JPS63287730A - Percutaneous absorption promoter and skin external preparation containing said promoter - Google Patents
Percutaneous absorption promoter and skin external preparation containing said promoterInfo
- Publication number
- JPS63287730A JPS63287730A JP12133687A JP12133687A JPS63287730A JP S63287730 A JPS63287730 A JP S63287730A JP 12133687 A JP12133687 A JP 12133687A JP 12133687 A JP12133687 A JP 12133687A JP S63287730 A JPS63287730 A JP S63287730A
- Authority
- JP
- Japan
- Prior art keywords
- external preparation
- derivative
- promoter
- transdermal absorption
- polyethyleneimine
- 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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- 229940124532 absorption promoter Drugs 0.000 title 1
- 238000010521 absorption reaction Methods 0.000 claims abstract description 34
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- 125000004122 cyclic group Chemical group 0.000 claims description 2
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- -1 cyclic aliphatic hydrocarbon Chemical class 0.000 abstract description 10
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- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 239000004020 conductor Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- 229960005156 digoxin Drugs 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009313 farming Methods 0.000 description 1
- LPEPZBJOKDYZAD-UHFFFAOYSA-N flufenamic acid Chemical compound OC(=O)C1=CC=CC=C1NC1=CC=CC(C(F)(F)F)=C1 LPEPZBJOKDYZAD-UHFFFAOYSA-N 0.000 description 1
- 229960004369 flufenamic acid Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- YUFWAVFNITUSHI-UHFFFAOYSA-N guanethidine monosulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.NC(=N)NCCN1CCCCCCC1 YUFWAVFNITUSHI-UHFFFAOYSA-N 0.000 description 1
- 229960004848 guanethidine sulfate Drugs 0.000 description 1
- 239000000118 hair dye Substances 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 239000008311 hydrophilic ointment Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000005554 hypnotics and sedatives Substances 0.000 description 1
- 229940005535 hypnotics and sedatives Drugs 0.000 description 1
- 239000000077 insect repellent Substances 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 150000002632 lipids Chemical group 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- 230000008099 melanin synthesis Effects 0.000 description 1
- 229960004469 methoxsalen Drugs 0.000 description 1
- SQBBOVROCFXYBN-UHFFFAOYSA-N methoxypsoralen Natural products C1=C2OC(=O)C(OC)=CC2=CC2=C1OC=C2 SQBBOVROCFXYBN-UHFFFAOYSA-N 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000001333 moisturizer Effects 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229940105132 myristate Drugs 0.000 description 1
- CSDTZUBPSYWZDX-UHFFFAOYSA-N n-pentyl nitrite Chemical compound CCCCCON=O CSDTZUBPSYWZDX-UHFFFAOYSA-N 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 1
- 229960005301 pentazocine Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 229960003253 procainamide hydrochloride Drugs 0.000 description 1
- ABTXGJFUQRCPNH-UHFFFAOYSA-N procainamide hydrochloride Chemical compound [H+].[Cl-].CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 ABTXGJFUQRCPNH-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 108090000623 proteins and genes Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 238000007151 ring opening polymerisation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960005158 sulfamethizole Drugs 0.000 description 1
- VACCAVUAMIDAGB-UHFFFAOYSA-N sulfamethizole Chemical compound S1C(C)=NN=C1NS(=O)(=O)C1=CC=C(N)C=C1 VACCAVUAMIDAGB-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- NGSWKAQJJWESNS-ZZXKWVIFSA-N trans-4-coumaric acid Chemical compound OC(=O)\C=C\C1=CC=C(O)C=C1 NGSWKAQJJWESNS-ZZXKWVIFSA-N 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 229960003223 tripelennamine Drugs 0.000 description 1
- 239000002966 varnish 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
- 229930003231 vitamin Natural products 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 150000003700 vitamin C derivatives Chemical class 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 230000008673 vomiting Effects 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
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は経皮吸収促進剤及びこれ全含有してなる外用剤
に関し、更に詳しくはポリエチレンイミンおよび/また
はその誘導体を有効成分とする経皮吸収剤及び該経皮吸
収剤と薬効成分とを含有してなる外用剤に関する。Detailed Description of the Invention [Industrial Application Field] The present invention relates to a transdermal absorption enhancer and an external preparation containing the same, and more particularly to a transdermal absorption enhancer containing polyethyleneimine and/or its derivatives as an active ingredient. The present invention relates to an absorbent and an external preparation containing the transdermal absorbent and a medicinal ingredient.
薬物の投与方法としては従来から経口投与、直腸投与、
皮肉投与等が通常行われており、中でも経口投与が広く
用いられている。しかしながら、経口投与の場合には胃
腸障害、食欲不振、嘔吐、腹痛等の副作用を惹起するこ
とがあるとともに、その効果を発揮するためには大量の
投与が必要である場合が多いことなどの欠点があった。Conventional drug administration methods include oral administration, rectal administration,
Subcutaneous administration and the like are commonly used, with oral administration being the most widely used. However, oral administration may cause side effects such as gastrointestinal disorders, loss of appetite, vomiting, and abdominal pain, and disadvantages include the fact that large doses are often required to be effective. was there.
近年、かかる欠点を解消する目的で、この副作用全低下
し、薬理効果をより安全に発現することが期待できるも
のとして経皮投与による外用剤の開発が行われ、製品も
上布されている。しかしながら、かかる外用剤における
薬効成分の経皮吸収性は未だ不十分な場合も多く、その
目的を十分に達成し得ているとは言い難い。すなわち、
本来皮膚、中でもその最外層を形成する角質層は体内へ
の物質透過に対する防御壁としての生理的機能を果たし
ているものであり、通、常の外用剤に使用される基剤単
独では配合された薬効成分の十分な経皮吸収は得難い場
合が多い。そのため、角質層を通しての薬物の透過性を
制御し、薬物の経皮吸収性を高める工夫が必要である。In recent years, in order to eliminate such drawbacks, external preparations for transdermal administration have been developed and products are also being marketed as products that can be expected to completely reduce these side effects and more safely develop pharmacological effects. However, the transdermal absorption of the medicinal ingredients in such external preparations is still often insufficient, and it cannot be said that the objective has been fully achieved. That is,
The skin, especially the stratum corneum, which forms the outermost layer, has a physiological function as a protective barrier against substances penetrating into the body. It is often difficult to obtain sufficient transdermal absorption of medicinal ingredients. Therefore, it is necessary to devise ways to control drug permeability through the stratum corneum and increase transdermal absorption of drugs.
かかる目的でいわゆる経皮吸収促進剤を基剤に配合する
ことが一般に行われている。そのような吸収促進剤とし
ては、ジメチルスルホキサイド、ジメチルアセトアミド
、ジメチルホルムアミド、N、N−ジエチル−m−)ル
アミドなどのアミド化合物;1−ドデシルアゾシクロへ
ブタン−2−オンなどのアザシクロアルカン−2−オン
誘導体;6るいはイソプロピルミリステート、イソノロ
ビルノ4ルミテート、ジエチルセパケート、ジイソノロ
ピルアジペートなどのアルコールとカルボン酸のエステ
ルあるいはクロトニル−N−エチル−〇−トルイジンな
どが公知である。For this purpose, it is common practice to incorporate a so-called transdermal absorption enhancer into the base. Such absorption enhancers include amide compounds such as dimethylsulfoxide, dimethylacetamide, dimethylformamide, N,N-diethyl-m-)ylamide; Alkan-2-one derivatives; esters of alcohol and carboxylic acid such as 6- or isopropyl myristate, isonorobyl 4-lumitate, diethyl sepacate, and diisonolopyl adipate, or crotonyl-N-ethyl-〇-toluidine are known.
しかしながらこれら吸収促進剤はその吸収促進効果が未
だ十分とは言えず、これら吸収促進剤を用いた皮膚外用
剤は実用的な薬理効果が得られない場合も多くあり、ま
た吸収促進剤自体が不可逆的な角質変成作用や皮膚刺激
作用を示したり、あるいは強力な溶剤としての性質から
合成樹脂を腐食して薬剤容器や衣類、装身具などから刺
激性物質や感作性物質等全溶出することなどのため一般
の適応や使用法が制限されるなど実用化には尚多くの問
題点が残ってhるのが現状である。However, the absorption promoting effect of these absorption enhancers is still not sufficient, and external skin preparations using these absorption enhancers often do not have practical pharmacological effects, and the absorption enhancers themselves are irreversible. It exhibits keratin alteration and skin irritation effects, or corrodes synthetic resins due to its strong solvent properties, causing irritants and sensitizing substances to be completely eluted from drug containers, clothing, jewelry, etc. Therefore, there are still many problems remaining in practical application, such as restrictions on general adaptation and usage.
本発明者らはこのような実情Kiみ鋭意研究を重ねた結
果、ポリエチレンイミンおよび/またはその誘導体が優
れた経皮吸収促進効果を有するとともに、該ポリエチレ
ンイミンおよび/またはその誘導体を含有する皮膚外用
剤が生体へ副作用を及ぼすことなく、薬効成分の薬理効
果を十分に発揮させ得ることを見出し、本発明を完成さ
せるに至った。The inventors of the present invention have carried out extensive research in light of the above-mentioned circumstances, and have found that polyethyleneimine and/or its derivatives have an excellent transdermal absorption promoting effect, and that a skin external application containing the polyethyleneimine and/or its derivatives has been developed. The inventors have discovered that the drug can fully exhibit the pharmacological effects of its medicinal ingredients without causing side effects on living organisms, and have completed the present invention.
即ち、本発明は2リエチレンイミン(以下PEIという
。)および/またはその誘導体(A)’を有効成分とす
る経皮吸収促進剤並びに該経皮吸収促進剤および薬効成
分(B) =に含有してなる皮膚外用剤に関するもので
ある。That is, the present invention provides a transdermal absorption enhancer containing 2-lyethylenimine (hereinafter referred to as PEI) and/or its derivative (A)' as an active ingredient, and a transdermal absorption enhancer containing the transdermal absorption enhancer and a medicinal ingredient (B). This article relates to a skin preparation for external use.
本発明におけるPEIおよび/またはその誘導体(3)
は従来からメッキ浴助剤、界面活性剤、キレート樹脂、
ラミネート・アンカー剤、接着助剤、凝薬剤等に効果を
発揮することは周知である。しかしながら、これらが経
皮吸収促進効果を有することは予想すらできなかったこ
とであり、この新しい発見は長年PgIやその誘導体の
研究に携わってきた本発明者らの研究成果に基づくもの
である。PEI and/or its derivative in the present invention (3)
has traditionally been used as plating bath aids, surfactants, chelate resins,
It is well known that it is effective as a laminate anchor agent, adhesion aid, coagulant, etc. However, it was not even expected that these substances would have the effect of promoting transdermal absorption, and this new discovery is based on the research results of the present inventors, who have been involved in research on PgI and its derivatives for many years.
本発明の経皮吸収促進剤はPEIおよび/またはその誘
導体(A)を有効成分とするものであるが、PEI誘導
体(A−2)としては、下記式(Il〜QI[)(−C
H2−C)(2−N −)−(1)C=0
■
暑
H
CH2
HC−Of(
(式中、Rは水素、炭素数1〜30の不飽和基を有して
もよい直鎖状、分岐状もしくけ環状脂肪族炭化水素基ま
たは芳香族炭化水素基を示す。)で表わされる単位の1
種以上を必須の構成単位として有するものが好ましい。The transdermal absorption enhancer of the present invention contains PEI and/or its derivative (A) as an active ingredient, and the PEI derivative (A-2) has the following formula (Il~QI[)(-C
H2-C)(2-N-)-(1)C=0 ■ Hot H CH2 HC-Of( (wherein, R is hydrogen, a straight chain which may have an unsaturated group having 1 to 30 carbon atoms) One of the units represented by (1) represents a branched or branched cyclic aliphatic hydrocarbon group or an aromatic hydrocarbon group.
Those having at least one species as essential structural units are preferred.
かかるPEI誘導体は、従来から公知の技術(例えば日
本化学工業協会月報、1984年5月号)で容易に製造
できるものである。例えば、Iリエチレンイミンを適当
な溶媒(例えば水、ピリジン、ジメチルホルムアミドな
ど)に溶解し、ポリエチレンイミン中のアミノ基の一部
もしくけ全量を
■ 酸、酸無水物、アシルノ・ライドを、必要ならば冷
却下に添加、反応させることによって式(I)で表わさ
れる構成単位を有するPEI 誘導体(A−2)力;、
■ イソシアネート類を同様にして反応させることによ
り弐ω)で表わされる構成単位を有するPEI誘導体(
A−2)が、
■ エポキシ化合物を同様にして反応させることにより
式(2)で表わされる構成単位を有するPEI誘導体(
A−2)が、
それぞれ得られる。更に■〜■の反応の2種以上を組み
合わせることにより式(1)〜(2)のうちの2種以上
の構成単位を有するPEI誘導体(A−2) ’jr得
ることができる。Such PEI derivatives can be easily produced using conventionally known techniques (eg, Japan Chemical Industry Association Monthly Report, May 1984 issue). For example, dissolve polyethyleneimine in a suitable solvent (e.g., water, pyridine, dimethylformamide, etc.), add some or all of the amino groups in polyethyleneimine, and add acid, acid anhydride, or acylnolide, if necessary. PEI derivative (A-2) having a structural unit represented by the formula (I) by adding and reacting with cooling; ■ By reacting isocyanates in the same manner, a structural unit represented by 2ω) is obtained. A PEI derivative having (
A-2) is prepared by (i) reacting an epoxy compound in the same manner to produce a PEI derivative (
A-2) are obtained respectively. Furthermore, by combining two or more of the reactions (1) to (2), a PEI derivative (A-2)'jr having two or more structural units of formulas (1) to (2) can be obtained.
また、2−メチルオキサゾリン、2−エチルオキサゾリ
ン、2−プロピルオキサゾリン、2−フェニルオキサゾ
リン等に代表される2−アルキルオキサゾリンを開環重
合して得られるポリ2−アルキルオキサゾリンの部分加
水分解物も本発明におけるpgr g導体(A−2>に
該当するものである。In addition, partial hydrolysates of poly-2-alkyloxazolines obtained by ring-opening polymerization of 2-alkyloxazolines, such as 2-methyloxazoline, 2-ethyloxazoline, 2-propyloxazoline, and 2-phenyloxazoline, are also available. This corresponds to the pgr g conductor (A-2>) in the invention.
但し、本発明におけるPEI誘導体の農法はこれらの方
法のみによって制限されるものではない。However, the farming method for PEI derivatives in the present invention is not limited only to these methods.
このよりなPEI 誘導体のうち特に好ましいものの具
体例としては、Nニホルミルポリエチレンイミン、N−
アセチルポリエチレンイミン、N−ノロピオニルポリエ
チレンイミン、N−ブチリルポリエチレンイミン、N−
イソブチリルポリエチレンイミン N−ハレリルホリエ
チレンイミン、N−ヘキサノイルポリエチレンイミン、
N−オクタノイルポリエチレンイミン、N−デカノイル
ポリエチレンイミン、N−ラフロイルポリエチレンイミ
ン、N−)臂ルミトイルポリエチレンイミン、N−ステ
アロイルポリエチレンイミン、N−シクロヘキサンカル
♂ニルポリエチレンイミン、N−p−トルイルポリエチ
レンイミンおよびこれらの部分N−アシル化ポリエチレ
ンイミン類;
N−7セチルアミノポリエチレンイミン、N−ノロピオ
ニルアミノポリエチレンイミン、N−ブチリルアミノポ
リエチレンイミン、N−イソプチリルアミノポリエチレ
/イミン、N−ノ々レリルアミノポリエチレンイミン、
N−ヘキサノイルアミノポリエチレンイミン、N−オク
タノイルアミノIリエチレンイミン、N−デカノイルア
ミノポリエチレンイミン、N−ラフロイルアミノポリエ
チレンイミン、N −A?ルミトイルアミノポリエチレ
ンイミン、N−ステアロイルアミノポリエチレンイミン
、N−シクロヘキサンカルゲニルアミノポリエチレンイ
ミン、 N−p−)ルイルアミノポリエチレンイミンお
よびこれらの部分N−アミドポリエチレンイミン類:
N−2−ヒドロキシエチルポリエチレンイミン、N−2
−ヒドロキシプロピルポリエチレンイミン、N−2−ヒ
ドロキシブチルポリエチレンイミン、N−2−ヒドロキ
シペンチルチリエチレンイミン、N′−2−ヒドロキシ
ヘキシルポリエチレンイミン、N−2−ヒドロキシオク
チルポリエチレンイミン、N−2−ヒドロキシデシルポ
リエチレンイミン、N−2−ヒドロキシドデシルポリエ
チレンイミン、N−2−ヒドロキシヘキサデシルポリエ
チレンイミン、N−2−ヒドロキシオクタデシルポリエ
チレンイミン、N−2−ヒドロキシエチルポリエチレン
イミン、N−2−シクロヘキシル−2−ヒドロキシエチ
ルポリエチレンイミン、N−2−フェニル−2−ヒドロ
キシエチルポリエチレンイミンおよびこれらの部分N−
2−ヒドロキシアルキルIリエチレンイミン類;並びに
これらイミン類の4級化物や酸基導入による両イオン性
化合物などを挙げることができる。Specific examples of particularly preferable PEI derivatives include N-niformylpolyethyleneimine, N-
Acetylpolyethyleneimine, N-noropionylpolyethyleneimine, N-butyrylpolyethyleneimine, N-
Isobutyrylpolyethyleneimine N-halerylpolyethyleneimine, N-hexanoylpolyethyleneimine,
N-octanoylpolyethyleneimine, N-decanoylpolyethyleneimine, N-lafuroylpolyethyleneimine, N-)lumitoylpolyethyleneimine, N-stearoylpolyethyleneimine, N-cyclohexanecar♂ylpolyethyleneimine, N-p-toluyl Polyethyleneimine and their partially N-acylated polyethyleneimines; N-7cetylaminopolyethyleneimine, N-noropionylaminopolyethyleneimine, N-butyrylaminopolyethyleneimine, N-isobutyrylaminopolyethylene/imine, N-7 -Nononerylaminopolyethyleneimine,
N-hexanoylaminopolyethyleneimine, N-octanoylamino Ilyethylenimine, N-decanoylaminopolyethyleneimine, N-lafuroylaminopolyethyleneimine, N-A? Lumitoylaminopolyethyleneimine, N-stearoylaminopolyethyleneimine, N-cyclohexanecargenylaminopolyethyleneimine, N-p-)ruylaminopolyethyleneimine and their partial N-amide polyethyleneimines: N-2-hydroxyethylpolyethylene imine, N-2
-Hydroxypropylpolyethyleneimine, N-2-hydroxybutylpolyethyleneimine, N-2-hydroxypentylthiethyleneimine, N'-2-hydroxyhexylpolyethyleneimine, N-2-hydroxyoctylpolyethyleneimine, N-2-hydroxydecyl Polyethyleneimine, N-2-hydroxydodecylpolyethyleneimine, N-2-hydroxyhexadecylpolyethyleneimine, N-2-hydroxyoctadecylpolyethyleneimine, N-2-hydroxyethylpolyethyleneimine, N-2-cyclohexyl-2-hydroxyethyl Polyethyleneimine, N-2-phenyl-2-hydroxyethylpolyethyleneimine and their moieties N-
Examples include 2-hydroxyalkyl I-lyethylenimines, quaternized products of these imines, and amphoteric compounds obtained by introducing acid groups.
本発明の経皮吸収促進剤に用いるPEIおよび/または
その誘導体は、水又は低級アルコール、グロビレングリ
コール、トリアセチン等の適当な溶媒に溶解、分散若し
くけ懸濁せしめることにより調製される。溶媒として炭
素数1〜3の低級アルコール及び/又は水を使用すると
、本発明の経皮吸収促進剤の経皮吸収作用が促進される
ので好適である。また、本発明の経皮吸収促進剤には、
更に必要に応じて従来公知の経皮吸収作用を有する化合
物、例えばジメチルスルホキサイド、ジメチルアセトア
ミド、ジメチルホルムアミド、N、N−ジエチル−m−
)ルアミド、1−ドデシル7ザシクロへブタン−2−オ
ンなどのアゾシクロアルカン−2オン誘導体、イソゾロ
ピルミリステート、イソゾロピルノ母ルミテート、ジエ
チルセパケート、ジイソゾロピルアジペートなどのアル
コールとカルゲン酸のエステル、クロトニル−N−エチ
ル−〇−トルイジン等を配合することもできる。PEI and/or its derivatives used in the transdermal absorption enhancer of the present invention are prepared by dissolving, dispersing, or suspending them in a suitable solvent such as water, lower alcohol, globylene glycol, triacetin, or the like. It is preferable to use a lower alcohol having 1 to 3 carbon atoms and/or water as a solvent because the transdermal absorption action of the transdermal absorption enhancer of the present invention is promoted. In addition, the transdermal absorption enhancer of the present invention includes:
Furthermore, if necessary, conventionally known compounds having transdermal absorption effects, such as dimethyl sulfoxide, dimethylacetamide, dimethylformamide, N,N-diethyl-m-
), azocycloalkan-2one derivatives such as 1-dodecyl-7-cyclohebutan-2-one, esters of alcohols and calgenic acids such as isozolopyl myristate, isozolopyrnolumitate, diethyl sepacate, and diisozolopyradipate. , crotonyl-N-ethyl-〇-toluidine, etc. can also be blended.
本発明の経皮吸収促進剤の利用により薬効が増加するも
のの例としては、プレドニゾロン、デキサメタシンなど
のステロイド系抗炎症剤、インドメタシン、フルフェナ
ム酸、メフェナム酸等の非ステロイド系杭長症剤、トリ
ペレナミン、インサイベンジル、クロルフェニラミン、
ジフェンヒドラミン、プロメタシン等の抗ヒスタミン剤
、スル77−E−ツメトキシン、スルファメチゾールな
どのサルファ剤、ペニシリン、セファロスポリン、エリ
スロマイシン、テトラサイクリン、クロラムフェニコー
ル、ストレットマイシンなどの抗生物質、ナフチオメー
ト、クロトリマゾールなどの抗真菌剤、5−フルオロウ
ラシル、シクロホスファミド、プスルファン、アクチノ
マイシンなどの抗悪性腫瘍剤、モルヒネ、コディン、ナ
ロルフイン、ペンタゾシン、アスピリン、アセトアリニ
ド、アミノピリンなどの鎮痛剤、グロスタグランジン類
製剤、パルビタール、チオベンタールなどの催眠剤およ
ヒ鎮静剤、クロルノロマジン、レセルピン、クロルジア
ゼポキシドなどの向精神病剤、抗癲澗剤、クロルゾキサ
ゾン、しはトノやなどの抗パーキンソン病剤、ジキトキ
シン、ジゴキシンなどの強心剤、塩酸プロカインアミド
、塩酸プロゲラノールなどの抗不整脈剤、ジビリダモー
ル、亜硝酸アミルなどの抗狭心症剤、レセルピン、硫酸
グアネチジンなどの抗高血圧剤、パラアミノベンゾエー
トニスf /l/ fz トの紫外線抑制剤、ハイドロ
キノン、ビタミンCエステル類、ノぐラハイドロキシシ
ンナメートなどのメラニン生成抑制剤、8−メトキシソ
ラーレンなどの乾癖のPUVA治療薬、ビタミンA、ビ
タミンE、ビタミンCなどのビタミン類、インシュリン
、エストラジオール、メチルテストステロンなどのホル
モン剤、診断薬、ノ4ツチテスト用アレルrン、防虫剤
、殺虫剤、あるいは保湿剤、角質柔軟剤、染毛剤などが
挙げられるが、これらのみに限定されるものではない。Examples of drugs whose medicinal efficacy is increased by the use of the transdermal absorption enhancer of the present invention include steroidal anti-inflammatory drugs such as prednisolone and dexamethacin, non-steroidal pile length drugs such as indomethacin, flufenamic acid and mefenamic acid, tripelenamine, Incybenzil, chlorpheniramine,
Antihistamines such as diphenhydramine and promethacin, sulfa drugs such as sul77-E-tumetoxin and sulfamethizole, antibiotics such as penicillin, cephalosporin, erythromycin, tetracycline, chloramphenicol, and stretmycin, naphthiomate, clotrimazole, etc. antifungal agents, antineoplastic agents such as 5-fluorouracil, cyclophosphamide, pusulfan, actinomycin, analgesics such as morphine, codine, nalorufine, pentazocine, aspirin, acetalinide, aminopyrine, glostaglandin preparations, parbital , hypnotics and sedatives such as thiobental, psychotropic agents such as chlornorromazine, reserpine, and chlordiazepoxide, antiepileptic agents, antiparkinsonian agents such as chlorzoxazone and Shiha Tonoya, inotropes such as dioquitoxin and digoxin, Antiarrhythmic agents such as procainamide hydrochloride and progeranol hydrochloride; antianginal agents such as diviridamol and amyl nitrite; antihypertensive agents such as reserpine and guanethidine sulfate; ultraviolet inhibitors such as para-aminobenzoate varnish; hydroquinone; , vitamin C esters, melanin production inhibitors such as Nogura hydroxycinnamate, PUVA treatments for xerosis such as 8-methoxypsoralen, vitamins such as vitamin A, vitamin E, and vitamin C, insulin, estradiol, Examples include, but are not limited to, hormonal agents such as methyltestosterone, diagnostic agents, allergens for the No4tsuchi test, insect repellents, insecticides, moisturizers, keratin softeners, and hair dyes. .
また本発明の経皮吸収促進剤は動物、昆虫、植物などに
適用することにより吸収されて薬理効果が期待される多
くの薬物、農薬、成長ホルモンなどにも有効である。The transdermal absorption enhancer of the present invention is also effective for many drugs, pesticides, growth hormones, etc. that are expected to be absorbed and have pharmacological effects when applied to animals, insects, plants, etc.
橋
本発明における吸収促進効果の作用機4iI−は不明で
あるが、角質層の脂質および蛋白構造のコンホメーショ
ンを可逆的に変えることにより活性物質が真皮へ浸透し
やすくするものと推定される。Although the mechanism of action 4iI- of the absorption promoting effect in Hashimoto's invention is unknown, it is presumed that the active substance is made easier to penetrate into the dermis by reversibly changing the conformation of lipid and protein structures in the stratum corneum.
壜
本発明に従った経皮吸収促進の作用機奉は上記の通り推
定されるものの、その作用機奉はなお推壜
定の域であり、本発明をかかる作用機奉に限定するもの
でないことはいうまでもない。Although the mechanism of action for promoting transdermal absorption according to the present invention is presumed as described above, the mechanism of action is still in the realm of speculation, and the present invention is not limited to such a mechanism of action. Needless to say.
本発明の皮膚外用剤はPgIおよび/またはその誘導体
(A)および薬効成分(B) =に含有してなるもので
あるが、これら両成分は水または低級アルコール、ノロ
ビレングリコール、トリアセチレン等の適当な溶媒に溶
解、分散若しくは懸濁せしめて調整するのが薬効を十分
に発揮させる上で好適である。The skin external preparation of the present invention contains PgI and/or its derivative (A) and a medicinal ingredient (B), both of which are water, lower alcohol, norobylene glycol, triacetylene, etc. In order to fully exhibit its medicinal efficacy, it is preferable to prepare the drug by dissolving, dispersing, or suspending it in an appropriate solvent.
これら溶媒のうち水および低級アルコールが好ましい。Among these solvents, water and lower alcohols are preferred.
本発明の皮膚外用剤の得る上で好ましい配合割合は、P
E工および/又はその誘導体(A)1〜40重量%、薬
効成分(B) 0.01〜5重量%、水10〜80重量
%および低級アルコール10〜80i&量チ(但し、こ
れら全成分の合計は100重量%である。)の割合であ
る。The preferred blending ratio for obtaining the skin external preparation of the present invention is P
E and/or its derivative (A) 1 to 40% by weight, medicinal ingredient (B) 0.01 to 5% by weight, water 10 to 80% by weight, and lower alcohol 10 to 80% by weight (however, the amount of all these ingredients The total is 100% by weight).
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、エアゾール、ローション、バッグ剤、テープ剤な
どの皮膚外用剤の製造に使用されるとそれ自体薬効を示
さない物質であり、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水性基剤、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、ダル
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、カルビキシビニルポリマー、Iリアクリル
酸ナトリウム、Iリビニルアルコールなどの合成水溶性
高分子などをあげることができる。The base used in the external skin preparation according to the present invention is a substance that itself does not exhibit medicinal efficacy when used in the manufacture of general skin external preparations such as ointments, aerosols, lotions, bags, and tapes. , for example, vegetable oil, lard, oily bases such as petrolatum, hydrophilic petrolatum, purified lanolin, water-absorbing ointments,
Water-absorbing bases such as hydrated lanolin, hydrophilic bases such as hydrophilic ointments, water-soluble bases such as macrogol ointments, natural water-soluble polymers such as starch, dalulan, gelatin, water-soluble cellulose derivatives, carboxyvinyl polymers. , I-sodium lyacrylate, I-rivinyl alcohol, and other synthetic water-soluble polymers.
テープ剤、バッグ剤などの列形の外用剤の場合には、前
記した基剤の中で天然水溶性高分子及び/又は合成水溶
性高分子を好適に用いることができる。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、トラがカントがム、グアールがム、カラヤゴ
ム、クインスシードデンノ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)、カルゲ
キシメチルセルロース及びその塩(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、好ましくけ繊維素系水溶性高分子であ
り、特に好ましくはヒドロキシプロピルセルロースであ
る。In the case of line-type external preparations such as tapes and bags, natural water-soluble polymers and/or synthetic water-soluble polymers can be suitably used among the above-mentioned bases. Natural water-soluble polymers that can be used in the present invention include plant-based water-soluble polymers such as gum arabic, gum arabic, gum gum, gum karaya, and quince seed denone;
Seaweed-based water-soluble polymers such as alginic acid and carrageenan, animal-based water-soluble polymers such as gelatin, microbial-based water-soluble polymers such as dextran, methylcellulose (MC), calgeximethylcellulose and its salts (CMC), hydroxyethyl cellulose Cellulose-based water-soluble polymers such as (HEC) and hydroxypropylcellulose (RPC) can be mentioned, and cellulose-based water-soluble polymers are preferred, and hydroxypropylcellulose is particularly preferred.
本発明の経皮吸収促進剤は皮膚への浸透性に優れ、しか
も生体への副作用の恐れがないPEIおよび/またはそ
の誘導体(A)全有効成分としてなるために、種々の薬
効成分(Blの経皮吸収性を向上させてその薬効の効果
を著しく増大させることができる。しかもPEIおよび
/またばその誘導体(A)は、適宜その構造を選択して
親水性・疎水性のバランスを所望に応じて任意に調節す
ることができるため、基材の選定が極めて容易になる。The transdermal absorption enhancer of the present invention has excellent permeability into the skin and contains all the active ingredients of PEI and/or its derivatives (A) without fear of side effects on the living body. By improving transdermal absorption, the medicinal efficacy can be significantly increased.Moreover, the structure of PEI and/or its derivative (A) can be appropriately selected to achieve a desired balance of hydrophilicity and hydrophobicity. Since it can be adjusted as desired, it is extremely easy to select the base material.
その結果、各種薬効成分(B)に対し相溶性に優れたP
EIおよび/捷たけその誘導体久)を選択することがで
き、水に離溶解性の薬効成分(B) ffi fi水性
基材に高濃度溶解せしめて、使用感が良好で、がっ薬効
に優れた皮膚外用剤を設計することも可能となった。As a result, P has excellent compatibility with various medicinal ingredients (B).
A medicinal ingredient (B) that is soluble in water and has a good feeling of use and excellent medicinal effect because it is dissolved in a high concentration in an aqueous base material. It has also become possible to design external preparations for the skin.
次に実施例を挙げて本発明を具体的に説明するが、本発
明はこれら実施例にのみ限定されるものではない。EXAMPLES Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited only to these Examples.
実施例1〜3
インドメタシン1重量%含有の市販ダル状外用剤インチ
パン軟膏95重量部に第1表に示すN−アシル化ポリエ
チレンイミン5部を混和して皮膚外用剤(1)〜(3)
ヲ得た。これらの経皮吸収性を試験した結果は第1表に
示した通りであった。Examples 1 to 3 External skin preparations (1) to (3) prepared by mixing 5 parts of N-acylated polyethyleneimine shown in Table 1 with 95 parts by weight of Inchipan ointment, a commercially available gelatinized external preparation containing 1% by weight of indomethacin.
I got it. The results of testing these transdermal absorbabilities are shown in Table 1.
比較例1
実施例1における市販ダル状外用剤インチパン軟膏をN
−アシル化ポリエチレンイミンを混和せずにそのまま比
較用皮膚外用剤α)とした。この経皮吸収性を試験した
結果は第1表に示した通りであった。Comparative Example 1 The commercially available dal-shaped external preparation Inchipan ointment in Example 1 was
- A comparative skin external preparation α) was prepared without mixing with acylated polyethyleneimine. The results of this transdermal absorption test are shown in Table 1.
実施例4
インドメタシン1部、N−ラウロイルポリエチレンイミ
ン9部、エタノール65部および蒸溜水25部を混合攪
拌して皮膚外用剤(A)を得た。その経皮吸収性は第1
表に示した通りでめった。Example 4 1 part of indomethacin, 9 parts of N-lauroyl polyethyleneimine, 65 parts of ethanol, and 25 parts of distilled water were mixed and stirred to obtain a skin external preparation (A). Its transdermal absorption is the highest
It was as shown in the table.
実施例5〜6
実施例4におけるN−ラウロイルポリエチレンイミンに
代えてそれぞれN−ラウロイルアミノポリエチレンイミ
ンまたはN−2−ヒドロキシドデシルポリエチレンイミ
ンを用いた以外は実施例4と同じ操作をくり返して皮膚
外用剤(5)および(6)ヲ得た。Examples 5 to 6 External skin preparations were prepared by repeating the same operations as in Example 4, except that N-lauroylaminopolyethyleneimine or N-2-hydroxydodecylpolyethyleneimine was used in place of N-lauroylpolyethyleneimine in Example 4. I got (5) and (6).
これらの経皮吸収性は第1表に示した通りであった。Their transdermal absorbability was as shown in Table 1.
比較例2〜3
実施例4においてそれぞれN−ラウロイルポリエチレン
イミンを用いなかったか、またI′iN−ラウロイルポ
リエチレンイミンの代りにジメチルスルホキサイドを用
いた以外は実施例4と同じ操作をくり返して比較用皮膚
外用剤(2)および(3)ヲ得た。Comparative Examples 2 to 3 Comparisons were made by repeating the same operations as in Example 4, except that N-lauroyl polyethyleneimine was not used in Example 4, and dimethyl sulfoxide was used in place of I'iN-lauroyl polyethyleneimine. External skin preparations (2) and (3) were obtained.
これらの経皮吸収性を試験した結果は第1表に示した通
りであった。The results of testing these transdermal absorbabilities are shown in Table 1.
第 1 表
(注1)
実験前夜に皮膚を傷つけないよう注意して背部200m
”i剪毛しておAた体ii2.5〜3.5ゆの家兎に各
皮膚外用剤を塗布した後、耳静脈より採血し、インドメ
タシンの血中最高濃度を測定した。Table 1 (Note 1) The night before the experiment, the patient was examined 200 m from the back, being careful not to damage the skin.
After each topical skin preparation was applied to a shaved domestic rabbit with a body size of 2.5 to 3.5 cm, blood was collected from the ear vein and the maximum concentration of indomethacin in the blood was measured.
上記結果から明らかなように、本発明の皮膚外用剤は比
較用皮膚外用剤に比べて著しく高い薬効性を有していた
。As is clear from the above results, the external skin preparation of the present invention had significantly higher efficacy than the comparative skin external preparation.
Claims (1)
)を有効成分とする経皮吸収促進剤。 2、ポリエチレンイミン誘導体(A)が下記式( I )
〜(III) ▲数式、化学式、表等があります▼( I ) ▲数式、化学式、表等があります▼(II) ▲数式、化学式、表等があります▼(III) (式中、Rは水素、炭素数1〜30の不飽和基を有して
もよい直鎖状、分岐状もしくは環状脂肪族炭化水素基ま
たは芳香族炭化水素基を示す。)で表わされる単位の1
種以上を必須の構成単位として有する特許請求の範囲第
1項記載の経皮吸収促進剤。 3、ポリエチレンイミンおよび/またはその誘導体(A
)および薬効成分(B)を含有してなる皮膚外用剤。 4、更に、低級アルコールおよび/または水を含有する
特許請求の範囲第3項記載の皮膚外用剤。[Claims] 1. Polyethyleneimine and/or its derivatives (A
) as an active ingredient is a transdermal absorption enhancer. 2. Polyethyleneimine derivative (A) has the following formula (I)
~(III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R is hydrogen , a linear, branched or cyclic aliphatic hydrocarbon group or an aromatic hydrocarbon group which may have an unsaturated group having 1 to 30 carbon atoms.
The transdermal absorption enhancer according to claim 1, which has at least one species as an essential structural unit. 3. Polyethyleneimine and/or its derivatives (A
) and a medicinal ingredient (B). 4. The skin external preparation according to claim 3, further containing a lower alcohol and/or water.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12133687A JPS63287730A (en) | 1987-05-20 | 1987-05-20 | Percutaneous absorption promoter and skin external preparation containing said promoter |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP12133687A JPS63287730A (en) | 1987-05-20 | 1987-05-20 | Percutaneous absorption promoter and skin external preparation containing said promoter |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS63287730A true JPS63287730A (en) | 1988-11-24 |
Family
ID=14808735
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP12133687A Pending JPS63287730A (en) | 1987-05-20 | 1987-05-20 | Percutaneous absorption promoter and skin external preparation containing said promoter |
Country Status (1)
Country | Link |
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JP (1) | JPS63287730A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007526340A (en) * | 2004-03-03 | 2007-09-13 | ルバンス セラピュティックス | Compositions and methods for topical application and transdermal delivery of botulinum toxin |
US8092788B2 (en) | 2004-03-03 | 2012-01-10 | Revance Therapeutics, Inc. | Compositions and methods for topical diagnostic and therapeutic transport |
US9180081B2 (en) | 2005-03-03 | 2015-11-10 | Revance Therapeutics, Inc. | Compositions and methods for topical application and transdermal delivery of botulinum toxins |
US9211248B2 (en) | 2004-03-03 | 2015-12-15 | Revance Therapeutics, Inc. | Compositions and methods for topical application and transdermal delivery of botulinum toxins |
-
1987
- 1987-05-20 JP JP12133687A patent/JPS63287730A/en active Pending
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007526340A (en) * | 2004-03-03 | 2007-09-13 | ルバンス セラピュティックス | Compositions and methods for topical application and transdermal delivery of botulinum toxin |
US8092788B2 (en) | 2004-03-03 | 2012-01-10 | Revance Therapeutics, Inc. | Compositions and methods for topical diagnostic and therapeutic transport |
US8974774B2 (en) | 2004-03-03 | 2015-03-10 | Revance Therapeutics, Inc. | Compositions and methods for topical diagnostic and therapeutic transport |
US9211248B2 (en) | 2004-03-03 | 2015-12-15 | Revance Therapeutics, Inc. | Compositions and methods for topical application and transdermal delivery of botulinum toxins |
US10172877B2 (en) | 2004-03-03 | 2019-01-08 | Revance Therapeutics, Inc. | Compositions and methods for topical diagnostic and therapeutic transport |
US9180081B2 (en) | 2005-03-03 | 2015-11-10 | Revance Therapeutics, Inc. | Compositions and methods for topical application and transdermal delivery of botulinum toxins |
US9314416B2 (en) | 2005-03-03 | 2016-04-19 | Revance Therapeutics, Inc. | Compositions and methods for topical application and transdermal delivery of botulinum toxins |
US10080786B2 (en) | 2005-03-03 | 2018-09-25 | Revance Therapeutics, Inc. | Methods for treating pain by topical application and transdermal delivery of botulinum toxin |
US10744078B2 (en) | 2005-03-03 | 2020-08-18 | Revance Therapeutics, Inc. | Compositions and methods for topical application and transdermal delivery of botulinum toxins |
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