JP2669951B2 - Transdermal composition containing narcotic analgesic - Google Patents
Transdermal composition containing narcotic analgesicInfo
- Publication number
- JP2669951B2 JP2669951B2 JP3087394A JP8739491A JP2669951B2 JP 2669951 B2 JP2669951 B2 JP 2669951B2 JP 3087394 A JP3087394 A JP 3087394A JP 8739491 A JP8739491 A JP 8739491A JP 2669951 B2 JP2669951 B2 JP 2669951B2
- Authority
- JP
- Japan
- Prior art keywords
- composition
- transdermal
- morphine
- present
- hydrochloride
- 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 - Lifetime
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、経皮吸収製剤に用
いるのに適した経皮吸収組成物に関し、詳しくは塩酸モ
ルヒネ、硫酸モルヒネ、塩酸コカインまたはクエン酸フ
ェンタニ−ルのうちのいずれかの麻薬性鎮痛剤を含有す
る経皮吸収組成物に関する。TECHNICAL FIELD The present invention relates to a percutaneous absorption composition suitable for use in a percutaneous absorption preparation, and more specifically, it is one of morphine hydrochloride, morphine sulfate, cocaine hydrochloride or fentanyl citrate. The present invention relates to a transdermal composition containing a narcotic analgesic.
【０００２】[0002]
【従来の技術】術後の疼痛または癌性の疼痛等の疼痛を
和らげるために用いられる塩酸モルヒネ、硫酸モルヒ
ネ、塩酸コカインおよびクエン酸フェンタニ−ル等の麻
薬性鎮痛剤は、従来注射剤または経口剤として投与され
ている。ところが、これらの鎮痛剤を注射剤の形で投与
する場合には、その投与に、患者以外の特定の専門家、
例えば医師または看護婦による投与を必要とするので、
この注射剤の投与を伴う在宅治療は難しく、しかもモル
ヒネのように作用時間が短い薬物では投与頻度を増加さ
せなければならないので、患者の疼痛が激しい時に、そ
の激痛を満足に抑えるための適切な投与を施すのは難し
いという問題があった。BACKGROUND OF THE INVENTION Narcotic analgesics such as morphine hydrochloride, morphine sulfate, cocaine hydrochloride and fentanyl citrate, which are used for relieving post-operative pain or pain such as cancerous pain, are conventionally injected or orally. It is administered as a drug. However, when these analgesics are administered in the form of injections, the administration must be performed by a specific specialist other than the patient,
For example, because it requires administration by a doctor or nurse,
At-home treatment involving the administration of this injection is difficult, and the frequency of administration must be increased for drugs with a short duration of action, such as morphine, so when the patient has severe pain, it is appropriate to suppress the severe pain satisfactorily. There was a problem that administration was difficult.
【０００３】また、他方の経口投与剤では、鎮痛剤の投
与を注射剤よりも簡便にすることを目的として開発され
ているところから、上記のような注射剤の欠点は幾分克
服されているけれども、作用時間については注射剤に比
べて余り改善されてなく、それに製剤的な工夫を凝らし
て薬物の徐放化を図っても、その薬物が消化器官内で順
次移行していく挙動およびそれの滞留時間を制御するの
が困難であって、薬効の持続時間を長くするには限度が
あり、薬効について十分な持続時間を得るのは難しいと
いう問題があった。On the other hand, the other orally administered drug has been developed for the purpose of simplifying the administration of the analgesic drug as compared with the injectable drug, so that the above-mentioned drawbacks of the injectable drug have been somewhat overcome. However, the action time was not much improved compared to the injection, and even if the drug was devised for sustained release to achieve sustained release of the drug, the behavior of the drug gradually migrating in the digestive system and its It is difficult to control the residence time of the drug, and there is a limit to increase the duration of the drug effect, and there is a problem that it is difficult to obtain a sufficient drug effect duration.
【０００４】さらに、末期癌にまで病状が進行している
患者の中には、抗癌剤の副作用によって生ずる吐き気や
嘔吐のために、経口投与では鎮痛剤を投与できない患者
が出てくるという問題もあった。一方、経皮的に投与さ
れる製剤では１回の投与で２４時間〜１週間程度に及ぶ
薬効の持続性が期待できるばかりでなく、経口的に投与
できない患者にも投与できるという利点があるけれど
も、この製剤における薬物の経皮吸収性は一般に低く、
モルヒネやその塩類を始めとする麻薬性鎮痛剤もその例
外ではなかった。Further, there is a problem that some patients who have advanced disease to end-stage cancer may not be able to administer analgesics by oral administration due to nausea and vomiting caused by side effects of anticancer agents. It was On the other hand, a preparation to be administered transdermally has the advantage that it can be expected to have a sustained effect for about 24 hours to 1 week with a single administration and can be administered to patients who cannot be orally administered. , The transdermal absorbability of drugs in this formulation is generally low,
Narcotic analgesics such as morphine and its salts were no exception.
【０００５】薬物の経皮吸収の主なバリヤ−が皮膚の角
質層にあるところから、その角質層の脂質等に働いて薬
物の経皮吸収性を高める種々の経皮吸収促進剤が開発さ
れてきたけれども、角質層以外の表皮部分も薬物透過性
のバリヤ−となっているために、単にこの角質層に作用
する促進剤またはその組み合わせでは、十分な経皮吸収
性を達成することができず、満足な経皮吸収促進剤は未
だ開発されていない現状にある。Since the main barrier for the percutaneous absorption of drugs is the stratum corneum of the skin, various transdermal absorption enhancers have been developed which act on the lipids of the stratum corneum to enhance the transdermal absorbability of drugs. However, since the epidermal portions other than the stratum corneum are also barriers to drug permeability, sufficient transdermal absorbability can be achieved only by the accelerator or its combination acting on the stratum corneum. Therefore, a satisfactory transdermal absorption enhancer has not yet been developed.
【０００６】[0006]
【発明が解決しようとする課題】したがって、モルヒネ
やその塩類等の鎮痛剤の十分な経皮吸収性が発揮される
経皮吸収組成物の開発が望まれていた。Therefore, there has been a demand for the development of a percutaneous absorption composition capable of exerting sufficient percutaneous absorption of analgesics such as morphine and salts thereof.
【０００７】[0007]
【課題を解決するための手段】そこで、本発明者等は、
このような従来技術の不十分な点に鑑み、従来注射剤ま
たは経口剤としてしか使用されていなかったモルヒネ等
の鎮痛剤を軟膏、クリ−ム、テ−プ剤、プラスタ−剤、
パッチ剤またはパップ剤等の外用剤へと利用するのに適
した経皮吸収組成物を得るべく鋭意研究した結果、ｌ-
メント−ル、テルピネオ−ルおよびハッカ油から選ばれ
る１種または２種以上の経皮吸収促進剤に、エタノ−ル
と水またはグリセリン、あるいはイソプロパノ−ルと水
からなる経皮吸収促進助剤を組み合わせると、これらの
経皮吸収促進剤と経皮吸収促進助剤との相乗効果によっ
て塩酸モルヒネ、硫酸モルヒネ、塩酸コカインまたはク
エン酸フェンタニ−ルのような薬物の経皮吸収性が向上
すること、を見出した。Therefore, the present inventors have
In view of such inadequacies of conventional techniques, analgesics such as morphine, which have been conventionally used only as injections or oral preparations, ointments, creams, tapes, plasters,
As a result of intensive research to obtain a transdermal composition suitable for use as an external preparation such as a patch or a poultice, 1-
One or more percutaneous absorption enhancers selected from menthol, terpineol, and peppermint oil, and a percutaneous absorption enhancer consisting of ethanol and water or glycerin, or isopropanol and water. When combined, the transdermal absorbability of drugs such as morphine hydrochloride, morphine sulfate, cocaine hydrochloride or fentanyl citrate is improved by the synergistic effect of these transdermal absorption enhancers and transdermal absorption enhancers, Found.
【０００８】本発明は、このような知見に基づいて発明
されたもので、モルヒネ等の鎮痛剤について十分な経皮
吸収性を発揮する優れた経皮吸収組成物を提供すること
を目的とし、そしてこのような目的は、ｌ- メント−
ル、テルピネオ−ルおよびハッカ油から選ばれる１種ま
たは２種以上の経皮吸収促進剤、エタノ−ルと水または
グリセリン、あるいはイソプロパノ−ルと水からなる経
皮吸収促進助剤、および塩酸モルヒネ、硫酸モルヒネ、
塩酸コカインまたはクエン酸フェンタニ−ルのうちのい
ずれかの麻薬性鎮痛剤を含有する経皮吸収組成物によっ
て、達成される。The present invention was invented on the basis of such findings, and an object thereof is to provide an excellent transdermal absorption composition exhibiting sufficient transdermal absorbability for analgesics such as morphine, And such purpose is l-ment-
Or terpineol and peppermint oil, or one or more transdermal absorption enhancers, ethanol and water or glycerin, or isopropanol and water, and a morphine hydrochloride. , Morphine sulfate,
This is accomplished by a transdermal composition containing a narcotic analgesic, either cocaine hydrochloride or fentanyl citrate.
【０００９】[0009]
【発明の実施の形態】本発明の経皮吸収組成物では、上
述の通り、麻薬性鎮痛剤として塩酸モルヒネ、硫酸モル
ヒネ、塩酸コカインおよびクエン酸フェンタニ−ルが、
経皮吸収促進剤としてｌ- メント−ル、テルピネオ−ル
およびハッカ油が、そして経皮吸収促進助剤としてエタ
ノ−ルと水またはグリセリン、あるいはイソプロパノ−
ルと水がそれぞれ用いられれる。BEST MODE FOR CARRYING OUT THE INVENTION As described above, in the transdermal absorption composition of the present invention, morphine hydrochloride, morphine sulfate, cocaine hydrochloride and fentanyl citrate are used as narcotic analgesics.
Transdermal absorption enhancers include l-menthol, terpineol and peppermint oil, and percutaneous absorption enhancers such as ethanol and water or glycerin, or isopropanol.
Le and water are used respectively.
【００１０】本発明の組成物中における経皮吸収促進剤
および経皮吸収促進助剤の配合割合は、その組成物の重
量を基にして、それぞれ２〜２０重量％および２０〜６
０重量％であるのが好ましい。本発明の組成物中に含有
される経皮吸収促進剤は皮膚の一部を構成している角質
層が示すバリヤ−作用を物理的に取り除いて皮膚の薬物
透過性を高め、一方、経皮吸収促進助剤は、この組成物
中で薬物の溶解度を増大させるとともに皮膚の薬物透過
性を高める作用を有し、この経皮吸収促進剤と経皮吸収
促進助剤とが相乗的に作用することによって薬物の経皮
吸収性が著しく向上する。The proportions of the percutaneous absorption enhancer and the percutaneous absorption enhancer in the composition of the present invention are 2 to 20% by weight and 20 to 6%, respectively, based on the weight of the composition.
It is preferably 0% by weight. The transdermal absorption enhancer contained in the composition of the present invention physically removes the barrier action exhibited by the stratum corneum forming a part of the skin to enhance the drug permeability of the skin, while the transdermal The absorption enhancer has the effects of increasing the solubility of the drug in this composition and enhancing the drug permeability of the skin, and the transdermal absorption enhancer and the transdermal absorption enhancer act synergistically. This significantly improves the transdermal absorbability of the drug.
【００１１】[0011]
【実施例】ついで、実施例によって本発明をさらに詳し
く説明する。 実施例１ 表１に示される本発明組成物１および比較組成物１〜３
を調製し、これらの組成物に関する皮膚透過量の経時変
化を、下記の皮膚透過試験によって調べた。EXAMPLES Next, the present invention will be described in more detail by way of examples. Example 1 Inventive Composition 1 and Comparative Compositions 1-3 shown in Table 1
Was prepared, and the time-dependent change in skin permeation amount of these compositions was examined by the following skin permeation test.
【００１２】〈皮膚透過試験〉 ３７℃に保たれている２- チャンバ−拡散セル（接触面
積：１．０cm2 ）にヘアレスラット（オス、体重：１５
０ｇ、埼玉実験動物株式会社から入手）の腹部摘出皮膚
を挟み、角質層側のチャンバ−に薬物溶液２．５mlを、
そして真皮側のチャンバ−に水２．５mlを入れて、１０
個用意されている上記拡散セルの真皮側溶液を経時的に
サンプリングしながら、２、４、６、８および１０時間
後における薬物の皮膚透過量を測定した。その結果は表
２および図１に示される。<Skin Permeation Test> Hairless rats (male, weight: 15) were placed in a 2-chamber-diffusion cell (contact area: 1.0 cm 2 ) kept at 37 ° C.
0 g, obtained from Saitama Experimental Animal Co., Ltd.) was sandwiched between the abdominal excised skins, and 2.5 ml of the drug solution was placed in the chamber on the stratum corneum side,
Add 2.5 ml of water to the dermis side chamber and
The skin permeation amount of the drug was measured after 2, 4, 6, 8 and 10 hours while sampling the dermis side solution of each of the diffusion cells prepared individually with time. The results are shown in Table 2 and FIG.
【００１３】[0013]
【表１】 [Table 1]
【００１４】[0014]
【表２】 [Table 2]
【００１５】表２および図１に示される結果から、経皮
吸収促進剤であるｌ- メント−ルと経皮吸収促進助剤で
あるエタノ−ルおよび水とを併用した本発明組成物１
が、水だけを用いた比較組成物１、経皮吸収促進剤を用
いないで経皮吸収促進助剤であるエタノ−ルおよび水だ
けを用いた比較組成物２および経皮吸収促進助剤の必須
成分であるエタノ−ルを用いなかった比較組成物３より
も優れた経皮吸収性を示すことが判る。From the results shown in Table 2 and FIG. 1, the composition 1 of the present invention in which 1-menthol, which is a percutaneous absorption promoter, and ethanol and water, which are percutaneous absorption promoters, are used in combination.
Of Comparative Composition 1 using water only, Ethanol which is a transdermal absorption promoting aid without using a transdermal absorption enhancer, and Comparative Composition 2 using only water and a transdermal absorption promoting aid. It can be seen that the composition has a better transdermal absorbability than Comparative Composition 3 which does not use the essential component ethanol.
【００１６】実施例２ 塩酸モルヒネ（図２中ではＭＰＨと表されている）の濃
度が、この塩酸モルヒネの皮膚透過性に及ぼす影響を調
べるために表３に示される本発明組成物２および３を調
製し、これらの組成物に関する経時的な皮膚透過量を、
実施例１と同様に測定し、その結果を前記本発明組成物
１の結果と合わせて表４および図２に示した。Example 2 Compositions 2 and 3 of the present invention shown in Table 3 for investigating the effect of the concentration of morphine hydrochloride (denoted as MPH in FIG. 2) on the skin permeability of this morphine hydrochloride. And the amount of skin permeation over time for these compositions,
The measurement was performed in the same manner as in Example 1, and the results are shown in Table 4 and FIG. 2 together with the results of the composition 1 of the present invention.
【００１７】[0017]
【表３】 [Table 3]
【００１８】[0018]
【表４】 [Table 4]
【００１９】表４および図２に示される結果から、塩酸
モルヒネの濃度の増加に応じて塩酸モルヒネの皮膚透過
量が増加し、また、経時的な皮膚透過性のパタ−ンは塩
酸モルヒネの濃度が著しく変化しても変わらないことが
判った。 実施例３ 表５に示されるように、経皮吸収促進助剤の種類と量は
変えないで、経皮吸収促進剤の種類だけを変えて、すな
わち、経皮吸収促進助剤としていずれもエタノ−ルと水
とを同じ量で配合し、そして経皮吸収促進剤としていず
れも５重量％のｌ- メント−ル、テルピネオ−ルおよび
ハッカ油をそれぞれ配合した本発明組成物４および５を
調製して、これらの組成物に関する経時的な皮膚透過量
を、実施例１と同様に測定した。その結果を前記本発明
組成物１の結果と合わせて表６および図３に示した。From the results shown in Table 4 and FIG. 2, the skin permeation amount of morphine hydrochloride increases with the increase of the concentration of morphine hydrochloride, and the pattern of skin permeation with time is the concentration of morphine hydrochloride. It was found that the value did not change even if it changed significantly. Example 3 As shown in Table 5, the type and amount of the percutaneous absorption enhancer was not changed, but only the type of the percutaneous absorption enhancer was changed, that is, as a transdermal absorption enhancer. Of water and water in the same amount, and 5% by weight of l-menthol, terpineol and peppermint oil as the transdermal absorption enhancers, respectively, were prepared as Compositions 4 and 5 of the present invention. Then, the time-dependent skin permeation amount of these compositions was measured in the same manner as in Example 1. The results are shown in Table 6 and FIG. 3 together with the results of the composition 1 of the present invention.
【００２０】[0020]
【表５】 [Table 5]
【００２１】[0021]
【表６】 [Table 6]
【００２２】表６および図３に示される結果から、いず
れの組成物においても、すなわち、どの経皮吸収促進剤
も塩酸モルヒネについて優れた経皮吸収性を示したが、
なかでもテルピネオ−ルが塩酸モルヒネの経皮吸収性を
増進させる作用が最も大きいことが判った。 実施例４ 経皮吸収促進剤としてｌ- メント−ルを、そして経皮吸
収促進助剤としてエタノ−ルと水とを用いたｌ- メント
−ル・エタノ−ル・水系組成物から塩酸モルヒネが放出
される塩酸モルヒネの皮膚透過性に及ぼすｌ- メント−
ルの濃度の影響を調べるために、表７に示される本発明
組成物６および７並びに比較組成物４および５を調製し
て、これらの組成物に関する塩酸モルヒネの経時的な皮
膚透過量を、実施例１と同様に測定した。その結果を前
記本発明組成物１の結果と合わせて表８および図４に示
した。From the results shown in Table 6 and FIG. 3, in any of the compositions, that is, any of the transdermal absorption enhancers showed excellent transdermal absorbability with respect to morphine hydrochloride.
Among them, it was found that terpineol has the greatest effect of enhancing the transdermal absorbability of morphine hydrochloride. Example 4 From a l-menthol / ethanol / water composition using l-menthol as a transdermal absorption enhancer and ethanol and water as a transdermal absorption enhancer, morphine hydrochloride was obtained. On the Skin Permeability of Released Morphine Hydrochloride-
Inventive compositions 6 and 7 and comparative compositions 4 and 5 shown in Table 7 were prepared in order to investigate the effect of the concentration of glutinic acid on the skin with respect to morphine hydrochloride over time. The measurement was performed in the same manner as in Example 1. The results are shown in Table 8 and FIG. 4 together with the results of the composition 1 of the present invention.
【００２３】[0023]
【表７】 [Table 7]
【００２４】[0024]
【表８】 [Table 8]
【００２５】表８および図４に示される結果から、本発
明組成物１、６および７では比較組成物４および５より
も遙に優れた経皮吸収性を示すこと、すなわちｌ- メン
ト−ルの濃度が２．５重量％以上である場合には、その
濃度が１重量％以下である場合よりも格段に優れた経皮
吸収性を示すことが判る。 実施例５ 経皮吸収促進剤としてｌ- メント−ルを、そして経皮吸
収促進助剤としてエタノ−ルと水とを用いたｌ- メント
−ル・エタノ−ル・水系組成物から塩酸モルヒネが放出
される塩酸モルヒネの皮膚透過性に及ぼすエタノ−ルの
濃度の影響を調べるために、表９に示される本発明組成
物８および９並びに比較組成物６および７を調製して、
これらの組成物に関する塩酸モルヒネの経時的な皮膚透
過量を、実施例１と同様に測定した。その結果を前記本
発明組成物１の結果と合わせて表１０および図５に示し
た。From the results shown in Table 8 and FIG. 4, the compositions 1, 6 and 7 of the present invention show much better transdermal absorbability than the comparative compositions 4 and 5, namely 1-menthol. It can be seen that when the concentration is 2.5% by weight or more, the percutaneous absorbability is far superior to that when the concentration is 1% by weight or less. Example 5 1-menthol / ethanol / water system composition using l-menthol as a percutaneous absorption enhancer and ethanol and water as percutaneous absorption enhancer was used to obtain morphine hydrochloride. In order to investigate the effect of the concentration of ethanol on the skin permeability of morphine hydrochloride released, the inventive compositions 8 and 9 and the comparative compositions 6 and 7 shown in Table 9 were prepared,
The skin permeation amount of morphine hydrochloride with respect to these compositions was measured in the same manner as in Example 1. The results are shown in Table 10 and FIG. 5 together with the results of the composition 1 of the present invention.
【００２６】[0026]
【表９】 [Table 9]
【００２７】[0027]
【表１０】 [Table 10]
【００２８】表１０および図５に示される結果から、本
発明組成物１、８および９では比較組成物６および７よ
りも遙に優れた経皮吸収性を示すこと、すなわちエタノ
−ルの濃度が２０重量％以上ないし６０重量％以下であ
る場合に、塩酸モルヒネの優れた皮膚透過性を示すこと
が判る。 実施例６ 実施例５の組成物におけるエタノ−ルの代わりにイソプ
ロパノ−ル（図６中ではＩＰＡと表されている）を用い
て、すなわち、ｌ- メント−ル・イソプロパノ−ル・水
系組成物を用いて、この組成物から塩酸モルヒネが放出
される塩酸モルヒネの皮膚透過性に及ぼすイソプロパノ
−ルの濃度の影響を調べるために表１１に示される本発
明組成物１０〜１２を調製して、これらの組成物に関す
る塩酸モルヒネの経時的な皮膚透過量を、実施例１と同
様に測定した。その結果を前記本発明組成物１の結果と
合わせて表１２および図６に示した。From the results shown in Table 10 and FIG. 5, the compositions 1, 8 and 9 of the present invention show much better transdermal absorbability than the comparative compositions 6 and 7, that is, the concentration of ethanol. It can be seen that morphine hydrochloride shows excellent skin permeability when the content is 20% by weight or more and 60% by weight or less. Example 6 Instead of ethanol in the composition of Example 5, isopropanol (designated as IPA in FIG. 6) was used, that is, 1-menthol-isopropanol-water-based composition In order to investigate the effect of the concentration of isopropanol on the skin permeability of morphine hydrochloride from which morphine hydrochloride is released from this composition, compositions 10 to 12 of the present invention shown in Table 11 were prepared, The skin permeation amount of morphine hydrochloride with respect to these compositions was measured in the same manner as in Example 1. The results are shown in Table 12 and FIG. 6 together with the results of the composition 1 of the present invention.
【００２９】[0029]
【表１１】 [Table 11]
【００３０】[0030]
【表１２】 [Table 12]
【００３１】表１２および図６に示されるように、本発
明組成物１および１０〜１２では十分な経皮吸収性を示
すこと、すなわちイソプロパノ−ルもエタノ−ルと同様
に、その濃度が２０重量％以上ないし６０重量％以下で
ある場合に、塩酸モルヒネの優れた皮膚透過性を示すこ
とが判る。 実施例７ 実施例５の組成物における水の代わりにグリセリンを用
いて、すなわち、組成が表１３に示されているｌ- メン
ト−ル・エタノ−ル・グリセリン系の本発明組成物１３
を用いて、この組成物から塩酸モルヒネが放出される塩
酸モルヒネの経時的な皮膚透過量を、実施例１と同様に
測定した。その結果は本発明組成物１に関する前記の結
果とともに表１４および図７に示される。As shown in Table 12 and FIG. 6, the compositions 1 and 10 to 12 of the present invention show sufficient transdermal absorbability, that is, isopropanol has a concentration of 20 as in the case of ethanol. It can be seen that morphine hydrochloride has excellent skin permeability when the content is not less than 60% by weight. Example 7 Inventive composition 13 of the menthol ethanol glycerin system whose composition is shown in Table 13 using glycerin instead of water in the composition of Example 5
The amount of morphine hydrochloride released from this composition was measured with time using the same method as in Example 1. The results are shown in Table 14 and FIG. 7 together with the above results for the composition 1 of the present invention.
【００３２】[0032]
【表１３】 [Table 13]
【００３３】[0033]
【表１４】 [Table 14]
【００３４】表１４および図７に示されるように、本発
明組成物１３も本発明組成物１にほぼ匹敵する十分な経
皮吸収性を示すこと、すなわち水の代わりにグリセリン
を用いても、同様な経皮吸収性が維持されることが判
る。 実施例８ 実施例５のようなｌ- メント−ル・エタノ−ル・水系組
成物からクエン酸フェンタニ−ル（図８中ではＦＴＣと
表されている）または塩酸コカイン（図８中ではＣＣＨ
と表されている）が放出されて、これらの薬物が皮膚を
透過する経皮吸収性を調べるために、表１５に示される
本発明組成物１４および１５を調製して、これらの組成
物および実施例１で用いた本発明組成物１に関する各薬
物の経時的な皮膚透過量を、実施例１と同様に測定し
た。その結果は本発明組成物１に関する前記の結果とと
もに表１６および図８に示される。As shown in Table 14 and FIG. 7, the composition 13 of the present invention also exhibits sufficient transdermal absorbability which is almost comparable to that of the composition 1 of the present invention, that is, glycerin is used instead of water. It can be seen that similar transdermal absorbability is maintained. Example 8 Fentanyl citrate (denoted as FTC in FIG. 8) or cocaine hydrochloride (CCH in FIG. 8) from the 1-menthol-ethanol / water-based composition as in Example 5
In order to investigate the percutaneous absorption of these drugs through the skin, the compositions 14 and 15 of the present invention shown in Table 15 were prepared to The skin permeation amount of each drug for the composition 1 of the present invention used in Example 1 was measured in the same manner as in Example 1. The results are shown in Table 16 and FIG. 8 together with the above results for the composition 1 of the present invention.
【００３５】[0035]
【表１５】 [Table 15]
【００３６】[0036]
【表１６】 [Table 16]
【００３７】表１６および図８に示されるように、本発
明組成物１４および１５も本発明組成物１と同様に十分
な経皮吸収性を示すこと、すなわちｌ- メント−ル・エ
タノ−ル・水系組成物を用いると、クエン酸フェンタニ
−ルおよび塩酸コカインのいずれも、塩酸モルヒネと同
様な高い経皮吸収性を示すことが判る。As shown in Table 16 and FIG. 8, the compositions 14 and 15 of the present invention also exhibit sufficient transdermal absorbability similarly to the composition 1 of the present invention, that is, 1-menthol ethanol. -It is found that both fentanyl citrate and cocaine hydrochloride show high transdermal absorbability similar to that of morphine hydrochloride when an aqueous composition is used.
【００３８】[0038]
【発明の効果】以上述べた説明から明らかなように、本
発明によれば、実用できる十分な経皮吸収性を示す塩酸
モルヒネ、硫酸モルヒネ、クエン酸フェンタニ−ルまた
は塩酸コカインの経皮吸収組成物が提供されるので、投
与に苦痛を伴わないで長期にわたる薬効を期待できて、
投与が簡便な塩酸モルヒネ、硫酸モルヒネ、クエン酸フ
ェンタニ−ルまたは塩酸コカインの経皮吸収製剤が提供
される。As is apparent from the above description, according to the present invention, a percutaneous absorption composition of morphine hydrochloride, morphine sulfate, fentanyl citrate or cocaine hydrochloride showing sufficient transdermal absorbability for practical use. Since the product is provided, long-term medicinal effects can be expected without any pain in administration,
A percutaneous absorption preparation of morphine hydrochloride, morphine sulfate, fentanyl citrate or cocaine hydrochloride, which is easy to administer, is provided.
【図１】実施例１の表１に示される本発明組成物１およ
び比較組成物１〜３について実施した皮膚透過試験の結
果を表すグラフである。FIG. 1 is a graph showing the results of a skin permeation test carried out on Inventive Composition 1 and Comparative Compositions 1 to 3 shown in Table 1 of Example 1.
【図２】本発明の組成物中で塩酸モルヒネの濃度を変化
させた場合に、その濃度が塩酸モルヒネの皮膚透過量に
及ぼす影響を示すためのグラフであって、（ａ）は塩酸
モルヒネの濃度が０．０１重量％である場合のグラフで
あり、（ｂ）は塩酸モルヒネの濃度が１重量％である場
合のグラフであり、そして（ｃ）は塩酸モルヒネの濃度
が１０重量％である場合のグラフである。FIG. 2 is a graph showing the effect of varying the concentration of morphine hydrochloride on the skin permeation amount of morphine hydrochloride when the concentration of morphine hydrochloride is changed in the composition of the present invention. Fig. 5 is a graph when the concentration is 0.01% by weight, (b) is a graph when the concentration of morphine hydrochloride is 1% by weight, and (c) is a concentration of morphine hydrochloride is 10% by weight. It is a graph of a case.
【図３】塩酸モルヒネの経時的な皮膚透過量を３種のテ
ルペン類経皮吸収促進剤について比べた結果を示すグラ
フである。FIG. 3 is a graph showing the results of comparing the amount of morphine hydrochloride permeated through the skin with time for three terpene transdermal absorption enhancers.
【図４】本発明の組成物中でｌ- メント−ルの濃度を変
化させた場合に、その濃度が塩酸モルヒネの皮膚透過量
に及ぼす影響を示すグラフである。FIG. 4 is a graph showing the effect of varying the concentration of l-menthol in the composition of the present invention on the skin permeation amount of morphine hydrochloride.
【図５】本発明の組成物中でエタノ−ルの濃度を変化さ
せた場合に、その濃度が塩酸モルヒネの皮膚透過量に及
ぼす影響を示すグラフである。FIG. 5 is a graph showing the effect of varying the concentration of ethanol in the composition of the present invention on the skin permeation amount of morphine hydrochloride.
【図６】本発明の組成物中でイソプロパノ−ルの濃度を
変化させた場合に、その濃度が塩酸モルヒネの皮膚透過
量に及ぼす影響を示すグラフである。FIG. 6 is a graph showing the effect of varying the concentration of isopropanol in the composition of the present invention on the skin permeation amount of morphine hydrochloride.
【図７】本発明の組成物中で経皮吸収促進助剤としてエ
タノ−ル・水系を使用した場合と、エタノ−ル・グリセ
リン系を使用した場合とを比較した結果を示すグラフで
ある。FIG. 7 is a graph showing the results of comparison between the case where an ethanol / water system is used as the transdermal absorption promoting aid and the case where an ethanol / glycerin system is used in the composition of the present invention.
【図８】本発明のｌ- メント−ル・エタノ−ル・水系組
成物によるクエン酸フェンタニ−ル〔（ａ）のグラフ〕
および塩酸コカイン〔（ｂ）のグラフ〕の経時的な皮膚
透過量を示すグラフである。FIG. 8 is a graph of (a) of fentanyl citrate obtained from the l-menthol-ethanol / water-based composition of the present invention.
2 is a graph showing the amount of skin permeation of cocaine hydrochloride [graph of (b)] over time.
───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.6 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/46 Ａ６１Ｋ 31/46 31/485 31/485 47/10 47/10 Ｅ ─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. 6 Identification code Internal reference number FI Technical display area A61K 31/46 A61K 31/46 31/485 31/485 47/10 47/10 E
Claims (2)
ハッカ油から選ばれる１種または２種以上の経皮吸収促
進剤、エタノ−ルと水またはグリセリン、あるいはイソ
プロパノ−ルと水からなる経皮吸収促進助剤、および塩
酸モルヒネ、硫酸モルヒネ、塩酸コカインまたはクエン
酸フェンタニ−ルのうちのいずれかの麻薬性鎮痛剤を含
有する経皮吸収組成物。1. A transdermal absorption enhancer selected from the group consisting of l-menthol, terpineol and peppermint oil, a transdermal absorption enhancer, ethanol and water or glycerin, or isopropanol and water. A transdermal absorption composition containing a skin absorption promoting aid and a narcotic analgesic selected from morphine hydrochloride, morphine sulfate, cocaine hydrochloride or fentanyl citrate.
〜６０重量％の経皮吸収促進助剤を含有する請求項１の
経皮吸収組成物。2. 20 to 20% by weight of a percutaneous absorption enhancer
The percutaneous absorption composition according to claim 1, which comprises -60% by weight of a percutaneous absorption acceleration aid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3087394A JP2669951B2 (en) | 1991-03-28 | 1991-03-28 | Transdermal composition containing narcotic analgesic |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3087394A JP2669951B2 (en) | 1991-03-28 | 1991-03-28 | Transdermal composition containing narcotic analgesic |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP02081180 Division | 1990-03-30 | 1990-03-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04217926A JPH04217926A (en) | 1992-08-07 |
| JP2669951B2 true JP2669951B2 (en) | 1997-10-29 |
Family
ID=13913667
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3087394A Expired - Lifetime JP2669951B2 (en) | 1991-03-28 | 1991-03-28 | Transdermal composition containing narcotic analgesic |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2669951B2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008108286A1 (en) | 2007-03-02 | 2008-09-12 | Teika Pharmaceutical Co., Ltd. | Medicinal composition for transdermal absorption, medicinal composition storing unit and transdermal absorption preparation using the same |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2185227A1 (en) * | 1994-03-11 | 1995-09-14 | Michiari Hashimoto | Percutaneous absorption applying sheet comprising acid salt of morphine |
| JPH1036265A (en) | 1996-07-19 | 1998-02-10 | Nitto Denko Corp | Buprenorphine percutaneous absorption preparation |
| DE19652188C2 (en) * | 1996-12-16 | 2002-02-14 | Lohmann Therapie Syst Lts | Flat drug preparation for application and release of buprenorphine or a pharmacologically comparable substance in the oral cavity and process for its preparation |
| PT1102589E (en) * | 1998-07-16 | 2006-12-29 | Memorial Sloan Kettering Inst | Topical compositions comprising an opioid analgesic and an nmda antagonist |
| JP4659943B2 (en) | 2000-02-25 | 2011-03-30 | 帝三製薬株式会社 | Patch containing buprenorphine hydrochloride |
| CA2529983C (en) * | 2003-07-25 | 2010-07-20 | Bruce E. Reidenberg | Preoperative treatment of post operative pain |
| JP2006151927A (en) * | 2004-12-01 | 2006-06-15 | Toin Gakuen | Photodynamic therapy composition |
| JP2012020991A (en) | 2010-06-16 | 2012-02-02 | Takasago Internatl Corp | Transdermal absorption promoter, and external skin formulation thereof |
| WO2020158831A1 (en) * | 2019-01-30 | 2020-08-06 | 国立大学法人九州大学 | Transdermal absorption composition with controlled release of water-soluble hydrochloride |
-
1991
- 1991-03-28 JP JP3087394A patent/JP2669951B2/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008108286A1 (en) | 2007-03-02 | 2008-09-12 | Teika Pharmaceutical Co., Ltd. | Medicinal composition for transdermal absorption, medicinal composition storing unit and transdermal absorption preparation using the same |
| US9326979B2 (en) | 2007-03-02 | 2016-05-03 | Teika Pharmaceutical Co., Ltd. | Medicinal composition for transdermal absorption, medicinal composition storing unit and transdermal absorption preparation using the same |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH04217926A (en) | 1992-08-07 |
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