JP4295488B2 - Transdermal absorption patch - Google Patents

Description

【００２１】
で表される単位を主たる繰り返し単位とするポリマーであり、通常、当該式の繰り返し単位からなるホモポリマーが使用されるが、ポリマー全体に対する３０重量％を超えない範囲で、Ｎ−ビニル−２−ピロリドン以外のビニル単量体が共重合されていてもよい。このような共重合体も本発明における「ポリビニルピロリドン」に包含される。
【００２２】
本発明において、ポリビニルピロリドンは、塗工性、塗工液の調製のし易さ、メタケイ酸アルミン酸マグネシウムとの相溶性（分散性）の点から、その浸透圧法における数平均分子量が１００００以上のものが好ましく、１０００００以上のものが特に好ましい。また、分子量の上限は、特に限定はされないが、溶剤にて希釈でき、かつ、下塗り層用塗工液の調製（後述のポリビニルピロリドン及びメタケイ酸アルミン酸マグネシウムを溶媒に分散乃至溶解させた塗工液の調製）時に、メタケイ酸アルミン酸マグネシウムの均一分散を阻害しないような分子量であるのが好ましく、かかる観点から浸透圧法による数平均分子量が５００万以下が好ましく、特に好ましくは３００万以下である。
【００２３】
本発明において、ポリビニルピロリドン及びメタケイ酸アルミン酸マグネシウムの混合物からなる下塗り層を支持体の片面に形成する方法は特に限定されず、種々の方法を適用できる。例えば、支持体の片面にグラビア印刷などの手段によって、ポリビニルピロリドン及びメタケイ酸アルミン酸マグネシウムを適当な溶媒に分散又は溶解させた混合物液を塗布、乾燥することで下塗り層を形成することができる。該混合物液における溶媒としては、例えば、メチルアルコール、エチルアルコール、ｎ−プロピルアルコール、イソプロピルアルコール等が挙げられる。また、塗液の乾燥は４０〜８０℃程度で行うのがよい。温度が８０℃を超えると、塗膜が発泡して下塗り層が不均一となる虞があり、温度が４０℃未満では、無視することができない程度の溶媒が残存する虞があるためである。
【００２４】
本発明において、下塗り層におけるポリビニルピロリドンとメタケイ酸アルミン酸マグネシウムの混合比率（ポリビニルピロリドン／メタケイ酸アルミン酸マグネシウム）は、下塗り層の投錨性（支持体との結合性）、下塗り層形成時の混合物液（塗液）の塗布のしやすさ等の点から、５〜９０／９５〜１０（重量％）が好ましく、特に好ましくは２０〜７０／８０〜３０（重量％）である。かかる範囲を超えてポリビニルピロリドンの割合が少ないと（メタケイ酸アルミン酸マグネシウムの割合が多いと）、メタケイ酸アルミン酸マグネシウムによって支持体との結合力が低下し、十分な量の下塗り層が形成されににくくなり、逆に、ポリビニルピロリドンの割合が多いと（メタケイ酸アルミン酸マグネシウムの割合が少ないと）硬いフィルム状の下塗り層となって、支持体との結合力が低下するようになり、好ましくない。
【００２５】
本発明において下塗り層は、支持体の片面に当該混合物が固形分換算で０．０１ｇ／ｍ²〜５ｇ／ｍ²程度、好ましくは０．０５ｇ／ｍ²〜３ｇ／ｍ²程度の存在量となるように形成するのがよい。当該混合物の塗布量が０．０１ｇ／ｍ²に満たない場合、ポットライフが約１か月間程度と短くなり、また、本発明が目的とする糊残りを十分に少なくすることが困難になる虞がある。一方、塗布量が５ｇ／ｍ²を超える場合には、その上に形成する粘着剤層の粘着特性が変化したり、粘着剤層中に含有する経皮吸収薬物の放出性に悪影響を与える虞がある。
【００２６】
本発明の貼付製剤において、上記の下塗り層を有することで、糊残りを十分に少なくできる理由は明らかではないが、本発明者等は以下のように考えている。即ち、ポリビニルピロリドンは比較的極性の低いポリマーから極性の高いポリマーに対しても親和性が高いので、多くの支持体との結合性が良好であるとともに、ポリビニルピロリドンに分散したメタケイ酸アルミン酸マグネシウムと粘着剤層とがイオン性の擬似架橋を形成するのではないかと推定される。
【００２７】
本発明において、下塗り層の上に形成する粘着剤層中に含有させる経皮吸収性の薬物は、特に限定されない。例えば、全身性薬物としては、コルチコステロイド類、鎮痛消炎剤、催眠鎮静剤、精神安定剤、抗高血圧剤、降圧利尿剤、抗生物質、全身麻酔剤、抗菌剤、抗真菌剤、ビタミン剤、冠血管拡張剤、抗ヒスタミン剤、鎮咳剤、性ホルモン、抗鬱剤、脳循環改善剤、制吐剤、抗腫瘍剤、酵素剤、生体医薬等が挙げられる。また、局所性薬物としては、例えば、リドカイン等の局所麻酔剤、塩酸テトラサイクリン等の歯科用抗生物質、塩化セチルピリジニウム等の殺菌消毒剤、塩酸クロルヘキシジン等の感染予防治療剤、ジメチルイソプロピルアズレン等の消炎剤、酢酸ヒドロコルチゾン等の副腎皮質ホルモン等が挙げられる。好ましくは、コカイン、プロカイン、クロロプロカイン、テトラカイン、ベンゾカイン、リドカイン、メピバカイン、プリロカイン、プピバカイン、ジブカイン、プロポキシカイン、エチドカイン、ジクロニン、オキシブプロカイン、テーカイン、アメトカイン、プロピトカイン、ピペロカイン、カタカイン、ブタニカイン、へキソチオカイン、メプリルカイン、エピロカイン、アミロカイン、イソブカイン、トリカイン、パレトキシカイン、ピロカイン、ヘキシルカイン、メタブトキシカイン、キシロカイン、メタブテタミン、オキセサゼイン、ピリドキシン、ブロモキシン、ジメチソキン、アミノ安息香酸エチル、ピベリジノアセチルアミノ安息香酸エチル、ベンジルアルコール、クロロブタノール及びこれらの薬理学的に許容される塩からなる群より選択される少なくとも１種の局所麻酔剤であり、より好ましくは、リドカイン、塩酸リドカイン、塩酸プロカイン、塩酸メピバカイン、塩酸ジブカイン、塩酸プピバカイン、塩酸プロピトカイン、塩酸テトラカイン、塩酸トリカイン、オキセサゼインである。
【００２８】
粘着剤層中の薬物の含有量は、薬物の種類、投与目的等により適宜増減できるが、通常、粘着剤層全体当たり１〜８０重量％、好ましくは２〜７０重量％程度である。含有量が１重量％未満の場合、治療や予防に有効な量の薬物の放出が期待できず、また、８０重量％を超えると、粘着剤層の接着性が低下して治療や予防効果に限界が生じると共に経済的にも不利である。なお、薬物は、その薬効に応じて、粘着剤中に溶解状態、過飽和結晶析出状態もしくは分散状態にて含有させることができ、これにより、各種疾患の治療及び／または予防効果を目的とした経皮吸収製剤とすることができる。
【００２９】
本発明において、粘着剤層に使用する粘着剤は、特に限定されず、この種の貼付製剤で使用されている粘着剤を制限なく使用できる。例えば、アクリル系重合体からなるアクリル系粘着剤；スチレン−イソプレン−スチレンブロック共重合体、スチレン−ブタジエン−スチレンブロック共重合体、ポリイソプレン、ポリイソブチレン、ポリブタジエン等のゴム系粘着剤；シリコーンゴム、ジメチルシロキサンベース、ジフェニルシロキサンベース等のシリコーン系粘着剤；ポリビニルメチルエーテル、ポリビニルエチルエーテル、ポリビニルイソブチルエーテル等のビニルエーテル系粘着剤；酢酸ビニル−エチレン共重合体等のビニルエステル系粘着剤；ジメチルテレフタレート、ジメチルイソフタレート、ジメチルフタレート等のカルボン酸成分とエチレングリコール等の多価アルコール成分からなるポリエステル系粘着剤等が挙げられる。なかでも、支持体（特に布帛）との投錨性、貼着性、薬物溶解性、薬物安定性等の点からアクリル系粘着剤が好ましい。
【００３０】
また、アクリル系粘着剤（アクリル系重合体）としては、（メタ）アクリル酸アルキルエステルを主成分とし、これに官能性単量体を共重合して得られたものが好ましい。すなわち、（メタ）アクリル酸アルキルエステルを６０〜９９重量％（好ましくは６５〜９５重量％）含有し、残りが官能性単量体からなる共重合体が好ましい。
【００３１】
アクリル系粘着剤（アクリル系重合体）における（メタ）アクリル酸アルキルエステル（以下、主成分単量体ともいう）は、通常、アルキル基が炭素数４〜１３の直鎖又は分岐アルキル基（例えば、ブチル、ペンチル、ヘキシル、ヘプチル、オクチル、２−エチルヘキシル、ノニル、デシル、ウンデシル、ドデシル、トリデシル等）からなるものであり、これらは１種又は２種以上が使用される。なお、離型フィルムや被着体への粘着剤の残存を生じない範囲であれば、当該アルキル基の炭素数が４〜１３の（メタ）アクリル酸アルキルエステルとともに、アルキル基が炭素数１〜３のアルキル基（例えば、メチル基、エチル基、イソプロピル基等）からなる（メタ）アクリル酸アルキルエステルまたは／及びアルキル基が炭素数１４以上のアルキル基（例えば、テトラデシル基、ペンタデシル基、ヘキサデシル基等）からなる（メタ）アクリル酸アルキルエステルを併用することもできる。なお、この場合、アルキル基が炭素数１〜３のアルキル基からなる（メタ）アクリル酸アルキルエステルまたは／及びアルキル基が炭素数１４以上のアルキル基からなる（メタ）アクリル酸アルキルエステルの使用量は、アルキル基が炭素数４〜１３の（メタ）アクリル酸アルキルエステルに対して２０重量％以下である。
【００３２】
官能性単量体は、共重合反応に関与する不飽和二重結合を分子内に少なくとも一個有するとともに、官能基を側鎖に有するものであり、例えば、（メタ）アクリル酸、イタコン酸、マレイン酸、無水マレイン酸等のカルボキシル基含有単量体、（メタ）アクリル酸ヒドロキシエチルエステル、（メタ）アクリル酸ヒドロキシプロピルエステル等のヒドロキシル基含有単量体、スチレンスルホン酸、アリルスルホン酸、スルホプロピル（メタ）アクリレート、（メタ）アクリロイルオキシナフタレンスルホン酸、アクリルアミドメチルプロパン酸等のスルホキシル基含有単量体、（メタ）アクリル酸アミノエチルエステル、（メタ）アクリル酸ジメチルアミノエチルエステル、（メタ）アクリル酸ｔｅｒｔ−ブチルアミノエチルエステル等のアミノ基含有単量体、（メタ）アクリルアミド、ジメチル（メタ）アクリルアミド、Ｎ−メチロール（メタ）アクリルアミド、Ｎ−メチロールプロパン（メタ）アクリルアミド、Ｎ−ビニルアセトアミド等のアミド基含有単量体、（メタ）アクリル酸メトキシエチルエステル、（メタ）アクリル酸エトキシエチルエステル、（メタ）アクリル酸メトキシエチレングリコールエステル、（メタ）アクリル酸メトキシジエチレングリコールエステル、（メタ）アクリル酸メトキシポリエチレングリコールエステル、（メタ）アクリル酸メトキシポリプレングリコールエステル、（メタ）アクリル酸テトラヒドロフリルエステル等のアルコキシル基含有単量体が挙げられる。当該官能性単量体は１種または２種以上を使用でき、これらの中でも、粘着剤の感圧粘着性、凝集性、粘着剤層中に含有する薬物の放出性等の点から、カルボキシル基含有単量体が好ましく、特に好ましくは（メタ）アクリル酸である。
【００３３】
なお、本発明においては、アクリル系粘着剤として、上記の（メタ）アクリル酸アルキルエステル（主成分単量体）と官能性単量体との共重合体に、さらに他の単量体を共重合したものを使用することもできる。当該他の単量体としては、例えば、（メタ）アクリロニトリル、酢酸ビニル、プロピオン酸ビニル、Ｎ−ビニル−２−ピロリドン、メチルビニルピロリドン、ビニルピリジン、ビニルピペリドン、ビニルピリミジン、ビニルピペラジン、ビニルピロール、ビニルイミダゾール、ビニルカプロラクタム、ビニルオキサゾール等が挙げられ、これらは１種又は２種以上を使用できる。また、当該他の単量体の使用量は、（メタ）アクリル酸アルキルエステル（主成分単量体）と官能性単量体の合計重量に対して、通常、０〜４０重量％程度であり、好ましくは１０〜３０重量％程度である。
【００３４】
本発明におけるアクリル系粘着剤（アクリル系重合体）の好適な具体例として、（メタ）アクリル酸２−エチルヘキシルエステル６５〜９９重量％と（メタ）アクリル酸１〜３５重量％とからなる共重合体、（メタ）アクリル酸２−エチルヘキシルエステル６０〜９９重量％とＮ−ビニル−２−ピロリドン１〜４０重量％とからなる共重合体等が挙げられる。
【００３５】
本発明において、粘着剤には、必要に応じて、種々の添加剤を配合してもよく、該添加剤としては、例えば、可塑剤、経皮吸収促進剤、酸化防止剤等を挙げることができる。
【００３６】
可塑剤の添加によって粘着剤は可塑化され、貼付部位に対する粘着剤層の貼着力を調整することができる。可塑剤としては、例えば、ジイソプロピルアジペート、ジアセチルセパゲート等を挙げることができる。可塑剤は１種若しくは２種以上を用いることができ、その使用量は粘着剤１００重量部に対して５０〜２００重量部程度が好ましい。
【００３７】
経皮吸収促進剤は、粘着剤層内での薬物の溶解性や拡散性を向上させ得る機能を有する化合物であり、例えば、主に薬物溶解性を高める化合物として、エチレングリコール、ジエチレングリコール、プロピレングリコール、トリエチレングリコール、ポリエチレングリコール、ポリプロピレングリコール等のグリコール類、主に薬物拡散性を高める化合物として、オリーブ油、ヒマシ油、スクアラン、ラノリン等の油脂類等が挙げられる。また、その他の（経皮）吸収促進剤として、流動パラフィンのような炭化水素類；各種界面活性剤；エトキシ化ステアリルアルコール、オレイン酸モノグリセリド、カプリル酸モノグリセリド、ラウリル酸モノグリセリドのようなグリセリンモノエステル類；グリセリンジエステル、グリセリントリエステルまたはそれらの混合物等のグリセリン多価エステル類；ラウリル酸エチル、ミリスチン酸イソプロピル、ミリスチン酸イソトリデシル、パルミチン酸オクチル、パルミチン酸イソプロピル、オレイン酸エチル、アジピン酸ジイソプロピルのような高級脂肪酸エステル；オレイン酸、カプリル酸のような高級脂肪酸；Ｎ−メチルピロリドン；１，３−ブタンジオール等を挙げることができる。これらは、薬物の溶解性及び拡散性のうちの少なくとも一方を向上させ得るものである。本発明において、経皮吸収促進剤は１種若しくは２種以上を用いることができ、その使用量は粘着剤１００重量部当たり５〜２００重量部程度が好ましい。
【００３８】
経皮吸収促進剤は粘着剤との相溶性のよいものが選択されるので、可塑剤と同様に粘着剤を可塑化するものであり、可塑剤、経皮吸収促進剤等の添加により粘着剤の凝集力は低下する。しかし、本発明の貼付製剤においては、下塗り層の存在により、このような低凝集力の粘着剤からなる粘着剤層を設けても、糊残りを十分に少なくできる。
【００３９】
本発明の経皮吸収型製剤の製造方法は、特に限定されず、例えば、薬物、粘着剤及び必要に応じて配合されるその他の添加剤を溶媒に溶解または分散させ、得られた溶液または分散液を支持体の下塗り層が形成された片面上に塗布、乾燥して粘着剤層を形成する方法が挙げられる。また、上記の溶液または分散液を保護用の離型フィルム上に塗布、乾燥して離型フィルム上に粘着剤層を形成し、その後、下塗り層を形成した支持体の当該下塗り層を粘着剤層に接着させることによっても製造できる。
【００４０】
本発明において、粘着剤層の厚み（乾燥後厚み）は、通常、１０〜２００μｍ程度、好ましくは１５〜１５０μｍ程度である。粘着剤の支持体の片面当たりの付着量（固形分換算量）で示す場合、通常、１０〜２００ｇ／ｍ²程度、好ましくは１５〜１５０ｇ／ｍ²程度である。
【００４１】
本発明の貼付製剤には、その製造時、運搬時、保存時等における粘着剤層の器具や容器等の物体（物品）へ不要な接着（接触）の防止や製剤の劣化防止のために、被着体（皮膚、粘膜等）への貼付直前までは粘着剤層の露出面を離型フィルムにて被覆、保護するのが望ましい。使用時は、離型フィルムを剥がして、粘着剤層の面を露出させ、粘着剤層の露出面を被着体（皮膚、粘膜等）の貼付部位に貼付して、薬物の投与を行う。
【００４２】
離型フィルムの材質としては、ポリエステル、ポリ塩化ビニル、ポリ塩化ビニリデン、各種アクリル系及びメタクリル系ポリマー、ポリスチレン、ポリカーボネート、ポリイミド、酢酸セルロース（アセテート）、再生セルロース（セロファン）、セルロイド等のプラスチックフィルム；上質紙、グラシン紙等の紙；上質紙またはグラシン紙等とポリオレフィンとのラミネートフィルム等が挙げられる。これらの中でも、安全性、経済性、薬物移行性等の点からポリエステルフィルムが好ましい。ポリエステルフィルムを構成するポリエステルとしては、芳香族二塩基酸成分とジオール成分とからなる結晶性の線状飽和ポリエステルが好適であり、例えば、ポリエチレンテレフタレート、ポリブチレンテレフタレート、ポリプロピレンテレフタレート、ポリエチレン−２，６−ナフタレート等が挙げられる。こられの中でも、特に経済性の点から、ポリエチレンテレフタレート（ＰＥＴ）フィルムが好ましい。ポリエステルフィルムは、従来公知の方法で製造されたものであり、例えば、二軸延伸ポリエステルフィルム（押出し機で溶融後、Ｔ型ダイスやＩ型ダイスから回転ドラム上に押し出し、急冷却して未延伸フィルムとし、次にこの未延伸フィルムを二軸方向に延伸し、必要に応じて熱固定して得られたフィルム）は本発明においても好適に使用できる。本発明において、離型フィルムの厚みは、取り扱い性等の点から、通常１０〜２００μｍ、好ましくは５０〜１００μｍである。
【００４３】
離型フィルムの粘着剤層に重なる側の面に形成する離型処理層としては、通常、硬化性シリコーン樹脂が使用される。硬化性シリコーン樹脂には、溶剤付加型、溶剤縮合型、溶剤紫外線硬化型、無溶剤付加型、無溶剤縮合型、無溶剤紫外線硬化型、無溶剤電子線硬化型等の各種タイプがあり、本発明では、いずれのタイプも使用できる。硬化性シリコーン樹脂の具体例としては、信越化学工業（株）製のＫＳ−７７４、ＫＳ−７７５、ＫＳ−７７８、ＫＳ−７７９Ｈ、ＫＳ−８５６、Ｘ−６２−２４２２、Ｘ−６２−２４６１、ＫＮＳ−３０５、ＫＮＳ−３０００、Ｘ−６２−１２５６（いずれも商品名）、ダウコーニング・アジア（株）製のＤＫＱ３−２０２、ＤＫＱ３−２０３、ＤＫＱ３−２０４、ＤＫＱ３−２０５、ＤＫＱ３−２１０（いずれも商品名）、東芝シリコーン（株）製のＹＳＲ−３０２２、ＴＰＲ−６７００、ＴＰＲ−６７２０、ＴＰＲ−６７２１（いずれも商品名）等が挙げられる。
【００４４】
剥離処理層の形成方法としては、バーコート、リバースロールコート、グラビアコート、ロッドコート、エアドクターコート、ドクターブレードコート等従来より公知の塗布方法が用いられる。
【００４５】
本発明において、離型処理層の厚みは、０．０１μｍ〜５μｍが好ましく、特に好ましくは０．１μｍ〜３μｍである。離型処理層が０．０１μｍ未満の場合、塗布ムラが生じて塗膜の均一性が得られなくなるために好ましくなく、５μｍを超えると、粘着剤層からの薬物の移行量が増大したり、剥離性が低下する傾向となるために好ましくない。
【００４６】
本発明の経皮吸収型貼付製剤は、通常の皮膚及び口腔粘膜等の粘膜に適用でき、架橋処理や充填剤の添加等を行わない低凝集力の粘着剤（層）であっても、粘着剤（層）は被着体（皮膚、粘膜）からの良好な剥離性を示す。即ち、粘着剤に薬物や添加剤（経皮吸収促進剤、可塑剤等）を添加することで、粘着剤全体の凝集力が低下しても、架橋処理や充填剤の添加等の余分な処埋をすることなく、粘着剤（層）は良好な剥離性を示す。従って、離型フィルムを剥がす際に離型フィルムに粘着剤が多量に残存することがないので、製剤中の薬物含量が大きく低下せず、設計通りの良好な治療効果を得ることできる。また、被着体（皮膚、粘膜）から製剤を除去する際に、粘着剤が被着体（皮膚、粘膜）に多量に残留することもない。また、口腔粘膜等の生体における粘膜部は、凹凸の顕著な面状であったり、狭小な空間内に存在することが多く、そのために特に粘膜部への貼付を意図する製剤である場合、製剤の支持体には柔軟性の高い布帛又は布帛にプラスチックフィルムをラミネート加工した複合体を使用することが多いが、かかる布帛や複合体を支持体に使用した場合にも、本発明の製剤は糊残りを十分に少なくできるため、粘膜への貼付用として、治療効果に優れた、有用な製剤を得ることができる。
【００４７】
本発明書中の、「粘着剤の凝集力が高くない」、「低凝集力の粘着剤」とは、下記の実施例に記載の方法で測定される凝集力が、概ね１０Ｎ／ｃｍ以下である場合を意味している。
【００４８】
【実施例】
以下、実施例及び比較例を示して本発明をより具体的に説明するが、本発明は以下に示す実施例によって限定されるものではない。なお、以下の記載において、部は重量部を意味する。
【００４９】
〔粘着剤溶液Ａの調製〕
不活性ガス雰囲気下で、アクリル酸２−エチルヘキシルエステル９５部とアクリル酸５部とを酢酸エチル中で共重合させて、粘着剤溶液Ａを調製した。
【００５０】
〔実施例１〕
粘着剤溶液Ａ（固形分：４０部）にリドカイン６０部を加えて混合溶解し、得られた溶液を、片面に硬化性シリコーン処理を施したポリエステル製（ＰＥＴ製）の厚み７５μｍの離型フィルム（三菱化学ポリエステルフィルム社製、ＭＲＮ７５）の処理層上に乾燥後の厚みが約２０μｍとなるように塗布、乾燥して薬物含有粘着剤層を作製した。
一方、片面に硬化性シリコーン樹脂による剥離処理層を形成した厚み１２μｍのポリエステルフィルムを用い、この剥離処理面に、数平均分子量が１２０万ののポリビニルピロリドンＫ−９０（五協産業社製）５０部と、ノイシリン（富士化学工業社製（商品名）のメタケイ酸アルミン酸マグネシウム）５０部とを含む固形分濃度が１０％のイソプロピルアルコール混合分散液を固形分付着量が２ｇ／ｍ²となるように塗布、乾燥して下塗り層を形成した。このようにして得られた下塗り層を、ポリプロピレン含量５５重量％、ポリエステル含量４５重量％の複合繊維をスパンレース法により分割、絡合させて作製した分割繊維製不織布（厚み：０．４２ｍｍ、質量：９０ｇ／ｍ²、剛軟度（４５°カンチレバー法による）：５５ｍｍ）に転写し、下塗り層を有する支持体を作製した。
次いで、上記粘着剤層を上記支持体の下塗り層に貼り合わせて本発明の貼付製剤を作製した。
【００５１】
〔実施例２〕
剥離処理したポリエステルフィルムの剥離処理面に、ポリビニルピロリドンＫ−９０（五協産業社製）４０部と、ノイシリン（富士化学工業社製（商品名）のメタケイ酸アルミン酸マグネシウム）６０部を含む固形分濃度が１０％のエチルアルコール混合分散液を固形分付着量が０．５ｇ／ｍ²となるように塗布、乾燥して下塗り層を形成したこと以外は、実施例１と同様にして本発明の貼付製剤を作製した。
【００５２】
〔実施例３〕
離型処理したポリエステルフィルムの離型処理面に、数平均分子量が４万のポリビニルピロリドンＫ−３０（五協産業社製）７０部と、ノイシリン（富士化学工業社製（商品名）のメタケイ酸アルミン酸マグネシウム）３０部とを含む固形分濃度が５％のイソプロピルアルコール混合分散液を固形分付着量が３ｇ／ｍ²となるように塗布、乾燥して下塗り層を形成したこと以外は実施例１と同様にして本発明の貼付製剤を作製した。
【００５３】
〔比較例１〕
実施例１において、支持体の片面に下塗り層を形成しなかった以外は、実施例１と同様にして貼付剤を作製した。
【００５４】
〔比較例２〕
実施例２において、支持体の片面に下塗り層を形成しなかった以外は、実施例２と同様にして貼付剤を作製した。
【００５５】
〔比較例３〕
実施例３において、支持体の片面に下塗り層を形成しなかった以外は、実施例３と同様にして貼付剤を作成した。
【００５６】
〔比較例４〕
実施例１において、支持体の片面にポリビニルピロリドンＫ−９０（五協産業社製）単独で下塗り層（固形分付着量：２ｇ／ｍ²）を形成した以外は、実施例１と同様にして貼付剤を作成した。
【００５７】
〔比較例５〕
実施例１において、支持体にノイシリン（富士化学工業社製（商品名）のメタケイ酸アルミン酸マグネシウム）単独で下塗り層（固形分付着量：２ｇ／ｍ²）を形成した以外は、実施例１と同様にして貼付剤を作製した。
【００５８】
上記実施例及び比較例で得られた貼付製剤について、下記（１）〜（３）の性能評価を行い、その結果を表１に示した。
【００５９】
（１）凝集力の測定
製剤２枚を１０×２０ｍｍの形状に切断後、各製剤の離型フィルムを取り除き、２枚の製剤の粘着面同士を貼り合せ、２０００ｇのゴムローラーを１分間に３００ｍｍの速さで製剤の上を２回通過させ、室温で３０分間放置した。なお、調整したサンプルには、引張試験機のチャックでつかんで引き剥がしやすいように、必要に応じて補助紙を取り付けた。
次に、引張試験機を用いて１分間に１２０ｍｍの速度で２枚の製剤をＴ型に１８０°方向に引き剥がし、そのときの荷重を測定して、これを粘着剤（層）の凝集力とした。なお、この際、２枚の製剤の粘着剤層同士が十分に一体化して、引き剥がすときの状態が糸引き状態であることを確認し、２枚の製剤が糸引きせず、貼りあわせた界面できれいに剥がれるときは、その時の荷重を凝集力としなかった。
【００６０】
（２）剥離力の測定
製剤１枚を１０×３０ｍｍの大きさに切断してサンプルとし、１分間に１２０ｍｍの速度で製剤を離型フィルムからＴ型に１８０°方向に引き剥がす時の荷重を引張試験機にて測定して、これを剥離力とした。なお、サンプルを引張試験機のチャックでつかみ易いように、サンプルには、必要に応じて補助紙を取り付けた。
【００６１】
（３）薬物の離型フィルムへの移行率の測定
実施例及び比較例で得られた貼付製剤を包装袋で密封し、５０℃条件で３ヶ月間保存後、離型フィルムを剥がして、製剤（粘着剤層）中のリドカイン含量と離型剥ィルムに付着した薬物量をメタノールにてすべて抽出し、高速液体クロマトグラフ法にてリドカイン量を測定した。そして、離型フィルムへの薬物の移行率を次式にて算出した。
【００６２】
（離型フィルムへの移行率％）＝Ａ÷（Ａ＋Ｂ）×１００
Ａ：離型フィルムに付着したリドカイン量
Ｂ：製剤中のリドカイン量
【００６３】
表１は試験結果である。
【００６４】
【表１】

【００６５】
表１に示すように、実施例１〜３で得られた貼付製剤は離型フィルムへの粘着剤の付着がほとんど無く、離型フィルムへの薬物の移行が高いレベルで抑制される、安定性に優れた製剤であった。
一方、比較例１〜３の下塗り層を形成しなかった貼付製剤では、剥離力は実施例と変わらないが、離型フィルムへ粘着剤が付着が多いために、離型フィルムへの薬物が多量に移行し、製剤の薬物含有量が低下して、安定な製剤が得られなかった。
また、比較例４、５のポリビニルピロリドンまたはノイシリンからなる下塗り層を形成した製剤では、離型フィルムへの粘着剤の付着を十分に抑制できず、離型フィルムへの薬物の移行量は、下塗り層を設けない場合に比べて、却って、多くなった。
【００６６】
【発明の効果】
以上の説明により明らかなように、本発明によれば、低凝集力の粘着剤層であっても、糊残りが十分に少ない経皮吸収型貼付製剤を提供できる。すなわち、粘着剤に薬物や添加剤を添加することで、粘着剤層の凝集力が低下しても、架橋処理や充填剤の添加等の凝集力を高めるための処埋を行う必要なく、製剤使用時の離型フィルムへの粘着剤の移行が十分に抑制され、また、被着体から製剤を除去する際の被着体への糊残りも極めて少ない、良好な治療効果を有し、かつ、使用後の不快感も軽微な、極めて有用な、経皮吸収型貼付製剤を得ることができる。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a transdermal absorption patch preparation, and more particularly, to a transdermal absorption patch preparation with little adhesive residue on an adherend and a release film.
[0002]
[Prior art]
In recent years, an adhesive layer containing a drug is provided, and the adhesive layer is affixed to an adherend (biological skin or mucous membrane), whereby the drug is continuously administered into the living body through the skin or mucous membrane. Various types of mold patch preparations have been developed. By the way, in such a percutaneous absorption type patch preparation, in order to release the drug to the skin surface of the living body and absorb it in the living body, it is usually necessary to increase the drug concentration in the adhesive layer. Also proposed is a method (Patent Documents 1 to 3 and Non-Patent Document 1) for improving the absorbability of a drug without adding a drug concentration in particular by adding a transdermal absorption enhancer together with the drug in the adhesive layer. ing.
[0003]
However, when the drug concentration in the pressure-sensitive adhesive layer is increased, the drug becomes supersaturated or crystallized in the pressure-sensitive adhesive layer, and the adhesive strength of the paste, that is, the cohesive force of the pressure-sensitive adhesive in the pressure-sensitive adhesive layer is reduced. It becomes. In addition, even when a transdermal absorption enhancer is added, a transdermal absorption enhancer that is usually compatible with the pressure-sensitive adhesive is selected so that the enhancement effect is sufficiently expressed. The cohesive force of the pressure-sensitive adhesive is reduced. When the adhesive strength (adhesive strength of the adhesive in the adhesive layer) is low, the adhesive (adhesive) moves to the release film when the release film is removed from the preparation during use of the preparation. (Residual), resulting in a problem that the amount of drug in the preparation decreases and the therapeutic effect decreases. Further, there is a problem that the adhesive remains on the adherend when the preparation is removed from the adherend (skin or mucous membrane) after the preparation is used.
[0004]
As a method of solving the so-called adhesive residue problem in which the adhesive remains (transfers) to the adherend and the release film, generally, a cross-linking agent is added to the paste (adhesive layer). There are methods for crosslinking the pressure-sensitive adhesive (polymer component) in the body (Patent Document 4) and adding a filler to increase the cohesive strength of the pressure-sensitive adhesive (Patent Document 5). However, in the method of crosslinking the polymer component, crosslinking may be inhibited due to the added drug or transdermal absorption accelerator, and crosslinking may not be possible, and the method of adding a filler may not be sufficiently effective. .
[0005]
In general, fabrics such as woven fabrics and non-woven fabrics, and composite films obtained by bonding non-woven fabrics and plastic films are widely used as a support for patch preparations in terms of good texture and flexibility. When a highly flexible support such as such a fabric or composite film is used, the above problem of adhesive residue is particularly likely to occur.
[0006]
[Patent Document 1]
US Pat. No. 3,551,554
[Patent Document 2]
U.S. Pat. No. 3,472,931
[Patent Document 3]
US Patent No. 4017641
[Patent Document 4]
Japanese Patent No. 3014188
[Patent Document 5]
JP-A-6-65066
[Non-Patent Document 1]
DRUGS AND THE PHARMACEUTICAL SCIENCES vol, 31 `` Transdermal Controlled Systemic Medications '' p.67-75 (1987)
[0007]
[Problems to be solved by the invention]
In view of the above circumstances, the present invention provides a transdermal patch preparation capable of sufficiently reducing adhesive residue even when the cohesive strength of the adhesive in the adhesive layer is not high, particularly a fabric or a composite of a fabric and a plastic film. It is an object of the present invention to provide a transdermal absorption type patch preparation that can sufficiently reduce adhesive residue even when used as a support.
[0008]
[Means for Solving the Problems]
As a result of diligent research to achieve the above object, the present inventors have provided an undercoat layer made of a mixture of polyvinylpyrrolidone and magnesium aluminate metasilicate on a support, and formed an adhesive layer containing a drug thereon. As a result, it was found that the adhesive residue was extremely reduced, and the present invention was completed.
[0009]
That is, the present invention
(1) A transdermal absorption type patch preparation comprising a support layer laminated on one side of a pressure-sensitive adhesive layer containing a transdermally absorbable drug, wherein polyvinylpyrrolidone and aluminate metasilicate between the support and the pressure-sensitive adhesive layer A patch preparation characterized by having an undercoat layer comprising a mixture of magnesium;
(2) The adhesive preparation according to (1) above, wherein the support is a fabric,
(3) The patch preparation according to the above (1) or (2), wherein the drug is a local anesthetic,
(4) The adhesive preparation according to any one of (1) to (3) above, wherein the adhesive in the adhesive layer is an acrylic adhesive,
(5) The adhesive preparation according to any one of (1) to (4) above, having a release film on one side opposite to the one side on which the support of the pressure-sensitive adhesive layer is laminated, and
(6) The patch preparation according to any one of (1) to (5), which is for application to a mucosa.
[0010]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the present invention will be described in more detail.
The transdermal absorption type patch preparation of the present invention is characterized by having an undercoat layer comprising a mixture of polyvinylpyrrolidone and magnesium aluminate metasilicate between the support and the adhesive layer.
[0011]
That is, by providing an adhesive layer on an undercoat layer made of a mixture of polyvinyl pyrrolidone and magnesium aluminate metasilicate formed on one side of the support, a preparation can be obtained even if the adhesive cohesive strength in the adhesive layer is not high. The adhesive (residue residue) remaining on the release film that peels off during use can be extremely reduced, and there is also sufficient adhesive residue on the adherend when the applied preparation is removed from the adherend (skin, mucous membrane, etc.) Can be less.
[0012]
The support used in the patch preparation of the present invention is not particularly limited, and is known as a support used in this kind of patch preparation, such as paper; plastic film; fabric such as knitted fabric, woven fabric, and non-woven fabric. Material can be applied. Among them, a support with high flexibility is preferable from the viewpoints of good handleability, rich flexibility, good followability to the application site, good adhesion, etc., and particularly preferably a plastic film on a fabric or fabric. Is a laminated body, particularly preferably a fabric.
In the present specification, the term “fabric” refers to knitting, weaving, entanglement, etc., regardless of the type of fiber (that is, whether it is a natural fiber or a synthetic fiber). It is used as a general term for the sheet-like fiber aggregate to be formed.
[0013]
The fiber constituting the fabric is not particularly limited. For example, viscose rayon, copper ammonia rayon, diacetate, triacetate, nylon, polyvinylidene chloride, polyvinyl alcohol, polyvinyl chloride, polyester, polyacrylonitrile, polyethylene, polypropylene, Synthetic fibers such as polyurethane, polyalkylene paraoxybenzoate, and polyclar (a 1: 1 mixture of vinyl chloride and polyvinyl alcohol); natural fibers such as cotton, wool, silk, and hemp. Moreover, the split fiber which consists of 2 or more types of different fiber components can also be used conveniently. Here, “divided fiber” is obtained by dividing a composite fiber obtained by combining and spinning two or more different fiber components with a die (for example, a composite fiber obtained by spinning and combining polypropylene and polyester with a die). In particular, by extracting one component or applying a strong impact, it is possible to obtain a split fiber that is divided into finer fibers by dividing the tuft when the orange is cut into rounds.
[0014]
The fiber which comprises a fabric can use 1 type (s) or 2 or more types. The fibers are preferably hydrophobic, and among the above-exemplified fibers, polyolefin fibers such as polyethylene and polypropylene, and split fibers of polyolefin (preferably polypropylene) and polyester (preferably polyethylene terephthalate) are particularly preferable. Moreover, in the split fiber of polyolefin and polyester, the content ratio of polyolefin and polyester (polyolefin / polyester) is preferably 30 to 70/70 to 30 (% by weight), particularly preferably 40 to 60/60 to 40. (% By weight).
[0015]
The form of the fabric is not particularly limited, and examples thereof include knitted fabrics, woven fabrics, and nonwoven fabrics. Nonwoven fabrics are preferred from the viewpoints of economy, versatility, processability, and the like, and nonwoven fabrics of polyolefin fibers such as polyethylene and polypropylene, polypropylene. Particularly preferred are non-woven fabrics of polyester split fibers.
[0016]
In addition, a composite obtained by laminating a plastic film on a fabric is preferable in that the handleability is improved as compared with a single fabric and the back-through of the pressure-sensitive adhesive layer (plaster layer) can be prevented. Examples of plastic films in this case include polyolefins such as polyethylene and polypropylene, polyester, polyamide, polybutadiene, polybutene, polyisoprene, polyvinyl chloride, polyvinylidene chloride, ethylene-vinyl acetate copolymer, cellulose acetate, ethyl cellulose, polyvinyl alcohol, Examples thereof include a single layer or multilayer film composed of one or more resins selected from ethylene-ethyl acrylate copolymer, polytetrafluoroethylene, polyurethane, ionomer resin and the like. Among these, from the viewpoint of drug impermeability, processability, and economy, one or more selected from polyester film, polyolefin film, ethylene-vinyl acetate copolymer film, and polytetrafluoroethylene film are constituent elements. A film (single layer film, laminated film) is preferable, and a single layer film made of polyethylene, polypropylene or polyethylene terephthalate is particularly preferable from the viewpoint of economy and workability.
The thickness of the plastic film (the thickness in the case of a single layer film, the total thickness of a plurality of layers in the case of a multilayer film) is preferably about 1 to 50 μm, particularly preferably about 5 to 15 μm.
[0017]
In the nonwoven fabric, the production method is not particularly limited, and the dry binder method, thermal bond method, spun bond method, spun lace method, air lay poros method, needle punch method, TFC method, Benize method, wet method, melt blown method used in medical products Nonwoven fabrics manufactured by various manufacturing methods such as can be used, but in particular, the span lace method is used in terms of the degree of entanglement (that is, the degree of entanglement is large, supple and strong), safety, etc. What was manufactured is used preferably.
[0018]
In the present invention, the fabric has a mass specified in JIS-L1085 of 20 g / m. ² ~ 150g / m ² Is preferable, and the mass is more preferably 50 g / m. ² ~ 120g / m ² It is in the range. When the mass is smaller than this range, it is not preferable because it becomes too soft and the handling property of the preparation is lowered, and there is a risk that the adhesive containing the drug passes through the fibers of the fabric and escapes to the back side. Moreover, when mass is larger than this range, there exists a possibility that a fabric may become hard entirely, a softness | flexibility may be impaired and the favorable adhesiveness to a sticking site | part may become difficult to be obtained. Further, if the fabric is too thick, the flexibility is impaired and it becomes difficult to obtain good adhesion to the application site, and if it is too thin, the fabric becomes too soft and the handling property of the preparation is reduced. There is a risk of passing through between the fabric fibers, and therefore, the thickness specified in JIS-L1085 is preferably in the range of 0.1 mm to 1.0 mm, and in the range of 0.2 mm to 0.8 mm. Those are more preferred. The fabric preferably has a bending resistance (as determined by the 45 ° cantilever method) defined in JIS-L1085 in the range of 10 mm to 80 mm, and more preferably in the range of 30 mm to 70 mm. When the bending resistance of the fabric is within such a range, the handleability at the time of applying the preparation and the adhesion to the application site become better.
[0019]
In the patch preparation of the present invention, an undercoat layer made of a mixture of polyvinyl pyrrolidone and magnesium aluminate metasilicate is provided on at least one side of the support (one side on which the adhesive layer is formed). A commercially available product of magnesium aluminate metasilicate can be used as it is. On the other hand, polyvinylpyrrolidone has the formula:
[0020]
[Chemical 1]

[0021]
In general, a homopolymer composed of a repeating unit of the formula is used, but N-vinyl-2-butene is within a range not exceeding 30% by weight based on the whole polymer. Vinyl monomers other than pyrrolidone may be copolymerized. Such a copolymer is also included in the “polyvinylpyrrolidone” in the present invention.
[0022]
In the present invention, polyvinyl pyrrolidone has a number average molecular weight of 10,000 or more in the osmotic pressure method from the viewpoint of coating property, ease of preparation of a coating solution, and compatibility (dispersibility) with magnesium aluminate metasilicate. Are preferred, and those of 100,000 or more are particularly preferred. The upper limit of the molecular weight is not particularly limited, but it can be diluted with a solvent, and an undercoat layer coating solution can be prepared (coating in which polyvinylpyrrolidone and magnesium aluminate metasilicate described below are dispersed or dissolved in a solvent. It is preferable that the molecular weight does not inhibit the uniform dispersion of magnesium aluminate metasilicate at the time of preparation of the liquid. From this viewpoint, the number average molecular weight by the osmotic pressure method is preferably 5 million or less, particularly preferably 3 million or less. .
[0023]
In the present invention, the method for forming an undercoat layer comprising a mixture of polyvinylpyrrolidone and magnesium aluminate metasilicate on one side of the support is not particularly limited, and various methods can be applied. For example, the undercoat layer can be formed by applying and drying a mixture solution in which polyvinylpyrrolidone and magnesium aluminate metasilicate are dispersed or dissolved in a suitable solvent by means such as gravure printing on one side of the support. Examples of the solvent in the mixture liquid include methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol and the like. Moreover, it is good to dry a coating liquid at about 40-80 degreeC. If the temperature exceeds 80 ° C., the coating film may foam and the undercoat layer may become non-uniform. If the temperature is less than 40 ° C., there is a possibility that a solvent that cannot be ignored may remain.
[0024]
In the present invention, the mixing ratio of polyvinyl pyrrolidone and magnesium aluminate metasilicate in the undercoat layer (polyvinylpyrrolidone / magnesium aluminate metasilicate) is determined by the anchoring property of the undercoat layer (binding property to the support) and the mixture during the formation of the undercoat layer. From the viewpoint of ease of application of the liquid (coating liquid), it is preferably 5 to 90/95 to 10 (wt%), particularly preferably 20 to 70/80 to 30 (wt%). If the ratio of polyvinyl pyrrolidone is less than this range (when the ratio of magnesium aluminate metasilicate is large), the magnesium metasilicate aluminate will reduce the bonding strength with the support, and a sufficient amount of undercoat layer will be formed. On the contrary, when the proportion of polyvinyl pyrrolidone is large (when the proportion of magnesium aluminate metasilicate is small), it becomes a hard film-like undercoat layer, and the bond strength with the support is decreased, which is preferable. Absent.
[0025]
In the present invention, the undercoat layer is 0.01 g / m in terms of solid content on one side of the support. ² ~ 5g / m ² Degree, preferably 0.05 g / m ² ~ 3g / m ² It is good to form so that there may be a certain amount. The coating amount of the mixture is 0.01 g / m ² If it is less than 1, the pot life will be as short as about one month, and it may be difficult to sufficiently reduce the adhesive residue intended by the present invention. On the other hand, the coating amount is 5 g / m. ² In the case where it exceeds 1, the adhesive properties of the adhesive layer formed thereon may change, or the release properties of the transdermally absorbable drug contained in the adhesive layer may be adversely affected.
[0026]
The reason why the adhesive residue of the present invention can sufficiently reduce adhesive residue by having the above-mentioned undercoat layer is not clear, but the present inventors consider as follows. That is, since polyvinylpyrrolidone has a high affinity for a polymer having a relatively low polarity to a polymer having a high polarity, it has good binding properties to many supports, and magnesium aluminate metasilicate dispersed in polyvinylpyrrolidone. And the pressure-sensitive adhesive layer are presumed to form ionic pseudo-crosslinking.
[0027]
In the present invention, the percutaneously absorbable drug contained in the pressure-sensitive adhesive layer formed on the undercoat layer is not particularly limited. For example, systemic drugs include corticosteroids, analgesic anti-inflammatory agents, hypnotic sedatives, tranquilizers, antihypertensive agents, antihypertensive diuretics, antibiotics, general anesthetics, antibacterial agents, antifungal agents, vitamins, Examples include coronary vasodilators, antihistamines, antitussives, sex hormones, antidepressants, cerebral circulation improving agents, antiemetics, antitumor agents, enzyme agents, biopharmaceuticals and the like. Examples of local drugs include local anesthetics such as lidocaine, dental antibiotics such as tetracycline hydrochloride, bactericidal disinfectants such as cetylpyridinium chloride, infection preventive and therapeutic agents such as chlorhexidine hydrochloride, and anti-inflammatory drugs such as dimethylisopropylazulene. Agents, corticosteroids such as hydrocortisone acetate, and the like. Preferably, cocaine, procaine, chloroprocaine, tetracaine, benzocaine, lidocaine, mepivacaine, prilocaine, pupivacaine, dibucaine, propoxycaine, etidocaine, dichronin, oxybuprocaine, tecaine, amethocaine, propitocaine, prophetocaine, caliperine , Meprilucaine, epilocaine, amylocaine, isobucaine, tricaine, paretoxycaine, pilocaine, hexylcaine, metabutoxycaine, xylocaine, metabutetamine, oxesasein, pyridoxine, bromoxine, dimethisoquine, ethyl aminobenzoic acid, piberidinoacetylaminobenzoic acid , Chlorobutanol and pharmacologically acceptable salts thereof At least one local anesthetic selected from the group consisting of: lidocaine, lidocaine hydrochloride, procaine hydrochloride, mepivacaine hydrochloride, dibucaine hydrochloride, pupivacaine hydrochloride, propitocaine hydrochloride, tetracaine hydrochloride, tricaine hydrochloride, oxesazein is there.
[0028]
The content of the drug in the pressure-sensitive adhesive layer can be appropriately increased or decreased depending on the type of drug, the purpose of administration, etc., but is usually about 1 to 80% by weight, preferably about 2 to 70% by weight, based on the whole pressure-sensitive adhesive layer. When the content is less than 1% by weight, it is not possible to expect the release of a drug effective for treatment or prevention. When the content exceeds 80% by weight, the adhesiveness of the pressure-sensitive adhesive layer is lowered, which is effective for treatment or prevention. There is a limit and it is economically disadvantageous. The drug can be contained in the pressure-sensitive adhesive in a dissolved state, a supersaturated crystal precipitation state, or a dispersed state depending on its medicinal effect, and thereby, the treatment aimed at treating and / or preventing various diseases. It can be set as a skin absorption preparation.
[0029]
In the present invention, the pressure-sensitive adhesive used in the pressure-sensitive adhesive layer is not particularly limited, and the pressure-sensitive adhesive used in this type of patch preparation can be used without limitation. For example, an acrylic pressure-sensitive adhesive made of an acrylic polymer; a rubber-based pressure sensitive adhesive such as styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, polyisoprene, polyisobutylene, polybutadiene; silicone rubber, Silicone adhesives such as dimethylsiloxane base and diphenylsiloxane base; Vinyl ether adhesives such as polyvinyl methyl ether, polyvinyl ethyl ether and polyvinyl isobutyl ether; Vinyl ester adhesives such as vinyl acetate-ethylene copolymer; Dimethyl terephthalate, Examples thereof include polyester pressure-sensitive adhesives composed of a carboxylic acid component such as dimethyl isophthalate or dimethyl phthalate and a polyhydric alcohol component such as ethylene glycol. Among these, an acrylic pressure-sensitive adhesive is preferable from the viewpoints of anchoring property to a support (particularly a fabric), sticking property, drug solubility, drug stability and the like.
[0030]
Moreover, as an acrylic adhesive (acrylic polymer), what was obtained by copolymerizing a functional monomer in (meth) acrylic-acid alkylester as a main component is preferable. That is, a copolymer containing 60 to 99% by weight (preferably 65 to 95% by weight) of (meth) acrylic acid alkyl ester, and the rest being a functional monomer is preferable.
[0031]
The (meth) acrylic acid alkyl ester (hereinafter also referred to as main component monomer) in the acrylic pressure-sensitive adhesive (acrylic polymer) is usually a linear or branched alkyl group having an alkyl group of 4 to 13 carbon atoms (for example, Butyl, pentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl, undecyl, dodecyl, tridecyl, etc.), and one or more of these are used. In addition, if it is a range which does not produce the residual of an adhesive to a release film or a to-be-adhered body, an alkyl group is C1-C1 together with the (meth) acrylic-acid alkylester whose carbon number of the said alkyl group is 4-13. (Meth) acrylic acid alkyl ester consisting of 3 alkyl groups (for example, methyl group, ethyl group, isopropyl group, etc.) and / or alkyl groups having 14 or more carbon atoms (for example, tetradecyl group, pentadecyl group, hexadecyl group) Etc.) can also be used in combination. In this case, the amount of (meth) acrylic acid alkyl ester whose alkyl group is an alkyl group having 1 to 3 carbon atoms and / or (meth) acrylic acid alkyl ester whose alkyl group is an alkyl group having 14 or more carbon atoms is used. Is 20% by weight or less based on (meth) acrylic acid alkyl ester having 4 to 13 carbon atoms in the alkyl group.
[0032]
The functional monomer has at least one unsaturated double bond involved in the copolymerization reaction in the molecule and has a functional group in the side chain. For example, (meth) acrylic acid, itaconic acid, malein Carboxyl group-containing monomers such as acid and maleic anhydride, hydroxyl group-containing monomers such as (meth) acrylic acid hydroxyethyl ester and (meth) acrylic acid hydroxypropyl ester, styrene sulfonic acid, allyl sulfonic acid, sulfopropyl Sulfoxyl group-containing monomers such as (meth) acrylate, (meth) acryloyloxynaphthalenesulfonic acid, acrylamidomethylpropanoic acid, (meth) acrylic acid aminoethyl ester, (meth) acrylic acid dimethylaminoethyl ester, (meth) acrylic Acid tert-butylaminoethyl ester An amide group-containing monomer such as (meth) acrylamide, dimethyl (meth) acrylamide, N-methylol (meth) acrylamide, N-methylolpropane (meth) acrylamide, N-vinylacetamide, ) Acrylic acid methoxyethyl ester, (meth) acrylic acid ethoxyethyl ester, (meth) acrylic acid methoxyethylene glycol ester, (meth) acrylic acid methoxydiethylene glycol ester, (meth) acrylic acid methoxypolyethylene glycol ester, (meth) acrylic acid Examples include alkoxyl group-containing monomers such as methoxypolyprene glycol ester and (meth) acrylic acid tetrahydrofuryl ester. The functional monomer can be used singly or in combination of two or more. Among these, from the viewpoints of pressure-sensitive adhesiveness, cohesiveness of the adhesive, release of the drug contained in the adhesive layer, etc., the carboxyl group The containing monomer is preferable, and (meth) acrylic acid is particularly preferable.
[0033]
In the present invention, as the acrylic pressure-sensitive adhesive, a copolymer of the above (meth) acrylic acid alkyl ester (main component monomer) and a functional monomer is further mixed with another monomer. A polymerized product can also be used. Examples of the other monomers include (meth) acrylonitrile, vinyl acetate, vinyl propionate, N-vinyl-2-pyrrolidone, methyl vinyl pyrrolidone, vinyl pyridine, vinyl piperidone, vinyl pyrimidine, vinyl piperazine, vinyl pyrrole and vinyl. Examples thereof include imidazole, vinyl caprolactam, vinyl oxazole and the like, and these can be used alone or in combination. Moreover, the usage-amount of the said other monomer is about 0 to 40 weight% normally with respect to the total weight of a (meth) acrylic-acid alkylester (main component monomer) and a functional monomer. The amount is preferably about 10 to 30% by weight.
[0034]
As a preferable specific example of the acrylic pressure-sensitive adhesive (acrylic polymer) in the present invention, a copolymer consisting of 65 to 99% by weight of (meth) acrylic acid 2-ethylhexyl ester and 1 to 35% by weight of (meth) acrylic acid And a copolymer composed of 60 to 99% by weight of 2-ethylhexyl ester of (meth) acrylic acid and 1 to 40% by weight of N-vinyl-2-pyrrolidone.
[0035]
In the present invention, the pressure-sensitive adhesive may contain various additives as necessary, and examples of the additives include plasticizers, percutaneous absorption accelerators, antioxidants and the like. it can.
[0036]
By adding the plasticizer, the pressure-sensitive adhesive is plasticized, and the adhesive force of the pressure-sensitive adhesive layer to the application site can be adjusted. Examples of the plasticizer include diisopropyl adipate and diacetylseparate. The plasticizer can use 1 type (s) or 2 or more types, and the usage-amount is about 50-200 weight part with respect to 100 weight part of adhesives.
[0037]
The transdermal absorption enhancer is a compound having a function capable of improving the solubility and diffusibility of the drug in the pressure-sensitive adhesive layer. For example, as a compound mainly improving the drug solubility, ethylene glycol, diethylene glycol, propylene glycol Examples of glycols such as triethylene glycol, polyethylene glycol, and polypropylene glycol, and compounds that mainly enhance drug diffusibility include oils and fats such as olive oil, castor oil, squalane, and lanolin. As other (transdermal) absorption accelerators, hydrocarbons such as liquid paraffin; various surfactants; glycerin monoesters such as ethoxylated stearyl alcohol, oleic acid monoglyceride, caprylic acid monoglyceride, lauric acid monoglyceride Glycerol polyesters such as glycerol diester, glycerol triester or mixtures thereof; higher grades such as ethyl laurate, isopropyl myristate, isotridecyl myristate, octyl palmitate, isopropyl palmitate, ethyl oleate, diisopropyl adipate Fatty acid esters; higher fatty acids such as oleic acid and caprylic acid; N-methylpyrrolidone; 1,3-butanediol and the like. These can improve at least one of the solubility and diffusibility of the drug. In the present invention, one or more percutaneous absorption accelerators can be used, and the amount used is preferably about 5 to 200 parts by weight per 100 parts by weight of the adhesive.
[0038]
Since a percutaneous absorption enhancer having a good compatibility with the adhesive is selected, the adhesive is plasticized in the same manner as the plasticizer. By adding a plasticizer, a transdermal absorption enhancer, etc., the adhesive The cohesive strength of is reduced. However, in the patch preparation of the present invention, due to the presence of the undercoat layer, the adhesive residue can be sufficiently reduced even if such an adhesive layer made of an adhesive having a low cohesive strength is provided.
[0039]
The method for producing the transdermally absorbable preparation of the present invention is not particularly limited. For example, a drug, an adhesive, and other additives blended as necessary are dissolved or dispersed in a solvent, and the resulting solution or dispersion is obtained. The method of apply | coating and drying a liquid on the single side | surface in which the undercoat layer of the support body was formed, and forming an adhesive layer is mentioned. Further, the above solution or dispersion is applied on a protective release film and dried to form an adhesive layer on the release film, and then the undercoat layer of the support on which the undercoat layer has been formed is used as an adhesive. It can also be produced by adhering to a layer.
[0040]
In this invention, the thickness (thickness after drying) of an adhesive layer is about 10-200 micrometers normally, Preferably it is about 15-150 micrometers. When expressed in terms of the adhesion amount (solid content conversion amount) per one side of the support of the pressure-sensitive adhesive, it is usually 10 to 200 g / m. ² Degree, preferably 15-150 g / m ² Degree.
[0041]
In the patch preparation of the present invention, in order to prevent unnecessary adhesion (contact) to the object (article) such as a device or container of the pressure-sensitive adhesive layer at the time of production, transportation, storage, etc. and prevention of deterioration of the preparation, It is desirable to cover and protect the exposed surface of the pressure-sensitive adhesive layer with a release film until immediately before application to an adherend (skin, mucous membrane, etc.). In use, the release film is peeled off to expose the surface of the pressure-sensitive adhesive layer, and the exposed surface of the pressure-sensitive adhesive layer is applied to the application site of the adherend (skin, mucous membrane, etc.) to administer the drug.
[0042]
The release film is made of polyester, polyvinyl chloride, polyvinylidene chloride, various acrylic and methacrylic polymers, polystyrene, polycarbonate, polyimide, cellulose acetate (acetate), regenerated cellulose (cellophane), celluloid and other plastic films; Paper such as high-quality paper and glassine paper; a laminate film of high-quality paper or glassine paper and polyolefin and the like. Among these, a polyester film is preferable from the viewpoints of safety, economy, drug migration, and the like. As the polyester constituting the polyester film, a crystalline linear saturated polyester composed of an aromatic dibasic acid component and a diol component is suitable. For example, polyethylene terephthalate, polybutylene terephthalate, polypropylene terephthalate, polyethylene-2,6 -Naphthalate etc. are mentioned. Among these, a polyethylene terephthalate (PET) film is particularly preferable from the viewpoint of economy. The polyester film is produced by a conventionally known method. For example, a biaxially stretched polyester film (after being melted by an extruder, extruded from a T-type die or I-type die onto a rotating drum, rapidly cooled and unstretched. A film obtained by forming a film and then stretching the unstretched film in the biaxial direction and heat-setting as necessary can be suitably used in the present invention. In the present invention, the thickness of the release film is usually 10 to 200 μm, preferably 50 to 100 μm, from the viewpoint of handleability and the like.
[0043]
As the release treatment layer formed on the surface of the release film that overlaps the pressure-sensitive adhesive layer, a curable silicone resin is usually used. There are various types of curable silicone resins such as solvent addition type, solvent condensation type, solvent ultraviolet curing type, solventless addition type, solventless condensation type, solventless ultraviolet curing type, and solventless electron beam curing type. Any type can be used in the invention. Specific examples of the curable silicone resin include KS-774, KS-775, KS-778, KS-779H, KS-856, X-62-2422, X-62-2461, manufactured by Shin-Etsu Chemical Co., Ltd. KNS-305, KNS-3000, X-62-1256 (all trade names), DKQ3-202, DKQ3-203, DKQ3-204, DKQ3-205, DKQ3-210 (all available from Dow Corning Asia) And YSR-3022, TPR-6700, TPR-6720, TPR-6721 (all are trade names) manufactured by Toshiba Silicone Co., Ltd., and the like.
[0044]
As a method for forming the release treatment layer, conventionally known coating methods such as bar coating, reverse roll coating, gravure coating, rod coating, air doctor coating, and doctor blade coating are used.
[0045]
In the present invention, the thickness of the release treatment layer is preferably 0.01 μm to 5 μm, particularly preferably 0.1 μm to 3 μm. When the mold release treatment layer is less than 0.01 μm, it is not preferable because the coating unevenness occurs and the uniformity of the coating film cannot be obtained, and when it exceeds 5 μm, the migration amount of the drug from the adhesive layer increases, This is not preferable because the peelability tends to decrease.
[0046]
The percutaneous absorption type patch preparation of the present invention can be applied to normal skin and mucous membranes such as oral mucosa, and even if it is a low cohesive force adhesive (layer) which does not undergo crosslinking treatment or addition of a filler or the like. The agent (layer) exhibits good peelability from the adherend (skin, mucous membrane). In other words, even if drugs or additives (transdermal absorption enhancers, plasticizers, etc.) are added to the adhesive, even if the cohesive strength of the entire adhesive is reduced, extra treatments such as cross-linking treatment and addition of fillers are required. The adhesive (layer) exhibits good peelability without being buried. Accordingly, when the release film is peeled off, a large amount of the pressure-sensitive adhesive does not remain on the release film, so that the drug content in the preparation is not greatly reduced, and a good therapeutic effect as designed can be obtained. Further, when the preparation is removed from the adherend (skin, mucous membrane), the adhesive does not remain in a large amount on the adherend (skin, mucous membrane). In addition, the mucous membrane part in a living body such as the oral mucosa is often a surface with marked irregularities or is present in a narrow space. Therefore, if the preparation is particularly intended to be applied to the mucous membrane part, In many cases, a high-flexible fabric or a composite obtained by laminating a plastic film on a fabric is used as the support. However, even when such a fabric or composite is used as a support, the preparation of the present invention is a paste. Since the remainder can be reduced sufficiently, a useful preparation excellent in therapeutic effect can be obtained for application to the mucous membrane.
[0047]
In the present invention, “the cohesive strength of the pressure-sensitive adhesive is not high” and “low-cohesive strength pressure-sensitive adhesive” means that the cohesive force measured by the method described in the examples below is approximately 10 N / cm or less. It means that there is a case.
[0048]
【Example】
EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated more concretely, this invention is not limited by the Example shown below. In the following description, parts mean parts by weight.
[0049]
[Preparation of adhesive solution A]
Under an inert gas atmosphere, 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid were copolymerized in ethyl acetate to prepare an adhesive solution A.
[0050]
[Example 1]
60 parts of lidocaine is added to the adhesive solution A (solid content: 40 parts), mixed and dissolved, and the resulting solution is a release film made of polyester (PET) having a thickness of 75 μm and having one side subjected to curable silicone treatment. A drug-containing pressure-sensitive adhesive layer was prepared by applying and drying on a treated layer (MRN75, manufactured by Mitsubishi Chemical Polyester Film Co., Ltd.) so that the thickness after drying was about 20 μm.
On the other hand, using a polyester film having a thickness of 12 μm having a release treatment layer formed of a curable silicone resin on one side, polyvinylpyrrolidone K-90 (made by Gokyo Sangyo Co., Ltd.) 50 having a number average molecular weight of 1,200,000 is provided on this release treatment surface. Part and a isopropyl alcohol mixed dispersion having a solid content concentration of 10% containing 50 parts of neucillin (magnesium aluminate metasilicate manufactured by Fuji Chemical Industry Co., Ltd. (trade name)) with a solid content of 2 g / m. ² An undercoat layer was formed by coating and drying so that The undercoat layer thus obtained was divided fiber nonwoven fabric (thickness: 0.42 mm, mass) prepared by splitting and entanglement of a composite fiber having a polypropylene content of 55% by weight and a polyester content of 45% by the spunlace method. : 90 g / m ² And a soft support (45 ° cantilever method): 55 mm) to prepare a support having an undercoat layer.
Subsequently, the adhesive layer was bonded to the undercoat layer of the support to prepare a patch preparation of the present invention.
[0051]
[Example 2]
The solid surface containing 40 parts of polyvinylpyrrolidone K-90 (manufactured by Gokyo Sangyo Co., Ltd.) and 60 parts of neucillin (magnesium metasilicate magnesium (manufactured by Fuji Chemical Co., Ltd.) (trade name)) on the peel-treated surface of the peeled polyester film. 10% ethyl alcohol mixed dispersion with a solid content of 0.5 g / m ² A patch preparation of the present invention was prepared in the same manner as in Example 1 except that an undercoat layer was formed by coating and drying.
[0052]
Example 3
70 parts of polyvinylpyrrolidone K-30 (manufactured by Gokyo Sangyo Co., Ltd.) having a number average molecular weight of 40,000 and metasilic acid of Neusilin (trade name, manufactured by Fuji Chemical Industry Co., Ltd.) A solid dispersion amount of 3 g / m of an isopropyl alcohol mixed dispersion containing 30 parts of magnesium aluminate) and having a solid content concentration of 5%. ² A patch preparation of the present invention was prepared in the same manner as in Example 1 except that an undercoat layer was formed by coating and drying.
[0053]
[Comparative Example 1]
A patch was prepared in the same manner as in Example 1 except that the undercoat layer was not formed on one side of the support in Example 1.
[0054]
[Comparative Example 2]
In Example 2, a patch was prepared in the same manner as in Example 2 except that the undercoat layer was not formed on one side of the support.
[0055]
[Comparative Example 3]
In Example 3, a patch was prepared in the same manner as in Example 3 except that the undercoat layer was not formed on one side of the support.
[0056]
[Comparative Example 4]
In Example 1, an undercoat layer (solid content adhesion amount: 2 g / m) alone on one side of the support was polyvinylpyrrolidone K-90 (manufactured by Gokyo Sangyo Co., Ltd.). ² ) Was formed in the same manner as in Example 1 except that the adhesive patch was formed.
[0057]
[Comparative Example 5]
In Example 1, an undercoat layer (solid content adhesion amount: 2 g / m) was used alone for the support as Neusilin (magnesium aluminate metasilicate manufactured by Fuji Chemical Industry Co., Ltd. (trade name)). ² ) Was formed in the same manner as in Example 1 except that the adhesive patch was formed.
[0058]
The patch preparations obtained in the above Examples and Comparative Examples were subjected to the following performance evaluations (1) to (3), and the results are shown in Table 1.
[0059]
(1) Measurement of cohesive force
After cutting 2 preparations into a 10 x 20 mm shape, remove the release film of each preparation, paste the adhesive faces of the 2 preparations together, and apply a 2000 g rubber roller on the preparation at a speed of 300 mm per minute. Was passed twice and left at room temperature for 30 minutes. In addition, auxiliary paper was attached to the adjusted sample as needed so that it could be easily grasped and peeled off by a chuck of a tensile tester.
Next, using a tensile tester, two preparations are peeled off in a 180 ° direction at a rate of 120 mm per minute in a 180 ° direction, the load at that time is measured, and the cohesive force of the adhesive (layer) is measured. It was. At this time, the adhesive layers of the two preparations were sufficiently integrated with each other, and it was confirmed that the state when peeling was a stringing state, and the two preparations were stuck together without stringing. When it peeled cleanly at the interface, the load at that time was not regarded as cohesive force.
[0060]
(2) Measurement of peeling force
A single preparation is cut into a size of 10 x 30 mm to make a sample, and the tensile tester is used to measure the load when the preparation is peeled from the release film to the T-type in a direction of 180 ° at a speed of 120 mm per minute. This was taken as the peel force. In addition, auxiliary paper was attached to the sample as needed so that the sample could be easily grasped by the chuck of the tensile tester.
[0061]
(3) Measurement of drug transfer rate to release film
The patch preparations obtained in Examples and Comparative Examples were sealed in a packaging bag, stored for 3 months at 50 ° C., then the release film was peeled off, and the lidocaine content and release release film in the preparation (adhesive layer) The amount of drug adhering to was extracted with methanol, and the amount of lidocaine was measured by high performance liquid chromatography. And the transfer rate of the drug to a release film was computed by the following formula.
[0062]
(Transition rate% to release film) = A ÷ (A + B) × 100
A: Lidocaine amount adhering to the release film
B: Lidocaine content in the preparation
[0063]
Table 1 shows the test results.
[0064]
[Table 1]

[0065]
As shown in Table 1, the adhesive preparations obtained in Examples 1 to 3 have almost no adhesion of the adhesive to the release film, and the migration of the drug to the release film is suppressed at a high level. It was an excellent formulation.
On the other hand, in the adhesive preparations in which the undercoat layer of Comparative Examples 1 to 3 was not formed, the peel force was the same as in the Examples, but because the adhesive was attached to the release film, the drug on the release film was large. The drug content of the preparation decreased and a stable preparation could not be obtained.
In addition, in the preparations in which the undercoat layer made of polyvinylpyrrolidone or neucillin of Comparative Examples 4 and 5 was formed, the adhesion of the adhesive to the release film could not be sufficiently suppressed, and the amount of drug transferred to the release film was Compared to the case where no layer is provided, the number is increased.
[0066]
【The invention's effect】
As is apparent from the above explanation, according to the present invention, a transdermal patch preparation with sufficiently little adhesive residue can be provided even with a low cohesive strength adhesive layer. That is, even if the cohesive force of the pressure-sensitive adhesive layer is reduced by adding a drug or an additive to the pressure-sensitive adhesive, there is no need to perform a treatment for increasing the cohesive force such as a crosslinking treatment or addition of a filler. The transfer of the adhesive to the release film during use is sufficiently suppressed, and there is very little adhesive residue on the adherend when removing the preparation from the adherend, and has a good therapeutic effect, and It is possible to obtain an extremely useful transdermal absorption patch preparation with little discomfort after use.

Claims (6)

A transdermal absorption patch preparation comprising a support laminated on one side of an adhesive layer containing a transdermally absorbable drug, and a mixture of polyvinylpyrrolidone and magnesium aluminate metasilicate between the support and the adhesive layer have a subbing layer comprising a mixing ratio of polyvinylpyrrolidone and magnesium metasilicate aluminate, characterized in that 5 to 90/95 to 10 wt% adhesive preparation.   The patch preparation according to claim 1, wherein the support is a fabric.   The medicated patch according to claim 1 or 2, wherein the drug is a local anesthetic.   The adhesive preparation according to any one of claims 1 to 3, wherein the adhesive in the adhesive layer is an acrylic adhesive.   The adhesive preparation according to any one of claims 1 to 4, which has a release film on one side opposite to the one side on which the support of the pressure-sensitive adhesive layer is laminated.   The patch preparation according to any one of claims 1 to 5, which is for application to a mucosa.