JP2910857B2 - Prostaglandin E1 transdermal preparation - Google Patents
Prostaglandin E1 transdermal preparationInfo
- Publication number
- JP2910857B2 JP2910857B2 JP1084088A JP8408889A JP2910857B2 JP 2910857 B2 JP2910857 B2 JP 2910857B2 JP 1084088 A JP1084088 A JP 1084088A JP 8408889 A JP8408889 A JP 8408889A JP 2910857 B2 JP2910857 B2 JP 2910857B2
- Authority
- JP
- Japan
- Prior art keywords
- pge
- prostaglandin
- preparation
- skin
- present
- 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.)
- Expired - Fee Related
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は、プロスタグランジンE1を有効成分として含
有する経皮吸収製剤に関し、さらに詳しくは、皮膚透過
促進剤を添加してプロスタグランジンE1の皮膚からの吸
収性を高めた経皮吸収製剤に関する。Description: TECHNICAL FIELD The present invention relates to a transdermal absorption preparation containing prostaglandin E1 as an active ingredient, and more particularly to a prostaglandin E1 containing a skin permeation enhancer. Percutaneously absorbable preparations having enhanced absorbability from the skin.
（従来の技術） プロスタグランジン（以下、PGと略記する）類は、平
滑筋収縮刺激作用、血圧降下作用、利尿作用、気管支拡
張作用、脂肪分解阻害作用、血小板凝集抑制作用、胃酸
分泌抑制作用、抗腫瘍作用などの幅広い薬理作用を示
し、各種疾病の治療や予防に用いられている。(Prior art) Prostaglandins (hereinafter abbreviated as PG) are smooth muscle contraction stimulating action, blood pressure lowering action, diuretic action, bronchodilator action, lipolysis inhibitory action, platelet aggregation inhibitory action, gastric acid secretion inhibitory action. It has a wide range of pharmacological actions such as antitumor action and is used for treatment and prevention of various diseases.
PG類の中で、プロスタグランジンE1（以下、PGE,と略
記する）と呼ばれる化合物は、 次式 で示され、血管拡張、血小板擬集抑制などの薬理活性を
示すため、これまで各種の疾病の治療や予防に用いられ
ている。Among PGs, a compound called prostaglandin E1 (hereinafter abbreviated as PGE) has the following formula: It has been used in the treatment and prevention of various diseases because of its pharmacological activity such as vasodilation and suppression of platelet aggregation.
このPGE1を生体内へ投与するには、静脈内、動脈内な
どに限定されて行われており、経皮投与型製剤について
も広く研究が行われ（例えば、特開昭59−34619、同55
−102512、同56−142208、同57−3636の各号公報参
照）、PGE1経皮投与型製剤であって日焼け防止化粧料、
口腔内製剤、発毛促進剤なども開発されている（特開昭
59−170011、同60−116631、同61−218510、同62−2554
16の各号公報参照）。さらに、PGE1を貼付剤の形にし
て、多層構造となし、PGE1放出抑制の工夫がなされ、持
続性のある製剤も開発されている（特開昭57−70816、
同58−134019の名号公報参照）。To administer this PGE 1 into the living body, intravenously, have been carried out are limited to such an artery, is extensively studied also transdermal administration type pharmaceutical preparation is performed (e.g., JP-A 59-34619, the 55
-102512, the 56-142208, see the JP in the same 57-3636), sunscreen cosmetics a PGE 1 transdermal administration type preparation,
Oral preparations, hair growth promoters, etc. have also been developed (Japanese
59-170011, 60-116631, 61-218510, 62-2554
16). Further, the PGE 1 in the form of the patch, the multilayer structure and without, devised PGE 1 release suppression is performed, the formulation with a sustained has also been developed (JP 57-70816,
No. 58-134019).
（発明が解決しようとする課題） しかしながら、従来のPGE1含有経皮吸収型製剤は、上
述したように、持続放出型のものが開発されてはいる
が、経皮透過性の促進という観点からは、未だ研究が行
われていないように思われる。(Problems to be Solved by the Invention) However, as described above, as a conventional PGE 1 -containing transdermal preparation, a sustained-release preparation has been developed, but from the viewpoint of promoting percutaneous permeability. Seems to have not been studied yet.
そこで、本発明者らは、PGE1含有経皮吸収製剤であっ
て、PGE1の皮膚透過性の高いものを開発すべく鋭意研究
を行った結果、本発明に到達した。Accordingly, the present invention we provide a PGE 1 containing transdermal absorption preparation, result of extensive studies to develop a high of PGE 1 skin permeability, we have reached the present invention.
（課題を解決するための手段） 本発明は、アクリル系粘着剤、PGE1及び皮膚透過促進
剤を含むPGE1含有経皮吸収剤である。(SUMMARY for a) the invention, acrylic pressure-sensitive adhesive, a PGE 1 containing transdermal agent comprising PGE 1 and skin penetration enhancers.
本発明に用いられるアクリル系粘着剤としては、メタ
クリル酸エステル及びアクリル酸エステルの重合体又は
これらのモノマーと他の重合性ビニル基を有するモノマ
ーとの共重合体さらには、これらのモノマーとアクリル
酸もしくはメタクリル酸の共重合体が挙げられる（特開
昭63−13533号公報第５ページ参照）。就中、本願の目
的である皮膚透過性の促進という観点から、２−エチル
ヘキシルアクリレートの単独重合休もしくは、このモノ
マーと少量のアクリル酸又はメタクリル酸の共重合体が
好ましい。Examples of the acrylic pressure-sensitive adhesive used in the present invention include polymers of methacrylic acid esters and acrylic acid esters or copolymers of these monomers and other monomers having a polymerizable vinyl group, and further, these monomers and acrylic acid Alternatively, a methacrylic acid copolymer may be used (see Japanese Patent Application Laid-Open No. Sho 63-13533, page 5). In particular, from the viewpoint of promoting skin permeability, which is the object of the present invention, homopolymerization of 2-ethylhexyl acrylate or a copolymer of this monomer and a small amount of acrylic acid or methacrylic acid is preferred.
本発明の皮膚透過促進剤としては、PGE1の皮膚透過能
促進作用を有するものであれば、いかなるものであって
もよいが、中鎖脂肪酸グリセリドが好ましい。ここで、
中鎖脂肪酸グリセリドとは、炭素数８〜14の脂肪酸のモ
ノー、ジーもしくはトリグリセリドあるいはそれらの混
合物を言うが、就中、グリセリル・モノカプリレート
（カプリル酸モノグリセリド）が特に好ましい。The skin permeation enhancer of the present invention, as long as it has a skin permeation-enhancing effect of PGE 1, may be any, but medium-chain fatty acid glycerides are preferred. here,
The medium-chain fatty acid glyceride refers to mono-, di- or triglycerides of fatty acids having 8 to 14 carbon atoms, or a mixture thereof. Among them, glyceryl monocaprylate (caprylic acid monoglyceride) is particularly preferable.
本発明の経皮吸収製剤中の有効成分であるPGE1の含量
は、製剤全体に対し、重量で、通常、１〜10％、好まし
くは１〜３％である。また、皮膚透過促進剤は、製剤全
体に対し、重量で、通常、１〜20％、好ましくは３〜15
％である。Content of PGE 1 is an active ingredient of the percutaneously absorbable preparation of the present invention, relative to the whole formulation, by weight, usually 1-10%, preferably 1-3%. The skin permeation enhancer is usually 1 to 20%, preferably 3 to 15% by weight based on the whole preparation.
%.
本発明のアクリル系粘着剤には、さらに、粘着性付与
成分として、ロジン、変性ロジン、石油系樹脂、クマロ
ンインデン樹脂、ポリテルペン樹脂、ポリブテン、液状
ポリイソブチレン等を添加することもでき、さらには、
軟化剤あるいは可塑剤として通常使用されるものを製剤
に加えてもよい。In the acrylic pressure-sensitive adhesive of the present invention, as a tackifier, rosin, modified rosin, petroleum resin, coumarone indene resin, polyterpene resin, polybutene, liquid polyisobutylene, and the like can be added. ,
Those commonly used as softeners or plasticizers may be added to the formulation.
本発明の製剤の形態は、製剤を構成する成分の均一な
混合物、すなわち、均一組成物の形態であってもよい
が、この均一組成物を支持体上に塗布した形態が好まし
い。支持体が一定サイズのシート、あるいは、テープで
ある場合には、必要に応じて、必要部位に適宜貼付する
ことができ、使用にあたって大変便利である。The preparation of the present invention may be in the form of a uniform mixture of the components constituting the preparation, that is, in the form of a uniform composition, but the form in which the uniform composition is applied on a support is preferred. When the support is a sheet of a certain size or a tape, it can be appropriately affixed to a necessary portion as needed, which is very convenient for use.
かかる支持体としては、医療用貼付剤の支持体として
用いられているものが使用できるが、例えば、ポリ塩化
ビニル、ポリエチレン、ポリプロピレン、ポリエチレン
テレフタレート、ポリカーボネート、ポリアクリル酸エ
ステル、ポリスルホン、セルロースエステルなどで形成
されたフィルム又はシート、あるいは、これらにアルミ
ニウムを蒸着ないしはラミネートしたフィルムやシー
ト、さらには、布、不織布、紙などが挙げられる。As such a support, those used as a support for a medical patch can be used.For example, polyvinyl chloride, polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polyacrylate, polysulfone, cellulose ester and the like can be used. Examples include a formed film or sheet, a film or sheet obtained by depositing or laminating aluminum on these, a cloth, a nonwoven fabric, and a paper.
貼付剤を調製するには、これらの支持体のうえに、上
記均一組成物を、通常、2.0mg/cm2〜8.0mg/cm2、好まし
くは4.0mg/cm2〜5.0mg/cm2塗布するが、このときPGE1の
含有量は、通常20μg/cm2〜500μg/cm2、好ましくは50
μg/cm2〜150μg/cm2となる。To prepare the patches, on top of these supports, the homogeneous composition, typically, 2.0mg / cm 2 ~8.0mg / cm 2, preferably from 4.0mg / cm 2 ~5.0mg / cm 2 coating Suruga content of PGE 1 this time is usually 20μg / cm 2 ~500μg / cm 2 , preferably 50
the μg / cm 2 ~150μg / cm 2 .
貼付剤の製法は、従来から通常行われている方法、す
なわち、均一組成物の調製、場合によっては、この組成
物の溶液化あるいは分散液化、塗布、乾燥工程を経る。
このとき、PGE1の分解を極力抑える条件下で、工程を行
わねばならない。The patch is produced by a method conventionally used, that is, preparation of a uniform composition, and depending on the case, solution or dispersion liquefaction of the composition, coating and drying steps.
In this case, under the condition of suppressing the degradation of PGE 1 as much as possible, it must be carried out the process.
かくして得られた、本発明の均一組成物の形の製剤お
よび貼付剤の形の製剤は、次のようにして使用される。The thus-prepared preparation in the form of a homogeneous composition and the preparation in the form of a patch of the present invention are used as follows.
本発明の製剤は、持続性を有する血管拡張剤であり、
腕、胸などに貼付し、24時間に一度、貼り変えられるこ
とにより副作用の少ない安定した薬効が得られる。The formulation of the present invention is a long-lasting vasodilator,
It can be applied to the arm, chest, etc., and can be applied once every 24 hours.
（実施例） 以下、実施例及び比較例を掲げて、本発明をさらに詳
しく説明するが、本発明は、これにより制限を受けるも
のではない。EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.
実施例１ アクリル酸とアクリル酸・２−エチルヘキシルの共重
合体（分子量:300,000〜500,000,モノマー組成（モル
比）：アクリル酸／アクリル酸・２−エチルヘキシル＝
10/90）4gに溶媒11.6gを加えて粘着剤溶液を調製した。
この溶液に、PGE170mgと、皮膚透過促進剤としてグリセ
ロールモノカプリレート（SEFSOL−318、日光ケミカル
社製、商品名）を0.4gすなわち、乾燥後の割合が、それ
ぞれ、２重量％及び10重量％となるように加え、均一に
混合し、溶解せしめた。かくして得られたPGE1含有溶液
を、ポリエチレンテレフタレートフィルム上にPGE1含有
量が70μg/cm2となるように塗布し、120℃で２分間乾燥
して、PGE1含有貼付剤を調製した。Example 1 Copolymer of acrylic acid and 2-ethylhexyl acrylate (molecular weight: 300,000 to 500,000, monomer composition (molar ratio): acrylic acid / 2-ethylhexyl acrylate =
10/90) 11.6 g of a solvent was added to 4 g to prepare an adhesive solution.
To this solution, a PGE 1 70 mg, glycerol monocaprylate as a skin permeation enhancer (Sefsol-318, Nikko Chemicals Co., Ltd., trade name) to 0.4g i.e., the ratio after drying, respectively, 2 wt% and 10 wt %, Mixed uniformly, and dissolved. The PGE 1- containing solution thus obtained was applied on a polyethylene terephthalate film so that the PGE 1 content became 70 μg / cm 2, and dried at 120 ° C. for 2 minutes to prepare a PGE 1- containing patch.
比較例 皮膚透過促進剤を添加しなかったほかは、実施例と全
く同様に操作して、PGE1含有・透過促進剤非含有貼付剤
を、比較貼付剤として調製した。Except that was not added Comparative Example skin permeation enhancers, operates in exactly the same manner as in Example, the PGE 1 containing, permeation enhancer-free patch was prepared as a comparative patch.
試験例 上記、実施例及び比較例において調製された試験片を
用いて、ヘアレスラット腹部摘出皮膚透過試験を行っ
た。試験法の詳細は、次のとおりである。Test Example Using the test pieces prepared in the above Examples and Comparative Examples, an abdominal excised skin permeation test of a hairless rat was performed. Details of the test method are as follows.
６週令の雄性ヘアレスラット（埼王実験動物）をペン
トバルビタールで麻酔し、腹部の皮膚を分取する。その
皮膚に試験片を貼付したのち、拡散セルに装着し、放出
液としてpH5.0の緩衝液を用いて、皮膚を透過するPGE1
を高速液体クロマトグラフィーにて定量する。試験はす
べて37℃で実施した。Six-week-old male hairless rats (Saioh experimental animals) are anesthetized with pentobarbital, and the skin of the abdomen is collected. After attaching the test piece to the skin, the sample was attached to a diffusion cell, and PGE 1 penetrating the skin was used using a buffer solution of pH 5.0 as a release solution.
Is determined by high performance liquid chromatography. All tests were performed at 37 ° C.
かくして得られた結果を、図に示す。これによれば、
時間に対する累積透過量は、本発明の製剤の方が、比較
例のものに比べてはるかに多いことがわかる。The results obtained are shown in the figure. According to this,
It can be seen that the cumulative permeation amount with respect to time is much higher in the preparation of the present invention than in the comparative example.
（効果） 実施例、比較例、及び試験例の結果からも明らかなよ
うに、本発明の透過促進剤を用いたPGE1含有製剤のPGE1
皮膚透過能はすぐれており、本発明製剤は、持続性を有
する血管拡張剤として血圧降下、末梢血管拡張に用いて
特に有用であり、産業上資するところ大である。(Effect) Example, Comparative Example, and from the results of Test Example As is apparent, PGE 1 of PGE 1 containing formulations using permeation enhancers of the present invention
The skin permeability is excellent, and the formulation of the present invention is particularly useful as a persistent vasodilator for lowering blood pressure and peripheral vasodilatation, and has great industrial applicability.
図は、実施例及び比較例において得られた試験片を用い
て行われた皮膚透過試験の結果を示すグラフである。The figure is a graph showing the results of a skin permeation test performed using the test pieces obtained in Examples and Comparative Examples.
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.6，ＤＢ名) A61K 31/557 A61K 9/70 ＣＡ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. 6 , DB name) A61K 31/557 A61K 9/70 CA (STN)
Claims (2)
ル酸との共重合体（ここで、２−エチルヘキシルアクリ
レート／アクリル酸のモル比は、90/10以上である）で
あるアクリル系粘着剤、プロスタグランジンEl及び皮膚
透過促進剤を含むプロスタグランジンEl経皮吸収製剤。1. An acrylic pressure-sensitive adhesive which is a copolymer of 2-ethylhexyl acrylate and acrylic acid (where the molar ratio of 2-ethylhexyl acrylate / acrylic acid is 90/10 or more), prostaglandin A prostaglandin El transdermal absorption preparation containing El and a skin permeation enhancer.
ある、請求項１記載の経皮吸収製剤。2. The percutaneous absorption preparation according to claim 1, wherein the skin penetration enhancer is a medium-chain fatty acid glyceride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1084088A JP2910857B2 (en) | 1989-04-04 | 1989-04-04 | Prostaglandin E1 transdermal preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1084088A JP2910857B2 (en) | 1989-04-04 | 1989-04-04 | Prostaglandin E1 transdermal preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02264725A JPH02264725A (en) | 1990-10-29 |
| JP2910857B2 true JP2910857B2 (en) | 1999-06-23 |
Family
ID=13820749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1084088A Expired - Fee Related JP2910857B2 (en) | 1989-04-04 | 1989-04-04 | Prostaglandin E1 transdermal preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2910857B2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006118173A1 (en) | 2005-04-28 | 2006-11-09 | Ono Pharmaceutical Co., Ltd. | Trenadermal absorption preparation |
| WO2008050848A1 (en) | 2006-10-26 | 2008-05-02 | Ono Pharmaceutical Co., Ltd. | Adhesive preparation |
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|---|---|---|---|---|
| US5380760A (en) * | 1993-11-19 | 1995-01-10 | Minnesota Mining And Manufacturing Company | Transdermal prostaglandin composition |
| US6825234B2 (en) | 1998-12-10 | 2004-11-30 | Nexmed (Holdings) , Inc. | Compositions and methods for amelioration of human female sexual dysfunction |
| US6486207B2 (en) | 1998-12-10 | 2002-11-26 | Nexmed (Holdings), Inc. | Compositions and methods for amelioration of human female sexual dysfunction |
| US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| ES2885523T3 (en) | 2011-11-23 | 2021-12-14 | Therapeuticsmd Inc | Natural combination hormone replacement formulations and therapies |
| MX367596B (en) * | 2012-01-26 | 2019-08-27 | Therapeuticsmd Inc | Transdermal hormone replacement therapies. |
| US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
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| US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
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| US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
| CA2947767A1 (en) | 2014-05-22 | 2015-11-26 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
| US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
-
1989
- 1989-04-04 JP JP1084088A patent/JP2910857B2/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006118173A1 (en) | 2005-04-28 | 2006-11-09 | Ono Pharmaceutical Co., Ltd. | Trenadermal absorption preparation |
| WO2008050848A1 (en) | 2006-10-26 | 2008-05-02 | Ono Pharmaceutical Co., Ltd. | Adhesive preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02264725A (en) | 1990-10-29 |
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