JPS6261929A - Dermatic drug for external use having improved transcutaneous absorbability of water-soluble drug - Google Patents
Dermatic drug for external use having improved transcutaneous absorbability of water-soluble drugInfo
- Publication number
- JPS6261929A JPS6261929A JP20173885A JP20173885A JPS6261929A JP S6261929 A JPS6261929 A JP S6261929A JP 20173885 A JP20173885 A JP 20173885A JP 20173885 A JP20173885 A JP 20173885A JP S6261929 A JPS6261929 A JP S6261929A
- Authority
- JP
- Japan
- Prior art keywords
- skin
- drug
- polyoxyethylene
- water
- nonionic
- 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
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- 239000003814 drug Substances 0.000 title claims abstract description 63
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- 125000002091 cationic group Chemical group 0.000 claims abstract description 25
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- 238000002360 preparation method Methods 0.000 claims description 91
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- SMVRDGHCVNAOIN-UHFFFAOYSA-L disodium;1-dodecoxydodecane;sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O.CCCCCCCCCCCCOCCCCCCCCCCCC SMVRDGHCVNAOIN-UHFFFAOYSA-L 0.000 description 5
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- 229910019142 PO4 Inorganic materials 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 230000010534 mechanism of action Effects 0.000 description 4
- 235000021317 phosphate Nutrition 0.000 description 4
- 159000000000 sodium salts Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- FKKAGFLIPSSCHT-UHFFFAOYSA-N 1-dodecoxydodecane;sulfuric acid Chemical compound OS(O)(=O)=O.CCCCCCCCCCCCOCCCCCCCCCCCC FKKAGFLIPSSCHT-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
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- 229920002125 Sokalan® Polymers 0.000 description 3
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- 229960003830 acebutolol hydrochloride Drugs 0.000 description 3
- KTUFKADDDORSSI-UHFFFAOYSA-N acebutolol hydrochloride Chemical compound Cl.CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 KTUFKADDDORSSI-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
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- 150000001875 compounds Chemical class 0.000 description 3
- JGKVKXPDDVRUKC-UHFFFAOYSA-N dimethothiazine mesylate Chemical compound CS(O)(=O)=O.C1=C(S(=O)(=O)N(C)C)C=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 JGKVKXPDDVRUKC-UHFFFAOYSA-N 0.000 description 3
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- 239000008279 sol Substances 0.000 description 3
- XFHHCPRMDXAWDO-UHFFFAOYSA-K trisodium;1-dodecoxydodecane;phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O.CCCCCCCCCCCCOCCCCCCCCCCCC XFHHCPRMDXAWDO-UHFFFAOYSA-K 0.000 description 3
- XPALGXXLALUMLE-UHFFFAOYSA-N 2-(dimethylamino)tetradecanoic acid Chemical compound CCCCCCCCCCCCC(N(C)C)C(O)=O XPALGXXLALUMLE-UHFFFAOYSA-N 0.000 description 2
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- 239000000654 additive Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002998 adhesive polymer Substances 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229960001656 amikacin sulfate Drugs 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 235000015278 beef Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229950002568 bucumolol Drugs 0.000 description 1
- CIJVBYRUFLGDHY-UHFFFAOYSA-N bucumolol Chemical compound O1C(=O)C=CC2=C1C(OCC(O)CNC(C)(C)C)=CC=C2C CIJVBYRUFLGDHY-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 229960004201 cinepazide Drugs 0.000 description 1
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 description 1
- 229960001200 clindamycin hydrochloride Drugs 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960003075 dibenzepin Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960001640 dimetotiazine Drugs 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 229940005494 general anesthetics Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- XZZXIYZZBJDEEP-UHFFFAOYSA-N imipramine hydrochloride Chemical group [Cl-].C1CC2=CC=CC=C2N(CCC[NH+](C)C)C2=CC=CC=C21 XZZXIYZZBJDEEP-UHFFFAOYSA-N 0.000 description 1
- 229960002102 imipramine hydrochloride Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- MPGBPFMOOXKQRX-UHFFFAOYSA-N indenolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CC2 MPGBPFMOOXKQRX-UHFFFAOYSA-N 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 229960004184 ketamine hydrochloride Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960001300 metoprolol tartrate Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000259 polyoxyethylene lauryl ether Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940071089 sarcosinate Drugs 0.000 description 1
- 108700004121 sarkosyl Proteins 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229960001435 sisomicin sulfate Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229940080236 sodium cetyl sulfate Drugs 0.000 description 1
- 229940045885 sodium lauroyl sarcosinate Drugs 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940032085 sucrose monolaurate Drugs 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- KFVSLSTULZVNPG-UHFFFAOYSA-N terbutaline sulfate Chemical compound [O-]S([O-])(=O)=O.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1 KFVSLSTULZVNPG-UHFFFAOYSA-N 0.000 description 1
- 229960005105 terbutaline sulfate Drugs 0.000 description 1
- WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 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
- 210000003462 vein Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
【発明の詳細な説明】
産業上の利用分野
本発明は、陽イオン性水浴性薬物の経皮吸収性を高めた
皮膚外用剤に関し、更に詳しくは、基剤中に特定のイオ
ン性吸収助剤および非イオン性吸収助剤を含有せしめる
ことにより、陽イオン性水浴性薬物の経皮吸収性を高め
た皮珂外用剤に関する。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a skin preparation for external use that has enhanced transdermal absorption of cationic water-based drugs, and more particularly, it relates to a skin preparation that has increased transdermal absorption of cationic water-based drugs. The present invention also relates to a skin preparation for external use that improves transdermal absorption of cationic water-based drugs by containing a nonionic absorption aid.
従来の技術
従来、皮膚局所での疾患治療全目的とした皮膚外用剤に
ついては数多くの知見がある。まな近年全身作用の発現
を目的としたものの開発も盛んになっておシ、皮膚外用
剤の有用性が高く評価されて来ている。しかし、これら
の殆んどは本来経皮吸収され易い脂溶性かつ中性の薬物
に関するものである。（例えば、Ｄｒｕｇ Ｄ＠ｖ、Ｉ
ｎｄ、Ｐｈａｒｍ＊、９ （４）６７１（１９８３）参
照）
一方、現在臨床において有用性を高く評価されてｂる薬
物の多くは水浴性薬物である。これらをプロドラッグ化
等の化学修飾を施すことなく、経皮吸収によシ全身的に
薬効を発現させることは、薬効の持続化、副作用の低減
、投与薬量及び投与回数の低減、治療の簡便化、服薬忌
避の防止などを達成でき、その臨床治療での有益性は極
めて高いものである（例えば、Ｄｒｕｇ Ｄｓｖ、Ｉｎ
ｄｓＰｈａｒｍ、、９（４） 、 ７２５ （１９８３
）参照）。BACKGROUND OF THE INVENTION Conventionally, there is a large amount of knowledge regarding external preparations for skin that are intended for treating diseases locally on the skin. In recent years, the development of products aimed at exerting systemic effects has become active, and the usefulness of external preparations for the skin has been highly evaluated. However, most of these involve lipid-soluble and neutral drugs that are easily absorbed through the skin. (For example, Drug D@v, I
On the other hand, many of the drugs currently highly evaluated for their usefulness in clinical practice are bath drugs. Systemically expressing these drug effects through transdermal absorption without chemical modification such as prodrugs can prolong drug efficacy, reduce side effects, reduce the amount and frequency of administration, and improve treatment. It can simplify the process and prevent drug avoidance, and is extremely useful in clinical treatment (for example, Drug Dsv, In
dsPharm, 9(4), 725 (1983
)reference).
しかし、水溶性薬物を経皮吸収させようとすると、皮屑
の角質が強力なバリヤーとなってその吸収を阻止すると
言われておＩ）（例えば、ＤｒｕｇＤｅｖ、Ｉｎｄ、Ｐ
ｈａｒｍ−、９（４） 、 ６２７ （１９８３）参照
）、水溶性薬物の経皮吸収に関しては、本発明者らの知
る限シごく少数の知見しか得られていない。例えば、メ
タアクリル酸アルキルエステルを主成分とする粘着性高
分子物質溶液に、水溶性薬物の水及び／又はアルコール
溶液を溶解してフィルムを作成する方法（特開昭５９−
陰４７１５号公報参照）や水溶性抗アレルギー剤の塩酸
インチベンジルと水溶性塩基性物質あるいは非イオン性
界面活性剤を含有する皮膚外用剤（特開昭５９−５１２
１２号公報、特開昭５９−９８０１４号公報参照）、親
水性薬物と有機酸又は有機酸の金属（Ｍｇ、 Ｃａ、
Ｚｎ又はＡｌ ）塩を含有するテープ（特開昭５９−陰
４７１４号公報参照）及びポリアクリル酸ナトリウムと
水酸化アルミニウムと経皮吸収され得る薬物を含有する
皮膚外用剤（特開昭５９−２５３２０号公報参照）等の
報告がある。However, when attempting to absorb water-soluble drugs transdermally, it is said that the keratin of the skin acts as a strong barrier and blocks absorption (for example, DrugDev, Ind., P.
harm-, 9(4), 627 (1983)); to the best of the present inventors' knowledge, only a small number of findings have been obtained regarding the transdermal absorption of water-soluble drugs. For example, a method of preparing a film by dissolving a water and/or alcohol solution of a water-soluble drug in a solution of an adhesive polymer substance containing methacrylic acid alkyl ester as the main component (JP-A-59-1999)
4715) and skin external preparations containing a water-soluble antiallergic agent, inthibenzyl hydrochloride, and a water-soluble basic substance or nonionic surfactant (Japanese Patent Application Laid-Open No. 59-512).
12, JP-A-59-98014), hydrophilic drugs and organic acids or metals of organic acids (Mg, Ca,
Zn or Al) salt-containing tapes (see JP-A-59-4714) and skin external preparations containing sodium polyacrylate, aluminum hydroxide, and transdermally absorbable drugs (JP-A-59-25320). (Refer to the Publication No.)).
しかしながら、これらは何れも、製剤中での主薬の安定
性、溶解性、製剤からの主薬の放出性、あるいは製造の
煩雑さの改善を目的としたものであり、問題となる角質
を含めた経皮吸収促進効果あるいは薬効発現改良効果に
関しては、何ら充分な説明がなされていない。However, all of these are aimed at improving the stability and solubility of the active ingredient in the formulation, the release of the active ingredient from the formulation, or the complexity of manufacturing, and they are aimed at improving the stability and solubility of the active ingredient in the formulation, or the complexity of manufacturing. No sufficient explanation has been given regarding the effect of promoting skin absorption or the effect of improving the expression of drug efficacy.
一方、経皮吸収の改善を目的としたものとしては、水性
溶媒中でＰＨ４〜８を示す陰イオン性及び／又は両性界
面活性剤を含む皮膚外用剤（特開昭５１−３２７２４号
公報、特開昭５２−８３９１４号公報参照）の報告があ
る。しかし実際には、これらの公報には極めて難水溶性
の薬物の経皮吸収促進についてしか説明が無く、水溶性
薬物については何ら触れられていない。またジメチルス
ルホキンド（ＤＭＳＯ）がスコポラミンに対する角質の
バリヤー機能ヲ減少し、経皮吸収性を高めるとの報告が
あるが（Ｄｒｕｇ Ｄｅｖ、Ｉｎｄ、Ｐｈａｒｍ、 、
９ （４） ＊６２７（１９８３））、これはＤＭＳ
Ｏが角質を部分的に破壊してスコポラミンの角質透過性
を高めることによるとされている。この様な方法は皮膚
刺激の点から、長期治療を必要とする疾患には適用する
ことができない。On the other hand, external skin preparations containing anionic and/or amphoteric surfactants exhibiting a pH of 4 to 8 in an aqueous medium (JP-A-51-32724; There is a report on the method (see Japanese Patent Publication No. 1983-83914). However, in reality, these publications only explain the promotion of transdermal absorption of extremely poorly water-soluble drugs, and do not mention water-soluble drugs at all. There are also reports that dimethyl sulfoquine (DMSO) reduces the barrier function of the stratum corneum against scopolamine and increases transdermal absorption (Drug Dev, Ind, Pharm,
9 (4) *627 (1983)), this is DMS
It is believed that O partially destroys the stratum corneum and increases the permeability of scopolamine to the stratum corneum. Such methods cannot be applied to diseases requiring long-term treatment due to skin irritation.
更に、ｉｎ ｖｉｔｌｏで長鎖アミンがサリチル酸ナト
リウムのミリスチン哨イングロビル膜の透過性全促進す
るとの報告がおる（ Ｊ、Ｐｈａｒｍ、Ｐｂａｒｍａｃ
ｏｌ、ｅ３６ （５ｕｐｐ、Ｄｅｃ、 ） 、 Ｐ ２
２ （１９８４） ）。しかしこれは皮Ｊｎ脂質への薬
物移行の改善を示唆するものの、生体における経皮吸収
促進効果を裏付けるものではない。Furthermore, it has been reported that long-chain amines promote the permeability of sodium salicylate through myristic and inglovir membranes in vitro (J, Pharm, Pbarmac).
ol, e36 (5upp, Dec, ), P 2
2 (1984)). However, although this suggests an improvement in drug transfer to skin Jn lipids, it does not support the effect of promoting transdermal absorption in living bodies.
この様に、水ｆ６注薬物については、その有用な薬効を
発現するのに充分なｆを経皮吸収させる技術が未だ確豆
されていないのが現状である。As described above, the current state of the art for water f6 injections is that the technology for percutaneously absorbing enough f to exhibit its useful medicinal effects has not yet been established.
前述の如く、水浴性薬物は角質を透過しにくいため、経
皮吸収により投与することが実用上従来困難であったと
いう実情に鑑み、水沼性薬物全効果的に経皮吸収せしめ
ることができる皮１ｄ外用剤徂戊物を開発することが本
発明の目的でるる。As mentioned above, bathing drugs have difficulty penetrating the stratum corneum, so it has been difficult to administer them through transdermal absorption. It is an object of the present invention to develop a 1d topical preparation.
本発明者らは、水浴性薬物を効果的に経皮吸収させる方
法について種々研究した結果、これまでに基剤中に陰イ
オン性界面活性剤あるいは両性界面活性剤から選ばれた
吸収助剤を含有させる事により、陽イオン性水溶性薬物
の経皮吸収を効果的に促進することができることを見出
した（特願昭６０−９３８２１および特願昭６０−１０
０４８４）。As a result of various studies on methods for effectively percutaneously absorbing bath-based drugs, the present inventors have found that an absorption aid selected from anionic surfactants or amphoteric surfactants is added to the base. It has been found that transdermal absorption of cationic water-soluble drugs can be effectively promoted by incorporating them (Japanese Patent Applications No. 60-93821 and No. 60-10).
0484).
また同様にして特定の非イオン性吸収助剤を含有させる
事により、陽イオン性水溶性薬物の経皮吸収を効果的に
促進することができることを見出した（特願昭６Ｏ−１
０８３３２）。In addition, we have similarly discovered that transdermal absorption of cationic water-soluble drugs can be effectively promoted by incorporating a specific nonionic absorption aid (Patent Application No. 6 O-1
08332).
しかし、これら吸収助剤の効果は、必ずしもその配合量
に比例するものではなく、ある配合量以上では効果が頭
打ちとなる。さらには吸収助剤の配合量を増やす事は、
皮膚刺激の恐れがあり好ましくない。However, the effects of these absorption aids are not necessarily proportional to the amount of the absorption aid, and the effects reach a plateau at a certain amount or more. Furthermore, increasing the amount of absorption aid added,
Undesirable as it may cause skin irritation.
本発明者らは、この点を解決すべく更に研究を重ねた結
果、陰イオン性界面活性剤あるいは両性界面活性剤から
選ばれたイオン性吸収助剤と、特定の非イオン性吸収助
剤とを基剤中に配合することにより、おのおのの吸収助
剤の効果が相乗的に高まる事を見出した。As a result of further research to solve this problem, the present inventors discovered that an ionic absorption aid selected from anionic surfactants or amphoteric surfactants and a specific nonionic absorption aid It has been discovered that the effects of each absorption aid can be synergistically enhanced by incorporating them into the base.
本発明はかかる知見に基いて完成されたものであり、本
発明に従えば、皮膚外用剤中に陽イオン性水溶性薬物と
特定のイオン性吸収助剤および非イオン性吸収助剤を配
合することによシ、イオン性吸収助剤あるいは非イオン
性吸収助剤のおのおのを配合した場合と比較して、陽イ
オン性水溶性薬物の経皮吸収を相乗的に高めることがで
きる。The present invention has been completed based on such knowledge, and according to the present invention, a cationic water-soluble drug, a specific ionic absorption aid, and a nonionic absorption aid are blended into a skin external preparation. In particular, the transdermal absorption of cationic water-soluble drugs can be synergistically enhanced compared to the case where an ionic absorption aid or a nonionic absorption aid is incorporated individually.
本発明における吸収促進効果の作用機序は不明であるが
、皮膚表面の−において主として陽イオン型で存在する
と考えられる薬物に対して、分子構造中に陰イオン性基
を有する物質を添加する事によシ、例えばイオン対生成
の様な相互作用を生じ、これによって薬物の脂溶性が増
大して皮膚を透過し易くなるものと推定される。Although the mechanism of action of the absorption promoting effect in the present invention is unknown, it is possible to add a substance having an anionic group in the molecular structure to a drug that is thought to exist mainly in the cationic form on the skin surface. It is presumed that interactions such as ion pair formation occur, thereby increasing the fat solubility of the drug and making it easier to penetrate the skin.
更には、イオン性吸収助剤および非イオン性吸収助剤の
角質に対する作用（例えば角質の水和。Furthermore, the effects of ionic absorption aids and nonionic absorption aids on stratum corneum (for example, hydration of stratum corneum).
保湿作用、角質表面の脂質除去作用など）によって陽イ
オン性薬物に対する角質のバリヤー能を緩和し、結果と
して相乗的な吸収促進効果をもたらすものと推定される
。It is presumed that the barrier ability of the stratum corneum against cationic drugs is alleviated by its moisturizing effect, lipid removal effect on the stratum corneum surface, etc., resulting in a synergistic absorption-promoting effect.
本発明に従った経皮吸収促進の作用機序は上記の通シ推
定されるものの、その作用機序はなお推定の域であり、
本発明をかかる作用機序に限定するものでないことはい
うまでもない。Although the mechanism of action of promoting percutaneous absorption according to the present invention is generally presumed as described above, the mechanism of action is still in the realm of speculation.
It goes without saying that the present invention is not limited to this mechanism of action.
本発明において使用される陰イオン性界面活性剤として
は、アルキル硫酸およびその塩、ポリオキシエチレンア
ルキルエーテル硫酸およびその塩、ポリオキンエチレン
アルキルエーテルリン酸およびその塩、サルコシン誘導
体およびその塩等を挙げることができる。Examples of the anionic surfactant used in the present invention include alkyl sulfates and salts thereof, polyoxyethylene alkyl ether sulfates and salts thereof, polyoxyethylene alkyl ether phosphates and salts thereof, sarcosine derivatives and salts thereof, etc. be able to.
前記したアルキル硫酸およびその塩としては、アルキル
基の炭素数がＣ６〜Ｃ２０％好捷しくはＣ１ｏ”’−Ｃ
１８のアルキル硫酸およびその塩（例えばナトリウム塩
、カリウム塩、トリエタノールアミン塩など）を挙げる
ことができ、特に日本薬局方収載のラウリル硫酸ナトリ
ウム（例えば日光ケミカルズ社製Ｎｊｋｋｏｌ ＳＬＳ
” ） 、および化粧品原料基準収載のラウリル硫酸ト
リエタノールアミン、セチル硫酸ナトリウム（例えば日
光ケミカルズ社製Ｎｊｋｋｏｌ ＴＥＡＬＳ■、 Ｎ１
ｋｋｏｌ ＳＣ８■）等を好適に使用することができる
。The alkyl sulfuric acid and its salt have an alkyl group having a carbon number of C6 to C20%, preferably C1o"'-C
18 alkyl sulfates and their salts (e.g., sodium salt, potassium salt, triethanolamine salt, etc.), particularly sodium lauryl sulfate listed in the Japanese Pharmacopoeia (e.g., Njkkol SLS manufactured by Nikko Chemicals).
), and triethanolamine lauryl sulfate and sodium cetyl sulfate listed in the Cosmetic Raw Materials Standards (for example, Njkkol TEALS■, N1 manufactured by Nikko Chemicals).
kkol SC8■) etc. can be suitably used.
また、ポリオキシエチレンアルキルエーテル硫酸および
その塩としては、アルキル基の炭素数がＣ６〜Ｃ２ｏ１
好ましくはＣ１ｏ−Ｃ１８であシ、かつエチレンオキサ
イドの付加モル数が１〜２０、好ましくは２〜１２であ
るポリオキシエチレンアルキルエーテル硫酸およびその
塩（例えばナトリウム塩、カリウム塩、トリエタノール
アミン塩など）を挙げることができ、特に化粧品原料基
準収載のポリオキシエチレンラウリルエーテル硫酸ナト
リウム、ポリオキシエチレンラウリルエーテル硫酸トリ
エタノールアミン（例えば日光ケミカルズ社製Ｎ１ｋｋ
ｏｌ ５ＢＬ−４Ｊ 、 Ｎ１ｋｋｏｌ ５１３Ｉ、−
４Ｔｏ）等を好適に使用することができる。ポリオキシ
エチレンアルキルエーテルリン酸およびその塩としては
、アルキル基の炭素数がＣ６〜Ｃ２０％好ましくはｃ１
ｏ〜Ｃ１８であり、かつエチレンオキサイドの付加モル
数が１〜２０、好ましくは２〜１０であるポリオキンエ
チレンアルキルエーテルリン酸およびその塩（例えば、
ナトリウム塩、カリウム塩、トリエタノールアミン塩な
ど）を挙げることができ、特に化粧品原料基準収載のポ
リオキシエチレンラウリルエーテルリン酸、ポリオキシ
エチレンラウリルエーテルリン酸ナトリウム、ポリオキ
シエチレンセチルエーテルリン酸、ポリオキシエチレン
セチルエーテルリン酸ナトリウム、ポリオキシエチレン
オレイルエーテルリン酸、ポリオキシエチレンオレイル
エーテルリン酸ナトリウム（例えば日光ケミカルス社製
Ｎ１ｋｋｏｌ ＴＬＰ−４■Ｉ Ｎ１ｋｋｏｌＤＬＰ−
１０■、 Ｎ１ｋｋｏｌ ＴＣＰ−５■、 Ｎ１ｋｋｏ
ｌ ＤＯＰ−８’Ｄ ）等を好適に使用することができ
る。In addition, as polyoxyethylene alkyl ether sulfuric acid and its salts, the number of carbon atoms in the alkyl group is C6 to C2o1.
Polyoxyethylene alkyl ether sulfuric acid, preferably C1o-C18, and the number of moles of ethylene oxide added is 1 to 20, preferably 2 to 12, and its salts (e.g., sodium salt, potassium salt, triethanolamine salt, etc.) ), particularly sodium polyoxyethylene lauryl ether sulfate and triethanolamine polyoxyethylene lauryl ether sulfate (e.g. N1kk manufactured by Nikko Chemicals Co., Ltd.) listed in the Cosmetic Raw Materials Standards.
ol 5BL-4J, N1kkol 513I, -
4To) etc. can be suitably used. As polyoxyethylene alkyl ether phosphoric acid and its salt, the number of carbon atoms in the alkyl group is C6 to C20%, preferably c1
o to C18, and the number of added moles of ethylene oxide is 1 to 20, preferably 2 to 10, and its salts (e.g.,
In particular, polyoxyethylene lauryl ether phosphate, sodium polyoxyethylene lauryl ether phosphate, polyoxyethylene cetyl ether phosphate, polyoxyethylene cetyl ether phosphate, etc. listed in the Cosmetic Raw Materials Standards Sodium oxyethylene cetyl ether phosphate, polyoxyethylene oleyl ether phosphate, sodium polyoxyethylene oleyl ether phosphate (for example, Nikko Chemicals N1kkol TLP-4I N1kkol DLP-
10■, N1kkol TCP-5■, N1kko
lDOP-8'D) etc. can be suitably used.
サルコシン誘導体およびその塩としては、アルキル基の
炭素数が０６〜０２０％好ましくはＣ４゜り、−８のＮ
−メチルグリシンあるいはＮ−メチル−β−アラニン誘
導体およびその塩（例えばナトリウム塩、カリウム塩な
ど〕を挙げることができ、特に化粧品原料基準収載のラ
ウロイルサルコシンナトリウム（例えば日光ケミカルス
社製Ｎｉ ｋｋｏ １サルコシネートＬａ）を好適に使
用することができる。As for sarcosine derivatives and salts thereof, the number of carbon atoms in the alkyl group is preferably from 06 to 020%, preferably from C4° to -8N
-Methylglycine or N-methyl-β-alanine derivatives and their salts (e.g. sodium salt, potassium salt, etc.), and especially sodium lauroyl sarcosinate listed in the Standards for Cosmetic Raw Materials (e.g. Nikko Chemicals Co., Ltd.'s Nikko 1 Sarcosinate La). ) can be suitably used.
また、本発明において使用される両性界面活性剤として
は、アルキルベタイン、イミダゾリニウムベタイン等を
挙げることができる。Furthermore, examples of the amphoteric surfactant used in the present invention include alkyl betaines, imidazolinium betaines, and the like.
前記したアルキルベタインとしては、窒素原子上に炭素
数Ｃ４〜Ｃ２ＯＮ好ましくはＣ４゜〜Ｃ１８のアルキル
基と、２個のメチル基あるいはヒドロキシエチル基と、
酢酸基あるいはゾロピオン酸基を有するアルキルベタイ
ンであシ、例えば、ラウリルジメチルアミノ酢酸ベタイ
ン、ラウリルゾメチルアミノゾロビオン酸ベタイン、ミ
リスチルジメチルアミノ酢酸ベタイン、ミリスチルジメ
チルアミノゾロピオン酸ベタイン、ステアリルジメチル
アミノ酢酸ベタイン、ステアリルジヒドロキシエチルア
ミノ酢酸ベタイン等を挙げることができ、等に化粧品原
料基準収載のラウリル・ジメチルアミノ酢酸ベタイン（
例えば日光ケミカルス社製Ｎ１ｋｋｏｌ ＡＭ−３０１
■）を好適に使用することができる。The alkyl betaine described above has an alkyl group having a carbon number of C4 to C2ON, preferably C4° to C18, and two methyl groups or hydroxyethyl groups on the nitrogen atom,
Alkyl betaines having an acetate group or a zolopionate group, such as lauryldimethylaminoacetic acid betaine, laurylzomethylaminozolobionic acid betaine, myristyldimethylaminoacetic acid betaine, myristyldimethylaminozolopionic acid betaine, stearyldimethylaminoacetic acid betaine , stearyl dihydroxyethylaminoacetic acid betaine, etc., and lauryl dimethylaminoacetic acid betaine (listed in the standards for cosmetic raw materials).
For example, N1kkol AM-301 manufactured by Nikko Chemicals
(2) can be suitably used.
イミダゾリニウムベタインとしては化粧品原料基準収載
の２−アルキル−Ｎ−カルブキシメチル−Ｎ−ヒドロキ
シエチルイミダゾリニウムベタインであり、アルキル基
の炭素数がＣ−Ｃ，好ましくはＣ１ｏ−Ｃ１８であシ、
例えば２−ウンデシル−Ｎ−カルボキシメチル−Ｎ−ヒ
ドロキシエチルイミダゾリニウムベタイン、２−ラウリ
ル−Ｎ−カルビキンメチルーＮ−ヒドロキシエチルイミ
タソリニウムベタイン、２−オレイル−Ｎ−カルブキシ
メチル−Ｎ−ヒドロキシエチルイミダゾリニウムヘタイ
ン等（例えば日光ケミカルス社製Ｎ１ｋｋｏｌ ＡＭ−
１０１■、 Ｍｉｒａｎｏ１社製Ｍｉｒａｎｏｌ ＣＭ
５Ｍ１ｒａｎｏｌ Ｃ２Ｍ ）を好適に使用すること
ができる。The imidazolinium betaine is 2-alkyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine listed in the Cosmetic Raw Materials Standards, and the number of carbon atoms in the alkyl group is C-C, preferably C1o-C18. ,
For example, 2-undecyl-N-carboxymethyl-N-hydroxyethylimidazolinium betaine, 2-lauryl-N-carbiquinmethyl-N-hydroxyethylimitasolinium betaine, 2-oleyl-N-carboxymethyl-N- Hydroxyethyl imidazolinium hetaine, etc. (for example, N1kkol AM- manufactured by Nikko Chemicals)
101■, Miranol CM manufactured by Mirano1
5M1ranol C2M) can be suitably used.
更に、本発明において使用される非イオン性の吸収助剤
としては、ノリオキシエチレンアルキルエーテル、尿素
、ノソントテン酸誘導体、シヨ糖脂肪酸エステル等が挙
げられる。Furthermore, nonionic absorption aids used in the present invention include norioxyethylene alkyl ether, urea, nosontothenic acid derivatives, sucrose fatty acid esters, and the like.
前記した。４１Ｊオキシエチレンアルキルエーテルとし
ては、アルキル基の炭素数がＣ４〜Ｃ２０％好ましくは
Ｃ１ｏ−Ｃ４８であシ、かつエチレンオキサイドの付加
モル数が１〜５０好ましくは２〜２３のポリオキシエチ
レンアルキルエーテルを挙げることができ、特に日本薬
局方収載のポリオキシエチレンラウリルエーテル（例え
ば日光ケミカルス社製Ｎ１ｋｋｏｌ Ｂｔ、−逅、 Ｎ
１ｋｋｏｌ ＢＬ−９ＥＸ” 、 ＮｔｋｋｏｌＢＬ−
２１■）、および化粧品原料基準収載のポリオキシエチ
レンセチルエーテル（例えば日光ケミカルス社製Ｎ１ｋ
ｋｏｌ Ｂｃ−仲、 Ｎ１ｋｋｏｌ ＢＣ−１０Ｔ迎ｔ
Ｎｉｋｋｏｌ ＢＣ−２３■）、ポリオキシエチレンオ
レイルエーテル（例えば日光ケミカルス社製Ｎ１ｋｋｏ
ｌＢＯ−２■、 Ｎ１ｋｋｏｌ ＢＯ−１０ＴＸＧＩＤ
、 Ｎ１ｋｋｏｌ ＢＯ−２０■）等を好適に使用す
ることができる。As mentioned above. The 41J oxyethylene alkyl ether is a polyoxyethylene alkyl ether in which the number of carbon atoms in the alkyl group is C4 to C20%, preferably C1o to C48, and the number of added moles of ethylene oxide is 1 to 50, preferably 2 to 23. In particular, polyoxyethylene lauryl ether listed in the Japanese Pharmacopoeia (for example, N1kkol Bt, -N, manufactured by Nikko Chemicals)
1kkol BL-9EX", NtkkolBL-
21■), and polyoxyethylene cetyl ether listed in the Cosmetic Raw Materials Standards (for example, N1k manufactured by Nikko Chemicals)
kol Bc-Naka, N1kkol BC-10T pickup
Nikkol BC-23■), polyoxyethylene oleyl ether (for example, Nikkol BC-23■), polyoxyethylene oleyl ether (for example, Nikkol BC-23■),
lBO-2■, N1kkol BO-10TXGID
, N1kkol BO-20■), etc. can be suitably used.
尿素としては日本薬局方あるいは化粧品原料基準に適合
したものを好適に使用することができる。As the urea, urea that complies with the Japanese Pharmacopoeia or standards for cosmetic raw materials can be suitably used.
パントテン酸誘導体としては、炭素数１〜５の脂肪酸の
エステル体であシ、特にＤ−ジヒドロキシ・やントテン
酸エチル（例えば日光ケミカルス社製Ｎ１ｋｋｏｌビフ
パント鰻）を好適に使用することができる。As the pantothenic acid derivative, esters of fatty acids having 1 to 5 carbon atoms can be suitably used, particularly ethyl D-dihydroxy-yanotothenate (for example, N1kkol Bifpanto Unagi manufactured by Nikko Chemicals).
ショ糖脂肪酸エステルとしては、炭素数Ｃ３−Ｃ２゜好
ましくはＣ１０”””１Ｂの脂肪酸とショ糖とのモノ、
ノ、トリエステル体等を挙げることができ、例えば日本
薬局方あるいは化粧品原料基準適合のショ糖モノラウラ
ート、ショ糖シミリステート、ショ糖モノパルミテート
、ショ糖トリラウラート、ショ糖システアラード、ショ
糖モノオレエート、ショ糖牛脂エステル等（例えば東京
化成社製ショ糖脂肪酸エステル、三菱化成食品社製菱糖
シュガーエステル）を好適に使用することができる。The sucrose fatty acid ester is a monomer of a fatty acid having a carbon number of C3 to C2, preferably C10"""1B, and sucrose;
For example, sucrose monolaurate, sucrose similistate, sucrose monopalmitate, sucrose trilaurate, sucrose cystearade, sucrose monooleate, etc. that meet the Japanese Pharmacopoeia or cosmetic raw material standards. Sucrose beef tallow ester and the like (for example, sucrose fatty acid ester manufactured by Tokyo Kasei Co., Ltd. and lozenge sugar ester manufactured by Mitsubishi Kasei Foods Co., Ltd.) can be suitably used.
本発明に係る皮膚外用剤においてその経皮吸収性を高め
る対象となる陽イオン性水溶性薬物は、ｐＫａが６５以
上であり、かつその１１を２５℃にて溶解するのに必要
な水の量が１０−未満のものである。このような陽イオ
ン性水溶性薬物としては、例えば、塩酸フルラゼ・ぐム
等の催眠鎮静剤、塩酸ドラマドール、メタル酸ジメトチ
アジン等の消炎鎮痛剤、塩酸クロミグラミン、塩酸イミ
ゾラミン、塩酸ジベンゼピン、塩酸メチルセルロ−ス等
の精神神経用剤、塩酸ドハミン等の強心剤、塩酸アセブ
トロール、塩酸インデノロール、塩酸ブクモロール等の
不整脈用剤、塩酸ユカラジン、酒石酸メトプロロール等
の血圧降下剤、塩酸ジルチアゼム、マレイン酸シネパジ
ド等の血管拡張剤、塩酸クロルプレナリン、塩酸ピルブ
チロール、塩酸ソロブチロール、硫酸サルブタモール等
の鎮咳去痰剤、硫酸テルブタリン等の抗喘息剤、塩酸グ
ロ力ルバジン等の抗悪性腫瘍剤、塩酸クリンダマイシン
、塩酸ピプメシリナム、硫酸シソマイシン、硫酸アミカ
シン等の抗生物質、塩酸ケタミン等の全身麻酔剤等が挙
げられる。The cationic water-soluble drug whose transdermal absorption is to be increased in the skin external preparation according to the present invention has a pKa of 65 or more, and the amount of water required to dissolve 11 at 25°C. is less than 10-. Examples of such cationic water-soluble drugs include hypnotic sedatives such as flurase and gum hydrochloride, anti-inflammatory analgesics such as dramadol hydrochloride and dimethothiazine metalate, clomigramine hydrochloride, imizolamine hydrochloride, dibenzepine hydrochloride, and methyl cellulose hydrochloride. - Neuropsychiatric drugs such as dohamin hydrochloride, cardiac drugs such as dohamine hydrochloride, arrhythmia drugs such as acebutolol hydrochloride, indenolol hydrochloride, and bucumolol hydrochloride, antihypertensive drugs such as yucalazine hydrochloride and metoprolol tartrate, and vasodilators such as diltiazem hydrochloride and cinepazide maleate. antitussive and expectorant agents such as chlorprenaline hydrochloride, pirbutyrol hydrochloride, solobutyrol hydrochloride, and salbutamol sulfate; antiasthmatic agents such as terbutaline sulfate; antineoplastic agents such as gloruvazine hydrochloride; clindamycin hydrochloride, pipmecillinum hydrochloride, and sisomicin sulfate. , antibiotics such as amikacin sulfate, and general anesthetics such as ketamine hydrochloride.
本発明に従った皮膚外用剤中に配合される前記イオン性
吸収助剤および非イオン性吸収助剤は、薬効成分である
陽イオン性水溶性薬物の経皮吸収を促進する作用を有す
る物質であシ、その合計量の陽イオン性水溶性薬物に対
する配合比は１：０．１〜２００（重量比）、好ましく
は１：０．２〜乙
ｘｆｏ（重量比）で配合される。The ionic absorption aid and nonionic absorption aid that are incorporated into the skin external preparation according to the present invention are substances that have the effect of promoting transdermal absorption of a cationic water-soluble drug as a medicinal ingredient. The blending ratio of the total amount of cationic water-soluble drug to the cationic water-soluble drug is 1:0.1 to 200 (weight ratio), preferably 1:0.2 to 2xfo (weight ratio).
この配合比が少な過ぎると所望の吸収促進効果が得られ
ない。また、薬効成分が経皮吸収によシ全身的な作用を
発現するためには、ある程度の薬物量が必要であシ、従
って配合比が多過ぎると剤形調製が困難となったシ使用
感が悪くなるので好ましくない。If this blending ratio is too small, the desired absorption promoting effect cannot be obtained. In addition, in order for medicinal ingredients to exert systemic effects through transdermal absorption, a certain amount of drug is required. This is not preferable because it worsens the condition.
また、イオン性吸収助剤と非イオン性吸収助剤との配合
比は２：８〜８：２（重量比）、好ましくは３ニア〜７
：３で配合される。この範囲外では、所望の相乗的な経
皮吸収促進効果が得られない。In addition, the blending ratio of the ionic absorption aid and the nonionic absorption aid is 2:8 to 8:2 (weight ratio), preferably 3 to 7
:3 is blended. Outside this range, the desired synergistic transdermal absorption promoting effect cannot be obtained.
本発明に従った皮膚外用剤に使用される基剤は、一般的
な軟膏、硬膏、エアゾール、ローション、・千ツノ剤、
テープ剤などの皮膚外用剤の型造に使用されるとそれ自
体薬効を示さない物質であシ、例えば、植物油、豚脂、
ワセリンなどの油性基剤、親水ワセリン、精製ラノリン
、吸水軟膏、加水ラノリンなどの吸収性基剤、親水軟膏
などの親水性基剤、マクロゴール軟膏などの水溶性基剤
、澱粉、プルラン、ゼラチン、水溶性セルロース誘導体
などの天然水溶性高分子、カルブキシビニルポリマー、
テリアクリル酸ナトリウム、プリビニルアルコールなど
の合成水溶性高分子、ポリアルキルアクリレート、ポリ
アルキルビニルエーテル、アクリロニトリル−ブタジェ
ンコポリマー、スチレン−インプレン−スチレン−プロ
ンクコポリマーなどの合成樹脂などをあげることができ
る。The bases used in the skin external preparation according to the present invention include general ointments, plasters, aerosols, lotions,
Substances that do not themselves exhibit medicinal efficacy when used in the molding of external skin preparations such as tapes, such as vegetable oil, lard,
Oily bases such as petrolatum, hydrophilic petrolatum, purified lanolin, water-absorbing ointments, absorbent bases such as hydrated lanolin, hydrophilic bases such as hydrophilic ointments, water-soluble bases such as macrogol ointment, starch, pullulan, gelatin, Natural water-soluble polymers such as water-soluble cellulose derivatives, carboxyvinyl polymers,
Examples include synthetic water-soluble polymers such as sodium teracrylate and previnyl alcohol, and synthetic resins such as polyalkyl acrylates, polyalkyl vinyl ethers, acrylonitrile-butadiene copolymers, and styrene-imprene-styrene-Pronk copolymers.
テープ剤、バッグ剤などの剤形の外用剤の場合には、前
記した基剤のｒで天然水溶性高分子又は合成水溶性高分
子を好適に用いることができる。In the case of external preparations in the form of tapes, bags, etc., natural water-soluble polymers or synthetic water-soluble polymers can be suitably used in the above-mentioned base r.
本発明において使用することができる天然水溶性高分子
としては、アラビアゴム、トラガカントゴム、グアール
ゴム、カラヤゴム、クインスシードデンプン等の植物系
水溶性高分子、アルギン酸、カラギーナン等の海藻系水
溶性高分子、ゼラチン等の動物系水溶性高分子、デキス
トラン等の微生物系水溶性高分子、メチルセルロース（
ＭＣ）、カルブキシメチルセルロース及ヒソのｆｉ （
ＣＭＣ）、ヒドロキシエチルセルロース（ＨＥＣ） 、
ヒドロキシプロピルセルロース（ＲＰＣ）等の繊維素系
水溶性高分子、などをあげることができ、好ましくは繊
維素系水溶性高分子であシ、特に好ましくはヒドロキシ
ゾロビルセルロースでアル。Natural water-soluble polymers that can be used in the present invention include plant-based water-soluble polymers such as gum arabic, gum tragacanth, guar gum, gum karaya, and quince seed starch, seaweed-based water-soluble polymers such as alginic acid and carrageenan, and gelatin. animal-based water-soluble polymers such as dextran, microbial-based water-soluble polymers such as dextran, methylcellulose (
MC), carboxymethyl cellulose and hiso fi (
CMC), hydroxyethyl cellulose (HEC),
Examples include cellulose-based water-soluble polymers such as hydroxypropyl cellulose (RPC), preferably cellulose-based water-soluble polymers, and particularly preferably hydroxyzorobyl cellulose.
一方、本発明に係る皮膚外用剤の基剤として好適に使用
することができる合成水溶性高分子としては、例えば、
カルボキシビニルポリマー、ポリビニルアルコール、ポ
リエチレンオキサイド及びこれら架橋物などの任意の合
成水溶性高分子を使用することができ、特にアクリル酸
又はビニルアルコールを主たる構成モノマーとした化粧
品原料基準に適合したもの、例えば、ポリアクリル酸及
びそのナトリウム塩又はポリビニルアルコール及びこれ
らの架橋物を好適に使用することができる。On the other hand, examples of synthetic water-soluble polymers that can be suitably used as a base for the external skin preparation according to the present invention include:
Any synthetic water-soluble polymers such as carboxyvinyl polymers, polyvinyl alcohol, polyethylene oxide, and crosslinked products thereof can be used, especially those that meet the standards for cosmetic raw materials whose main constituent monomer is acrylic acid or vinyl alcohol, e.g. , polyacrylic acid and its sodium salt, or polyvinyl alcohol and crosslinked products thereof can be suitably used.
本発明に従った皮膚外用剤には、更に必要に応じてアラ
ビアゴム、レシチン、グリセリン、ゾロピレングリコー
ルなどの乳化剤、懸濁剤、保湿剤その他の慣用の添加剤
を配合する事ができる。The skin preparation according to the present invention may further contain emulsifiers, suspending agents, humectants, and other conventional additives such as gum arabic, lecithin, glycerin, and zoropylene glycol, if necessary.
本発明に従った皮膚外用剤は皮膚と成る程度の時間接触
する任意の剤形として適用することができ、例えば軟膏
、硬膏、エアゾール、ローション、・ぐツブ剤、テープ
剤などの形状とすることができる。The skin external preparation according to the present invention can be applied in any dosage form that is in contact with the skin for a sufficient period of time, such as ointments, plasters, aerosols, lotions, poultices, tapes, etc. I can do it.
本発明に従った皮膚外用剤は従来公知の様々な方法によ
って目的とする剤形とすることができる。The skin external preparation according to the present invention can be made into the desired dosage form by various conventionally known methods.
例えば、テープ剤の場合には前記イオン性吸収助剤およ
び非イオン性吸収助剤と陽イオン性水溶性薬物の溶液に
前記基剤、好ましくは水溶性セルロース誘導体およびあ
るいは、合成水溶性高分子を懸濁せしめてゾルを形成し
、以後公知の製法に準じて所望のテープ剤を製造するこ
とができる。For example, in the case of a tape preparation, the base material, preferably a water-soluble cellulose derivative and/or a synthetic water-soluble polymer, is added to a solution of the ionic absorption aid, nonionic absorption aid, and cationic water-soluble drug. A sol is formed by suspending the mixture, and a desired tape preparation can then be manufactured according to a known manufacturing method.
また硬膏剤では、弾性体、軟化剤、粘着付与剤。Also, in plasters, elastic bodies, softeners, and tackifiers are used.
酸化防止剤および充填剤の混合物を加熱して軟化させ、
これにイオン性吸収助剤および非イオン性吸収助剤と陽
イオン性水溶性薬物を練シ合わせ、以後公知の製法に準
じて調製することができる。heating the mixture of antioxidant and filler to soften it;
This can be mixed with an ionic absorption aid, a nonionic absorption aid, and a cationic water-soluble drug, and then prepared according to a known manufacturing method.
エアゾール剤では、乳化した基剤にイオン性吸収助剤お
よび非イオン性吸収助剤と陽イオン性水溶性薬物を加え
以後公知の製法に準じて調製することができる。Aerosols can be prepared by adding an ionic absorption aid, a nonionic absorption aid, and a cationic water-soluble drug to an emulsified base, and then following a known manufacturing method.
軟膏、ローション剤では、イオン性吸収助剤オよび非イ
オン性吸収助剤と陽イオン性水溶性薬物を混合し、これ
を少量の基剤と研和したのち残シの基剤で練合し、以後
公知の製法に準じて調製することができる。For ointments and lotions, an ionic absorption aid, a nonionic absorption aid, and a cationic water-soluble drug are mixed, this is mixed with a small amount of a base, and then kneaded with the remaining base. , it can be prepared according to a known manufacturing method.
更に・やツブ剤では、水溶性高分子の増粘剤、賦形剤、
保湿剤および水の混合物に、イオン性吸収助剤および非
イオン性吸収助剤と陽イオン性水溶性薬物を加えて練合
し、以後公知の製法に準じて調製することができる。In addition, thickening agents include water-soluble polymer thickeners, excipients,
It can be prepared by adding an ionic absorption aid, a nonionic absorption aid, and a cationic water-soluble drug to a mixture of a humectant and water, kneading the mixture, and then following a known manufacturing method.
実施例
以下、実施例に従って本発明を更に説明するが本発明の
技術的範囲を以下の実施例に限定するものでないことは
いうまでもない。EXAMPLES Hereinafter, the present invention will be further explained according to Examples, but it goes without saying that the technical scope of the present invention is not limited to the following Examples.
例１（実施例）
塩酸ゾルチアゼム０．６ｇおよびラウリル硫酸トリエタ
ノールアミン０．０４５９、ポリオキシエチレン（９）
ラウリルエーテルｏ、０４５．！ｉ＋を３０ ｖ／ｖ
Ｔ。Example 1 (Example) 0.6 g of soltiazem hydrochloride and 0.0459 g of triethanolamine lauryl sulfate, polyoxyethylene (9)
lauryl ether o, 045. ! i+ 30 v/v
T.
エタノール精製水７ｒＩＬｌに室温で溶解し、これにポ
リビニルアルコール０．６９とグリセリン０．６９ 全
攪拌下室温で徐々に添加して溶解せしめてゾルを形成し
た。The product was dissolved in 7 rIL of ethanol purified water at room temperature, and 0.69 g of polyvinyl alcohol and 0.69 g of glycerin were gradually added thereto at room temperature with full stirring to form a sol.
このゾルをガラス製プレート（寸法：２０口×２０ＣＭ
角）上に展延したのち、温度５０℃で乾燥してフィルム
を作成し、このフィルムを片面に粘着剤を塗布した多孔
性の不織布から成る粘着テープに転写してテープ状の皮
膚外用剤を製造（〜た。This sol is placed on a glass plate (dimensions: 20 holes x 20 cm)
After spreading it on top of the skin (corner), it is dried at a temperature of 50°C to create a film, and this film is transferred to an adhesive tape made of porous non-woven fabric coated with an adhesive on one side to form a tape-shaped skin preparation for external use. Manufacture (~ta)
例２（実施例）
例１において 、３９リオキシエチレン（９）ラウリル
エーテルに代えて、尿素０．０９．！ｉ＋を用いた以外
は、例１と同様にしてテープ状の皮膚外用剤を得た。Example 2 (Example) In Example 1, urea 0.09. ! A tape-shaped skin preparation for external use was obtained in the same manner as in Example 1, except that i+ was used.
例３（実施例）
例１において、ラウリル硫酸トリエタノールアミンに代
えて、ポリオキシエチレン（４）ラウＩＪ ルエーテル
リン酸ナトリウム０．０４５，９を用いた以外は、例１
と同様にしてテープ状の皮膚外用剤を得た。Example 3 (Example) Example 1 except that polyoxyethylene (4) lauryl ether phosphate sodium 0.045.9 was used in place of lauryl sulfate triethanolamine.
A tape-shaped skin preparation for external use was obtained in the same manner as above.
例４（実施例）
例３において、ポリオキシエチレン（９）ラウリルエー
テルに代えて、尿素０．０９ｇを用いた以外は、例３と
同様にしてテープ状の皮膚外用剤を得た。Example 4 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 3, except that 0.09 g of urea was used in place of polyoxyethylene (9) lauryl ether.
例５（実施例）
例３において、ポリオキシエチレン（９）ラウリルエー
テルに代えて、Ｄ−ノカル々トキシパントテン酸エチル
０．０６ｇを用いた以外は、例３と同様にしてテープ状
の皮膚外用剤を得た。Example 5 (Example) In the same manner as in Example 3, except that 0.06 g of ethyl D-nocartoxypantothenate was used in place of polyoxyethylene (9) lauryl ether, a tape-shaped skin external application was prepared. obtained the drug.
例６（実施例）
例３において、ポリオキシエチレン（９）ラウリルエー
テルに代えて、シヨ糖脂肪酸エステル０．０９ｇを用い
た以外は、例３と同様にしてテープ状の皮膚外用剤を得
た。Example 6 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 3, except that 0.09 g of sucrose fatty acid ester was used in place of polyoxyethylene (9) lauryl ether. .
例７（実施例）
例１において、ラウリル硫酸トリエタノールアミンに代
えて、ポリオキシエチレ／（４）ラウリルエーテル硫酸
ナトリウム０２０４５ｇを用いた以外は、例１と同様に
してテープ状の皮膚外用剤を得た。Example 7 (Example) A tape-shaped external preparation for skin was prepared in the same manner as in Example 1, except that 02,045 g of polyoxyethylene/(4) sodium lauryl ether sulfate was used in place of triethanolamine lauryl sulfate. Obtained.
例８（実施例）
例７において、ポリオキシエチレン（９）ラウリルエー
テルに代えて、尿素０．０９ｇを用いた以外は、例７と
同様にしてテープ状の皮膚外用剤を得た。Example 8 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 7, except that 0.09 g of urea was used instead of polyoxyethylene (9) lauryl ether.
例９（実施例）
例７において、ポリオキシエチレン（９）ラウリルエー
テルに代えて、Ｄ−ノカルベトキシノクントテン酸エチ
ル０．０６，９を用いた以外は、例７と同様にしてテー
プ状の皮膚外用剤を得た。Example 9 (Example) The tape was prepared in the same manner as in Example 7, except that 0.06.9 ethyl D-nocarbethoxynocuntothenate was used in place of polyoxyethylene (9) lauryl ether. A skin preparation for external use was obtained.
例１０（実施例）
例７において、ポリオキシエチレン（９）ラウリルエー
テルに代えて、シヨ糖脂肪酸エステル０．０９を用いた
以外は、例７と同様にしてテープ状の皮膚外用剤を得た
。Example 10 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 7, except that 0.09 sucrose fatty acid ester was used in place of polyoxyethylene (9) lauryl ether. .
例１１（実施例）
例１において、ラウリル硫酸トリエタノールアミンに代
えて、ラウロイルサルコシンナトリウム０．０４１９を
用いた以外は、例１と同様にしてテープ状の皮膚外用剤
を得た。Example 11 (Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that 0.0419 sodium lauroylsarcosine was used in place of triethanolamine lauryl sulfate.
例１２（実施例）
例１１において、ポリオキシエチレン（９）ラウリルエ
ーテルに代えて、尿素０．０９９を用いた以外は、例１
１と同様にしてテープ状の皮膚外用剤を得た。Example 12 (Example) Example 1 except that urea 0.099 was used instead of polyoxyethylene (9) lauryl ether in Example 11.
A tape-shaped external preparation for skin was obtained in the same manner as in 1.
例１３（実施例）
例１において、ラウリル硫酸トリエタノールアミンに代
えて、２−ウンデシル−Ｎ−カルがキシメチル−Ｎ−ヒ
ドロキシエチルイミダゾリニウムベタイン０．０４５．
９を用いた以外は、例１と同様にしてテープ状の皮膚外
用剤を得た。Example 13 (Example) In Example 1, instead of triethanolamine lauryl sulfate, 2-undecyl-N-cal was substituted with 0.045.
A tape-shaped skin preparation for external use was obtained in the same manner as in Example 1, except that Example 9 was used.
例１４（実施例）
例１３において、ポリオキシエチレン（９）ラウリルエ
ーテルに代えて、尿素０．０９ｇを用いた以外は、例１
３と同様にしてテープ状の皮膚外用剤を得た。Example 14 (Example) Example 1 except that 0.09 g of urea was used in place of polyoxyethylene (9) lauryl ether in Example 13.
A tape-shaped skin preparation for external use was obtained in the same manner as in 3.
例１５（実施例）
例１３において、ポリオキシエチレン（９）ラウリルエ
ーテルに代えて、Ｄ−・ゾカルペトキシｉｅントテン酸
エチル０．０６ｇを用いた以外は、例１３と同様にして
テープ状の皮膚外用剤を得た。Example 15 (Example) In the same manner as in Example 13, except that 0.06 g of ethyl D-zocarpetoxyietothenate was used in place of polyoxyethylene (9) lauryl ether, a tape-shaped skin external application was performed. obtained the drug.
例陰（実施例）
例１において、ラウリル硫酸トリエタノールアミンに代
えて、ラウリルジメチルアミノ酢酸ベタイン０．０４．
５．！９を用いた以外は、例１と同様にしてテープ状の
皮膚外用剤を得た。Example In Example 1, lauryldimethylaminoacetic acid betaine was replaced with 0.04.
5. ! A tape-shaped skin preparation for external use was obtained in the same manner as in Example 1, except that Example 9 was used.
例１７（実施例）
例１において、塩酸ゾルチアゼムに代えて、塩酸フルラ
ゼパム０．２ｇを用い、ラウリル硫酸トリエタノールア
ミンおよびポリオキシエチレン（９）ラウリルエーテル
の配合量をそれぞれ０．０３．！９とした以外は、例１
と同様にしてテープ状の皮膚外用剤を得た。Example 17 (Example) In Example 1, 0.2 g of flurazepam hydrochloride was used instead of soltiazem hydrochloride, and the amounts of triethanolamine lauryl sulfate and polyoxyethylene (9) lauryl ether were each 0.03 g. ! Example 1 except that it was set to 9.
A tape-shaped skin preparation for external use was obtained in the same manner as above.
例１８（実施例）
例１０において、塩酸ジルチアゼムに代えて、塩酸イミ
プラミン０．２．！ｉ＋を用い、ポリオキシエチレン（
４）ラウリルエーテル硫酸ナトリウムおよびショ糖脂肪
酸エステルの配合量をそれぞれ０．０３ｇおよび０．０
６，９とした以外は、例１０と同様にしてテープ状の皮
膚外用剤を得た。Example 18 (Example) In Example 10, diltiazem hydrochloride was replaced with imipramine hydrochloride 0.2. ! Using i+, polyoxyethylene (
4) The amounts of sodium lauryl ether sulfate and sucrose fatty acid ester were 0.03g and 0.0g, respectively.
A tape-shaped skin preparation for external use was obtained in the same manner as in Example 10, except that Sample No. 6 and No. 6 and 9 were used.
例１９（実施例）
例３において、塩酸ノルチアゼムに代えて、塩酸エカラ
ジン０．６．９を用い、ポリオキシエチレン（４）ラウ
リルエーテルリン酸ナトリウムおよびポリオキシエチレ
ン（９）ラウリルエーテルの配合量をそれぞれ０．０３
ｇとした以外は、例３と同様にしてテープ状の皮膚外用
剤を得た。Example 19 (Example) In Example 3, ecalazine hydrochloride 0.6.9 was used instead of nortiazem hydrochloride, and the amounts of polyoxyethylene (4) sodium lauryl ether phosphate and polyoxyethylene (9) lauryl ether were changed. 0.03 each
A tape-shaped skin preparation for external use was obtained in the same manner as in Example 3, except that g was used.
例２０（実施例）
例４において、塩酸ジルチアゼムに代えて塩酸アセブト
ロール０．２ｇを用い、ポリオキシエチレン（４）ラウ
リルエーテルリン酸ナトリウムおよび尿素の配合量をそ
れぞれ０．０７ｇとした以外は、例４と同様にしてテー
プ状の皮膚外用剤を得た。Example 20 (Example) Example 4 except that 0.2 g of acebutolol hydrochloride was used in place of diltiazem hydrochloride, and the amounts of sodium polyoxyethylene (4) lauryl ether phosphate and urea were each 0.07 g. A tape-shaped skin preparation for external use was obtained in the same manner as in 4.
例２１（実施例）
例８において、塩酸ジルチアゼムに代えて塩酸アセブト
ロール０．２．９を用い、ポリオキシエチレン（４）ラ
ウリルエーテル硫酸ナトリウムおよび尿素の配合量をそ
れぞれ０．０７９とした以外は、例８と同様にしてテー
プ状の皮膚外用剤を得た。Example 21 (Example) In Example 8, except that 0.2.9 of acebutolol hydrochloride was used in place of diltiazem hydrochloride, and the amounts of polyoxyethylene (4) sodium lauryl ether sulfate and urea were each 0.079. A tape-shaped external preparation for skin was obtained in the same manner as in Example 8.
例２２（実施例）
例３において、塩酸ゾルチアゼムに代えて、塩体
酸クタミン０．５ｇを用い、ポリオキシエチレン（６）
ラウリルエーテルリン酸ナトリウムおよびポリオキシエ
チレン（９）ラウリルエーテルの配合量をそれぞれ０．
１０ｇとした以外は、例３と同様にしてテープ状の皮膚
外用剤を得た。Example 22 (Example) In Example 3, 0.5 g of cutamine hydrochloride was used in place of soltiazem hydrochloride, and polyoxyethylene (6) was used.
The amounts of sodium lauryl ether phosphate and polyoxyethylene (9) lauryl ether were each 0.
A tape-shaped external preparation for skin was obtained in the same manner as in Example 3, except that the amount was 10 g.
例２３（実施例）
塩酸ノルチアゼム５ｇおよびポリオキシエチレン（４）
ラウリルエーテル硫酸ナトリウム１．２５ｇ、尿素２．
５ｇを乳鉢に秤り取って混合し、スラリー状としだ。こ
れに少量の水溶性軟膏基剤を加えてよく練り合わせたの
ち、更に水溶性軟膏基剤を加えて十分に練シ合わせて全
量を５０！！とし、軟膏状の皮膚外用剤を製造した。Example 23 (Example) Nortiazem hydrochloride 5g and polyoxyethylene (4)
Sodium lauryl ether sulfate 1.25g, urea 2.
Weigh out 5g in a mortar and mix to make a slurry. Add a small amount of water-soluble ointment base to this and mix well, then add water-soluble ointment base and knead thoroughly to make a total volume of 50! ! An ointment-like preparation for external use on the skin was prepared.
例２４（実施例）
例２３において、塩酸ゾルチアゼムに代えて、メシル酸
ジメトチアジン３ｇを用い、ポリオキシエチレン（４）
ラウリルエーテル硫酸ナトリウムおよび尿素の配合量を
それぞれ０．７５ｇおよび１．５ｇとした以外は、例２
３と同様にして軟膏状の皮膚外用剤を得た。Example 24 (Example) In Example 23, 3 g of dimethothiazine mesylate was used in place of soltiazem hydrochloride, and polyoxyethylene (4) was used.
Example 2 except that the amounts of sodium lauryl ether sulfate and urea were 0.75 g and 1.5 g, respectively.
An ointment-like skin preparation for external use was obtained in the same manner as in 3.
例２５（実施例）
例２４において、メシル酸ジメトチアノンに代えて、硫
酸サルブタモール０．８９を用いた以外は、例２４と同
様にして軟膏状の皮膚外用剤を得た。Example 25 (Example) An ointment-like external preparation for skin was obtained in the same manner as in Example 24, except that 0.89% of salbutamol sulfate was used in place of dimethothianone mesylate.
例２６（実施例）
親水軟膏５ｇを７０℃に加温溶解し、これに７０℃に加
温した精製水を徐々に加えて１００ ｍｌとし、冷却し
ながら十分に混和した。室温まで冷却したのち、メシル
酸ジメトチアジン１５＆と、ラウリル硫酸トリエタノー
ルアミン２．５ｇおよびポリオキシエチレン（９）ラウ
リルエーテル２．５ｇを加えて振とうし、ローション状
の皮膚外用剤を製造した。Example 26 (Example) 5 g of hydrophilic ointment was heated and dissolved at 70° C., purified water heated to 70° C. was gradually added to make 100 ml, and the mixture was thoroughly mixed while cooling. After cooling to room temperature, dimethothiazine mesylate 15&, 2.5 g of triethanolamine lauryl sulfate, and 2.5 g of polyoxyethylene (9) lauryl ether were added and shaken to produce a lotion-like skin preparation.
例２７（実施例）
６０℃の温水３０ｍ１に２ｇのゼラチンを加えて溶解し
た溶液にカオリン（無菌）２ｇを加えて練合した。これ
に塩酸ジルチアゼム１０ｇ、ポリオキシエチレン（４）
ラウリルエーテルリン酸ナトリウム５ｇ１シヨ糖脂肪酸
エステル１０ｇおよびハツカ油０．５ｇを加えて練合し
た。Example 27 (Example) To a solution in which 2 g of gelatin was added and dissolved in 30 ml of 60°C warm water, 2 g of kaolin (sterile) was added and kneaded. Add to this 10 g of diltiazem hydrochloride, polyoxyethylene (4)
5 g of sodium lauryl ether phosphate, 10 g of sucrose fatty acid ester, and 0.5 g of peppermint oil were added and kneaded.
次にあらかじめ濃グリセリン２０．９にポリビニ／ｌｚ
７ ／Ｌ７ ：７−ル６ｇとヒドロキシプロピルセル
ロース４．５ｇとを分散させた混合液を加えて練合した
のち、不織布（寸法：９×９α角）上に展延して・ぐツ
ブ状の皮膚外用剤を製造した。Next, add polyvinyl/lz to concentrated glycerin 20.9 in advance.
7/L7: After adding and kneading a mixture of 6 g of 7-ru and 4.5 g of hydroxypropyl cellulose, spread it on a non-woven fabric (dimensions: 9 x 9 α angle) to form a lump-like shape. A skin external preparation was manufactured.
例２８（実施例）
例２７において、塩酸ジルチアゼムに代えて、塩酸クタ
ミン３０ｇを用いた以外は、例２７と同様にしてノクッ
デ状の皮膚外用剤を得た。Example 28 (Example) A skin external preparation in the form of Nokudde was obtained in the same manner as in Example 27, except that 30 g of cutamine hydrochloride was used in place of diltiazem hydrochloride.
例２９（比較例）
例１において、ポリオキシエチレン（９）ラウリルエー
テルを用いなかった以外は、例１と同様にしてテープ状
の皮膚外用剤を得た。Example 29 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that polyoxyethylene (9) lauryl ether was not used.
例３０（比較例）
例１において、ポリオキシエチレン（９）ラウリルエー
テルを用いず、かつラウリル硫酸トリエタノールアミン
の配合量を０．０９ｇとした以外は、例１と同様にして
テープ状の皮膚外用剤を得た。Example 30 (Comparative Example) A tape-shaped skin was prepared in the same manner as in Example 1, except that polyoxyethylene (9) lauryl ether was not used and the amount of lauryl sulfate triethanolamine was 0.09 g. A topical preparation was obtained.
例３１（比較例）
例３において、ポリオキシエチレン（９）ラウリルエー
テルを用いなかった以外は、例３と同様にしてテープ状
の皮膚外用剤を得た。Example 31 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 3, except that polyoxyethylene (9) lauryl ether was not used.
例３２（比較例）
例３において、ポリオキシエチレン（９）ラウリルエー
テルを用いず、かつポリオキシエチレン（４）ラウリル
エーテルリン酸の配合量を０．０９ｇとした以外は、例
３と同様にしてテープ状の皮膚外用剤を得た。Example 32 (Comparative Example) The procedure was the same as in Example 3, except that polyoxyethylene (9) lauryl ether was not used and the amount of polyoxyethylene (4) lauryl ether phosphoric acid was 0.09 g. A tape-shaped skin preparation for external use was obtained.
例３３（比較例）
例７において、ポリオキシエチレン（９）ラウリルエー
テルを用いなかった以外は、例７と同様にしてテープ状
の皮膚外用剤を得た。Example 33 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 7, except that polyoxyethylene (9) lauryl ether was not used.
例３４（比較例）
例１１において、ポリオキシエチレン（９）ラウリルエ
ーテルを用いなかった以外は、例１１と同様にしてテー
プ状の皮膚外用剤を得た。Example 34 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 11, except that polyoxyethylene (9) lauryl ether was not used.
例３５（比較例）
例１３において、ポリオキシエチレン（９）ラウリルエ
ーテルを用いなかった以外は、例１３と同様にしてテー
プ状の皮膚外用剤を得た。Example 35 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 13, except that polyoxyethylene (9) lauryl ether was not used.
例３６（比較例）
例陰において、ポリオキシエチレン（９）ラウリルエー
テルを用いなかった以外は、例陰と同様にしてテープ状
の皮膚外用剤を得た。Example 36 (Comparative Example) A tape-shaped skin preparation for external use was obtained in the same manner as in Example 1 except that polyoxyethylene (9) lauryl ether was not used.
例３７（比較例）
例１において、ラウリル硫酸トリエタノールアミンを用
いなかった以外は、例１と同様にしてテープ状の皮膚外
用剤を得た。Example 37 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that triethanolamine lauryl sulfate was not used.
例３８（比較例）
例１において、ラウリル硫酸トリエタノールアミンを用
いず、かつポリオキシエチレン（９）ラウリルエーテル
の配合量を０．０９ｇとした以外は、例１と同様にして
テープ状の皮膚外用剤を得た。Example 38 (Comparative Example) A tape-shaped skin was prepared in the same manner as in Example 1, except that triethanolamine lauryl sulfate was not used and the amount of polyoxyethylene (9) lauryl ether was 0.09 g. A topical preparation was obtained.
例３９（比較例）
例６において、ポリオキシエチレン（４）ラウリルエー
テルリン酸ナトリウムを用いなかった以外は、例６と同
様にしてテープ状の皮膚外用剤を得た。Example 39 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 6, except that sodium polyoxyethylene (4) lauryl ether phosphate was not used.
例４０（比較例）
例６において、ポリオキシエチレン（４）ラウリルエー
テルリン酸ナトリウムを用いず、かつショ糖脂肪酸エス
テルの配合量を０．１８ｇとした以外は、例６と同様に
してテープ状の皮膚外用剤を得た。Example 40 (Comparative Example) A tape-shaped product was prepared in the same manner as in Example 6, except that polyoxyethylene (4) sodium lauryl ether phosphate was not used and the amount of sucrose fatty acid ester was 0.18 g. A skin preparation for external use was obtained.
例４１（比較例）
例２において、ラウリル硫酸トリエタノールアミンを用
いなかった以外は、例２と同様にしてテープ状の皮膚外
用剤を得た。Example 41 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 2, except that triethanolamine lauryl sulfate was not used.
例４２（比較例）
例５において、ポリオキシエチレン（４）ラウリルエー
テルリン酸ナトリウムを用いなかった以外は、例５と同
様にしてテープ状の皮膚外用剤を得だ。Example 42 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 5, except that sodium polyoxyethylene (4) lauryl ether phosphate was not used.
例４３（比較例）
例１において、ラウリル硫酸トリエタノールアミンおよ
びポリオキシエチレン（９）ラウリルエーテルを用いな
かった以外は、例１と同様にしてテープ状の皮膚外用剤
を得た。Example 43 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 1, except that triethanolamine lauryl sulfate and polyoxyethylene (9) lauryl ether were not used.
例４４（比較例）
例２０において、尿素を用いなかった以外は、例２０と
同様にして、テープ状の皮膚外用剤を得た。Example 44 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 20, except that urea was not used.
例４５（比較例）
例２１において、尿素を用いなかった以外は、例２０と
同様にして、テープ状の皮膚外用剤を得た。Example 45 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 20, except that urea was not used in Example 21.
例４６（比較例）
例２１において、ポリオキシエチレン（４）ラウリルエ
ーテル硫酸す） ＩＪウムを用いなかった以外は、例２
１と同様にして、テープ状の皮膚外用剤を得た。Example 46 (Comparative Example) Example 2 except that polyoxyethylene (4) lauryl ether sulfate was not used in Example 21.
In the same manner as in 1, a tape-shaped skin preparation for external use was obtained.
例４７（比較例）
例２０において、ポリオキシエチレン（４）ラウリルエ
ーテルリン酸す） ｌ）ラムおよび尿素を用いなかった
以外は、例２０と同様にしてテープ状の皮膚外用剤を得
た。Example 47 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 20, except that polyoxyethylene (4) lauryl ether phosphate l) rum and urea were not used.
例４８（比較例）
例２２において、ポリオキシエチレン（９）ラウリルエ
ーテルを用いなかった以外は、例２２と同様にしてテー
プ状の皮膚外用剤を得た。Example 48 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 22, except that polyoxyethylene (9) lauryl ether was not used.
例４９（比較例）
例２２において、ポリオキシエチレン（９）ラウリルエ
ーテルを用いず、かつポリオキシエチレン（４）ラウリ
ルエーテルリン酸ナトリウムの配合量を０．２ｇとした
以外は、例２２と同様にしてテープ状の皮膚外用剤を得
た。Example 49 (Comparative Example) Same as Example 22 except that polyoxyethylene (9) lauryl ether was not used and the amount of polyoxyethylene (4) lauryl ether sodium phosphate was 0.2 g. A tape-shaped skin preparation for external use was obtained.
例５０（比較例）
例２２において、ポリオキシエチレン（４）ラウリルエ
ーテルリン酸ナトリウムを用いなかった以外は例２２と
同様にしてテープ状の皮膚外用剤を得た。Example 50 (Comparative Example) A tape-shaped external preparation for skin was obtained in the same manner as in Example 22, except that sodium polyoxyethylene (4) lauryl ether phosphate was not used.
例５１（比較例）
例２２において、ポリオキシエチレン（４）ラウリルエ
ーテルリン酸ナトリウムを用いず、かつポリオキシエチ
レン（９）ラウリルエーテルの配合量を０．２ｇとした
以外は、例２２と同様にしてテープ状の皮膚外用剤を得
た。Example 51 (Comparative Example) Same as Example 22 except that polyoxyethylene (4) lauryl ether sodium phosphate was not used and the amount of polyoxyethylene (9) lauryl ether was 0.2 g. A tape-shaped skin preparation for external use was obtained.
例５２（比較例）
例２２において、ポリオキシエチレン（４）ラウリルエ
ーテルリン酸ナトリウムおよびポリオキシエチレン（９
）ラウリルエーテルを用いなかった以外は、例２２と同
様にしてテープ状の皮膚外用剤を得た。Example 52 (Comparative Example) In Example 22, polyoxyethylene (4) sodium lauryl ether phosphate and polyoxyethylene (9
) A tape-shaped external preparation for skin was obtained in the same manner as in Example 22, except that lauryl ether was not used.
例５３（比較例）
例２３において、尿素を用いなかった以外は、例２３と
同様にして軟膏状の皮膚外用剤を得た。Example 53 (Comparative Example) An ointment-like external preparation for skin was obtained in the same manner as in Example 23, except that urea was not used.
例５４（比較例）
例２３において、ポリオキシエチレン（４）ラウリルエ
ーテル硫酸ナトリウムを用いなかった以外は、例２３と
同様にして軟膏状の皮膚外用剤を得た。Example 54 (Comparative Example) An ointment-like external preparation for skin was obtained in the same manner as in Example 23, except that sodium polyoxyethylene (4) lauryl ether sulfate was not used.
例５５（比較例）
例２３において、ポリオキシエチレン（４）ラウリルエ
ーテル硫酸ナトリウムおよび尿素を用いなかった以外は
、例２３と同様にして軟膏状の皮膚外用剤を得た。Example 55 (Comparative Example) An ointment-like external preparation for skin was obtained in the same manner as in Example 23, except that sodium polyoxyethylene (4) lauryl ether sulfate and urea were not used.
例５６（比較例）
例２７において、ショ糖脂肪酸エステルを用いなかった
以外は、例２７と同様にして／ぐツブ状の皮膚外用剤を
得た。Example 56 (Comparative Example) A skin external preparation in the form of a bulge was obtained in the same manner as in Example 27, except that the sucrose fatty acid ester was not used.
例５７（比較例）
例２７において、ポリオキシエチレン（４）ラウリルエ
ーテルリン酸す） ＩＪウムを用いなかった以外は、例
２７と同様にしてパッジ状の皮膚外用剤を得た。Example 57 (Comparative Example) A patch-like external preparation for skin was obtained in the same manner as in Example 27, except that polyoxyethylene (4) lauryl ether phosphate (IJ) was not used.
例５８（比較例）
例２７において、ポリオキシエチレン（４）ラウリルエ
ーテルリン酸ナトリウムおよび尿素を用いなかった以外
は、例２７と同様にしてｉ９ツノ状の皮膚外用剤を得た
。Example 58 (Comparative Example) An i9 horn-shaped external preparation for skin was obtained in the same manner as in Example 27, except that sodium polyoxyethylene (4) lauryl ether phosphate and urea were not used.
例５９（評価例１）
例１２例３９例４１例５１例６２例８９例９゜例１１１
例１２２例１３２例１４２例１５２例陰、例２０．例２
１２例２２（実施例）および例２９〜例５２（比較例）
で製造したテープ状の皮膚外用剤のサンプル（７ｃｍ
Ｘ ７ ｃｍ角）を、動物として日本白色系雄性家兎（
体重的３ ｋｇ ）を用い、前日に腹部を除毛し、試験
当日に除毛部に貼シ付けた。Example 59 (Evaluation Example 1) Example 12 Example 39 Example 41 Example 51 Example 62 Example 89 Example 9゜Example 111
Example 122 Examples 132 Examples 142 Examples 152 Examples Yin, Example 20. Example 2
12 Example 22 (Example) and Examples 29 to 52 (Comparative Examples)
A sample (7 cm) of a tape-shaped external skin preparation manufactured by
x 7 cm square) and a Japanese white male domestic rabbit (
The abdominal area was dehaired the day before, and a patch was applied to the dehaired area on the day of the test.
貼付後経時的に耳静脈よシ採血し、常法によって得だ血
漿を高速液体クロマトグラフィーで分析して血漿中の化
合物の濃度を測定した。After application, blood was collected from the ear vein over time, and the plasma obtained was analyzed by high performance liquid chromatography in a conventional manner to measure the concentration of the compound in the plasma.
結果は第１図〜第８図に示した通りであった。The results were as shown in FIGS. 1 to 8.
第１図〜第８図の結果から明らかな様に、本発明による
イオン性吸収助剤および非イオン性吸収助剤の両方を含
有する場合（例１１例３２例４１例５、例６２例８２例
９２例１１１例１２２例１３゜例１４２例１５９例陰２
例２０９例２１２例２２）には、イオン性吸収助剤ある
いは非イオン性吸収助剤のいずれかを含有する場合（例
２９〜例４２１例４４〜例４６１例４８〜例５１）およ
びいずれの吸収助剤も含有しない場合（例４３゜例４７
１例５２）と比較して、極めて高い血中濃度を示した。As is clear from the results shown in FIGS. 1 to 8, when both the ionic absorption aid and the nonionic absorption aid according to the present invention are contained (Example 11, Example 32, Example 41, Example 5, Example 62, Example 82 Example 92 Example 111 Example 122 Example 13゜Example 142 Example 159 Example Yin 2
Example 209 Example 212 Example 22) contains either an ionic absorption aid or a nonionic absorption aid (Examples 29 to 421 Examples 44 to 461 Examples 48 to 51) and When no auxiliary agent is included (Example 43゜Example 47
Compared to Example 152), the blood concentration was extremely high.
捷だ、例１で示した様に、テープ剥離後は速やかに血中
薬物濃度が減少し、副作用発現時等での投与中止が容易
に行なえることが確認された。As shown in Example 1, it was confirmed that the drug concentration in the blood decreased quickly after the tape was removed, making it easy to discontinue administration in the event of side effects.
例６０（評価例２）
例２３（実施例）および例５３〜例５５（比較例）で製
造した軟膏状の皮膚外用剤サンプルを、動物として日本
白色系家兎（体重的３ ｋｌ？ ）を用い、前日に腹部
を除毛し、試験当日に除毛部に塗布（面積７ ｃｍ Ｘ
７ ｃｍ角）した。Example 60 (Evaluation Example 2) The ointment-like external skin preparation samples produced in Example 23 (Example) and Examples 53 to 55 (Comparative Examples) were used as animals: Japanese white domestic rabbits (weight: 3 kl?). The abdomen was removed the day before, and on the day of the test, it was applied to the area where the hair was removed (area 7 cm x
7 cm square).
塗布後側５９（評価例１）と同様の方法で、血漿中の化
合物濃度を測定した。The compound concentration in plasma was measured in the same manner as on the post-coating side 59 (Evaluation Example 1).
結果は第９図に示した通りであった。第９図の結果から
明らかな様に、本発明によるイオン性吸収助剤および非
イオン性吸収助剤の両方を含有する場合（例２３）には
、イオン性吸収助剤あるいは非イオン性吸収助剤のいず
れかを含有する場合（例５３１例５４）およびいずれの
吸収助剤も含有しない場合（例５５）と比較して、極め
て高い血中濃度を示しだ。The results were as shown in FIG. As is clear from the results in Figure 9, when containing both the ionic absorption aid and nonionic absorption aid according to the present invention (Example 23), The blood concentration was extremely high compared to cases containing any of the absorption aids (Example 531 and Example 54) and cases containing no absorption aid (Example 55).
例６１（評価例３）
例２７（実施例）および例５６〜例５８（比較例）で製
造した・やツブ状の皮膚外用剤サンプル（７Ｘ７ｃｒｎ
角）を、例５９（評価例１）と同様の方法で貼付し、血
漿中の化合物濃度を測定した。Example 61 (Evaluation Example 3) Slightly lumpy skin external preparation samples produced in Example 27 (Example) and Examples 56 to 58 (Comparative Examples) (7X7crn
(Evaluation Example 1) was applied in the same manner as in Example 59 (Evaluation Example 1), and the compound concentration in plasma was measured.
結果は第１０図に示した通シであった。第１０図の結果
から明らかな様に、本発明によるイオン性吸収助剤およ
び非イオン性吸収助剤の両方を含有する場合（例２７）
には、イオン性吸収助剤あるいは非イオン性吸収助剤の
いずれかを含有する場合（例５６２例５７）およびいず
れの吸収助剤も含有しない場合（例５８）と比較して、
極めて高い血中濃度を示した。The results were as shown in Figure 10. As is clear from the results in Figure 10, the case containing both the ionic absorption aid and nonionic absorption aid according to the present invention (Example 27)
In comparison with cases containing either an ionic absorption aid or a nonionic absorption aid (Example 562, Example 57) and a case containing neither absorption aid (Example 58),
It showed an extremely high blood concentration.
従って、例５９〜例６１（評価例１〜３）の結果より、
基剤中にイオン性吸収助剤および非イオン性吸収助剤の
両方を含有させる事により、いずれか片方の吸収助剤を
含有させた場合、あるいはいずれの吸収助剤も含有させ
ない場合と比較して、陽イオン性水溶性薬物がより速や
かに体内に吸収されてより高い血中濃度を持続的に与え
、吸収促進効果が相乗的に高まる事が確認された。Therefore, from the results of Examples 59 to 61 (Evaluation Examples 1 to 3),
By containing both an ionic absorption aid and a nonionic absorption aid in the base material, the results are compared to cases where either one of the absorption aids is included or when neither of the absorption aids is included. It was confirmed that cationic water-soluble drugs are more rapidly absorbed into the body, providing a sustained higher blood concentration, and synergistically increasing the absorption promoting effect.
第１図〜第８図は、例１２例３１例４２例５゜例６２例
８１例９２例１１２例１２８例１３２例１４、例１５．
例陰１例２０２例２１１例２２（実施例）で製造したテ
ープ状の皮膚外用剤の経皮吸収効果を、例２９〜例５２
（比較例）の皮膚外用剤の経皮吸収効果と対比して示し
たグラフ図である。
また第９図は、例２３（実施例）で製造した軟膏状の皮
膚外用剤の経皮吸収効果を、例５３〜例５５（比較例）
の皮膚外用剤の経皮吸収効果と対比して示したグラフ図
であり、第１０図は、例２７（実施例）で製造した・ｅ
ノブ状の皮膚外用剤の経皮吸収効果を、例５６〜例５８
（比較例）の皮膚外用剤の経皮吸収効果と対比して示し
たグラフ図である。Figures 1 to 8 show examples 12, 31, 42, 5, 62, 81, 92, 112, 128, 132, 14, and 15.
Example 1 Example 202 Example 211 The transdermal absorption effect of the tape-shaped skin external preparation prepared in Example 22 (Example) was evaluated in Examples 29 to 52.
It is a graph diagram shown in comparison with the transdermal absorption effect of the skin external preparation of (comparative example). Further, FIG. 9 shows the transdermal absorption effect of the ointment-like external skin preparation prepared in Example 23 (Example) and Examples 53 to 55 (Comparative Example).
FIG. 10 is a graph showing the transdermal absorption effect of the external skin preparation prepared in Example 27 (Example).
The transdermal absorption effect of knob-shaped external preparations for skin was evaluated in Examples 56 to 58.
It is a graph diagram shown in comparison with the transdermal absorption effect of the skin external preparation of (comparative example).
Claims (1)
界面活性剤、両性界面活性剤の群の中から選ばれた１種
類のイオン性吸収助剤、およびポリオキシエチレンアル
キルエーテル、尿素、パントテン酸誘導体、ショ糖脂肪
酸エステルの群の中から選ばれた１種類の非イオン性吸
収助剤とを基剤中に含ませて成る、陽イオン性水溶性薬
物の経皮吸収性を高めた皮膚外用剤。 ２、陽イオン水溶性薬物のｐＫａが６．５以上であり、
かつその１ｇを２５℃にて溶解するのに必要な水の量が
１０ｍｌ未満である、特許請求の範囲第１項記載の皮膚
外用剤。 ３、イオン性吸収助剤と非イオン性吸収助剤の合計量の
、陽イオン性水溶性薬物に対する配合比（重量比）が０
．１〜２００であり、かつイオン性吸収剤と非イオン性
吸収助剤の配合比（重量比）が２：８〜８：２である特
許請求の範囲第１項記載の皮膚外用剤。 ４、陰イオン性界面活性剤が、アルキル硫酸およびその
塩、ポリオキシエチレンアルキルエーテル硫酸およびそ
の塩、ポリオキシエチレンアルキルエーテルリン酸およ
びその塩、サルコシン誘導体およびその塩の中のいずれ
かである、特許請求の範囲第１項記載の皮膚外用剤。 ５、両性界面活性剤が、アルキルベタイン、アルキルイ
ミダゾリニウムベタインの中のいずれかである、特許請
求の範囲第１項記載の皮膚外用剤。[Scope of Claims] 1. A cationic water-soluble drug as the main drug, one type of ionic absorption aid selected from the group of anionic surfactants and amphoteric surfactants, and polyoxy A cationic water-soluble drug comprising a nonionic absorption aid selected from the group of ethylene alkyl ethers, urea, pantothenic acid derivatives, and sucrose fatty acid esters. A topical skin preparation with enhanced skin absorption. 2. The pKa of the cationic water-soluble drug is 6.5 or more,
The external preparation for skin according to claim 1, wherein the amount of water required to dissolve 1 g of the preparation at 25° C. is less than 10 ml. 3. The blending ratio (weight ratio) of the total amount of ionic absorption aid and nonionic absorption aid to the cationic water-soluble drug is 0.
．． 1 to 200, and the compounding ratio (weight ratio) of the ionic absorbent to the nonionic absorption aid is 2:8 to 8:2. 4. The anionic surfactant is any one of alkyl sulfuric acid and its salt, polyoxyethylene alkyl ether sulfuric acid and its salt, polyoxyethylene alkyl ether phosphoric acid and its salt, sarcosine derivative and its salt, The skin external preparation according to claim 1. 5. The skin external preparation according to claim 1, wherein the amphoteric surfactant is either an alkyl betaine or an alkylimidazolinium betaine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20173885A JPS6261929A (en) | 1985-09-13 | 1985-09-13 | Dermatic drug for external use having improved transcutaneous absorbability of water-soluble drug |
| EP86100939A EP0189861A3 (en) | 1985-01-26 | 1986-01-24 | Percutaneous absorption accelerator for ionic water-soluble medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20173885A JPS6261929A (en) | 1985-09-13 | 1985-09-13 | Dermatic drug for external use having improved transcutaneous absorbability of water-soluble drug |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS6261929A true JPS6261929A (en) | 1987-03-18 |
Family
ID=16446115
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20173885A Pending JPS6261929A (en) | 1985-01-26 | 1985-09-13 | Dermatic drug for external use having improved transcutaneous absorbability of water-soluble drug |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6261929A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63208537A (en) * | 1987-02-26 | 1988-08-30 | Shiseido Co Ltd | Percutaneous absorption promoter and skin external preparation containing said promoter |
| JPS6456622A (en) * | 1987-08-28 | 1989-03-03 | Ss Pharmaceutical Co | Percutaneous absorbefacient base composition |
| JP2008273985A (en) * | 1998-05-22 | 2008-11-13 | Thornton & Ross Ltd | Pharmaceutical composition comprising amphoteric surfactant, alkoxylated cetyl alcohol and polar drug |
-
1985
- 1985-09-13 JP JP20173885A patent/JPS6261929A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63208537A (en) * | 1987-02-26 | 1988-08-30 | Shiseido Co Ltd | Percutaneous absorption promoter and skin external preparation containing said promoter |
| JPS6456622A (en) * | 1987-08-28 | 1989-03-03 | Ss Pharmaceutical Co | Percutaneous absorbefacient base composition |
| JP2008273985A (en) * | 1998-05-22 | 2008-11-13 | Thornton & Ross Ltd | Pharmaceutical composition comprising amphoteric surfactant, alkoxylated cetyl alcohol and polar drug |
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