液劑，其為洗液劑形。
- 如請求項1或2之外用液劑，其為多汗症治療用。
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| JP??2016-034620 | 2016-02-25 |
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| US (1) | US20190046493A1 (zh) |
| EP (1) | EP3421049B1 (zh) |
| JP (1) | JP6564927B2 (zh) |
| KR (1) | KR102094626B1 (zh) |
| CN (1) | CN108495654B (zh) |
| ES (1) | ES2815849T3 (zh) |
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| CN113520996B (zh) * | 2021-06-18 | 2022-11-18 | 北京斯利安药业有限公司 | 一种盐酸苯海索溶液剂及其制备方法与应用 |
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| WO2002083091A1 (en) * | 2001-04-11 | 2002-10-24 | Unilever Plc | Antiperspirant compositions comprising microemulsions |
| EP1696013A2 (en) * | 2005-02-28 | 2006-08-30 | Hisamitsu Pharmaceutical Co., Inc. | Pressure sensitive adhesive and patch |
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| KR100674108B1 (ko) * | 1999-04-13 | 2007-01-26 | 히사미쓰 세이야꾸 가부시키가이샤 | 경피흡수형 제제 |
| AU3536799A (en) * | 1999-04-26 | 2000-11-10 | Lead Chemical Co., Ltd. | Percutaneous preparations containing oxybutynin |
| KR100333956B1 (ko) * | 1999-07-02 | 2002-04-24 | 서경배 | 라우릴디에탄올아미드를 함유하는 옥시부티닌의 투과증진제 조성물 |
| US7029694B2 (en) * | 2000-04-26 | 2006-04-18 | Watson Laboratories, Inc. | Compositions and methods for transdermal oxybutynin therapy |
| US8476280B2 (en) * | 2002-05-09 | 2013-07-02 | Versi Group, Llc | Compositions and methods for combating lower urinary tract dysfunctions with delta opioid receptor agonists |
| AU2012216593B2 (en) * | 2002-11-01 | 2014-09-25 | Allergan Sales, Llc | Compositions and methods for transdermal oxybutynin therapy |
| 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 |
| US20140037713A1 (en) | 2012-08-03 | 2014-02-06 | Antares Pharma Ipl, Ag | Transdermal compositions for anti-cholinergic agents |
| WO2014105446A1 (en) * | 2012-12-27 | 2014-07-03 | Microdose Therapeutx, Inc. | Methods and compositions for administration of oxybutynin |
| 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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| WO2002083091A1 (en) * | 2001-04-11 | 2002-10-24 | Unilever Plc | Antiperspirant compositions comprising microemulsions |
| EP1696013A2 (en) * | 2005-02-28 | 2006-08-30 | Hisamitsu Pharmaceutical Co., Inc. | Pressure sensitive adhesive and patch |
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| Publication number | Publication date |
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| CN108495654A (zh) | 2018-09-04 |
| EP3421049B1 (en) | 2020-07-29 |
| WO2017145441A1 (ja) | 2017-08-31 |
| KR102094626B1 (ko) | 2020-03-27 |
| KR20180091041A (ko) | 2018-08-14 |
| CN108495654B (zh) | 2022-10-25 |
| TW201729802A (zh) | 2017-09-01 |
| EP3421049A1 (en) | 2019-01-02 |
| JP6564927B2 (ja) | 2019-08-21 |
| EP3421049A4 (en) | 2019-10-02 |
| US20190046493A1 (en) | 2019-02-14 |
| ES2815849T3 (es) | 2021-03-30 |
| JPWO2017145441A1 (ja) | 2018-09-13 |
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