JP2004043450A

JP2004043450A - Quickly soluble filmy preparation

Info

Publication number: JP2004043450A
Application number: JP2003135676A
Authority: JP
Inventors: Hanayo Yasuda; 安田　華代; Tadatoshi Okubo; 大窪　忠利; Yoshihiro Sawai; 澤井　義弘
Original assignee: Kyukyu Pharmaceutical Co Ltd
Current assignee: Kyukyu Pharmaceutical Co Ltd
Priority date: 2002-05-16
Filing date: 2003-05-14
Publication date: 2004-02-12

Abstract

<P>PROBLEM TO BE SOLVED: To provide a thin filmy preparation quickly soluble in the mouth. <P>SOLUTION: This quickly soluble filmy preparation contains a drug and an edible polymer. The film has a breaking strength of 200-3,000 g/ψ7mm, a tensile strength of 200-3,000 g/15 mm and a water-disintegration time Y[sec] of ≤300 sec (Y≤300) and satisfies the formula (water-disintegration time Y[sec])≥7500X<SP>2</SP>wherein X is the reciprocal [mg/mm<SP>2</SP>] of the specific surface area of the film (X≥0). The edible polymer is a hydroxypropyl cellulose and/or a hydroxypropyl methylcellulose, the ratio of the drug is 0.01-40 wt.% based on the total preparation, the ratio of the edible polymer is 40-99.99 wt.% based on the total preparation and the filmy preparation is composed of a single layer containing the drug or has supporting layers on one or both surfaces of the drug-containing layer. <P>COPYRIGHT: (C)2004,JPO

Description

【０００１】
【発明の属する技術分野】
本発明は、病気の治療や診断に有用な薬物を含み、水なしで服用可能な口腔内溶解型のフィルム状製剤に関する。更に詳しくは、本発明製剤は薬物及び可食性高分子物質を含有し、口腔内に投与されると口腔内水分により速やかに（おおよそ６０秒以内）溶解する口腔内溶解型のフィルム状製剤である。
【０００２】
【従来の技術】
従来、口腔内投与される剤型としては、錠剤、チューワブル錠、舌下錠、カプセル剤、丸薬、トローチ錠、水薬、口腔内粘膜貼付型製剤を含めて口腔内溶解型製剤などがあり、このうち錠剤が最も広く利用されているが、カプセル剤、水薬なども広く利用されている。
そして、口腔内溶解型の製剤については、以下のようなものが一般的に知られている。（１）賦形剤、可塑剤及び結合剤を配合してなるシート状可食性成形物からなるものであり、賦形剤、可塑剤、結合剤の食品素材及び／又は薬物とを混合し、この混合物をスクリュー押出機より押し出して得られるものであり、その押し出し厚みが０．１〜５ｍｍ、好ましくは０．５〜３ｍｍである製剤（例えば特許文献１参照）。（２）２０〜６０重量％のフィルム形成剤と、２〜４０重量％のゲル形成剤と、０．１〜３５重量％の活性物質と、更に４０重量％未満の不活性充填剤とを有する物質をキャリア上に施すか、またはサポートなしの経口投与または取り入れを行う医薬、菓子、その他の食料、化粧料等のシート状の個々に投与される投与形成物からなり、物質の層の厚みは０．００３〜４ｍｍ、好ましくは２０〜４００μｍ、特に７０〜１５０μｍであり、製法としては、スプレッドあるいは押し出したもので、そして１０分以内に口中で完全に分解するものである製剤（例えば特許文献２参照）。（３）作用物質及び／又は分離剤を溶かしないしは懸濁させ、フォイル形成剤及び場合により充填剤を混入し、場合により均質化し、同溶液ないしは懸濁液をフォイル形成機上にフォイル状に塗布し、塗布物の乾燥により得られるフォイルを任意の小片（単位）に分割することにより得られるフォイル形状の薬剤であって、乾燥フォイルの厚さは約０．１〜２ｍｍ、有利には０．０７〜０．３ｍｍである製剤（例えば特許文献３参照）等が知られている。
【０００３】
【特許文献１】特開平１０−１７９０４５号公報（第２頁左欄及び第３頁右欄〔００１６〕の項）、
【特許文献２】特開平７−１００１８６号公報（第２頁及び第４頁右欄〔００３５〕の項）、
【特許文献３】特開昭５１−２９２１８号公報（第１頁及び第３頁）。
【０００４】
【発明が解決しようとする課題】
前記の口腔内溶解型製剤である特許文献１（特開平１０−１７９０４５号）のものは押し出し成型のものであるので、その実施例にあるように単軸スクリュー押出し機により製造され、フィルム厚は１ｍｍ或いは２ｍｍであって厚いものとなり、溶解には時間がかかり、口腔内で６０秒以内に溶解されるのは無理であると考えられる。そして、この厚さでは製剤として異物感が出て来る。
この製剤はスクリュー押出し機で製造するものであるが、スクリュー押出し機で製造した製剤は、必ずブロッキング防止剤（この引用例では澱粉）を必要としている（ブロッキング防止剤を使用しないと、製品同志が付着してしまう）。これは、少量の水で容易に製剤を溶解させるために用いられる高分子の特性に起因するもと考えられるが、工程数を増やしコスト高が懸念される。また、特に医薬品やその他診断薬を含有した製剤の場合その視覚的価値は重要であるが、ブロッキング剤によってそれを低下させる可能性がある。
又、ここで、スクリュー押出し機で製造した製剤は、比較的低温（２０℃）で１２時間エージングを行っている。この製造法の場合、乾燥工程を必要としないため熱安定性の低い素材の使用が可能となると言う利点はあるが、１２時間と非常に長い時間がかかるので製造効率も悪い。
前記特許文献２（特開平７−１００１８６号）のものは各種方法によって製造され、その厚さは０．００３〜４ｍｍである。因みに実施例において医薬品はプランジャー型押出し機により製造されているが、押出し法の場合はどうしてもその厚みが大きくなる傾向があり、溶解に１０分間かかるとあるようにその溶解時間が長い欠点がある。この溶解時間が長すぎると異物感が持続し好ましくない。
この特許文献２にフィルム形成剤として列挙されているものは、通常、賦形剤、可塑剤、崩壊剤、溶解補助剤等として使用されるものであって、フィルム形成能を有しているものとは言い難いものである。どちらかというと、特許文献２でゲル形成剤として用いられているものの中にフィルム形成能を有している高分子が見うけられる。しかし、そのゲル形成剤の配合量が少ないために（殊に実施例２参照）、このゲル形成剤はフィルム形成能を発揮することはないと考えられる。
例えば、この特許文献２の実施例２でフィルム形成剤として使用されているポリエチレングリコールは、室温にて固体状であり、この室温での凝固性によって１ｍｍの厚さのシート状形成物を形成している。このシート状形成物は、口腔内温度である程度の溶解性を期待できるものの、室温での凝固性を利用したものなので、その強度はそれほど期待出来ない。事実、この特許文献２の記述では、製造上である程度の強度を必要とするとしており（段落番号〔００１７〕）、製剤の厚さは、いやが上でも厚くなる。この厚さのために、その溶解時間がより長くなると考えられる。しかも、実施例２の如く、薬物含有量が３．７５重量％と低いために含有できる薬物の種類に制限があり、利用性に欠ける。
更に、特許文献３（特開昭５１−２９２１８号）のものは、箔を形成するとしているフォイル形成剤が溶液又は懸濁液中に６〜２０％であり、その割合が少ない。そして、この特許文献３にはフィルム強度についての記載はなく、このように少ない割合のフォイル形成剤では形成されたフィルムの破断強度や引張強度は小さく、製品が脆く取り扱いにくいものとなる。そしてその上、「速溶性」があるものでもない。
以上のように、従来の口腔内溶解型製剤は、厚すぎたり、異物感があったり、強度が小さく脆い、薬物含有量が低い等の不都合があった。　このようなことから、薄いフィルム状のもので口の中で簡単に溶解する利用性の高い製剤の出現が望まれていた。即ち、口腔内の水分で容易に溶解し、薬物が速やかに消化管吸収や口腔粘膜吸収が行われると共に、所要により薬物含有量を大きくできる口腔内溶解型フィルム状製剤の出現が望まれていた。
【０００５】
【課題を解決するための手段】
本発明者らは、前記の課題を解決すべく、即ち口腔内水分で容易に溶解するフィルム状製剤を提供すべく、鋭意検討した。
即ち、速溶性フィルム状製剤に求められる製剤特性として以下の点、
（１）速く溶けること、即ちおおよそ６０秒以内で口内で溶解可能であること、
（２）使用し易い剤形であること、即ち、服用時製剤が破損しない強度を保持していること、強度が強すぎて口腔内で違和感が生じないものであること、製剤が薄すぎることでハンドリングが不都合なものでないこと、および服用しやすい製剤サイズであること、
（３）適用される薬剤の許容性が広いこと、即ち、薬物含有量の限界値が高いもの、薬物の物理化学的性質に製剤が対応できるものであること、
が必要であるとの知見を得た。
そして、（１）を可能にするためには、製剤の厚さを薄くすればよいが、薄くすることで（３）の薬物含有量の限界値が数ミリグラムと少なくなり、また薄いことでも影響が出、（２）も満たされなくなる可能性がある。
（２）を可能にするためには、ある程度の強度が要求されるので、強度を保持させるために通常は高分子物質の配合比率を高く設定したり、重合度の比較的高い高分子物質を用いるが、結果として（１）及び／または（３）が満たされない可能性がある。そして、高分子が多くなると溶けにくくなると共に、口腔内で違和感が生じてしまう。
そして、（１）〜（３）の中でも（３）の含有させる薬物の限界値を高く設定出来ることが、フィルム状製剤を普及させる上で重要である。これを満たすためには、薬剤の配合比率を高く設定したり、製剤サイズを大きくすればよいが、薬剤配合比率を高く設定することで強度が保てなくなったり、また製剤サイズが大きすぎると服用に不都合が生じ、（２）が満たされない可能性がある。さらに製剤の厚さを厚くすることも考えられるが、その結果として（１）が満たされなくなる。
【０００６】
以上の点を考慮し検討を進めた結果、フィルムの破断強度が２００〜３，０００ｇ／φ７ｍｍ（後述のＦＵＤＯＨレオメーターにより測定）、フィルムの引張強度が２００〜３，０００ｇ／１５ｍｍ（後述のＦＵＤＯＨレオメーターにより測定）であるものが好適であることを見出した。
また製剤が薄すぎることでハンドリングが不都合でないものということを考慮すると、フィルムは３０μｍ以上の厚さが必要であり、また服用し易い製剤サイズであることを考慮すると３００μｍ以下の厚さが好適であることも見出した。そして、上記のフィルムの破断強度が２００〜３，０００ｇ／φ７ｍｍ、フィルムの引張強度が２００〜３，０００ｇ／１５ｍｍのフィルム状製剤、及びこの範囲を越えているものを後述の実施例及び比較例のようにして作成し、その口腔内溶解時間［秒］をＹとし、フィルムの比表面積［ｍｍ^２／ｍｇ］の逆数［ｍｇ／ｍｍ^２］をＸとしプロットしてみたところ、驚くべきことに、図１のフィルム製剤の口腔内溶解時間とフィルムの比表面積の逆数との関係を示すグラフが得られた。即ち、フィルムの破断強度が２００〜３，０００ｇ／φ７ｍｍ、フィルムの引張強度が２００〜３，０００ｇ／１５ｍｍのフィルム状製剤はその口腔内溶解時間が全て６０秒以内であり、本願で求めている速溶性フィルム状製剤が得られているものであった。
本発明者らは上記の条件について更に検討を重ねた結果、上記のフィルム製剤の口腔内溶解時間に代えて水崩壊時間（水崩壊性試験については後述の通り）をＹとしフィルムの比表面積［ｍｍ^２／ｍｇ］の逆数［ｍｇ／ｍｍ^２］をＸとしてプロットしてみたところ、図２のフィルム製剤の水崩壊時間とフィルムの比表面積の逆数との関係を示すグラフが得られ、図１における口腔内溶解時間６０秒以内が図２の水崩壊時間３００秒以内に相当することも見出した。
本発明はこの水崩壊時間（Ｙ）がフィルムの比表面積［ｍｍ^２／ｍｇ］の逆数（Ｘ）と相関しているという、これまでに全く知られていない新規な知見に基いて達成されたものであり、以下の点をその要旨とするものである。
【０００７】
即ち、本発明は（１）薬物および可食性高分子物質を含有し、そのフィルムの破断強度が２００〜３０００ｇ／φ７ｍｍ、フィルムの引張強度が２００〜３０００ｇ／１５ｍｍであり、かつ口腔内において６０秒以内で溶ける速溶性フィルム状製剤；（２）薬物および可食性高分子物質を含有し、そのフィルムの破断強度が２００〜３０００ｇ／φ７ｍｍ、フィルムの引張強度が２００〜３０００ｇ／１５ｍｍであり、かつ水崩壊時間Ｙ［秒］が３００秒以内であって（Ｙ≦３００）、フィルムの比表面積の逆数［ｍｇ／ｍｍ^２］をＸとした場合（Ｘ≧０）、水崩壊時間Ｙ［秒］≧７５００Ｘ^２の関係にある速溶性フィルム状製剤；（３）薬物は、一回の投与量が０．００１ｍｇ〜５０ｍｇの量であるように含有し、水−エタノール系溶媒に可溶もしくは分散可能なものである（１）又は（２）記載の速溶性フィルム状製剤；（４）可食性高分子物質がヒドロキシプロピルセルロース及び／又はヒドロキシプロピルメチルセルロースである（１）、（２）又は（３）記載の速溶性フィルム状製剤；（５）薬物の配合比率は製剤全体に対して０．０１〜４０重量％、可食性高分子物質の配合比率は製剤全体に対して４０〜９９．９９重量％である（１）、（２）、（３）又は（４）記載の速溶性フィルム状製剤；（６）フィルム状製剤が薬物含有層単層からなる（１）、（２）、（３）、（４）又は（５）の速溶性フィルム状製剤；（７）薬物含有層の片面或いは両面に、可食性高分子物質を含有する支持層を有する（１）、（２）、（３）、（４）又は（５）の速溶性フィルム状製剤；（８）支持層の可食性高分子物質はヒドロキシプロピルメチルセルロースであり、その配合比率が５０重量％以上であり、薬物含有層の可食性高分子物質はヒドロキシプロピルセルロースであり、その配合比率が４０〜９９．９９重量％である、（１）、（２）、（３）、（４）、（５）、（６）又は（７）記載の速溶性フィルム状製剤；（９）更に糖質を含有する（１）、（２）、（３）、（４）、（５）、（６）、（７）又は（８）記載の速溶性フィルム状製剤；（１０）薬物と糖質の総和が、製剤全体に対して２５〜４０重量％である（９）記載の速溶性フィルム製剤；（１１）水崩壊時間Ｙ［秒］が６００００Ｘ^２≧Ｙ≧７５００Ｘ^２の関係にある（１）、（２）、（３）、（４）、（５）、（６）、（７）、（８）、（９）又は（１０）記載の速溶性フィルム製剤；に関するものである。
【０００８】
上記（２）において、「水崩壊時間Ｙ［秒］が３００秒以内」の意義は先に述べたように「口腔内において６０秒以内で溶ける」と同意であり、人種、個人差をなくし客観性を保つことができる。また、水崩壊時間Ｙ［秒］＜７５００Ｘ^２（図３のフィルム製剤の水崩壊時間とフィルムの比表面積の逆数との関係を示すグラフにおける（Ｂ）の領域）では、フィルム製剤の溶解は速いけれども、目的とする強度が保てないものである。本発明のフィルム製剤においては、その厚さが３０μｍ以上、３００μｍ以下が好適である。
破断強度が２００ｇ／φ７ｍｍより低いと製品が脆くなり取り扱いずらくなったりして好ましくない。又３，０００ｇ／φ７ｍｍ以上になると口に含んだ場合、違和感があり好ましくない。
引張強度が２００ｇ／１５ｍｍより低いと製品が脆くなり取り扱いずらくなったりして好ましくない。又３，０００ｇ／１５ｍｍ以上になると口に含んだ場合、違和感があり好ましくない。
そして、破断強度が３，０００ｇ／φ７ｍｍより大、引張強度が３，０００ｇ／１５ｍｍより大になると、溶解時間が長くなる恐れがあり、好ましくない。
上記（３）において、本発明の一つのフィルム製剤においては、必要により５０ｍｇという多量な薬物を含有できる。例えば、５０ｍｇの薬剤を含有した本発明のフィルム製剤の最小総重量や寸法を示すと、総重量では１２５ｍｇで最小寸法が２８ｍｍ×２０ｍｍ×１９０μｍとなる。
上記（７）において、フィルム状製剤を一層で形成するのでなく、薬物含有層の片面或いは両面に、可食性高分子物質を含有する支持層を設けてもよい。一層で薬物の配合比率を高く（例えば、２５〜４０重量％）設定すると、強度が所要の強度にならない場合があるが、薬物含有層の片面或いは両面に、可食性高分子物質を含有する支持層を設けると、速溶性フィルム状製剤に求められる製剤特性すべてを満たすことが可能となると共に、製剤同士のブロッキング性（付着性）を回避することが可能となり、さらには製剤の視覚的価値を飛躍的に向上させることが可能となるため、単に製剤強度を増すだけのメリットだけでなく、相乗的作用が期待できる。
上記（８）において、ヒドロキシプロピルメチルセルロースは、易水溶性の可食性高分子物質であり、外気の湿度の影響を受け難く、フィルム製剤にした場合光沢があり、かつ酸化チタンや着色料を入れても比較的強度が落ち難く、支持層に好適である。
一方、ヒドロキシプロピルセルロースは、水から１００％エタノールの全範囲において可溶性であり、薬物に対して水から１００％エタノールの広い範囲から可溶範囲を選択できるという長所がある。
また好ましい態様として、支持層には、ヒドロキシプロピルメチルセルロース５０重量％以上、糖質１０〜３０％及び可塑剤５〜２０％、並びに酸化チタン１５重量％以下又は着色料５．０％以下を配合、薬物層にはヒドロキシプロピルセルロース４０〜９９．９９重量％および薬物を必須配合とし、必要により糖質又は／および可塑剤を配合する。
上記（９）において、糖質は、薬物と混合させてもむろんよい。これにより、水溶性や水崩壊性が向上する。特に、糖質は薬物の性状に影響を及ぼさない点でも水溶性と水崩壊性とを向上するものとして好適である。薬物層と支持層に分ける場合は、支持層だけに含有させたり、支持層に多く含有させることが好ましい。
上記（１１）において、水崩壊時間Ｙ［秒］が６００００Ｘ^２≧Ｙ≧７５００Ｘ^２の関係にあるものは、図３のグラフにおける（Ａ）の領域がそれに当たる。６００００Ｘ^２≧水崩壊時間Ｙ［秒］の意義は、薬物を比較的多く含有出来る領域を示し、６００００Ｘ^２＜Ｙの範囲（図３のグラフにおける（Ｃ）の領域）であると薬物を極めて少なくしか含有できない状態を示すものである。
【０００９】
本発明のフィルム状製剤においては、その破断強度及び引張強度が上記の範囲内であれば、その厚さについては特に限定されないが、製品の取り扱い易さや、服用時の違和感など、更には溶解時間をも考慮すると３０〜３００μｍが好ましい。
本発明のフィルム状製剤は口腔内において大略６０秒以内で溶解し、違和感も少なく服用しやすく有利である。また、このように短時間で溶解することで、薬物は消化管吸収や口腔粘膜吸収が速やかに行われるものである。
本発明フィルム製剤が口腔内で速やかに（大略６０秒以内）溶解し、薬物の物理化学的性質により消化管吸収や口腔粘膜吸収が行われ、薬物の作用が速やかに発現される。特に、唾液量の少ない高齢者にとっても、水の飲用なしに服用しても口腔内で容易に溶解する。
したがって、本発明フィルム製剤は、錠剤やカプセル剤といった従来の経口製剤と同等の薬理効果を期待でき、且つ水無しで容易に服用できることから高齢者や小児にも安全に投与できるという利点を持つ。
【００１０】
以下に本発明を更に詳細に説明する。
本発明のフィルム製剤は、薬物を含有する薬物層一層でもよく、又薬物層の片面或いは両面に支持層を設けた二層或いは三層であってもよい。本発明の薬物層は、薬物と可食性高分子物質及び所望により糖類と可塑剤などを含有する。又支持層は可食性高分子物質と所望により糖類と可塑剤などを含有する。薬物層単層でも、薬物層と支持層の二層或いは三層であっても、厚さを３０〜３００μｍに調整し、その物の破断強度が２００〜３，０００ｇ／φ７ｍｍ、引張強度が２００〜３，０００ｇ／１５ｍｍであれば口腔内において大略６０秒以内で溶解し、薬物は消化管の方に送られる。そして製剤も取り扱いやすく、服用時も違和感がなく有利である。
支持層の存否による違いは、支持層を設けた場合、口腔内での高い溶解性を保持しつつ一定の強度を保ち易いという効果が得られる。更に製剤のブロッキング性を回避でき、製剤の視覚的価値を向上させ得ることなどが挙げられる。
【００１１】
本発明で用いられる可食性高分子物質としては、ヒドロキシプロピルセルロース（ＨＰＣ）、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、メチルセルロース（ＭＣ）、エチルセルロース（ＥＣ）、カルボキシメチルセルロース‐Ｎａ（ＣＭＣ−Ｎａ）、ポリビニールアルコール（ＰＶＡ）、ポリビニルピロリドン（ＰＶＰ）、アルギン酸−Ｎａなどを挙げることが出来るが、ＨＰＣやＨＰＭＣが好適に用いられる。所望により用いられる糖類としては、マルトース、還元麦芽糖水飴、マルチトール、エリスリトール、キシリトール、ショ糖、ソルビトールなどを挙げることが出来るが、マルトースやマルチトール、還元麦芽糖水飴が好適に用いられる。同様所望により用いられる可塑剤としては、ポリエチレングリコール（ＰＥＧ）、グリセリン、ソルビトールなどを挙げることが出来るがＰＥＧ‐４００やＰＥＧ‐４０００が好適に用いられる。又サッカリンナトリウム、アスパルテーム、アセスルファムカリウム、スクラロースなどの甘味料も所望により用いられる。更に種々の香料、酸化チタンなどの着色剤、各種色素等も勿論使用して差し支えない。
本発明で用いる薬物は、一回の投与量が０．００１ｍｇ〜５０ｍｇのものが適しており、水‐エタノール系溶媒に可溶もしくは分散可能な薬物であれば特に制限はない。そして本発明の速溶性フィルム製剤は、本来水の飲用なしに服用出来ることが有利な点であるので、そのような場合でも消化器官などに悪影響を与えない薬物が望ましい。例えば以下のごとき薬物を挙げることが出来る。
アルプラゾラム、フルジアゼパム、ロラゼパムなどのマイナートランキライザー、酒石酸ゾルピデムなどの入眠剤、カベルコリン、塩酸メチキセンなどの抗パーキンソン剤、塩酸ドネペジルなどのアルツハイマー型痴呆治療剤、コルヒチンなどの痛風治療剤、塩酸クレンブテロール、硫酸サルブタモール、臭化水素酸フェノテロール、塩酸プロカテロールなどの気管支拡張剤、ラベプラゾールＮａ、ファモチジン、ラフチジンなどの消化性潰瘍治療剤、ボグリボースなどの糖尿病用剤、塩酸インデノロール、塩酸ブフェトロールなどの不整脈用剤、マレイン酸エナラプリル、塩酸キナプリル、シラザプリル、ニフェジピン、フェロジピン、塩酸ベニジピンなどの降圧剤、シンバスタチンなどの高脂血症用剤、塩酸チアミン、酢酸ヒドロキソコバラミンなどのビタミン剤、タクロリムス水和物などの免疫抑制剤・アトピー性皮膚治療剤、エチニルエストラジオール・メチルエストレノロンなどのホルモン剤、塩酸ロメリジンなどの片頭痛治療剤、酒石酸イフェンプロジルなどの鎮うん剤、クロペラスチン、塩酸クロフェダノールなどの鎮咳剤、塩酸ロペラミドなどの止瀉剤、ピコスルファートＮａなどの下剤、塩酸アザセトロン、塩酸グラニセトロン、塩酸ラモセトロンなどの制吐剤、メキタジン、塩酸ホモクロルシクリジン、マレイン酸クロルフェニラミンなどの抗ヒスタミン剤、塩酸セチリジン、フマル酸エメダスチンなどの抗アレルギー剤、塩酸エチルモルヒネ、塩酸モルヒネなどのアヘンアルカロイド系鎮痛鎮咳剤などである。
本発明において、薬物の配合比率は製剤全体に対して０．０１〜４０重量％、可食性高分子物質は同じく４０〜９９．９９重量％、糖類は同じく０〜６０重量％、可塑剤は同じく０〜２０重量％、その他着色剤は同じく０〜１０重量％、香料は同じく０〜１．０重量％である。本発明のフィルム製剤において、支持層を設ける場合、支持層の厚さは５〜４０μｍ前後が好適であり、薬物層の厚さは１５〜２９０μｍが好適である。そして全体の厚さとしては上記の如く３０〜３００μｍが好適であり、更に好適な厚さは３５〜１６０μｍ、より好ましくは３５〜１３０μｍである。薬物層だけの場合でも、薬物層と支持層とから成る場合でも厚さが３００μｍを超えると服用時違和感があり好ましくない。３０μｍより薄いと取り扱いにくくなり、又主薬の含有量も制限されてしまい好ましくない。
【００１２】
本発明フィルム状製剤のフィルムの破断強度、フィルムの引張強度の測定及び水崩壊性試験、口腔内溶解試験については、次の方法により行った。
【試験方法】
１）［破断強度］
（１）破断強度測定装置はレオメータ（株式会社レオテック製、ＲＴ−３０２０Ｄ−ＣＷ型）を使用した。図４は本発明で使用する破断強度測定装置の斜視模式図であり、図５は該破断強度測定装置の破断応力用アダプターの一部の形状及び大きさを示す斜視模式図であり、図６は破断応力用アダプターの試験片固定用下部プレート及び該プレートに載置されるリング及び試験片の断面形状及び大きさを示すｘ−ｘ断面図である。図中１は破断応力用アダプター、２は粘性用アダプター、３は試験片用固定下部プレート、４はリング、５は試験片、６は試験片固定用中間プレート、７は試験片固定用上部プレート、８，８’は止めネジ、９は基板、１０，１０’は支柱、１１はアダプター固定用ネジ、１２は試験台、１３は試験台上下移動開口部、１４は移動速度用等間隔目盛、２１は棒状体、２２は球状体である。図４〜図６に示すように、この装置は破断応力用アダプター１と試験片を破断する粘性用アダプター２とからなる。破断応力用アダプター１は、中央部に直径３０ｍｍの穴の貫通する横４０ｍｍ、縦７０ｍｍ、厚さ５ｍｍのその両端部に固定手段を有する形状の試験片固定用下部プレート３、該下部プレート３の中央の穴上に嵌められる内径１７ｍｍ、厚さ２ｍｍのリング４、リング４の上の試験片５（３０ｍｍ×３０ｍｍ）（図５及び図６参照）、該試験片５上に設けられ中央に内径１６ｍｍの穴のあけられている試験片固定用中間プレート６（横４０ｍｍ、縦７０ｍｍ、厚さ３ｍｍの軟質塩化ビニル板）及び該中間プレート６上に置かれる中央に内径３０ｍｍの穴が開けられている試験片固定用上部プレート７（横４０ｍｍ、縦７０ｍｍ、厚さ３ｍｍ）が順次載置されるものからなり（図４参照）、該固定用下部プレート３は、その中央には、外径３５ｍｍ、内径１７ｍｍのリング４が嵌合するように、その表面より２ｍｍの深さで、その径が３５ｍｍの大きさの凹部が貫通する直径３０ｍｍの上部に設けられている（図６参照）。これらプレート３、６及び７はその両端部は止めネジ８，８’で固定され、基板９上に支柱１０，１０’で支えられ、アダプター固定用ネジ１１で該基板９と共に試験台１２に固定されている（図４参照）。基板９は横４０ｍｍ、縦８０ｍｍ、厚さ２ｍｍのステンレス製の板であり、基板９から試験片固定用下部プレート３の表面までの高さは５７ｍｍである（図５参照）。又、粘性用アダプター２は棒状体２１の先端部にステンレス製の直径７ｍｍの球状体２２が取付けられたものからなる（図４参照）。
そして、試験台１２は試験片の破断応力測定時には、図４に示す試験台上下移動用開口部１３に沿って、一定の速度で移動し、試験片を粘性用アダプターの球体２２により、押圧して破断させ、その破断応力を付属するレコーダー（図示せず）で、記録し、破断強度を求める。
（２）測定方法
試験台に固定された破断応力用アダプター１の試験片固定用下部プレート３上に嵌められているリング４上にフィルム製剤試験片５（３０ｍｍ×３０ｍｍ）をのせ、その上に中央に内径１６ｍｍの穴のあけられている試験片固定用中間プレート６（横４０ｍｍ、縦７０ｍｍ、厚さ３ｍｍの軟質塩化ビニル板）で上から押さえ、さらにその上に中央に内径３０ｍｍの穴のあけられている金属製試験片固定用上部プレート７（横４０ｍｍ、縦７０ｍｍ、厚さ３ｍｍ）で該試験片５を押さえ、これらの重ねられたプレートの該上部プレート７の両端に設けられている止めネジ８，８’を締めて試験片５を固定した。次いで破断応力用アダプター１が固定されている試験台１２を１０ｃｍ／ｍｉｎの速度で試験台上下移動開口部１３に沿って上昇させ、粘性用アダプター２の球状体２２で該試験片５を破断した。その破断応力を付属するレコーダーで記録し、３回の平均値を求め、それを破断強度とした。結果は表７に示す。
２）［引張強度］
（１）引張強度測定装置はレオメータ（株式会社レオテック製、ＲＴ−３０２０Ｄ−ＣＷ型）を使用した。図７は本発明で使用する引張強度測定装置の引張強度測定用アダプターの斜視模式図であり、図８は上部アダプターが取付けられている引張強度測定装置の検出部の斜視模式図である。図中３１は引張強度測定用アダプター、３２は試験片固定用上部アダプター、３３は試験片固定用下部アダプター、３４は試験片、３５は上部アダプター取付部、３６は試験台、３７は上部アダプター止めネジ、３８は下部アダプター止めネジ、３９は試験台上下移動開口部、４０は移動速度用等間隔目盛、４１は検出部、４２は指針粗調整ツマミ、４３は指針微調整ツマミである。
本発明で使用した引張強度測定装置の引張強度測定用アダプター３１は、図７及び図８に示すように、試験片固定用上部アダプター３２が上部アダプター取付部３５を介して検出部４１に取付けられ、下部に試験台３６上に試験片固定用下部アダプター３３が取付けられたものからなり、試験片３４を上部及び下部アダプター間に一定の長さに固定し、試験台を下部に下降させて試験片を切断し、試験片の最大張力を測定する。試験片固定用上部アダプター３２は上下に移動でき、試験片を所望の長さの位置で止めネジ３７を締めて固定する。試験片固定用下部アダプター３３は試験台を上下に移動でき、試験片を固定及び切断できるようにされており、試験片は試験片固定用上部アダプター３２と同下部アダプター３３との間の長さが７ｃｍになるようにその位置を調整し止めネジ３８で固定する。試験台３６は試験台上下移動用開口部３９に沿って上下に移動し、試験片の引張強度の測定にあたっては下方へ一定速度（６ｃｍ／ｍｉｎ）で移動させる。移動用開口部３９にはその移動速度用の等間隔目盛４０が刻まれている。
図８に示すように試験片固定用上部アダプター取付部３５は更に検出部４１が設置されている。この検出部４１は引張強度を検出するためのものであり、試験片が切断されたときの引張強度を検出記録し、測定値を算出する。検出部４１には指針粗調整ツマミ４２及び指針微調整ツマミ４３が設けられており、これは引張強度測定時に最初の値を０に調整するためのものである。上、下のアダプター３２、３３の大きさは横３０ｍｍ、縦３０ｍｍ、高さ３０ｍｍのものである。
（２）測定方法
試験片固定用上部アダプター３２に１５×１００ｍｍに切断した試験片３４を上から１．５ｃｍの部分で固定し、次に試験台を上方向へ移動させて試験片固定用下部アダプター３３に、上部アダプター３２に固定されている試験片３４の長さが７ｃｍになるように調整して、該試験片の下部を固定する。次いで試験台３６を６ｃｍ／ｍｉｎの速さで下降させ、試験片３４を切断する。試験片３４の切断に至るまでの最大引張力を付属するレコーダーで記録し、測定値を求めた。３回の試験測定の平均値を求めそれを引張強度とした。結果を表７に示した。
３）［水崩壊性試験］
フィルム製剤試験片の四隅に油性マジックで点をつける。予め２５℃に加温した精製水４００ｍｌを試験液とし５００ｍｌ用ビーカーに入れ、撹拌子を入れ１００ｒｐｍで撹拌する。そして、２５℃±１℃に保持した状態の試験液に、撹拌下で前記のフィルム製剤試験片を浮かべ、予め四隅に付けた油性マジックの点が分散するまでの時間を測定した。試験は５回行われ、結果は５回の平均値を求めた。結果は表７に示す。
４）本発明フィルム製剤の口腔内における溶解性は６０秒以内である。溶解性は下記の如く測定した。
本発明フィルム製剤を健康な成人の口腔内に水なしで含ませ、フィルム製剤が口腔内の唾液のみで完全に崩壊分散するまでの時間を測定した。試験は２回行い、その平均値を算出した。
本発明のフィルム製剤については特に溶解性について規定があるわけではないが、薬効の発現とか違和感の問題等種々の条件を考慮すると、６０秒以内というのが適切である。
【００１３】
本発明の速溶性フィルム製剤は、以下のような方法によって製造される。
（１）薬物層のみ（１層）の場合
適量の溶媒（水−エタノール系溶媒）に薬物、可食性高分子物質、所望により糖類や可塑剤を、更に必要により甘味料や着色剤を加えて攪拌溶解し、ポリエステルなどの剥離フィルム上に展延し乾燥してフィルムを得、それを適切な大きさに打ち抜き製品とする。なお、薬物が溶媒に溶解でなく分散するようなものであるときは、薬物を先に溶媒中に分散してから可食性高分子物質を加えるとよい。
（２）薬物層とその片面に支持層積層（２層）の場合
適量の溶媒（水−エタノール系溶媒）に可食性高分子物質、所望により糖類や可塑剤を、更に必要により着色剤（例えば酸化チタン）などを加えて攪拌溶解或いは分散して、支持層溶液とする。別に適量の溶媒（水−エタノール系溶媒）に薬物、可食性高分子物質、所望により糖類や可塑剤、更には甘味料、香料などを加えて攪拌溶解して薬物層溶液とする。次に、支持層溶液をポリエステルなどの剥離フィルム上に展延乾燥して適切な厚さのフィルムとする。その上に薬物層溶液を、支持層を含めた厚さが所望の値になるように展延乾燥してフィルムとする。これを適切な大きさに打ち抜き製品とする。
（３）薬物層とその両面に支持層積層（３層）の場合
（２）と同様に支持層溶液と薬物層溶液を用意し、上記同様２層のフィルムを作る。支持層のない薬物層面に支持層溶液を展延乾燥して所望の厚さのフィルムとする。このフィルムを適切な大きさに打ち抜き製品とする。
以下に実施例を示すが、本発明はこれらに限定されるものではない。
【００１４】
【実施例】
実施例１
適量のエタノール／水混合溶媒にマレイン酸クロルフェニラミン３０．０重量部、還元麦芽糖水飴１０．０重量部及びＨＰＭＣ　６０．０重量部をこの順に加えて撹拌溶解し、脱気後ポリエステル剥離フィルム上に展延乾燥して厚さ７４．２μｍのフィルムを得た。得られたフィルムを一辺１６ｍｍの正方形に打ち抜き、速溶性フィルム製剤とした。
実施例２
適量のエタノール／水混合溶媒に塩酸チアミン１５．０重量部、ポリエチレングリコール１５．０重量部及びＨＰＭＣ　７０．０重量部をこの順に加えて撹拌溶解し、脱気後ポリエステル剥離フィルム上に展延乾燥して厚さ６１．８μｍのフィルムを製造した。得られたフィルムを一辺１６ｍｍの正方形に打ち抜き、速溶性フィルム製剤を得た。
実施例３〜５
表１の処方で実施例２と同様にして速溶性フィルム製剤を得た。
【表１】

【００１５】
実施例６
適量のエタノール／水混合溶媒に塩酸チアミン２０．０重量部、還元麦芽糖水飴１０．０重量部及びＨＰＣ　７０．０重量部をこの順に加えて撹拌溶解し、脱気後ポリエステル剥離フィルム上に展延乾燥して厚さ８０．８μｍのフィルムを得た。得られたフィルムを一辺１６ｍｍの正方形に打ち抜き、速溶性フィルム製剤とした。
実施例７〜１０
表２の処方で実施例６と同様にして速溶性フィルム製剤とした。
【表２】

【００１６】
実施例１１
適量のエタノール／水混合溶媒に還元麦芽糖水飴２０．０重量部を加えて撹拌溶解後、酸化チタン１０．０重量部を加えて撹拌分散し、さらにＨＰＭＣ　７０．０重量部を加えて支持層溶液とする。別に適量のエタノール／水混合溶媒にマレイン酸クロルフェニラミン５０．０重量部、及びＨＰＣ　５０．０重量部を加えて撹拌溶解して薬物層溶液とする。次に、支持層溶液をポリエステル剥離フィルム上に展延乾燥して厚さ約１５μｍのフィルムとする。その上に薬物層溶液を展延乾燥して厚さ約４５μｍのフィルムとする。最後にその上に支持層溶液を展延乾燥して厚さ約１５μｍのフィルムとする。このように積層し全体として７４．６μｍのフィルムを得た。得られたフィルムを一辺１６ｍｍの正方形に打ち抜き、速溶性フィルム製剤とした。
実施例１２〜１４
表３の処方で実施例１１と同様にして速溶性フィルム製剤とした。
【表３】

【００１７】
実施例１５
適量のエタノール／水混合溶媒に還元麦芽糖水飴１０．０重量部及びＰＥＧ　５重量部を加えて撹拌溶解後、酸化チタン１５．０重量部を加えて撹拌分散し、さらにＨＰＭＣ　７０．０重量部を加えて支持層溶液とする。別に適量のエタノール／水混合溶媒にマレイン酸クロルフェニラミン５０．０重量部、及びＨＰＣ　５０．０重量部を加えて撹拌溶解して薬物層溶液とする。次に、支持層溶液をポリエステル剥離フィルム上に展延乾燥して厚さ約１６μｍのフィルムとする。その上に薬物層溶液を展延乾燥して厚さ約５０μｍのフィルムとする。最後にその上に支持層溶液を展延乾燥して厚さ約１６μｍのフィルムとする。このように積層し全体として８１．４μｍのフィルムを得た。得られたフィルムを一辺１６ｍｍの正方形に打ち抜き、速溶性フィルム製剤とした。
実施例１６〜１９
表４の処方で実施例１５と同様にして速溶性フィルム製剤とした。
【表４】

【００１８】
実施例２０
適量のエタノール／水混合溶媒に還元麦芽糖水飴１０．０重量部及びＰＥＧ　５．０重量部を加えて撹拌溶解後、酸化チタン１５．０重量部とＨＰＭＣ　７０．０重量部とを加えて撹拌分散して支持層溶液とする。別に適量のエタノール／水混合溶媒にマレイン酸クロルフェニラミン５０．０重量部、ＰＥＧ　１０．０重量部及びＨＰＣ　４０．０重量部を加えて撹拌溶解して薬物層溶液とする。次に、支持層溶液をポリエステル剥離フィルム上に展延乾燥して厚さ約１１μｍのフィルムとする。その上に薬物層溶液を展延乾燥して厚さ約６０μｍのフィルムとする。最後にその上に支持層溶液を展延乾燥して厚さ約１１μｍのフィルムとする。このように積層し全体として８２μｍのフィルムを得た。得られたフィルムを一辺１６ｍｍの正方形に打ち抜き、速溶性フィルム製剤とした。
実施例２１〜２３
表５の処方で実施例２０と同様にして速溶性フィルム製剤とした。
【表５】

【００１９】
実施例２４
適量のエタノール／水混合溶媒にマレイン酸クロルフェニラミン５．０重量部、エリスリトール３５．０重量部、サッカリンナトリウム　０．３重量部、ｌ−メントール０．３重量部及び香料　０．１重量部を加えて撹拌溶解し、さらにＨＰＣ　５９．３重量部を加えて脱気後、ポリエステル剥離フィルム上に展延乾燥して厚さ３４．２μｍのフィルムを得た。得られたフィルムを一辺１６ｍｍの正方形に打ち抜き、速溶性フィルム製剤とした。
実施例２５
適量のエタノール／水混合溶媒にマルチトール１０．０重量部及びＰＥＧ　５．０重量部を加えて撹拌溶解後、酸化チタン１５．０重量部及びＨＰＭＣ　７０．０重量部を加えて撹拌分散して支持層溶液とする。別にエタノール／水混合適量の溶媒にマレイン酸クロルフェニラミン５．０重量部、マルトース３５．０重量部、サッカリンナトリウム　０．３重量部、ｌ−メントール　０．３重量部、香料　０．１６重量部及びＨＰＣ　５９．２４重量部を加えて撹拌溶解して薬物層溶液とする。次に、支持層溶液をポリエステル剥離フィルム上に展延乾燥して厚さ約１７μｍのフィルムとする。その上に薬物層溶液を展延乾燥して厚さ約２６μｍのフィルムとする。このように積層し全体として４３．２μｍのフィルムを得た。得られたフィルムを一辺１６ｍｍの正方形に打ち抜き、速溶性フィルム製剤とした。
【００２０】
実施例２６
適量のエタノール／水混合溶媒に還元麦芽糖水飴１０．０重量部、及びＰＥＧ　５．０重量部を加えて撹拌溶解後、酸化チタン１５．０重量部及びＨＰＭＣ　７０．０重量部を加えて撹拌分散して支持層溶液とする。別にエタノール／水混合適量の溶媒にマレイン酸クロルフェニラミン５．０重量部、マルトース３５．０重量部、サッカリンナトリウム　０．５重量部、ｌ−メントール　０．３重量部、香料　０．１６重量部及びＨＰＣ　５９．０４重量部を加えて撹拌溶解して薬物層溶液とする。次に、支持層溶液をポリエステル剥離フィルム上に展延乾燥して厚さ約１８μｍのフィルムとする。その上に薬物層溶液を展延乾燥して厚さ約５０μｍのフィルムとする。最後にその上に支持層溶液を展延乾燥して厚さ約１８μｍのフィルムとする。このように積層し全体として８５．３μｍのフィルムを得た。得られたフィルムを一辺１６ｍｍの正方形に打ち抜き、速溶性フィルム製剤とした。
実施例２７〜３０、及び比較例１〜４
実施例２６と同じ処方で薬物層を表６の厚さになるように積層後、支持層を積層し、全体として各々の厚さのフィルムを得た。得られたフィルムを１４×２０ｍｍの長方形に打ち抜き、速溶性フィルム製剤とした。
【表６】

【００２１】
表７に、実施例及び比較例のフィルム状製剤の夫々の厚さにおける破断強度、引張強度、口腔内崩壊時間及び水崩壊時間を示すと共に、そのときのフィルム状製剤の比表面積の逆数を示す。
【表７】

【００２２】
【発明の効果】
本発明の速溶性フィルム製剤は、水の飲用なしに服用しても口腔内で容易に溶解するため、老人や小児にも安全に投与できる。又仰臥位（仰向け位置）での服用も容易であるので、寝たきりの老人などでも安心して投与できる。更に、本製剤は薄いフィルム状なので携帯するにも有利である。更に本発明の速溶性フィルム製剤は、薬物と糖質の総和が製剤全体に対して２５〜４０重量％とかなり多量の薬物を含有することができ、有効投与量が大きな薬物に対しても有効に用いることができる。
本発明の速溶性フィルム製剤は塗布により製造されるものであり、従来の押し出し成型のもののように滑沢剤の添加や、シート状形成物の表面にブロッキング防止の為に、粉糖、澱粉などをふりかけたり、糖衣などの表面コートを行う必要もなく、室温２０℃、湿度５０％での１２時間エージングなどの必要がないため、それら滑沢剤が製剤に及ぼす影響を懸念する必要が無く、その製造操作が極めて簡単であり、またコスト面でも有利である。
また、本発明の塗布によるもの、特に製剤の両面に支持層を有するものは、ブロッキング性を充分に回避でき、さらには製剤の視覚的価値を飛躍的に向上させることが出来る。
本発明の塗布によるものは、乾燥工程を必要とするがその乾燥時間は代表的なもので６０℃，５分であり、この場合だと熱安定性の低い素材の使用も可能であり、１２時間と非常に長いエージング行程を行わずして製剤を得ることが可能である。
本発明フィルム状製剤は、フィルム形成剤として可食性高分子物質（ＨＰＣやＨＰＭＣ等）を使用しているが、これら可食性高分子物質は、フィルム形成能を充分に有しており、さらに本発明フィルム状製剤は適度の強度を有しているため、特段に製剤を厚くする必要もなく速やかに（おおよそ６０秒）口腔内で溶解することが出来る。そして、本発明フィルム状製剤の破断強度は２００〜３０００ｇ／φ７ｍｍ、フィルムの引張強度は２００〜３０００ｇ／１５ｍｍであるが、この範囲内では製品は脆くなく、口に含んだ場合、違和感がなく、使用できるものである。
【００２３】
【図面の簡単な説明】
【図１】本発明の速溶性フィルム製剤の口腔内溶解時間とフィルムの比表面積［ｍｍ^２／ｍｇ］の逆数との関係を示すグラフである。
【図２】本発明の速溶性フィルム製剤の水崩壊時間とフィルムの比表面積［ｍｍ^２／ｍｇ］の逆数との関係を示すグラフである。
【図３】フィルム製剤の水崩壊時間とフィルムの比表面積［ｍｍ^２／ｍｇ］の逆数との関係を示すグラフにおいて、本発明の速溶性フィルム製剤が満たすべき領域を示すグラフである。
【図４】本発明で使用する破断強度測定装置の斜視模式図である。
【図５】破断強度測定装置における破断応力用アダプターの一部の形状及び大きさを示す斜視模式図である。
【図６】破断強度測定装置における破断応力用アダプターの試験片固定用下部プレート及び該プレートに載置されるリング及び試験片の断面形状及び大きさを示すｘ−ｘ断面図である。
【図７】本発明で使用する引張強度測定装置の引張強度測定用アダプターの斜視模式図である。
【図８】上部アダプターが取付られている引張強度測定装置の検出部の斜視模式図である。
【符号の説明】
１．破断応力用アダプター
２．粘性用アダプター
３．試験片固定用下部プレート
４．リング
５．試験片
６．試験片固定用中間プレート
７．試験片固定用上部プレート
８，８’．止めネジ
９．基板
１０，１０’．支柱
１１．アダプター固定用ネジ
１２．試験台
１３．試験台上下移動開口部
１４．移動速度用等間隔目盛
２１．棒状体
２２．球状体
３１．引張強度測定装置の引張強度測定用アダプター
３２．試験片固定用上部アダプター
３３．試験片固定用下部アダプター
３４．試験片
３５．上部アダプター取付部
３６．試験台
３７．上部アダプター止めネジ
３８．下部アダプター止めネジ
３９．試験台上下移動開口部
４０．移動速度用等間隔目盛
４１．検出部
４２．指針粗調整ツマミ
４３．指針微調整ツマミ[0001]
TECHNICAL FIELD OF THE INVENTION
TECHNICAL FIELD The present invention relates to an orally soluble film-form preparation containing a drug useful for treating or diagnosing a disease and can be taken without water. More specifically, the preparation of the present invention is an orally dissolvable film-form preparation containing a drug and an edible polymer substance, and is rapidly dissolved (within about 60 seconds) by intraoral water when administered into the oral cavity. .
[0002]
[Prior art]
Conventionally, dosage forms administered orally include tablets, chewable tablets, sublingual tablets, capsules, pills, troches, drenches, and oral dissolution-type preparations, including oral mucosal patches. Of these, tablets are the most widely used, but capsules, drenches and the like are also widely used.
The following are generally known as oral dissolution-type preparations. (1) A sheet-shaped edible molded product obtained by mixing an excipient, a plasticizer and a binder, and mixing the excipient, the plasticizer, a binder with a food material and / or a drug, This mixture is obtained by extruding the mixture from a screw extruder, and has a extrusion thickness of 0.1 to 5 mm, preferably 0.5 to 3 mm (for example, see Patent Document 1). (2) having from 20 to 60% by weight of a film former, 2 to 40% by weight of a gel former, 0.1 to 35% by weight of active substance and also less than 40% by weight of an inert filler; The substance consists of a sheet-form, individually administered dosage form such as pharmaceuticals, confectionery, other foodstuffs, cosmetics, etc., which is administered or taken orally without support on a carrier, the thickness of the layer of the substance being It is 0.003 to 4 mm, preferably 20 to 400 μm, particularly 70 to 150 μm. The preparation method is spread or extruded and completely decomposed in the mouth within 10 minutes (for example, Patent Document 2) reference). (3) The active substance and / or the separating agent are not dissolved or suspended, and the foil-forming agent and optionally the filler are mixed in, optionally homogenized, and the solution or suspension is applied in a foil form on a foil-forming machine. A medicine in the form of a foil obtained by dividing a foil obtained by drying a coating material into arbitrary small pieces (units), and having a thickness of about 0.1 to 2 mm, preferably 0.1 to 2 mm. A preparation having a thickness of from 07 to 0.3 mm (for example, see Patent Document 3) is known.
[0003]
[Patent Document 1] JP-A-10-179045 (the section on the left column on page 2 and the right column on page 3 [0016]),
[Patent Document 2] Japanese Patent Application Laid-Open No. Hei 7-100186 (page 0035, page 2 and page 4, right column)
[Patent Document 3] JP-A-51-29218 (pages 1 and 3).
[0004]
[Problems to be solved by the invention]
Since the oral dissolving-type preparation described in Patent Document 1 (Japanese Patent Application Laid-Open No. H10-179045) is an extrusion-molded one, it is manufactured by a single screw extruder as in the example, and the film thickness is It is 1 mm or 2 mm, which is thick, and it takes time to dissolve, and it is considered impossible to dissolve within 60 seconds in the oral cavity. At this thickness, a foreign substance sensation appears as a preparation.
This formulation is manufactured by a screw extruder, but a formulation manufactured by a screw extruder always requires an anti-blocking agent (starch in this cited example). Will adhere). This is thought to be due to the properties of the polymer used for easily dissolving the preparation with a small amount of water, but there is a concern that the number of steps is increased and the cost is high. In addition, the visual value is important, especially in the case of pharmaceuticals and other preparations containing diagnostic agents, but there is a possibility that it may be reduced by a blocking agent.
Here, the preparation manufactured by the screw extruder is aged at a relatively low temperature (20 ° C.) for 12 hours. This manufacturing method has an advantage that a material having low thermal stability can be used because a drying step is not required, but the manufacturing efficiency is poor because it takes a very long time of 12 hours.
Patent Document 2 (Japanese Patent Application Laid-Open No. 7-100186) is manufactured by various methods and has a thickness of 0.003 to 4 mm. Incidentally, in the examples, pharmaceuticals are manufactured by a plunger type extruder, but in the case of the extrusion method, there is a tendency that the thickness tends to be large and the dissolution time is long as it takes 10 minutes to dissolve. . If the dissolution time is too long, the feeling of foreign matter is undesirably maintained.
What is listed as a film forming agent in this Patent Document 2 is usually used as an excipient, a plasticizer, a disintegrant, a solubilizing agent, etc., and has a film forming ability. It is hard to say. If anything, a polymer having a film-forming ability can be seen among those used as a gel-forming agent in Patent Document 2. However, since the amount of the gel forming agent is small (particularly, see Example 2), it is considered that this gel forming agent does not exhibit a film forming ability.
For example, polyethylene glycol used as a film-forming agent in Example 2 of Patent Document 2 is solid at room temperature, and forms a 1 mm-thick sheet-like product due to solidification at room temperature. ing. Although this sheet-like product can be expected to have some solubility at the temperature in the oral cavity, its strength cannot be expected so much because it utilizes the coagulability at room temperature. In fact, the description of Patent Document 2 requires a certain level of strength in production (paragraph number [0017]), and the thickness of the preparation becomes thicker even at the top. It is believed that this dissolution time is longer due to this thickness. Moreover, as in Example 2, the type of drug that can be contained is limited due to the low drug content of 3.75% by weight, and thus lacks utility.
Further, in Patent Document 3 (Japanese Patent Application Laid-Open No. 51-29218), the foil-forming agent which forms a foil is 6 to 20% in a solution or suspension, and the ratio is small. Patent Document 3 does not describe the film strength. With such a small proportion of the foil-forming agent, the formed film has low breaking strength and tensile strength, making the product brittle and difficult to handle. Moreover, it is not "quickly soluble".
As described above, the conventional oral dissolution-type preparations have disadvantages such as too thick, foreign body sensation, low strength and brittleness, and low drug content. For this reason, there has been a demand for a highly utilizable preparation which is thin and easily dissolves in the mouth. In other words, it has been desired to develop an oral dissolvable film-like preparation which can be easily dissolved by the water in the oral cavity, rapidly absorbs the gastrointestinal tract or the oral mucosa, and increases the drug content if necessary. .
[0005]
[Means for Solving the Problems]
The present inventors have intensively studied to solve the above-mentioned problem, that is, to provide a film-form preparation which is easily dissolved by oral water.
That is, the following points as formulation characteristics required for a fast-dissolving film-form formulation,
(1) melting quickly, that is, dissolving in the mouth within about 60 seconds;
(2) The dosage form must be easy to use, that is, the preparation must be strong enough not to be damaged when taken, must be too strong to cause discomfort in the oral cavity, and the preparation must be too thin. The handling is not inconvenient, and the formulation size is easy to take,
(3) The tolerance of the applied drug is broad, that is, the drug content has a high limit, and the preparation can cope with the physicochemical properties of the drug.
Was found necessary.
In order to make (1) possible, the thickness of the preparation should be reduced. However, by making the preparation thinner, the limit value of the drug content of (3) is reduced to several milligrams. May occur and (2) may not be satisfied.
In order to make (2) possible, a certain level of strength is required. To maintain the strength, it is usually necessary to set a high blending ratio of the polymer substance or to use a polymer substance having a relatively high degree of polymerization. However, (1) and / or (3) may not be satisfied as a result. When the amount of the polymer increases, it becomes difficult to dissolve, and at the same time, an unpleasant sensation occurs in the oral cavity.
It is important that the limit value of the drug contained in (3) among (1) to (3) can be set high in order to spread the film-form preparation. In order to satisfy this, it is only necessary to set the compounding ratio of the drug high or increase the size of the drug.However, by setting the compounding ratio of the drug high, the strength cannot be maintained, and if the drug size is too large, it may be taken. May cause inconvenience, and (2) may not be satisfied. It is also conceivable to increase the thickness of the preparation, but as a result (1) is no longer satisfied.
[0006]
As a result of studying in consideration of the above points, the breaking strength of the film was 200 to 3,000 g / φ7 mm (measured by a FUDOH rheometer described later), and the tensile strength of the film was 200 to 3,000 g / 15 mm (FUDOH described later). (Measured by a rheometer) was found to be suitable.
Considering that handling is not inconvenient because the preparation is too thin, the film needs to have a thickness of 30 μm or more, and considering the preparation size that is easy to take, a thickness of 300 μm or less is preferable. I also found something. The film-form preparation having a breaking strength of the above-mentioned film of 200 to 3,000 g / φ7 mm, a tensile strength of the film of 200 to 3,000 g / 15 mm, and a film-form preparation exceeding this range are described in Examples and Comparative Examples below. And the dissolution time [sec] in the oral cavity is Y, and the specific surface area of the film [mm ² / Mg] [mg / mm] ² ] Was plotted as X, and surprisingly, a graph was obtained showing the relationship between the oral dissolution time of the film preparation of FIG. 1 and the reciprocal of the specific surface area of the film. That is, all of the film-form preparations having a breaking strength of the film of 200 to 3,000 g / φ7 mm and a tensile strength of the film of 200 to 3,000 g / 15 mm have an oral dissolution time of 60 seconds or less, and are determined in the present application. A fast-dissolving film-form preparation was obtained.
The present inventors have conducted further studies on the above conditions. As a result, the water disintegration time (the water disintegration test will be described later) is set to Y in place of the oral dissolution time of the above film preparation, and the specific surface area of the film [ mm ² / Mg] [mg / mm] ² ] Was plotted as X, and a graph showing the relationship between the water disintegration time of the film preparation of FIG. 2 and the reciprocal of the specific surface area of the film was obtained. The oral dissolution time of FIG. It was also found that the water disintegration time was within 300 seconds.
In the present invention, the water disintegration time (Y) is determined based on the specific surface area of the film [mm ² / Mg], which has been achieved based on a novel finding which has never been known so far, which is correlated with the reciprocal (X) of [/ mg], and has the following points as its gist.
[0007]
That is, the present invention comprises (1) a drug and an edible polymer substance, the breaking strength of the film is 200 to 3000 g / φ7 mm, the tensile strength of the film is 200 to 3000 g / 15 mm, and 60 seconds in the oral cavity. (2) It contains a drug and an edible polymer substance, the film has a breaking strength of 200 to 3000 g / φ7 mm, the tensile strength of the film is 200 to 3000 g / 15 mm, and water. When the disintegration time Y [sec] is within 300 seconds (Y ≦ 300), the reciprocal of the specific surface area of the film [mg / mm ² ] As X (X ≧ 0), water disintegration time Y [sec] ≧ 7500X ² (3) The drug is contained in a single dose of 0.001 mg to 50 mg and is soluble or dispersible in a water-ethanol solvent. (1) The quick-dissolving film-form preparation according to (1) or (2); (4) the quick-dissolving preparation according to (1), (2) or (3), wherein the edible polymer substance is hydroxypropylcellulose and / or hydroxypropylmethylcellulose. (5) The compounding ratio of the drug is 0.01 to 40% by weight based on the whole preparation, and the compounding ratio of the edible polymer substance is 40 to 99.99% by weight based on the whole preparation ( (1), (2), (3) or (4), a fast-dissolving film-form preparation; (6) a film-form preparation consisting of a single layer containing a drug (1), (2), (3), (4) ) Or the fast-dissolving film-form preparation of (5); (8) a fast-dissolving film-form preparation of (1), (2), (3), (4) or (5) having a support layer containing an edible polymer substance on one or both sides of the drug-containing layer; The edible polymer substance of the support layer is hydroxypropylmethylcellulose, the blending ratio of which is 50% by weight or more, and the edible polymer substance of the drug-containing layer is hydroxypropylcellulose, the blending ratio of which is 40-99. (1), (2), (3), (4), (5), (6) or (7), which is 99% by weight; (9) further containing a saccharide (1), (2), (3), (4), (5), (6), (7) or (8), the fast-dissolving film-form preparation; (10) the sum of the drug and the saccharide is: (11) water-soluble film preparation according to (9), which is 25 to 40% by weight based on the whole preparation; Time Y [sec] is 60000X ² ≧ Y ≧ 7500X ² (1), (2), (3), (4), (5), (6), (7), (8), (9) or (10), which has the following relationship: It is about.
[0008]
In the above (2), the meaning of “the water disintegration time Y [sec] is within 300 seconds” means that as described above, “melts in the oral cavity within 60 seconds”, and eliminates race and individual differences. Objectivity can be maintained. In addition, water disintegration time Y [sec] <7500X ² In the region (B) in the graph showing the relationship between the water disintegration time of the film preparation and the reciprocal of the specific surface area of the film in FIG. 3, the dissolution of the film preparation is fast, but the intended strength cannot be maintained. is there. In the film preparation of the present invention, the thickness is preferably 30 μm or more and 300 μm or less.
If the breaking strength is lower than 200 g / φ7 mm, the product becomes brittle and becomes difficult to handle, which is not preferable. In addition, when the weight is more than 3,000 g / φ7 mm, when it is contained in the mouth, there is a sense of incongruity, which is not preferable.
If the tensile strength is lower than 200 g / 15 mm, the product becomes brittle and difficult to handle, which is not preferable. In addition, when the weight is more than 3,000 g / 15 mm, it is not preferable because the mouth contains uncomfortable feeling.
If the breaking strength is larger than 3,000 g / φ7 mm and the tensile strength is larger than 3,000 g / 15 mm, the dissolution time may be long, which is not preferable.
In the above (3), one of the film preparations of the present invention can contain a large amount of a drug of 50 mg if necessary. For example, when the minimum total weight and the size of the film preparation of the present invention containing 50 mg of a drug are shown, the total weight is 125 mg and the minimum size is 28 mm × 20 mm × 190 μm.
In the above (7), a support layer containing an edible polymer substance may be provided on one or both sides of the drug-containing layer, instead of forming the film-form preparation in one layer. If the compounding ratio of the drug is set high (for example, 25 to 40% by weight) in one layer, the strength may not be the required strength, but the support containing the edible polymer substance on one or both sides of the drug-containing layer may be provided. By providing a layer, it is possible to satisfy all of the formulation characteristics required for a fast-dissolving film-form formulation, to avoid blocking properties (adhesion) between formulations, and to further reduce the visual value of the formulation. Since it can be dramatically improved, not only the merit of simply increasing the strength of the preparation but also a synergistic effect can be expected.
In the above (8), hydroxypropyl methylcellulose is an easily water-soluble edible polymer substance, is hardly affected by the humidity of the outside air, has a gloss when formed into a film, and contains titanium oxide and a coloring agent. Also, the strength is relatively hard to decrease, so that it is suitable for the support layer.
On the other hand, hydroxypropylcellulose is soluble in the whole range from water to 100% ethanol, and has the advantage that the soluble range of the drug can be selected from a wide range from water to 100% ethanol.
In a preferred embodiment, the support layer contains 50% by weight or more of hydroxypropyl methylcellulose, 10 to 30% of a saccharide, 5 to 20% of a plasticizer, and 15% by weight or less of titanium oxide or 5.0% or less of a coloring agent. In the drug layer, 40 to 99.99% by weight of hydroxypropylcellulose and a drug are essential components, and a saccharide or / and a plasticizer are optionally added.
In the above (9), the saccharide may of course be mixed with a drug. Thereby, water solubility and water disintegration are improved. In particular, saccharides are suitable for improving the water solubility and water disintegration in that they do not affect the properties of the drug. When the drug is divided into a drug layer and a support layer, it is preferable that the drug layer is contained only in the support layer or that the support layer contains a large amount.
In the above (11), the water disintegration time Y [second] is 60000X ² ≧ Y ≧ 7500X ² The relationship (A) corresponds to the region (A) in the graph of FIG. 60000X ² The significance of ≧ water disintegration time Y [seconds] indicates a region in which a relatively large amount of drug can be contained. ² The range of <Y (region (C) in the graph of FIG. 3) indicates a state in which the drug can be contained in an extremely small amount.
[0009]
In the film-form preparation of the present invention, the thickness is not particularly limited as long as its breaking strength and tensile strength are within the above ranges.However, ease of handling of the product, discomfort when taking the product, and further, dissolution time In consideration of the above, 30 to 300 μm is preferable.
The film-form preparation of the present invention dissolves in the oral cavity in about 60 seconds or less, is less uncomfortable, is easy to take, and is advantageous. Also, by dissolving in such a short time, the drug can be rapidly absorbed into the digestive tract and the oral mucosa.
The film preparation of the present invention dissolves rapidly (within approximately 60 seconds) in the oral cavity, and is absorbed in the gastrointestinal tract and oral mucosa by the physicochemical properties of the drug, whereby the action of the drug is promptly exhibited. In particular, even for elderly people with a small amount of saliva, they are easily dissolved in the oral cavity even if taken without drinking water.
Therefore, the film preparation of the present invention is expected to have the same pharmacological effects as conventional oral preparations such as tablets and capsules, and can be easily taken without water, so that it can be safely administered to elderly people and children.
[0010]
Hereinafter, the present invention will be described in more detail.
The film preparation of the present invention may have a single drug layer containing a drug, or may have two or three layers in which a support layer is provided on one or both sides of the drug layer. The drug layer of the present invention contains a drug, an edible polymer substance, and optionally a saccharide and a plasticizer. The support layer contains an edible polymer substance and, if desired, a saccharide and a plasticizer. Regardless of whether the drug layer is a single layer or two or three layers of a drug layer and a support layer, the thickness is adjusted to 30 to 300 μm, the breaking strength of the product is 200 to 3,000 g / φ7 mm, and the tensile strength is 200. If it is ３，3,000 g / 15 mm, it dissolves in the oral cavity within about 60 seconds, and the drug is sent to the digestive tract. The preparation is also easy to handle, and has no discomfort even when taken.
The difference depending on the presence or absence of the support layer is that when the support layer is provided, an effect is obtained that it is easy to maintain a certain strength while maintaining high solubility in the oral cavity. Furthermore, the blocking property of the preparation can be avoided, and the visual value of the preparation can be improved.
[0011]
The edible polymer substance used in the present invention includes hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), ethylcellulose (EC), carboxymethylcellulose-Na (CMC-Na), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), alginic acid-Na, and the like can be given, and HPC or HPMC is preferably used. Examples of the saccharides used as desired include maltose, reduced maltose syrup, maltitol, erythritol, xylitol, sucrose, sorbitol, and the like. Maltose, maltitol, and reduced maltose syrup are preferably used. Similarly, as a plasticizer optionally used, polyethylene glycol (PEG), glycerin, sorbitol and the like can be mentioned, and PEG-400 and PEG-4000 are preferably used. Also, sweeteners such as saccharin sodium, aspartame, acesulfame potassium, sucralose and the like can be used if desired. Further, various fragrances, coloring agents such as titanium oxide, various dyes, and the like may of course be used.
The drug used in the present invention is preferably in a dose of 0.001 mg to 50 mg per dose, and is not particularly limited as long as it is a drug that can be dissolved or dispersed in a water-ethanol solvent. The advantage of the fast-dissolving film preparation of the present invention is that it can be taken without drinking water. Therefore, a drug which does not adversely affect the digestive organs even in such a case is desirable. For example, the following drugs can be mentioned.
Minor tranquilizers such as alprazolam, fludiazepam, lorazepam, sleep-inducing agents such as zolpidem tartrate, antiparkinson agents such as cabelcholine and methixene hydrochloride, Alzheimer-type dementia therapeutic agents such as donepezil hydrochloride, gout therapeutic agents such as colchicine, clenbuterol hydrochloride, salbutamol sulfate , Bronchodilators such as fenoterol hydrobromide and procaterol hydrochloride, peptic ulcer treatments such as rabeprazole Na, famotidine and raftidine, diabetes agents such as voglibose, arrhythmic agents such as indenolol hydrochloride and bufetrol hydrochloride, maleic acid Antihypertensive agents such as enalapril, quinapril hydrochloride, cilazapril, nifedipine, felodipine, and benidipine hydrochloride, hyperlipidemic agents such as simvastatin, thiamine hydrochloride, hydroxocoacetate Vitamins such as lamin; immunosuppressants such as tacrolimus hydrate; atopic skin treatments; hormones such as ethinylestradiol / methylestrenolone; migraine treatments such as lomerizine hydrochloride; Antitussives such as cloperastine and clofedanol hydrochloride, antidiarrheals such as loperamide hydrochloride, laxatives such as picosulfate Na, antiemetics such as azasetron hydrochloride, granisetron hydrochloride, ramosetron hydrochloride, mequitazine, homochlorcyclidine hydrochloride, chlorpheni maleate Antihistamines such as lamin; antiallergic agents such as cetirizine hydrochloride and emedastine fumarate; and opiate alkaloid analgesic and antitussives such as ethyl morphine hydrochloride and morphine hydrochloride.
In the present invention, the compounding ratio of the drug is 0.01 to 40% by weight based on the whole preparation, the edible polymer substance is also 40 to 99.99% by weight, the saccharide is also 0 to 60% by weight, and the plasticizer is the same. 0 to 20% by weight, other colorants are also 0 to 10% by weight, and fragrances are also 0 to 1.0% by weight. When a support layer is provided in the film preparation of the present invention, the thickness of the support layer is preferably about 5 to 40 μm, and the thickness of the drug layer is preferably 15 to 290 μm. As described above, the total thickness is preferably 30 to 300 μm, and the more preferable thickness is 35 to 160 μm, and more preferably 35 to 130 μm. When the thickness is more than 300 μm, even when only the drug layer is used, or when it is composed of the drug layer and the support layer, unpleasant sensation when taking the drug is not preferable. If the thickness is less than 30 μm, it becomes difficult to handle, and the content of the main drug is also limited, which is not preferable.
[0012]
The measurement of the breaking strength of the film and the tensile strength of the film, the water disintegration test, and the oral dissolution test of the film-form preparation of the present invention were carried out by the following methods.
【Test method】
1) [Breaking strength]
(1) Rheometer (RT-3020D-CW type, manufactured by Leotech Co., Ltd.) was used as a breaking strength measuring device. FIG. 4 is a schematic perspective view of a breaking strength measuring apparatus used in the present invention, and FIG. 5 is a schematic perspective view showing a part of the shape and size of a breaking stress adapter of the breaking strength measuring apparatus. FIG. 3 is an xx cross-sectional view illustrating a cross-sectional shape and a size of a test piece fixing lower plate of the adapter for rupture stress, a ring mounted on the plate, and a test piece. In the figure, 1 is an adapter for breaking stress, 2 is an adapter for viscosity, 3 is a lower plate for fixing a test piece, 4 is a ring, 5 is a test piece, 6 is an intermediate plate for fixing a test piece, and 7 is an upper plate for fixing a test piece. , 8, 8 'are set screws, 9 is a substrate, 10 and 10' are supporting posts, 11 is an adapter fixing screw, 12 is a test stand, 13 is a test stand vertical moving opening, 14 is a uniform scale for moving speed, 21 is a rod-like body, 22 is a spherical body. As shown in FIGS. 4 to 6, the apparatus comprises an adapter 1 for rupture stress and an adapter 2 for viscousness for breaking a test piece. The adapter for rupture stress 1 has a lower plate 3 for fixing a test piece having a width of 40 mm, a length of 70 mm, and a thickness of 5 mm and having fixing means at both ends of a hole having a diameter of 30 mm in the center. A ring 4 having an inner diameter of 17 mm and a thickness of 2 mm to be fitted on the center hole, a test piece 5 (30 mm × 30 mm) on the ring 4 (see FIGS. 5 and 6), provided on the test piece 5, An intermediate plate 6 for fixing a test piece (a 40 mm wide, 70 mm long, 3 mm thick soft vinyl chloride plate) having a 16 mm hole and a hole having an inner diameter of 30 mm formed in the center placed on the intermediate plate 6. The upper plate 7 for fixing the test piece (width 40 mm, length 70 mm, thickness 3 mm) is successively placed (see FIG. 4). m, as a ring having an inner diameter of 17 mm 4 is fitted, and a depth of 2mm from the surface, its diameter is provided at the top of the 30mm diameter which is sized recess of 35mm through (see FIG. 6). The

plates

3, 6 and 7 are fixed at both ends by set screws 8, 8 ', supported on a substrate 9 by supporting columns 10, 10', and fixed to a test stand 12 together with the substrate 9 by an adapter fixing screw 11. (See FIG. 4). The substrate 9 is a stainless steel plate having a width of 40 mm, a length of 80 mm, and a thickness of 2 mm, and the height from the substrate 9 to the surface of the test piece fixing lower plate 3 is 57 mm (see FIG. 5). The viscous adapter 2 is formed by attaching a stainless steel spherical body 22 having a diameter of 7 mm to the tip of a rod 21 (see FIG. 4).
Then, when measuring the breaking stress of the test piece, the test stand 12 moves at a constant speed along the opening 13 for vertically moving the test stand shown in FIG. 4, and presses the test piece by the sphere 22 of the viscous adapter. And the breaking stress is recorded by an attached recorder (not shown) to determine the breaking strength.
(2) Measurement method
A film preparation test piece 5 (30 mm × 30 mm) is placed on a ring 4 fitted on a test piece fixing lower plate 3 of a rupture stress adapter 1 fixed to a test table. A metal plate having a hole with a 30 mm inner diameter in the center is pressed down from above with a test plate fixing intermediate plate 6 (40 mm wide, 70 mm long, 3 mm thick soft vinyl chloride plate) with holes. The test piece 5 is held by an upper plate 7 (40 mm in width, 70 mm in length, 3 mm in thickness) for fixing the test piece, and set

screws

8, 8 provided on both ends of the upper plate 7 of these stacked plates 'To tighten the test piece 5. Next, the test table 12 to which the breaking stress adapter 1 is fixed is raised along the test table vertical movement opening 13 at a speed of 10 cm / min, and the test piece 5 is broken by the spherical body 22 of the viscous adapter 2. . The breaking stress was recorded by an attached recorder, an average value of three times was obtained, and the obtained value was defined as breaking strength. The results are shown in Table 7.
2) [Tensile strength]
(1) A rheometer (RT-3020D-CW type, manufactured by Leotech Co., Ltd.) was used as a tensile strength measuring device. FIG. 7 is a schematic perspective view of a tensile strength measuring adapter of the tensile strength measuring device used in the present invention, and FIG. 8 is a schematic perspective view of a detecting portion of the tensile strength measuring device to which an upper adapter is attached. In the figure, 31 is an adapter for measuring tensile strength, 32 is an upper adapter for fixing a test piece, 33 is a lower adapter for fixing a test piece, 34 is a test piece, 35 is a mounting part for an upper adapter, 36 is a test stand, and 37 is a stopper for the upper adapter. A screw 38 is a lower adapter set screw, 39 is an opening for vertically moving the test stand, 40 is a scale for moving speed at equal intervals, 41 is a detecting unit, 42 is a coarse adjustment knob of the pointer, and 43 is a fine adjustment knob of the pointer.
In the tensile strength measuring adapter 31 of the tensile strength measuring device used in the present invention, as shown in FIGS. 7 and 8, an upper adapter 32 for fixing a test piece is attached to a detecting portion 41 via an upper adapter attaching portion 35. The lower part is provided with a lower adapter 33 for fixing a test piece on a test table 36 at the lower part. The test piece 34 is fixed at a fixed length between the upper and lower adapters, and the test table is lowered to the lower part to perform the test. The specimen is cut and the maximum tension of the specimen is measured. The upper adapter 32 for fixing the test piece can be moved up and down, and the test piece is fixed at a position of a desired length by tightening the set screw 37. The lower adapter 33 for fixing the test piece can move the test table up and down so that the test piece can be fixed and cut, and the test piece has a length between the upper adapter 32 for fixing the test piece and the lower adapter 33. Is adjusted to be 7 cm, and fixed with a set screw 38. The test table 36 moves up and down along the test table vertical movement opening 39, and moves downward at a constant speed (6 cm / min) when measuring the tensile strength of the test piece. The moving opening 39 is provided with an equally spaced scale 40 for the moving speed.
As shown in FIG. 8, a detection unit 41 is further provided on the upper adapter mounting unit 35 for fixing a test piece. The detection unit 41 detects the tensile strength, detects and records the tensile strength when the test piece is cut, and calculates a measured value. The detecting section 41 is provided with a pointer coarse adjustment knob 42 and a pointer fine adjustment knob 43, which are used to adjust the initial value to zero when measuring the tensile strength. The size of the upper and

lower adapters

32 and 33 is 30 mm in width, 30 mm in length, and 30 mm in height.
(2) Measurement method
The test piece 34 cut to 15 × 100 mm was fixed to the upper adapter 32 for fixing the test piece at a portion 1.5 cm from the top, and then the test table was moved upward to move the upper adapter to the lower adapter 33 for fixing the test piece. The length of the test piece 34 fixed to the adapter 32 is adjusted to be 7 cm, and the lower part of the test piece is fixed. Next, the test table 36 is lowered at a speed of 6 cm / min, and the test piece 34 is cut. The maximum tensile force up to the cutting of the test piece 34 was recorded by an attached recorder, and a measured value was obtained. The average value of three test measurements was determined and defined as the tensile strength. The results are shown in Table 7.
3) [Water disintegration test]
Mark the four corners of the film formulation test specimen with oily magic. 400 ml of purified water preliminarily heated to 25 ° C. is used as a test solution, placed in a 500 ml beaker, a stirrer is put in, and the mixture is stirred at 100 rpm. Then, the above-mentioned film preparation test piece was floated on the test solution kept at 25 ° C. ± 1 ° C. with stirring, and the time required for dispersing the oil-based magic points previously attached to the four corners was measured. The test was performed five times, and the results were averaged over five times. The results are shown in Table 7.
4) The solubility of the film preparation of the present invention in the oral cavity is within 60 seconds. Solubility was measured as follows.
The film preparation of the present invention was contained in the mouth of a healthy adult without water, and the time required for the film preparation to completely disintegrate and disperse with only the saliva in the mouth was measured. The test was performed twice, and the average value was calculated.
The solubility of the film preparation of the present invention is not particularly limited, but it is appropriate to be within 60 seconds in consideration of various conditions such as the manifestation of a medicinal effect and a problem of discomfort.
[0013]
The fast-dissolving film preparation of the present invention is produced by the following method.
(1) In the case of drug layer only (one layer)
Drugs, edible polymer substances, saccharides and plasticizers as needed, and sweeteners and coloring agents as needed are added to an appropriate amount of solvent (water-ethanol solvent), and the mixture is stirred and dissolved, and spread on a release film such as polyester. It is rolled and dried to obtain a film, which is cut into an appropriate size to obtain a product. When the drug is not dissolved but dispersed in the solvent, the drug may be dispersed in the solvent first, and then the edible polymer substance may be added.
(2) In the case of a drug layer and a support layer laminated on one side (two layers)
An edible polymer substance, a saccharide or a plasticizer as required, and a coloring agent (for example, titanium oxide) as necessary are added to an appropriate amount of a solvent (water-ethanol solvent), and the mixture is stirred and dissolved or dispersed. I do. Separately, a drug, an edible polymer substance, a saccharide or a plasticizer, if necessary, a sweetener, a flavor, and the like are added to an appropriate amount of a solvent (water-ethanol solvent), and the mixture is stirred and dissolved to form a drug layer solution. Next, the support layer solution is spread and dried on a release film such as polyester to obtain a film having an appropriate thickness. The drug layer solution is spread thereon and dried so that the thickness including the support layer becomes a desired value to form a film. This is punched into an appropriate size to obtain a product.
(3) In the case of a drug layer and a support layer laminated on both sides (three layers)
A support layer solution and a drug layer solution are prepared in the same manner as in (2), and a two-layer film is formed in the same manner as described above. The support layer solution is spread and dried on the drug layer surface without the support layer to obtain a film having a desired thickness. This film is punched to an appropriate size to obtain a product.
Examples are shown below, but the present invention is not limited to these.
[0014]
【Example】
Example 1
30.0 parts by weight of chlorpheniramine maleate, 10.0 parts by weight of reduced maltose starch syrup and 60.0 parts by weight of HPMC are added in this order to an appropriate amount of a mixed solvent of ethanol / water, stirred and dissolved. And dried to obtain a film having a thickness of 74.2 μm. The obtained film was punched into a square having a side of 16 mm to obtain a fast-dissolving film preparation.
Example 2
15.0 parts by weight of thiamine hydrochloride, 15.0 parts by weight of polyethylene glycol and 70.0 parts by weight of HPMC are added in this order to an appropriate amount of a mixed solvent of ethanol / water, stirred and dissolved, and after degassing, spread and dried on a polyester release film. As a result, a film having a thickness of 61.8 μm was produced. The obtained film was punched into a square having a side of 16 mm to obtain a fast-dissolving film preparation.
Examples 3 to 5
A fast-dissolving film preparation was obtained in the same manner as in Example 2 using the formulation shown in Table 1.
[Table 1]

[0015]
Example 6
20.0 parts by weight of thiamine hydrochloride, 10.0 parts by weight of reduced maltose starch syrup and 70.0 parts by weight of HPC were added in this order to an appropriate amount of a mixed solvent of ethanol / water, stirred and dissolved, and after degassing, spread on a polyester release film. After drying, a film having a thickness of 80.8 μm was obtained. The obtained film was punched into a square having a side of 16 mm to obtain a fast-dissolving film preparation.
Examples 7 to 10
The formulation of Table 2 was used to prepare a fast-dissolving film preparation in the same manner as in Example 6.
[Table 2]

[0016]
Example 11
After adding 20.0 parts by weight of reduced maltose starch syrup to an appropriate amount of a mixed solvent of ethanol / water and stirring and dissolving, 10.0 parts by weight of titanium oxide is added and dispersed by stirring. Further, 70.0 parts by weight of HPMC is added and the support layer solution is added. And Separately, 50.0 parts by weight of chlorpheniramine maleate and 50.0 parts by weight of HPC are added to an appropriate amount of a mixed solvent of ethanol / water, and the mixture is stirred and dissolved to prepare a drug layer solution. Next, the support layer solution is spread and dried on the polyester release film to obtain a film having a thickness of about 15 μm. The drug layer solution is spread thereon and dried to form a film having a thickness of about 45 μm. Finally, the support layer solution is spread thereon and dried to form a film having a thickness of about 15 μm. By laminating in this way, a film of 74.6 μm as a whole was obtained. The obtained film was punched into a square having a side of 16 mm to obtain a fast-dissolving film preparation.
Examples 12 to 14
The formulation of Table 3 was used to prepare a fast-dissolving film preparation in the same manner as in Example 11.
[Table 3]

[0017]
Example 15
After adding 10.0 parts by weight of reduced maltose starch syrup and 5 parts by weight of PEG to an appropriate amount of a mixed solvent of ethanol / water and stirring and dissolving, 15.0 parts by weight of titanium oxide is added, and the mixture is stirred and dispersed, and 70.0 parts by weight of HPMC is further added. In addition, a support layer solution is prepared. Separately, 50.0 parts by weight of chlorpheniramine maleate and 50.0 parts by weight of HPC are added to an appropriate amount of a mixed solvent of ethanol / water, and the mixture is stirred and dissolved to prepare a drug layer solution. Next, the support layer solution is spread and dried on the polyester release film to obtain a film having a thickness of about 16 μm. The drug layer solution is spread thereon and dried to form a film having a thickness of about 50 μm. Finally, the support layer solution is spread thereon and dried to form a film having a thickness of about 16 μm. By laminating in this way, a film of 81.4 μm as a whole was obtained. The obtained film was punched into a square having a side of 16 mm to obtain a fast-dissolving film preparation.
Examples 16 to 19
The formulation of Table 4 was used to prepare a fast-dissolving film preparation in the same manner as in Example 15.
[Table 4]

[0018]
Example 20
10.0 parts by weight of reduced maltose starch syrup and 5.0 parts by weight of PEG are added to an appropriate amount of a mixed solvent of ethanol / water, and the mixture is dissolved by stirring. Then, 15.0 parts by weight of titanium oxide and 70.0 parts by weight of HPMC are added and dispersed by stirring. To form a support layer solution. Separately, 50.0 parts by weight of chlorpheniramine maleate, 10.0 parts by weight of PEG and 40.0 parts by weight of HPC are added to an appropriate amount of a mixed solvent of ethanol / water and dissolved by stirring to prepare a drug layer solution. Next, the support layer solution is spread and dried on the polyester release film to obtain a film having a thickness of about 11 μm. The drug layer solution is spread thereon and dried to form a film having a thickness of about 60 μm. Finally, the support layer solution is spread thereon and dried to form a film having a thickness of about 11 μm. By laminating in this way, a film of 82 μm as a whole was obtained. The obtained film was punched into a square having a side of 16 mm to obtain a fast-dissolving film preparation.
Examples 21 to 23
A fast-dissolving film preparation was prepared in the same manner as in Example 20 using the formulation shown in Table 5.
[Table 5]

[0019]
Example 24
To an appropriate amount of a mixed solvent of ethanol / water, add 5.0 parts by weight of chlorpheniramine maleate, 35.0 parts by weight of erythritol, 0.3 parts by weight of saccharin sodium, 0.3 parts by weight of l-menthol, and 0.1 parts by weight of fragrance. Then, 59.3 parts by weight of HPC was added and deaerated, and then spread and dried on a polyester release film to obtain a film having a thickness of 34.2 μm. The obtained film was punched into a square having a side of 16 mm to obtain a fast-dissolving film preparation.
Example 25
After adding 10.0 parts by weight of maltitol and 5.0 parts by weight of PEG to an appropriate amount of a mixed solvent of ethanol / water and stirring and dissolving, 15.0 parts by weight of titanium oxide and 70.0 parts by weight of HPMC are added and stirred and dispersed. The solution is a support layer solution. Separately, 5.0 parts by weight of chlorpheniramine maleate, 35.0 parts by weight of maltose, 0.3 parts by weight of sodium saccharin, 0.3 parts by weight of l-menthol, 0.16 parts by weight of fragrance and 59.24 parts by weight of HPC is added and dissolved by stirring to obtain a drug layer solution. Next, the support layer solution is spread and dried on a polyester release film to obtain a film having a thickness of about 17 μm. The drug layer solution is spread thereon and dried to form a film having a thickness of about 26 μm. By laminating in this way, a film of 43.2 μm as a whole was obtained. The obtained film was punched into a square having a side of 16 mm to obtain a fast-dissolving film preparation.
[0020]
Example 26
10.0 parts by weight of reduced maltose starch syrup and 5.0 parts by weight of PEG are added to an appropriate amount of a mixed solvent of ethanol / water, and the mixture is stirred and dissolved. Then, 15.0 parts by weight of titanium oxide and 70.0 parts by weight of HPMC are added and dispersed by stirring. To form a support layer solution. Separately, 5.0 parts by weight of chlorpheniramine maleate, 35.0 parts by weight of maltose, 0.5 parts by weight of sodium saccharin, 0.3 parts by weight of l-menthol, 0.16 parts by weight of fragrance and 59.04 parts by weight of HPC is added and dissolved by stirring to obtain a drug layer solution. Next, the support layer solution is spread and dried on a polyester release film to obtain a film having a thickness of about 18 μm. The drug layer solution is spread thereon and dried to form a film having a thickness of about 50 μm. Finally, the support layer solution is spread thereon and dried to form a film having a thickness of about 18 μm. By laminating in this way, a film of 85.3 μm as a whole was obtained. The obtained film was punched into a square having a side of 16 mm to obtain a fast-dissolving film preparation.
Examples 27 to 30 and Comparative Examples 1 to 4
After laminating the drug layers with the same formulation as in Example 26 so as to have the thickness shown in Table 6, the support layers were laminated to obtain films of each thickness as a whole. The obtained film was punched into a rectangle of 14 × 20 mm to obtain a fast-dissolving film preparation.
[Table 6]

[0021]
Table 7 shows the breaking strength, tensile strength, oral disintegration time and water disintegration time at each thickness of the film-form preparations of Examples and Comparative Examples, and shows the reciprocal of the specific surface area of the film-form preparation at that time. .
[Table 7]

[0022]
【The invention's effect】
The fast-dissolving film preparation of the present invention dissolves easily in the oral cavity even when taken without drinking water, so that it can be safely administered to elderly people and children. Also, since it is easy to take in the supine position (upturned position), it can be administered safely even to bedridden elderly people. Furthermore, since the present preparation is in the form of a thin film, it is advantageous for carrying around. Further, the fast-dissolving film preparation of the present invention can contain a considerably large amount of a drug in which the sum of the drug and the carbohydrate is 25 to 40% by weight based on the whole preparation, and is effective for a drug having a large effective dose. Can be used.
The fast-dissolving film preparation of the present invention is produced by coating. For example, as in the case of the conventional extrusion molding, a lubricant is added, and in order to prevent blocking on the surface of the sheet-like product, powdered sugar, starch, etc. No need to sprinkle or apply a surface coat such as sugar coating and aging at room temperature of 20 ° C. and humidity of 50% for 12 hours, so there is no need to worry about the effect of these lubricants on the formulation. The manufacturing operation is extremely simple, and the cost is also advantageous.
In the case of the coating of the present invention, particularly those having a support layer on both sides of the preparation, the blocking property can be sufficiently avoided, and the visual value of the preparation can be significantly improved.
The coating method of the present invention requires a drying step, but the drying time is typically 60 ° C. for 5 minutes. In this case, a material having low thermal stability can be used. It is possible to obtain the formulation without time and very long aging steps.
The film-form preparation of the present invention uses an edible polymer substance (such as HPC or HPMC) as a film-forming agent. These edible polymer substances have a sufficient film-forming ability. Since the inventive film-form preparation has an appropriate strength, it can be dissolved in the oral cavity promptly (about 60 seconds) without particularly needing to thicken the preparation. And the breaking strength of the film-form preparation of the present invention is 200 to 3000 g / φ7 mm, and the tensile strength of the film is 200 to 3000 g / 15 mm, but within this range, the product is not brittle, and when contained in the mouth, there is no sense of incongruity, It can be used.
[0023]
[Brief description of the drawings]
FIG. 1 shows the dissolution time in the oral cavity and the specific surface area of the film [mm ² / Mg] is a graph showing the relationship with the reciprocal.
FIG. 2 shows the water disintegration time of the fast-dissolving film preparation of the invention and the specific surface area of the film [mm ² / Mg] is a graph showing the relationship with the reciprocal.
FIG. 3 shows the water disintegration time of a film preparation and the specific surface area of the film [mm ² / Mg] is a graph showing a region to be satisfied by the fast-dissolving film preparation of the present invention in a graph showing a relationship with the reciprocal of / mg].
FIG. 4 is a schematic perspective view of a breaking strength measuring device used in the present invention.
FIG. 5 is a schematic perspective view showing a part of a shape and a size of a breaking stress adapter in a breaking strength measuring device.
FIG. 6 is an xx sectional view showing a sectional shape and a size of a lower plate for fixing a test piece of the adapter for breaking stress, a ring placed on the plate, and a test piece in the breaking strength measuring device.
FIG. 7 is a schematic perspective view of a tensile strength measuring adapter of the tensile strength measuring device used in the present invention.
FIG. 8 is a schematic perspective view of a detection unit of a tensile strength measuring device to which an upper adapter is attached.
[Explanation of symbols]
1. Adapter for breaking stress
2. Viscosity adapter
3. Lower plate for fixing test specimen
4. ring
5. Test pieces
6. Intermediate plate for fixing test pieces
7. Upper plate for fixing test specimen
8, 8 '. Set screw
9. substrate
10, 10 '. Prop
11. Adapter fixing screw
12. Test bench
13. Test table vertical movement opening
14． Equidistant scale for moving speed
21. Rod
22. Sphere
31. Adapter for measuring tensile strength of tensile strength measuring device
32. Upper adapter for specimen fixing
33. Lower adapter for specimen fixing
34. Test pieces
35. Upper adapter mounting part
36. Test bench
37. Upper adapter set screw
38. Lower adapter set screw
39. Test table vertical movement opening
40. Equidistant scale for moving speed
41. Detection unit
42. Pointer coarse adjustment knob
43. Pointer fine adjustment knob

Claims

A fast-dissolving film-form preparation containing a drug and an edible polymer substance, having a breaking strength of the film of 200 to 3000 g / φ7 mm, a tensile strength of the film of 200 to 3000 g / 15 mm, and dissolving in the oral cavity within 60 seconds. .

It contains a drug and an edible polymer substance, the breaking strength of the film is 200 to 3000 g / φ7 mm, the tensile strength of the film is 200 to 3000 g / 15 mm, and the water disintegration time Y [second] is within 300 seconds. Te (Y ≦ 300), if the inverse of the specific surface area of the film [mg / mm ^2] was X (X ≧ 0), rapidly soluble film-form preparation in the water disintegration time Y [sec] of ≧ 7500X ² relationship.

3. The fast-dissolving film-form preparation according to claim 1 or 2, wherein the drug is contained such that a single dose is 0.001 to 50 mg, and is soluble or dispersible in a water-ethanol solvent. .

4. The fast-dissolving film-form preparation according to claim 1, wherein the edible polymer substance is hydroxypropylcellulose and / or hydroxypropylmethylcellulose.

The compounding ratio of the drug is 0.01 to 40% by weight based on the whole preparation, and the compounding ratio of the edible polymer substance is 40 to 99.99% by weight based on the whole preparation. The fast-dissolving film-form preparation according to the above.

The fast-dissolving film-form preparation according to claim 1, wherein the film-form preparation comprises a single layer.

6. The fast-dissolving film-form preparation according to claim 1, which has a support layer containing an edible polymer substance on one or both sides of the layer containing the drug.

The edible polymer substance of the support layer is hydroxypropylmethylcellulose, the blending ratio of which is 50% by weight or more. The edible polymer substance of the drug-containing layer is hydroxypropylcellulose, the blending ratio of which is 40 to 99. 8. The fast-dissolving film-form preparation according to claim 1, which is 99% by weight.

The quick-dissolving film-form preparation according to claim 1, further comprising a carbohydrate.

The fast-dissolving film preparation according to claim 9, wherein the sum of the drug and the saccharide is 25 to 40% by weight based on the whole preparation.

Rapidly soluble film preparation according to claim 7, 8, 9 or 10 wherein the water disintegration time Y [sec] is in the relation of 60000X ^² ≧ Y ≧ 7500X ^2.