JP3599766B2 - Patch preparation - Google Patents
Patch preparation Download PDFInfo
- Publication number
- JP3599766B2 JP3599766B2 JP32994093A JP32994093A JP3599766B2 JP 3599766 B2 JP3599766 B2 JP 3599766B2 JP 32994093 A JP32994093 A JP 32994093A JP 32994093 A JP32994093 A JP 32994093A JP 3599766 B2 JP3599766 B2 JP 3599766B2
- Authority
- JP
- Japan
- Prior art keywords
- weight
- preparation
- reservoir
- acid
- tizanidine
- 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
Links
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- XFYDIVBRZNQMJC-UHFFFAOYSA-N tizanidine Chemical compound ClC=1C=CC2=NSN=C2C=1NC1=NCCN1 XFYDIVBRZNQMJC-UHFFFAOYSA-N 0.000 claims description 23
- 229960000488 tizanidine Drugs 0.000 claims description 22
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Landscapes
- Medicinal Preparation (AREA)
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Description
【０００１】
【産業上の利用分野】
本発明は、有機酸と、薬理活性物質としてのチザニジンまたはその塩とを含有し、吸収性が高く、しかも皮膚へ着色を与えることがない貼付製剤に関する。
【０００２】
【従来の技術】
本発明の薬理活性物質であるチザニジンは、化学名５−クロロ−４−（２−イミダゾリン−２−イル−アミノ）−２，１，３−ベンゾチアジアゾールを有する化合物である。チザニジンは、多シナプス反射を選択的に抑制する中枢性の筋弛緩薬であり、筋弛緩作用と疼痛緩和作用を合わせ持ち、頸肩腕症侯群、腰痛症、痙性麻痺等の筋緊張性疾患の緩和剤として広く用いられており、一般的には錠剤として経口投与されている。
しかしながら、経口投与されたチザニジン及び特にその塩酸塩は、肝臓での初回通過効果が大きく吸収された薬物の２０％しか利用されず、消化器系の副作用も報告されている。
薬理活性物質の吸収性や消化器系での副作用に関するこのような問題点を解決するべく、特表昭６１−５０１３２４号には、親水性ポリマーからなるリザーバー型やマトリックス型の経皮投与製剤の技術が提案されており、その製剤中に配合され得る薬理活性物質の一つとして、チザニジンの名が記載されている。
さらに、特表昭６４−５００１１５号公報には、リザーバー型の経皮投与製剤の技術に関する発明が開示されており、その製剤中に配合され得る薬理活性物質の一つとして、チザニジンの名が記載されている。
【０００３】
【発明が解決しようとする課題】
上記各公報中には、経皮投与製剤に関する技術が開示されているが、チザニジンについては、単に、明細書中に、配合され得る薬理活性物質の一つとしてその名が挙げられているに過ぎず、具体的実施例においてチザニジンを配合した製剤の効果が示されているわけでもなく、チザニジンを含有する経皮投与製剤に特有の着色等の問題点については何等検討がなされていない。
そこで、本発明はかかる従来技術の問題点を解決するべく、チザニジンを効率良く、持続的に吸収させることができ、しかも、皮膚に対して低刺激性で着色を与えることがなく、さらに、薬物の安定性が優れたチザニジン含有の貼付製剤を提供することを目的とする。
【０００４】
【課題を解決するための手段】
本発明者らは、鋭意研究を重ねた結果、チザニジンまたはその薬学的に許容され得る塩を含有する貼付製剤中に、特定の有機酸を含有させることにより、上記課題を解決することができることを見出し、本発明を完成させるに至った。
すなわち、本発明は、有機酸と、薬理活性物質としてのチザニジンまたはその薬学的に許容され得る塩とを含有し、前記有機酸が、Ｎ−２−ヒドロキシエチルピペリジン−Ｎ’−２−エタンスルホン酸（以下、「ＨＥＰＥＳ」と略記する）、乳酸または酢酸であることを特徴とする貼付製剤からなる。
本発明における前記貼付製剤は、リザーバー型製剤またはマトリックス型製剤であることが好ましい。
また、前記マトリックス型製剤は、テープ製剤または湿布製剤であることが好ましい。
【０００５】
本発明の前記貼付製剤がリザーバー型製剤である場合には、リザーバー層中の組成は、有機酸０．０１〜１５重量％、チザニジンまたはその薬学的に許容され得る塩０．１〜２０重量％、水性成分１０〜８０重量％、低級アルコール５〜７０重量％、保湿剤５〜７０重量％、吸収促進剤０．０１〜２０重量％及び刺激低減剤０．０１〜２０重量％並びに親水性ポリマー０．１〜３０重量％または不織布０．１〜１０重量％からなることが好ましい。
本発明の前記貼付製剤がマトリックス型製剤である場合には、粘着層中の組成は、有機酸０．０１〜１５重量％、チザニジンまたはその薬学的に許容され得る塩０．１〜２０重量％、吸収促進剤０．０１〜５０重量％及び刺激低減剤０．０１〜２０重量％並びに親水性ポリマー０〜７０重量％または脂溶性ポリマー０〜９９重量％からなることが好ましい。
本発明の前記貼付製剤において、リザーバー層または粘着層のｐＨは、４〜５であることが好ましい。
【０００６】
本発明の貼付製剤のうち、最初にリザーバー型製剤のリザーバー層中の組成に関して説明する。
本発明のリザーバー型製剤のリザーバー層において使用される有機酸は、ＨＥＰＥＳ、乳酸または酢酸である。
このような有機酸は、リザーバー型の組成全体の重量に基づいて、好ましくは、０．０１〜１５重量％、さらに好ましくは、０．０１〜１０重量％、特に好ましくは０．０１〜５重量％の量で配合されることができる。有機酸の配合が、０．０１重量％未満となると、リザーバー型製剤として充分な透過量が得られず、また、１５重量％を越えると、皮膚への刺激性が強くなるので好ましくない。
【０００７】
また、本発明のリザーバー型製剤のリザーバー層において使用される薬理活性物質としてのチザニジンまたは薬学的に許容され得る塩は、リザーバー層の組成全体の重量に基づいて、０．１〜２０重量％の量で配合されることができる。薬理活性物質の配合量が、０．１重量％未満となると、リザーバー型製剤として充分な透過量が得られず、また、２０重量％を越えると、皮膚への着色が見られ、また、発赤等の皮膚への刺激性が認められるので好ましくない。
また、薬学的に許容され得る塩の例としては、塩酸塩、酢酸塩、フマル酸塩、マレイン酸塩、硫酸塩、クエン酸塩等を挙げることができる。
【０００８】
本発明のリザーバー型製剤のリザーバー層において使用される水性成分としては、皮膚刺激性、皮膚への着色を考慮すると、前記有機酸を含有するｐＨ４〜５の緩衝液であることが望ましい。このような緩衝液の例としては、ｐＨ４．５の酢酸緩衝液、ｐＨ４．５の乳酸緩衝液またはリン酸やクエン酸等のｐＨ４〜５付近に緩衝能を持つ緩衝液に前記の有機酸を添加してｐＨ４〜５に調節した緩衝液を挙げることができ、特に、酢酸緩衝液は好ましい。
このような水性成分のうち有機酸を除く配合量は、リザーバー層の組成全体の重量に基づいて、好ましくは、１０〜８０重量％、さらに好ましくは、２０〜７０重量％、特に好ましくは、３０〜６０重量％の量とされることができる。水性成分の配合量が１０重量％未満となると、保湿剤と低級アルコールの配合比によるが、発赤、浮腫等の皮膚への刺激性が認められたり、または充分な透過性が得られなくなり、８０重量％を越えると、リザーバー製剤として充分な透過量が得られなくなるので好ましくない。
【０００９】
本発明のリザーバー型製剤のリザーバー層において使用される低級アルコールとしては、炭素数２〜５のもの望ましく、特にエタノールやイソプロパノールが望ましい。
このような低級アルコールは、リザーバー層の組成全体の重量に基づいて、好ましくは、５〜７０重量％、さらに好ましくは、１０〜５０重量％、特に好ましくは１０〜３０重量％の量で配合されることができる。低級アルコールの配合量が、５重量％未満となると、リザーバー製剤として充分な透過量が得られず、また、７０重量％を越えると、発赤、浮腫等の皮膚への刺激性が認められるので好ましくない。
【００１０】
本発明のリザーバー型製剤のリザーバー層において使用される保湿剤としては、例えば、グリセリン、ブチレングリコール、プロピレングリコール、ポリエチレングリコール、ソルビトール、ジグリセリン、ジプロピレングリコール、ナトリウムピロリドン、カルボキシレート、エチルカルビトール、Ｄ−キシトール、ヒアルロン酸等を望ましいものの例として挙げることができ、その中でも特にグリセリン及びポリエチレングリコールは望ましい。
このような保湿剤は、リザーバー層の組成全体の重量に基づいて、好ましくは、５〜７０重量％、さらに好ましくは、１０〜５０重量％、特に好ましくは１０〜３０重量％の量で配合されることができる。保湿剤の配合量が、５重量％未満となると、発赤等の皮膚への刺激性が認められ、また、７０重量％を越えると、リザーバー製剤として充分な透過性が得られないので好ましくない。
【００１１】
本発明のリザーバー型製剤のリザーバー層において使用される吸収促進剤としては、皮膚での吸収促進作用が認められている化合物であればいずれのものでもよく、例えば炭素鎖数６〜２０の脂肪酸、脂肪族アルコール、脂肪酸エステルまたはエーテル、芳香族系有機酸、芳香族系アルコール、芳香族系有機酸エステルまたはエーテルを挙げることができる。さらに、乳酸エステル類、酢酸エステル類、モノテルペン系化合物、セスキテルペン系化合物、アゾン（Ａｚｏｎｅ）またはその誘導体、グリセリン脂肪酸エステル類、ソルビタン脂肪酸エステル類（Ｓｐａｎ系）、ポリソルベート系（Ｔｗｅｅｎ系）、ポリエチレングリコール脂肪酸エステル類、ポリオキシエチレン硬化ヒマシ油系（ＨＣＯ系）、ショ糖脂肪酸エステル類等を挙げることができる。具体的にはカプリル酸、カプリン酸、カプロン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、オレイン酸、リノール酸、リノレン酸、ラウリルアルコール、ミリスチルアルコール、オレイルアルコール、セチルアルコール、ラウリン酸メチル、ミリスチン酸イソプロピル、ミリスチン酸ミリスチル、ミリスチン酸オクチルドデシル、パルミチン酸セチル、サリチル酸、サリチル酸メチル、サリチル酸エチレングリコール、ケイ皮酸、ケイ皮酸メチル、クレゾール、乳酸セチル、酢酸エチル、酢酸プロピル、ゲラニオール、チモール、オイゲノール、テルピネオール、ｌ−メントール、ボルネオロール、ｄ−リモネン、イソオイゲノール、イソボルネオール、ネロール、ｄｌ−カンフル、グリセリンモノラウレート、グリセリンモノオレエート、ソルビタンモノラウレート、ショ糖モノラウレート、ポリソルベート２０、ポリエチレングリコールモノラウレート、ポリエチレングリコールモノステアレート、ＨＣＯ−６０、１−［２−（デシルチオ）エチル］アザシクロペンタン−２−オン（以下、「ピロチオデカン」と略記する。）が望ましく、特にラウリルアルコール、ミリスチルアルコール、サリチル酸エチレングリコール及びピロチオデカンが望ましい。
このような吸収促進剤は、リザーバー層の組成全体の重量に基づいて、好ましくは、０．０１〜２０重量％、さらに好ましくは、０．１〜１０重量％、特に好ましくは０．１〜５重量％の量で配合されることができる。吸収促進剤の配合量が０．０１重量％未満であると、リザーバー製剤として充分な透過性が得られず、２０重量％を越えると、発赤、浮腫等の皮膚への刺激性が認められるので好ましくない。
【００１２】
本発明のリザーバー型製剤のリザーバー層において使用される刺激低減剤としては、グリチルリチン酸及びその水溶性塩類、クエン酸トリエチル、吸収促進剤として既知のグリセリン脂肪酸エステル類、ソルビタン脂肪酸エステル類、ショ糖脂肪酸エステル類またはこれらの混合物が望ましく、特に、グリセリンモノオレエート、グリセリンモノラウレート、ソルビタンモノラウレートまたはこれらの混合物は望ましい。
このような刺激低減剤は、リザーバー層の組成全体の重量に基づいて、好ましくは、０．０１〜２０重量％、さらに好ましくは、０．１〜１０重量％、特に好ましくは０．１〜５重量％の量で配合されることができる。刺激低減剤の配合量が０．０１重量％未満となると、発赤、浮腫等の皮膚への刺激性が認められ、２０重量％を越えると、同様に、発赤、浮腫等の皮膚への刺激性が認められるので好ましくない。
【００１３】
また、本発明のリザーバー型製剤のリザーバー層において、前記各成分を含有させるために使用されることができる前記の各成分を含有させる親水性ポリマーまたは不織布としては、保水作用を有し、有効成分と相互作用を起こさないものが望ましい。
このような親水性ポリマーとしては、例えば、セルロース誘導体（例えば、カルボキシメチルセルロース（ＣＭＣ）、カルボキシメチルセルロースナトリウム（ＣＭＣＮａ）、メチルセルロース（ＭＣ）、ヒドロキシプロピルメチルセルロール（ＨＰＭＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシエチルセルロース（ＨＥＣ）等）、デンプン誘導体（プルラン）、ポリビニルアルコール（ＰＶＡ）、ポリビニルピロリドン（ＰＶＰ）、酢酸ビニル（ＶＡ）、カルボキシビニルポリマー（ＣＶＰ）、エチル酢酸ビニル（ＥＶＡ）、オイドラギット、ゼラチン、ポリアクリル酸、ポリアクリル酸ソーダ、ポリイソブチレン無水マレイン酸共重合体、アルギン酸、アルギン酸ナトリウム、カラギーナン、アラビアゴム、トラガント、カラヤゴム、ポリビニルメタクリレートが望ましく、特にセルロース誘導体（ＣＭＣＮａ、ＨＰＭＣ、ＨＰＣ、ＭＣ）、ＰＶＡ、ＰＶＰ、ＶＡ、ＥＶＡ及びオイドラギットは望ましい。
このような親水性ポリマーは、リザーバー層の組成全体の重量に基づいて、好ましくは、０．１〜３０重量％、さらに好ましくは０．１〜２０重量％、特に好ましくは、０．１〜１０重量％の量で配合されることができる。親水性ポリマーの配合量が、０．１重量％未満となると、リザーバー層に溶液を保持するために充分な粘性が得られず、また３０重量％を越えると、薬物の放出性が悪くなり、リザーバー製剤として充分な透過量が得られなくなるので好ましくない。
【００１４】
また、不織布の素材としては、例えばポリプロピレン、ポリエステル、レーヨンまたはその混合物を挙げることができ、特にレーヨンは望ましい。このような不織布は、リザーバー層の組成全体の重量に基づいて、好ましくは、０．１〜１０重量％、さらに好ましくは０．１〜５重量％、特に好ましくは０．１〜２重量％の量で配合されることができる。不織布の配合量が、０．１重量％未満であると、リザーバー層に溶液を保持できず、１０重量％を越えると薬物の放出性が悪くなり、リザーバー製剤として充分な透過量が得られなくなるので好ましくない。
【００１５】
このような組成を有するリザーバー層は、いずれの方法によっても製造されることができる。例えば、アジホモミキサー２ＳＬ−７型（特殊機化工）またはマルチブレンダーミルＢＬ−１型（日本精機）等の軟膏混練機を用い、前記の組成の均一なゲル製剤を得てリザーバー層に封入するか、または前記の機械により得られた均一な溶液を不織布等に保持させるか、または粘着剤がＰＶＡの場合には、得られた均一なゲルを凍結−解凍した後、得られたマトリックスをリザーバー層とする。
本発明のリザーバー型製剤は、リザーバー層が、有機酸を含む上記のような組成であれば、その他の構成や各構成部分の素材は、いずれの種類のものであってもよい。
例えば、本発明のリザーバー型製剤は、上記リザーバー層の他、支持体層、薬物放出剤層、接着剤層及び剥離ライナー層から成ることができる。
【００１６】
支持体層となるフィルムとしては、通気性の低いものが望ましく、例えばポリエチレン、ポリエチレンテレフタレート、ポリ塩化ビニリデン、ポリエチレン、ポリエステル、ポリ塩化ビニリデン等の素材が挙げられるが、その中でも、ポリエチレンとポリエチレンテレフタレート、ポリ塩化ビニリデンとポリエチレン、またはポリエステルとポリ塩化ビニリデン等の２種類のフィルムによりラミネート加工されたフィルムが特に望ましい。
また、薬物放出剤層は、薬剤が流動してしまうおそれがないような固形性を保っていれば、必ずしも設ける必要がないが、例えば、ポリエチレン、ポリプロピレン、ポリメタアクリル酸エステル、ポリウレタン、ポリエステル、ポリビニルアルコール−エチレン共重合体、ポリビニルアルコール、ポリ塩化ビニル、ポリアミド等の素材が好適に使用される。
また、接着剤層は、例えばアクリル系接着剤、シリコン系接着剤、スチレン−イソプレンのブロック共重合体、ポリイソブチレン等が好適に使用される。
さらに、剥離ライナー層としては、例えば、アルミニウム、セルロース、ポリエステル、ポリエチレン、ポリプロピレン等が好ましい。
本発明のリザーバー型製剤として製剤化可能な薬物放出剤層の面積は、４０ｃｍ２であり、薬剤としては４０ｃｍ２以下の面積とすることが望ましい。
【００１７】
次に、本発明の貼付製剤がマトリックス型製剤である場合の粘着層の組成について説明する。
本発明のマトリックス型製剤の粘着層において使用される有機酸とその配合量は、リザーバー型製剤に関して説明したものと同じであることが望ましい。
また、本発明のマトリックス型製剤において使用される薬理活性物質としてのチザニジンまたは薬学的に許容され得るその配合量も、リザーバー型製剤に関して説明したものと同じであることが望ましい。
また、本発明のマトリックス型製剤において使用される吸収促進剤は、リザーバー型製剤に関して説明したものであることが望ましい。
このような吸収促進剤は、粘着層の組成全体の重量に基づいて、好ましくは、０．０１〜５０重量％、さらに好ましくは、０．０１〜３０重量％、特に好ましくは０．０１〜１０重量％の量で配合されることができる。吸収促進剤の配合量が、０．０１重量％未満となると、充分な透過量が得られず、５０重量％を越えると、発赤、浮腫等の皮膚への刺激性が認められるので好ましくない。
また、本発明のマトリックス型製剤において使用される刺激低減剤と、その配合量は、リザーバー型製剤に関して説明したものと同じであることが望ましい。
【００１８】
本発明のマトリックス型製剤においては、親水性ポリマーまたは脂溶性ポリマーのいずれか一方を含有することが望ましいが、親水性ポリマーとしては、リザーバー型製剤に関して説明したものであることが望ましい。
この親水性ポリマーは、粘着層の組成全体の重量に基づいて、好ましくは、０〜７０重量％、さらに好ましくは、０〜５０重量％、特に好ましくは０〜３０重量％の量であることができる。親水性ポリマーの配合量は７０重量％を越えると、残りの成分の配合比によって異なるが、凝集力が弱くなったり、柔軟性が小さくなったり、または粘着力が小さくなるので好ましくない。
また、脂溶性ポリマーとしては、例えば、ポリイソブチレン、スチレン−イソプレンブロック共重合体（ＳＩＳ）、イソプレンゴム、スチレン−ブタジエンブロック共重合体（ＳＢＳ）、アクリル系ポリマー（２−エチルヘキシルアクリレート、酢酸ビニル、メタクリレート、メトキシエチルアクリレート、アクリル酸の少なくとも２種の共重合体）等を望ましいものとして挙げることができる。 このような脂溶性ポリマーの粘着層の組成全体の重量に基づく配合量は、好ましくは、０〜９９重量％、さらに好ましくは０〜７０重量％、特に好ましくは０〜５０重量％の量であることができる。脂溶性ポリマーの配合量が９９重量％を越えると、充分な透過性が得られないので好ましくない。
【００１９】
本発明のマトリックス型製剤の粘着層中には、必要に応じてタキファイヤーを配合することができる。タキファイヤーとしては、アルコン系タキファイヤー、ロジン系タキファイヤー、ポリブテン等を望ましいものの例として挙げることができる。
タキファイヤーは、マトリックス型製剤の粘着層の組成全体の重量に基づいて、好ましくは、０〜７０重量％、さらに好ましくは、０〜５０重量％、特に好ましくは、０〜３０重量％の量で配合されることができる。
さらに、保湿剤または油脂を配合することもでき、保湿剤としてはリザーバー型製剤について説明したものをが望ましい。また、油脂としては、例えば、流動パラフィン、スクワラン、スクワレン、オリーブ油、ツバキ油、バーッショク油、ラッカセイ油等が望ましい。
保湿剤または油脂は、マトリックス型製剤の粘着層の組成全体の重量に基づいて、好ましくは、０〜６０重量％、さらに好ましくは、０〜４０重量％、特に好ましくは、０〜３０重量％の量で配合されることができる。
【００２０】
また、必要に応じて水性成分、架橋剤、防腐剤、抗酸化剤、紫外線吸収剤を配合することができる。水性成分としては、皮膚への刺激性及びチザニジンの着色性を考慮し、ｐＨ４〜５で、前記有機酸を含む緩衝液が望ましい。水性成分のうち有機酸を除く配合量は、マトリックス型製剤の粘着層の組成全体の重量に基づいて、好ましくは、０〜９０重量％、さらに好ましくは、０〜８０重量％、特に好ましくは、０〜６０重量％とすることができる。
架橋剤としては、アミノ樹脂、フェノール樹脂、エポキシ樹脂、アルキド樹脂、不飽和ポリエステル等の熱硬化性樹脂、イソシアネート化合物、ブロックイソシアネート化合物、有機系架橋剤、金属または金属化合物等の無機系架橋剤が望ましい。架橋剤は、マトリックス型製剤の粘着層の組成全体の重量に基づいて、好ましくは、０〜７０重量％、さらに好ましくは、０〜５０重量％、特に好ましくは、０〜３０重量％の量で配合されることができる。
防腐剤としては、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、パラオキシ安息香酸ブチル等が望ましい。抗酸化剤としては、トコフェロール及びそのエステル誘導体、アスコルビン酸、ステアリン酸エステル、ノルジヒトログアヤレチン酸、ジブチルヒドロキシトルエン、ブチルヒドロキシアニソール等が望ましい。紫外線吸収剤としては、ｐ−アミノ安息香酸誘導体、アントラニル酸誘導体、サリチル酸誘導体、クマリン誘導体、アミノ酸系化合物、イミダゾリン誘導体、ピリミジン誘導体、ジオキサン誘導体等が望ましい。
このような防腐剤、抗酸化剤、紫外線吸収剤は、合計で、マトリックス型製剤の粘着層の組成全体の重量に基づいて、好ましくは、０〜２０重量％、さらに好ましくは、０〜１０重量％、特に好ましくは０〜５重量％の量で配合されることができる。
【００２１】
このような組成を有する粘着層は、いずれの方法によっても製造されることができる。例えば、アクリル系ポリマーの場合は、溶剤法により作成され、ポリマーの酢酸エチル溶液に他の成分のメタノール溶液を添加、攪拌後、支持体に伸展して乾燥し本製剤を得る。また、ＳＩＳ系ポリマーの場合は、ホットメルト法により作成され、他の成分を抱摂した親水性ポリマーを添加、攪拌し、支持体に伸展して本製剤を得る。
また、本発明のマトリックス型製剤は、粘着層が、有機酸を含む上記のような組成であれば、その他の構成や各構成部分の素材は、いずれの種類のものであってもよい。
例えば、本発明のマトリックス型製剤は、上記粘着層の他、それを支持する支持体層及び粘着層上に設けられる剥離ライナー層から成ることができる。
支持体層は、マトリックス型製剤が、テープ製剤である場合には、例えばポリエチレンテレフタレート、ポリエチレン、ウレタン等から成り、湿布製剤である場合には、布、不織布及びポリエチレンとのラミネートフィルム等から成ることができる。
尚、本発明のマトリックス型製剤の皮膚に適応可能な面積は、２００ｃｍ２以下とすることが望ましい。
【００２２】
【発明の効果】
本発明の経皮投与製剤によれば、薬理活性物質であるチザニジンまたはその薬学的に許容され得る塩が、皮膚を介して循環血液中に持続的に吸収されることができる。しかも、かかる薬理活性物質を経口投与する場合に見られた肝臓での初回通過効果による薬物の代謝を受けることがなく、持続的な有効血中濃度を得ることができる。また、経口投与の場合に見られる消化器系の副作用や急激な血中濃度の上昇に伴って起こり得る中枢系の副作用も回避することができる。さらに、皮膚に対する刺激性及び着色性が著しく緩和されるため、経皮適用の外用製剤として特に有効である。
【００２３】
【実施例】
以下、本発明の実施例を示して、本発明をさらに具体的に説明するが、本発明はこれらの実施例に限定されるものではなく、本発明の技術的思想を逸脱しない範囲での種々の変更が可能である。尚、実施例において、「％」は、全て重量％を意味するものとする。
【００２４】
【００２５】
【００２６】
【００２７】
【００２８】
【００２９】
【００３０】
【００３１】
比較例１〜４
比較例１〜４はそれぞれ、実施例１〜４の各実施例に対応しており、実施例１〜４において用いられた有機酸の代わりに、０．３Ｍのリン酸緩衝液（ｐＨ４．５）を用いること以外は、同様にして貼付製剤を得た。
比較例５〜７
比較例５〜７はそれぞれ、実施例５〜７の各実施例に対応しており、実施例５〜７において用いられた有機酸及びその塩を配合しないこと以外は、同様にして貼付製剤を得た。
実施例１〜７及び比較例１〜７において得られた各貼付製剤の皮膚透過性を、ヒト皮膚を用いるｉｎ ｖｉｔｒｏの皮膚透過試験により評価した。また、皮膚刺激性については、下記表１に示す判定法を用いて皮膚刺激指数（ＳＩ値）を求めた。結果を表２に示す。
【００３２】
【表１】
【００３３】
【表２】
[Industrial applications]
The present invention relates to a patch preparation containing an organic acid and tizanidine or a salt thereof as a pharmacologically active substance, has high absorbability, and does not give coloring to the skin.
[0002]
[Prior art]
Tizanidine, a pharmacologically active substance of the present invention, is a compound having a chemical name of 5-chloro-4- (2-imidazolin-2-yl-amino) -2,1,3-benzothiadiazole. Tizanidine is a centrally acting muscle relaxant that selectively inhibits the polysynaptic reflex, has both muscle relaxing and pain relieving effects, and is useful for the treatment of muscle tonic disorders such as cervico-brachial syndrome, low back pain and spastic paralysis. It is widely used as an emollient and is generally administered orally as tablets.
However, orally-administered tizanidine and especially its hydrochloride utilize only 20% of the drug whose first-pass effect in the liver was greatly absorbed, and gastrointestinal side effects have also been reported.
In order to solve such problems relating to the absorption of pharmacologically active substances and side effects on the digestive system, Japanese Patent Application Laid-Open No. 61-501324 discloses a reservoir-type or matrix-type transdermal preparation comprising a hydrophilic polymer. Techniques have been proposed, and the name of tizanidine is described as one of the pharmacologically active substances that can be incorporated in the preparation.
Furthermore, Japanese Patent Publication No. 64-500115 discloses an invention relating to a technique of a reservoir-type transdermal administration preparation, and the name of tizanidine is described as one of pharmacologically active substances that can be incorporated in the preparation. Have been.
[0003]
[Problems to be solved by the invention]
In each of the above publications, a technique relating to a preparation for transdermal administration is disclosed. However, the name of tizanidine is merely mentioned as one of pharmacologically active substances that can be incorporated in the specification. In addition, the effects of the preparations containing tizanidine are not shown in the specific examples, and there is no study on problems such as coloring specific to transdermal administration preparations containing tizanidine.
Therefore, the present invention, in order to solve the problems of the prior art, can efficiently and continuously absorb tizanidine, furthermore, it does not give a color to the skin with low irritation, An object of the present invention is to provide a tizanidine-containing patch preparation having excellent stability.
[0004]
[Means for Solving the Problems]
The present inventors have conducted intensive studies and as a result, have found that the above-mentioned problems can be solved by including a specific organic acid in a patch preparation containing tizanidine or a pharmaceutically acceptable salt thereof. As a result, the present invention has been completed.
That is, the present invention comprises an organic acid and tizanidine or a pharmaceutically acceptable salt thereof as a pharmacologically active substance, wherein the organic acid is N-2-hydroxyethylpiperidine-N'-2-ethanesulfonic acid (hereinafter abbreviated as "HEPES"), lactic acid or acetic acid And a patch preparation characterized in that:
The patch preparation in the present invention is preferably a reservoir-type preparation or a matrix-type preparation.
Further, the matrix-type preparation is preferably a tape preparation or a poultice preparation.
[0005]
Book Invention Said When the patch preparation is a reservoir-type preparation, the composition in the reservoir layer is 0.01 to 15% by weight of an organic acid, 0.1 to 20% by weight of tizanidine or a pharmaceutically acceptable salt thereof, and an aqueous component 10 80 to 80% by weight, lower alcohol 5 to 70% by weight, humectant 5 to 70% by weight, absorption enhancer 0.01 to 20% by weight, irritation reducing agent 0.01 to 20% by weight, and hydrophilic polymer 0.1 to Preferably, it is 30% by weight or nonwoven fabric 0.1 to 10% by weight.
Of the present invention Said When the adhesive preparation is a matrix-type preparation, the composition in the adhesive layer is 0.01 to 15% by weight of an organic acid, 0.1 to 20% by weight of tizanidine or a pharmaceutically acceptable salt thereof, and an absorption enhancer. It preferably comprises 0.01 to 50% by weight, 0.01 to 20% by weight of a stimulant reducing agent and 0 to 70% by weight of a hydrophilic polymer or 0 to 99% by weight of a fat-soluble polymer.
The present invention The patch preparation of the above In the above, the pH of the reservoir layer or the pressure-sensitive adhesive layer is preferably 4 to 5.
[0006]
First, the composition in the reservoir layer of the reservoir-type preparation among the adhesive preparations of the present invention will be described.
Organic acids used in the reservoir layer of the reservoir-type preparation of the present invention Is HEPES, lactic acid or acetic acid It is.
Such an organic acid is preferably 0.01 to 15% by weight, more preferably 0.01 to 10% by weight, and particularly preferably 0.01 to 5% by weight, based on the total weight of the reservoir type composition. %. If the amount of the organic acid is less than 0.01% by weight, a sufficient amount of permeation as a reservoir-type preparation cannot be obtained, and if the amount exceeds 15% by weight, irritation to the skin increases, which is not preferable.
[0007]
In addition, tizanidine or a pharmaceutically acceptable salt as a pharmacologically active substance used in the reservoir layer of the reservoir-type preparation of the present invention may be 0.1 to 20% by weight based on the total weight of the composition of the reservoir layer. It can be formulated in an amount. If the amount of the pharmacologically active substance is less than 0.1% by weight, a sufficient amount of permeation as a reservoir-type preparation cannot be obtained. If the amount exceeds 20% by weight, coloring on the skin is observed, and redness is observed. It is not preferable because irritation to the skin such as is observed.
Examples of the pharmaceutically acceptable salt include hydrochloride, acetate, fumarate, maleate, sulfate, citrate and the like.
[0008]
The aqueous component used in the reservoir layer of the reservoir-type preparation of the present invention is preferably a buffer having a pH of 4 to 5 containing the organic acid in consideration of skin irritation and skin coloring. Examples of such a buffer include the above-mentioned organic acid in an acetate buffer having a pH of 4.5, a lactate buffer having a pH of 4.5, or a buffer having a buffering capacity near pH 4 to 5 such as phosphoric acid or citric acid. A buffer added to adjust the pH to 4 to 5 can be mentioned, and an acetate buffer is particularly preferable.
The amount of the aqueous component excluding the organic acid is preferably 10 to 80% by weight, more preferably 20 to 70% by weight, and particularly preferably 30 to 80% by weight, based on the total weight of the composition of the reservoir layer. It can be in the amount of ６０60% by weight. When the amount of the aqueous component is less than 10% by weight, irritation to the skin such as redness and edema is observed or sufficient permeability is not obtained, depending on the mixing ratio of the humectant and the lower alcohol. If the amount exceeds 100% by weight, a sufficient amount of permeation as a reservoir preparation cannot be obtained, which is not preferable.
[0009]
As the lower alcohol used in the reservoir layer of the reservoir-type preparation of the present invention, those having 2 to 5 carbon atoms are preferable, and ethanol and isopropanol are particularly preferable.
Such a lower alcohol is preferably blended in an amount of 5 to 70% by weight, more preferably 10 to 50% by weight, particularly preferably 10 to 30% by weight, based on the total weight of the reservoir layer composition. Can be If the amount of the lower alcohol is less than 5% by weight, a sufficient amount of permeation as a reservoir preparation cannot be obtained, and if it exceeds 70% by weight, irritation to the skin such as redness and edema can be observed. Absent.
[0010]
As the humectant used in the reservoir layer of the reservoir type preparation of the present invention, for example, glycerin, butylene glycol, propylene glycol, polyethylene glycol, sorbitol, diglycerin, dipropylene glycol, sodium pyrrolidone, carboxylate, ethyl carbitol, D-xitol, hyaluronic acid and the like can be mentioned as desirable examples, and among them, glycerin and polyethylene glycol are particularly desirable.
Such a humectant is preferably added in an amount of 5 to 70% by weight, more preferably 10 to 50% by weight, particularly preferably 10 to 30% by weight, based on the total weight of the reservoir layer composition. Can be If the amount of the humectant is less than 5% by weight, skin irritation such as redness is observed, and if it exceeds 70% by weight, sufficient permeability as a reservoir preparation cannot be obtained, which is not preferable.
[0011]
As the absorption enhancer used in the reservoir layer of the reservoir-type preparation of the present invention, any compound may be used as long as it is a compound that has been shown to have an absorption promoting effect on the skin, such as a fatty acid having 6 to 20 carbon chains. Examples thereof include aliphatic alcohols, fatty acid esters or ethers, aromatic organic acids, aromatic alcohols, aromatic organic acid esters or ethers. Further, lactic acid esters, acetic esters, monoterpene compounds, sesquiterpene compounds, Azone or derivatives thereof, glycerin fatty acid esters, sorbitan fatty acid esters (Span system), polysorbate systems (Tween system), polyethylene Glycol fatty acid esters, polyoxyethylene hydrogenated castor oil (HCO), sucrose fatty acid esters and the like can be mentioned. Specifically, caprylic acid, capric acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, cetyl alcohol, methyl laurate, Isopropyl myristate, myristyl myristate, octyl dodecyl myristate, cetyl palmitate, salicylic acid, methyl salicylate, ethylene glycol salicylate, cinnamic acid, methyl cinnamate, cresol, cetyl lactate, ethyl acetate, propyl acetate, geraniol, thymol, Eugenol, terpineol, l-menthol, borneolol, d-limonene, isoeugenol, isoborneol, nerol, dl-camphor, glycerin monolaurate, glycerin Monooleate, sorbitan monolaurate, sucrose monolaurate, polysorbate 20, polyethylene glycol monolaurate, polyethylene glycol monostearate, HCO-60, 1- [2- (decylthio) ethyl] azacyclopentan-2-one ( Hereinafter, abbreviated as "pyrothiodecane") is desirable, and lauryl alcohol, myristyl alcohol, ethylene glycol salicylate and pyrothiodecane are particularly desirable.
Such an absorption promoter is preferably 0.01 to 20% by weight, more preferably 0.1 to 10% by weight, and particularly preferably 0.1 to 5% by weight, based on the total weight of the composition of the reservoir layer. It can be formulated in an amount of% by weight. If the amount of the absorption enhancer is less than 0.01% by weight, sufficient permeability as a reservoir preparation cannot be obtained, and if it exceeds 20% by weight, skin irritation such as redness and edema is observed. Not preferred.
[0012]
Glycyrrhizic acid and its water-soluble salts, triethyl citrate, glycerin fatty acid esters, sorbitan fatty acid esters, and sucrose fatty acid known as absorption enhancers include glycyrrhizic acid and its water-soluble salts, which are used in the reservoir layer of the reservoir type preparation of the present invention. Esters or mixtures thereof are desirable, especially glycerin monooleate, glycerin monolaurate, sorbitan monolaurate or mixtures thereof.
Such a stimulant is preferably 0.01 to 20% by weight, more preferably 0.1 to 10% by weight, particularly preferably 0.1 to 5% by weight, based on the total weight of the composition of the reservoir layer. It can be formulated in an amount of% by weight. When the amount of the irritation-reducing agent is less than 0.01% by weight, irritation to the skin such as redness and edema is recognized, and when it exceeds 20% by weight, the irritation to the skin such as redness and edema is similarly observed. Is not preferred because
[0013]
In addition, in the reservoir layer of the reservoir-type preparation of the present invention, the hydrophilic polymer or the nonwoven fabric containing each of the above components that can be used to contain each of the above components has a water retention effect and has an active ingredient. Those that do not interact with are desirable.
Such hydrophilic polymers include, for example, cellulose derivatives (for example, carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMCNa), methylcellulose (MC), hydroxypropylmethylcellulol (HPMC), hydroxypropylcellulose (HPC), Hydroxyethylcellulose (HEC), etc.), starch derivatives (pullulane), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), vinyl acetate (VA), carboxyvinyl polymer (CVP), ethyl vinyl acetate (EVA), Eudragit, gelatin, Polyacrylic acid, sodium polyacrylate, polyisobutylene maleic anhydride copolymer, alginic acid, sodium alginate, carrageenan, gum arabic, tragacanth Karaya, polyvinyl methacrylate is desirable, in particular cellulose derivatives (CMCNa, HPMC, HPC, MC), PVA, PVP, VA, EVA and Eudragit desirable.
Such a hydrophilic polymer is preferably 0.1 to 30% by weight, more preferably 0.1 to 20% by weight, and particularly preferably 0.1 to 10% by weight, based on the total weight of the reservoir layer composition. It can be formulated in an amount of% by weight. If the amount of the hydrophilic polymer is less than 0.1% by weight, sufficient viscosity cannot be obtained to hold the solution in the reservoir layer, and if it exceeds 30% by weight, the drug release property becomes poor, It is not preferable because a sufficient permeation amount cannot be obtained as a reservoir preparation.
[0014]
Examples of the material of the nonwoven fabric include, for example, polypropylene, polyester, rayon or a mixture thereof, and rayon is particularly desirable. Such a nonwoven fabric is preferably 0.1 to 10% by weight, more preferably 0.1 to 5% by weight, particularly preferably 0.1 to 2% by weight, based on the total weight of the composition of the reservoir layer. It can be formulated in an amount. If the blending amount of the nonwoven fabric is less than 0.1% by weight, the solution cannot be retained in the reservoir layer, and if it exceeds 10% by weight, the release property of the drug becomes poor, and a sufficient permeation amount as a reservoir formulation cannot be obtained. It is not preferred.
[0015]
The reservoir layer having such a composition can be manufactured by any method. For example, using an ointment kneader such as Ajihomo Mixer 2SL-7 (Special Kika Co., Ltd.) or Multi-Blender Mill BL-1 (Nippon Seiki), a uniform gel preparation having the above composition is obtained and sealed in the reservoir layer. Alternatively, the uniform solution obtained by the above-mentioned machine is held on a non-woven fabric or the like, or when the adhesive is PVA, the obtained uniform gel is freeze-thawed, and then the obtained matrix is placed in a reservoir. Layers.
In the reservoir-type preparation of the present invention, as long as the reservoir layer contains the above-described composition containing an organic acid, the other components and the materials of each component may be of any type.
For example, the reservoir-type preparation of the present invention can comprise a support layer, a drug release agent layer, an adhesive layer, and a release liner layer in addition to the reservoir layer.
[0016]
As the film to be the support layer, those having low air permeability are desirable, and examples thereof include materials such as polyethylene, polyethylene terephthalate, polyvinylidene chloride, polyethylene, polyester, and polyvinylidene chloride, among which polyethylene and polyethylene terephthalate, A film laminated with two kinds of films, such as polyvinylidene chloride and polyethylene, or polyester and polyvinylidene chloride, is particularly desirable.
In addition, the drug release agent layer is not necessarily required to be provided as long as the solidity is maintained so that the drug does not flow, but for example, polyethylene, polypropylene, polymethacrylate, polyurethane, polyester, Materials such as polyvinyl alcohol-ethylene copolymer, polyvinyl alcohol, polyvinyl chloride, and polyamide are preferably used.
For the adhesive layer, for example, an acrylic adhesive, a silicon adhesive, a block copolymer of styrene-isoprene, polyisobutylene, or the like is suitably used.
Further, as the release liner layer, for example, aluminum, cellulose, polyester, polyethylene, polypropylene and the like are preferable.
The area of the drug release agent layer that can be formulated as the reservoir type formulation of the present invention is 40 cm2, and the area of the drug is 40 cm2. 2 It is desirable to have the following area.
[0017]
Next, the composition of the adhesive layer when the patch preparation of the present invention is a matrix-type preparation will be described.
The organic acid used in the adhesive layer of the matrix-type preparation of the present invention and the amount thereof are preferably the same as those described for the reservoir-type preparation.
It is also desirable that tizanidine as a pharmacologically active substance used in the matrix type preparation of the present invention or the pharmaceutically acceptable amount thereof is the same as that described for the reservoir type preparation.
Further, the absorption enhancer used in the matrix type preparation of the present invention is desirably the one described for the reservoir type preparation.
Such an absorption promoter is preferably 0.01 to 50% by weight, more preferably 0.01 to 30% by weight, and particularly preferably 0.01 to 10% by weight, based on the total weight of the composition of the adhesive layer. It can be formulated in an amount of% by weight. If the amount of the absorption enhancer is less than 0.01% by weight, a sufficient amount of permeation cannot be obtained. If the amount exceeds 50% by weight, skin irritation such as redness and edema is not preferable.
The irritation reducing agent used in the matrix-type preparation of the present invention and the amount thereof are desirably the same as those described for the reservoir-type preparation.
[0018]
The matrix-type preparation of the present invention desirably contains either a hydrophilic polymer or a fat-soluble polymer, but the hydrophilic polymer is desirably one described for the reservoir-type preparation.
The amount of the hydrophilic polymer is preferably 0 to 70% by weight, more preferably 0 to 50% by weight, and particularly preferably 0 to 30% by weight, based on the total weight of the composition of the adhesive layer. it can. If the amount of the hydrophilic polymer exceeds 70% by weight, it is not preferable because the cohesive strength is weakened, the flexibility is reduced, or the adhesive strength is reduced, although it depends on the blending ratio of the remaining components.
Examples of the fat-soluble polymer include polyisobutylene, styrene-isoprene block copolymer (SIS), isoprene rubber, styrene-butadiene block copolymer (SBS), and acrylic polymer (2-ethylhexyl acrylate, vinyl acetate, Methacrylate, methoxyethyl acrylate, at least two kinds of copolymers of acrylic acid) and the like can be mentioned as desirable ones. The compounding amount based on the weight of the entire composition of the adhesive layer of such a fat-soluble polymer is preferably 0 to 99% by weight, more preferably 0 to 70% by weight, and particularly preferably 0 to 50% by weight. be able to. When the amount of the fat-soluble polymer exceeds 99% by weight, sufficient permeability cannot be obtained, which is not preferable.
[0019]
In the adhesive layer of the matrix-type preparation of the present invention, a tackifier may be blended if necessary. Preferred examples of the tachyfire include an arcon-based tachyfire, a rosin-based tachyfire, polybutene and the like.
The tachyfire is preferably present in an amount of 0 to 70% by weight, more preferably 0 to 50% by weight, particularly preferably 0 to 30% by weight, based on the total weight of the composition of the adhesive layer of the matrix type preparation. Can be compounded.
Further, a humectant or an oil or fat may be blended, and as the humectant, those described for the reservoir-type preparation are preferable. Further, as the fats and oils, for example, liquid paraffin, squalane, squalene, olive oil, camellia oil, bashock oil, peanut oil and the like are desirable.
The humectant or fat is preferably from 0 to 60% by weight, more preferably from 0 to 40% by weight, particularly preferably from 0 to 30% by weight, based on the total weight of the composition of the adhesive layer of the matrix type preparation. It can be formulated in an amount.
[0020]
Further, an aqueous component, a cross-linking agent, a preservative, an antioxidant, and an ultraviolet absorber can be added as necessary. As the aqueous component, a buffer solution containing the organic acid at pH 4 to 5 is preferable in consideration of skin irritation and tizanidine coloring property. The amount of the aqueous component excluding the organic acid is preferably 0 to 90% by weight, more preferably 0 to 80% by weight, and particularly preferably 0 to 90% by weight, based on the total weight of the composition of the adhesive layer of the matrix type preparation. It can be 0 to 60% by weight.
Examples of the crosslinking agent include amino resins, phenol resins, epoxy resins, alkyd resins, thermosetting resins such as unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds. desirable. The crosslinking agent is preferably used in an amount of 0 to 70% by weight, more preferably 0 to 50% by weight, particularly preferably 0 to 30% by weight, based on the total weight of the composition of the adhesive layer of the matrix type preparation. Can be compounded.
As the preservative, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate and the like are desirable. As the antioxidant, tocopherol and its ester derivatives, ascorbic acid, stearic acid ester, nordihytologialetic acid, dibutylhydroxytoluene, butylhydroxyanisole and the like are desirable. As the ultraviolet absorber, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives and the like are desirable.
Such preservatives, antioxidants, and ultraviolet absorbers are preferably 0 to 20% by weight, more preferably 0 to 10% by weight, based on the total weight of the composition of the adhesive layer of the matrix-type preparation. %, Particularly preferably from 0 to 5% by weight.
[0021]
The pressure-sensitive adhesive layer having such a composition can be produced by any method. For example, in the case of an acrylic polymer, it is prepared by a solvent method, a methanol solution of another component is added to a solution of the polymer in ethyl acetate, stirred, then spread on a support and dried to obtain the present preparation. In the case of an SIS polymer, a hydrophilic polymer prepared by a hot melt method and containing other components is added, stirred, and spread on a support to obtain the present preparation.
In the matrix-type preparation of the present invention, as long as the adhesive layer contains the above-described composition containing an organic acid, the other components and the material of each component may be of any type.
For example, the matrix-type preparation of the present invention can be composed of the above-mentioned adhesive layer, a support layer for supporting the adhesive layer, and a release liner layer provided on the adhesive layer.
The support layer is composed of, for example, polyethylene terephthalate, polyethylene, urethane or the like when the matrix-type preparation is a tape preparation, and is composed of a cloth, a nonwoven fabric, a laminate film with polyethylene, or the like when the matrix-type preparation is a poultice preparation. Can be.
The area of the matrix-type preparation of the present invention that can be applied to the skin is 200 cm. 2 It is desirable to make the following.
[0022]
【The invention's effect】
According to the preparation for transdermal administration of the present invention, tizanidine or a pharmaceutically acceptable salt thereof, which is a pharmacologically active substance, can be continuously absorbed into the circulating blood through the skin. Moreover, a sustained effective blood concentration can be obtained without undergoing metabolism of the drug due to the first-pass effect in the liver observed when such pharmacologically active substance is orally administered. In addition, it is also possible to avoid the side effects of the digestive system and the central side that can be caused by a rapid increase in blood concentration observed in the case of oral administration. Furthermore, since the irritation and coloring properties on the skin are remarkably reduced, it is particularly effective as an external preparation for transdermal application.
[0023]
【Example】
Hereinafter, the present invention will be described in more detail with reference to Examples of the present invention. However, the present invention is not limited to these Examples, and various modifications may be made without departing from the technical idea of the present invention. Can be changed. In the examples, “%” means all weight%.
[0024]
[0025]
[0026]
[0027]
[0028]
[0029]
[0030]
[0031]
Comparative Examples 1-4
Comparative Examples 1 to 4 correspond to each of Examples 1 to 4, respectively. Instead of the organic acid used in Examples 1 to 4, a 0.3 M phosphate buffer (pH 4.5) was used. A patch preparation was obtained in the same manner, except that) was used.
Comparative Examples 5 to 7
Comparative Examples 5 to 7 correspond to the respective examples of Examples 5 to 7, respectively, except that the organic acid and its salt used in Examples 5 to 7 were not blended, and the patch preparation was prepared in the same manner. Obtained.
The skin permeability of each patch preparation obtained in Examples 1 to 7 and Comparative Examples 1 to 7 was evaluated by an in vitro skin permeation test using human skin. For skin irritation, a skin irritation index (SI value) was determined using the determination method shown in Table 1 below. Table 2 shows the results.
[0032]
[Table 1]
[0033]
[Table 2]
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32994093A JP3599766B2 (en) | 1993-12-01 | 1993-12-01 | Patch preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP32994093A JP3599766B2 (en) | 1993-12-01 | 1993-12-01 | Patch preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH07157429A JPH07157429A (en) | 1995-06-20 |
| JP3599766B2 true JP3599766B2 (en) | 2004-12-08 |
Family
ID=18226975
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP32994093A Expired - Lifetime JP3599766B2 (en) | 1993-12-01 | 1993-12-01 | Patch preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3599766B2 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU4972599A (en) * | 1998-07-07 | 2000-01-24 | Transdermal Technologies, Inc. | Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof |
| FR2792529B1 (en) * | 1999-04-26 | 2001-09-28 | Sod Conseils Rech Applic | NOVEL PHARMACEUTICAL COMPOSITIONS COMPRISING 2-ISOXAZOLE-8-AMINOTETRALINE DERIVATIVES |
| DE60034458T2 (en) * | 1999-07-27 | 2008-01-03 | Hisamitsu Pharmaceutical Co., Inc., Tosu | PLASTER FOR EXTERNAL APPLICATION |
| DE10159745A1 (en) * | 2001-12-05 | 2003-07-03 | Lohmann Therapie Syst Lts | Transdermal therapeutic system with improved long-term comfort |
| JP4468669B2 (en) * | 2003-09-22 | 2010-05-26 | 久光製薬株式会社 | Hypoallergenic patch |
-
1993
- 1993-12-01 JP JP32994093A patent/JP3599766B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07157429A (en) | 1995-06-20 |
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