JPS61204117A - Percutaneous absorption pharmaceutical for external use - Google Patents
Percutaneous absorption pharmaceutical for external useInfo
- Publication number
- JPS61204117A JPS61204117A JP4361285A JP4361285A JPS61204117A JP S61204117 A JPS61204117 A JP S61204117A JP 4361285 A JP4361285 A JP 4361285A JP 4361285 A JP4361285 A JP 4361285A JP S61204117 A JPS61204117 A JP S61204117A
- Authority
- JP
- Japan
- Prior art keywords
- percutaneous absorption
- animal
- vegetable oil
- mentioned
- sympathomimetic
- 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は交感神経β−受容体興奮薬を有効成分とする経
皮吸収外用剤に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a percutaneously absorbable topical preparation containing a sympathetic β-receptor stimulant as an active ingredient.
イソプロテレノール、オルシプレナリンなどの交感神経
β−受容体興奮薬はβ−受容体に選択的に作用し、各種
平滑筋に対して弛緩作用を呈する。この作用は特に気管
支筋において著明であり、気管支拡張剤として気管支喘
息、慢性気管支炎など臨床的にも幅広く使用されている
。Sympathetic nerve β-receptor stimulants such as isoproterenol and orciprenaline act selectively on β-receptors and exhibit relaxing effects on various smooth muscles. This effect is particularly pronounced in bronchial muscles, and it is widely used clinically as a bronchodilator for bronchial asthma, chronic bronchitis, etc.
現在これらの気管支拡張剤は吸入剤、注射剤及び経口剤
として供給されているが、気管支拡張剤の投′与形態と
して満足できる状況ではない。Currently, these bronchodilators are supplied as inhalants, injections, and oral preparations, but these are not satisfactory administration forms for bronchodilators.
例えば吸入剤は喘息発作の緩解に頻用されているが、吸
入剤の使用法を会得するには練習が必要であり、患者の
みならず指導する医師にとっても負担である。また吸入
剤は急速な治療効果を示すが、頻回使用による過量服用
に陥りやすく副作用の原因となる。気管支喘息、慢性気
管支炎の患者の多くは日常、健康人と全くかわらぬ生活
を営んでおり、自己投薬のできない注射剤は不便である
し、１日６回服用すべき経口剤でさえ、日常業務に追わ
れてしばしば飲み忘れ、そのため発作を起こして吸入剤
に頼らざるを得ないことになる。For example, inhalers are frequently used to relieve asthma attacks, but learning how to use inhalers requires practice, which is a burden not only to the patient but also to the doctor instructing them. Furthermore, although inhalants exhibit rapid therapeutic effects, they are prone to overdosing due to frequent use, causing side effects. Many patients with bronchial asthma and chronic bronchitis lead daily lives that are completely different from healthy people, and injectables that cannot be self-administered are inconvenient, and even oral medications that must be taken six times a day are difficult to administer on a daily basis. Due to the demands of his work, he often forgets to take his doses, resulting in seizures and having to rely on inhalants.
こうした状況に鑑み、本発明者らは投薬が容易でかつ治
療効果の高い投与形態として外用剤に着目し、気管支拡
張剤を白色ワセリン、ポリエチレングリコール、親水軟
膏など公知の基剤に練合してラット経皮吸収を調べたと
ころ、血中濃度の上昇はほとんど認められなかった。１
またサリチル酸、尿素など角質層に影響を与えて吸収促
進作用を示すといわれている物質を基剤に添加しても、
気管支拡張剤に対しては効果を示さなかった。ところが
、さらに研究を進めた結果、驚くべきことにこれらの基
剤に特定の液状油脂を加えることにより、気管支拡張剤
の経皮吸収が飛躍的に増大することを見い出した。In view of these circumstances, the present inventors focused on external preparations as a dosage form that is easy to administer and has a high therapeutic effect, and mixed a bronchodilator into a known base such as white petrolatum, polyethylene glycol, or hydrophilic ointment. When transdermal absorption was investigated in rats, almost no increase in blood concentration was observed. 1
Furthermore, even if substances such as salicylic acid and urea that are said to affect the stratum corneum and promote absorption are added to the base,
No effect was shown on bronchodilators. However, as a result of further research, it was surprisingly discovered that by adding a specific liquid oil to these bases, the transdermal absorption of bronchodilators was dramatically increased.
本発明はこの知見に基づいて完成されたもので、交感神
経β−受容体興奮薬を有効成分とし、さらに３７℃以下
の温度で液状の動植物油及び／又は有機酸エステルを含
有することを特徴とする、経皮吸収外用剤である。The present invention was completed based on this knowledge, and is characterized by containing a sympathetic β-receptor stimulant as an active ingredient, and further containing an animal or vegetable oil and/or an organic acid ester that is liquid at a temperature of 37°C or less. It is a transdermal absorption topical preparation.
本発明に用いられる交感神経β−受容体興奮薬（以下、
気管支拡張剤と呼ぶ）としては、例えばイソプロテレノ
ール、オルシプレナリン、サルブタモール、テルブタリ
ン、ヘキソプレナリンなどがあげられる。これらは遊離
塩基でもよく、また製薬上許容される塩でもよい。塩を
形成する酸としては、塩酸、燐酸などの無機酸、酢酸、
乳酸、メシル酸などの有機酸があげられる。製剤中の主
薬の含量は、基剤及び他の成分の種類及び量によって異
なるが、一般に０．１〜５重量％が好ましい。Sympathetic nerve β-receptor stimulant (hereinafter referred to as
Bronchodilators (referred to as bronchodilators) include, for example, isoproterenol, orciprenaline, salbutamol, terbutaline, and hexoprenaline. These may be free bases or pharmaceutically acceptable salts. Acids that form salts include inorganic acids such as hydrochloric acid and phosphoric acid, acetic acid,
Examples include organic acids such as lactic acid and mesylic acid. The content of the main drug in the formulation varies depending on the type and amount of the base and other ingredients, but is generally preferably 0.1 to 5% by weight.
本発明に用いられる３７℃以下において液状の動植物油
としては、オリーブ油、大豆油、落花生油、ごま油、と
うもろこし油、綿実油、やし油などの天然油のほか、天
然油を水素添加、脂肪酸交換、分割抽出などの手段によ
り改質した製品、例えば硬化油、スクヮレン、スクヮラ
ン、液体ラノリン、イソプロピルラノリン、ネオピー油
（ドリューケミカル社製品）などがあげられる。また３
７℃以下において液状のエステルとしては、１価又は多
価アルコールのエステルでよ（、例えばミリスチン酸イ
ソプロピル、パルミチン酸イソプロピルなどの低級アル
コールと高級脂肪酸のエステル、ラウリン酸ヘキサデシ
ル、ステアリン酸ヘキサデシルなどの高級アルコールと
高級脂肪酸のエステル、アジピン酸ジインプロピル、セ
バシン酸ジエチルなどの低級アルコールドジカルボン酸
のエステル、トリアセチン、マイバーセット（イースト
マンコダック社製品）などのアセトグリセリド、０ＤＯ
（日清製油社製品）、パナセート（日本油脂社製品）、
ミオグリオール（ダイナマイトノーベル社製品）などの
中鎖脂肪酸トリグリセリド、炭酸プロピレンなどがあげ
られる。これらは単独で用いてもよく、２種以上を併用
してもよい。The animal and vegetable oils that are liquid at 37°C or lower used in the present invention include natural oils such as olive oil, soybean oil, peanut oil, sesame oil, corn oil, cottonseed oil, and coconut oil, as well as natural oils that are hydrogenated, fatty acid exchanged, etc. Examples include products modified by means such as fractional extraction, such as hydrogenated oil, squalene, squalane, liquid lanolin, isopropyl lanolin, and neopylene oil (manufactured by Drew Chemical Company). Also 3
Esters that are liquid at temperatures below 7°C include esters of monohydric or polyhydric alcohols (for example, esters of lower alcohols and higher fatty acids such as isopropyl myristate and isopropyl palmitate, and higher esters such as hexadecyl laurate and hexadecyl stearate). Esters of alcohol and higher fatty acids, esters of lower alcohol dodicarboxylic acids such as diimpropyl adipate and diethyl sebacate, acetoglycerides such as triacetin and Myverset (product of Eastman Kodak), 0DO
(Nissin Oil Co. product), Panacet (Nippon Oil Co. product),
Examples include medium chain fatty acid triglycerides such as myoglyol (product of Dynamite Nobel), propylene carbonate, etc. These may be used alone or in combination of two or more.
動植物油及び／又はエステルの使用量は、通常は気管支
拡張剤１重量部に対して１〜１００重量部が好ましい。The amount of animal and vegetable oil and/or ester used is usually preferably 1 to 100 parts by weight per 1 part by weight of the bronchodilator.
５７℃以下において液状の動植物油及び有機酸エステル
は、皮膚に塗布又は貼布されたとき液状となり、基剤の
皮膚親和性を改善するとともに、基剤からの主剤の放出
を容易にして、主剤の経皮吸収を促進するものと考えら
れる。鯨ろう、蜜ろう、ミリスチン酸ミリシル、グリセ
リルモノステアレートなど融点の高い動植物油又はエス
テルは、単独で使用しても気管支拡張剤の経皮吸収は改
善されないが、粘度調整餠のため併用することが・でき
る。Animal and vegetable oils and organic acid esters that are liquid at temperatures below 57°C become liquid when applied or applied to the skin, improving the skin affinity of the base and facilitating the release of the base ingredient from the base. It is thought to promote transdermal absorption of. Animal and vegetable oils or esters with high melting points, such as spermaceti, beeswax, myricyl myristate, and glyceryl monostearate, do not improve the percutaneous absorption of bronchodilators when used alone, but they should be used in combination to adjust the viscosity. I can.
本発明の外用剤の剤形は、気管支拡張剤を配合しうるも
のであればいずれでもよ（、例えば液剤、ローション剤
、クリーム剤、軟膏剤、ゲル軟膏剤、硬膏剤などのほか
、パップ剤、テープ剤などとすることができる。The external preparation of the present invention may be in any form as long as it can contain a bronchodilator (e.g., liquid, lotion, cream, ointment, gel ointment, plaster, etc.), as well as poultices. , a tape agent, etc.
その除用いる基剤としては白色ワセリン、パラフィン、
ワックス、ステアリルアルコール、マクロゴールなど一
般に外用剤に用いられているものであれば、すべて好適
に用いることができる。The base used for its removal is white petrolatum, paraffin,
Any wax, stearyl alcohol, macrogol, etc. that are commonly used in external preparations can be suitably used.
本発明の外用剤にはそのほか、カルボキシメチルセルロ
ース、トラガントなどの懸濁化剤、ポリソルベート８０
１ ラウロマクロゴールなどの乳化剤、グリセリン、プ
ロピレングリコールなどの保湿剤、トコフェロール、ジ
ブチルヒドロキシトルエン、チオグリセロールなどの抗
酸化剤、くえん酸、ＥＤＴＡなとのキレート剤、パラオ
キシ安息香酸エステル、クロロブタノールなどの保存剤
、ポリアルキルビニルエーテノペポリアルキルアクリレ
ートなどの粘着剤なども加えることができる。In addition, the external preparation of the present invention includes suspending agents such as carboxymethyl cellulose and tragacanth, and polysorbate 80.
1. Emulsifiers such as lauromacrogol, humectants such as glycerin and propylene glycol, antioxidants such as tocopherol, dibutylhydroxytoluene, and thioglycerol, chelating agents such as citric acid and EDTA, paraoxybenzoate esters, and chlorobutanol. Preservatives, adhesives such as polyalkyl vinyl etherene polyalkyl acrylate, etc. can also be added.
本発明の外用剤は、前記の動植物油及び／又はエステル
と基剤を重量比でｉ：ｏ、ｏｓ〜１００の割合で用い、
必要に応じて他の助剤、添加剤等を加えて混合したのち
、この混合物に気管支拡張剤を加えてよく練合すること
により製造できる。また気管支拡張剤を、動植物油、エ
ステル又は基剤の一部に分散又は溶解したのち、残りの
成分を加えて練合してもよい。The external preparation of the present invention uses the above-mentioned animal and vegetable oil and/or ester and the base in a weight ratio of i:o, os to 100,
It can be manufactured by adding and mixing other auxiliaries, additives, etc. as necessary, and then adding a bronchodilator to this mixture and kneading well. Alternatively, the bronchodilator may be dispersed or dissolved in part of the animal or vegetable oil, ester, or base, and then the remaining ingredients may be added and kneaded.
さらにパップ剤、テープ剤などにするには粘着剤などを
加えたのち、織布、紙、プラスチックフィルムなどの担
持体に吸収、付着あるいは展延すればよい。Furthermore, in order to make a poultice, a tape, etc., an adhesive or the like may be added and then absorbed, attached, or spread onto a carrier such as woven cloth, paper, or plastic film.
本発明の外用剤は、耳介後部、頚部、胸部、上腕部など
に塗布又は貼布することが好ましい。The external preparation of the present invention is preferably applied or pasted to the rear part of the auricle, the neck, the chest, the upper arm, and the like.
下記実施例中の部は重量部を意味する。Parts in the following examples mean parts by weight.
実施例１゜
塩酸イソプロテレノール １部パラフィン
１５部スクワラン
５０部白色ワセリン ６４部塩酸
イソプロテレノール以外の成分を約７０℃で混合し攪拌
しながら冷却したのち、塩酸イソプロテレノールを加え
て均一になるまで練合し、軟膏剤を調製した。Example 1゜Isoproterenol hydrochloride 1 part paraffin
Part 15 Squalane
50 parts White petrolatum 64 parts The ingredients other than isoproterenol hydrochloride were mixed at about 70° C. and cooled with stirring, then isoproterenol hydrochloride was added and kneaded until homogeneous to prepare an ointment.
実施例２
塩酸イソプロテレノール １部サランミツロウ
１７部オリーブ油
５０部白色ワセリン ３２部実施
例６
塩酸イソプロテレノール １部パラフィン
１４部マイクロクリスタリンワック
ス １０部ミリスチン酸イングロビル ５２部白色
ワセリン ２６部実施例４
塩酸イソプロテレノール １部パラフィン
１５部＝ イ２’ ＋ ッＦ９−４
０Ｔｏ４６ ’１ａｌｓブチルヒドロキシアニソール
０．０１部白色ワセリン ３８部比
較例１
塩酸イソプロテレノール １部白色ワセリン
９９部前記の成分を均一になるまで練
合し、軟膏剤とした。Example 2 Isoproterenol hydrochloride 1 part Saran beeswax 17 parts Olive oil
50 parts White petrolatum 32 parts Example 6 Isoproterenol hydrochloride 1 part Paraffin
14 parts Microcrystalline wax 10 parts Inglovir myristate 52 parts White petrolatum 26 parts Example 4 Isoproterenol hydrochloride 1 part Paraffin
Part 15 = A2' + F9-4
0To46 '1als Butyl Hydroxy Anisole
0.01 part white petrolatum 38 parts Comparative Example 1 Isoproterenol hydrochloride 1 part white petrolatum
99 parts of the above ingredients were kneaded until homogeneous to prepare an ointment.
比較例２
塩酸イソプロテレノール １部サランミツロウ
１６部ステアリルアルコール
６部コレステロール ３部流動パ
ラフィン ４０部白色ワセリン
３７部塩酸イソプロテレノール以外の成分を
約７０℃で混合し攪拌しながら冷却したのち、塩酸イソ
プロテレノールを加えて均一になるまで練合し、軟膏剤
とした。Comparative Example 2 Isoproterenol hydrochloride 1 part Saran beeswax 16 parts Stearyl alcohol
6 parts cholesterol 3 parts liquid paraffin 40 parts white petrolatum
Components other than 37 parts of isoproterenol hydrochloride were mixed at about 70° C. and cooled with stirring, then isoproterenol hydrochloride was added and kneaded until homogeneous to obtain an ointment.
実験例゛
経皮吸収試験
除毛したラット（雄性、体重約３００１）の腹部４ ｃ
ｍ”の広さに本発明の外用剤をイソプロテレノールとし
て５ｍ９／ｋｙとなるように塗布し、合成樹脂フィルム
で塗布部を密封した。次いで経時的に採血し血漿中のイ
ソプロテレノール量を高速液体クロマトグラフィにより
測定した。Experimental example: Transdermal absorption test Abdomen of a dehaired rat (male, weight approx. 3001 kg) 4c
The topical preparation of the present invention was applied as isoproterenol at a concentration of 5 m9/ky to an area of 1.5 m'', and the applied area was sealed with a synthetic resin film.Blood was then collected over time to determine the amount of isoproterenol in the plasma. Measured by high performance liquid chromatography.
その結果を下記表に示す。比較例１及び２に比べ実施例
１〜４は極めて高い血中濃度を示し、経皮吸収が改善さ
れていることが知られる。The results are shown in the table below. It is known that Examples 1 to 4 showed extremely high blood concentrations compared to Comparative Examples 1 and 2, and that percutaneous absorption was improved.
Claims (1)
℃以下の温度で液状の動植物油及び／又は有機酸エステ
ルを含有することを特徴とする、経皮吸収外用剤。The active ingredient is a sympathetic β-receptor stimulant, and 37
An external preparation for transdermal absorption, characterized by containing an animal or vegetable oil and/or an organic acid ester that is liquid at a temperature of 0.degree. C. or lower.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4361285A JPS61204117A (en) | 1985-03-07 | 1985-03-07 | Percutaneous absorption pharmaceutical for external use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4361285A JPS61204117A (en) | 1985-03-07 | 1985-03-07 | Percutaneous absorption pharmaceutical for external use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS61204117A true JPS61204117A (en) | 1986-09-10 |
Family
ID=12668658
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4361285A Pending JPS61204117A (en) | 1985-03-07 | 1985-03-07 | Percutaneous absorption pharmaceutical for external use |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS61204117A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002518417A (en) * | 1998-06-25 | 2002-06-25 | ラヴィファム ラボラトリーズ インコーポレーテッド | Braces and methods for treating erectile dysfunction |
| WO2007066151A3 (en) * | 2005-12-07 | 2008-03-27 | Pharmakodex Ltd | Topical compositions for treatment of respiratory disorders |
-
1985
- 1985-03-07 JP JP4361285A patent/JPS61204117A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002518417A (en) * | 1998-06-25 | 2002-06-25 | ラヴィファム ラボラトリーズ インコーポレーテッド | Braces and methods for treating erectile dysfunction |
| WO2007066151A3 (en) * | 2005-12-07 | 2008-03-27 | Pharmakodex Ltd | Topical compositions for treatment of respiratory disorders |
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