JP3612011B2 - Drug dissolution test apparatus and test method - Google Patents

Drug dissolution test apparatus and test method Download PDF

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JP3612011B2
JP3612011B2 JP2000260087A JP2000260087A JP3612011B2 JP 3612011 B2 JP3612011 B2 JP 3612011B2 JP 2000260087 A JP2000260087 A JP 2000260087A JP 2000260087 A JP2000260087 A JP 2000260087A JP 3612011 B2 JP3612011 B2 JP 3612011B2
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JP2002071670A (en
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悦子 宮本
千恵子 毎田
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Japan Science and Technology Agency
National Institute of Japan Science and Technology Agency
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【０００１】
【発明の属する技術分野】
本発明は、経皮適用型製剤を設計または評価するに際し、薬物の放出挙動を的確に予測することが可能な薬物溶出試験装置及び試験方法に関するものである。
【０００２】
【従来の技術】
現在、日本薬局方には経皮適用型製剤の薬物放出性の測定及び品質評価を行うための試験方法についての記載は無く、米国薬局方（ＵＳＰ ＸＸＩＶ）のＰａｄｄｌｅ ｏｖｅｒ Ｄｉｓｋ法で実施されている。
【０００３】
【発明が解決しようとする課題】
しかし、この方法では媒質中に製剤を沈めるため、製剤を皮膚に適用した状態を反映できない。また媒質の撹拌はパドル回転数が５０〜１００ｒｐｍで実施されることで撹拌溶出の際に過剰に薬物が放出されることや支持体部分からも薬物が放出がされ、生体適用時の状態とは異なるという問題点が指摘されている。また、特開平８−１１４５８７号公報には製剤と媒質との直接の接触を防止し、支持体部分からの薬物放出に関する欠点を改良したものが開示されているが、媒質中に製剤を置くために皮膚に適用する状態を十分に反映できていない。
【０００４】
【発明が解決しようとする課題】
そこで、本発明は、前記欠点に鑑みてなされたものであって、その目的は、経皮適用型製剤の生体適用時の状態を反映できる薬物溶出試験装置および試験方法を提供することにある。具体的には、媒質中に製剤が存在しないこと、種々の透過性膜及び製剤を簡単に固定でき、膜は媒質に直接に接すること、全身型（吸収型）製剤を評価する場合では媒質の撹拌が血流を反映できること、等の条件を満足できる薬物溶出試験装置および方法を提供することであり、この装置および方法によって放出または透過する薬物量を正確に予測することが可能となる。
【０００５】
【課題を解決するための手段】
このため、本発明が採用した技術解決手段は、
溶出試験を受ける経皮適用型製剤を固定できる開口を有する半円筒状の内容器と、前記内容器を収納し前記内容器の開口と適当な隙間を保持しながら内容器の周りを回転でき媒質を保持攪拌することができる円筒状の外容器と、前記外容器を回転させる駆動装置とを備え、前記内容器の開口は半円筒状の下部に形成され、また前記内容器は前記円筒状の外容器よりも小さい径からなり、前記外容器と同軸となるように配置され、さらに前記外容器の両端板から突出し内容器を固定する軸を備えていることを特徴とする薬物溶出試験装置である。
また、前記内容器の開口には薬物透過性膜を固定する固定板を着脱自在に取り付けることができるようにしたことを特徴とする薬物溶出試験装置である。
また、前記内容器の開口には薬物透過性膜を固定し、その内側に経皮適用型製剤を貼付したことを特徴とする薬物溶出試験装置である。
また、前記内容器は製剤適用部としての下部と、容器固定部としての上部とに２分割して構成され、前記下部には薬物透過性膜を固定する固定板を装着する突出部を有し、さらに上部には内容器を固定する軸を有することを特徴とする薬物溶出試験装置である。
また、前記外容器内に注入する媒質は内・外容器の間に存在し、製剤と直接に接することはなく、また外容器が独立して回転し、試験容器と撹拌装置を兼ねていることを特徴とする薬物溶出試験装置である。
また、前記外容器は内容器挿入のため、一方の端板は開閉式として構成され、且つ開閉部は密封可能に構成されていることを特徴とする薬物溶出試験装置である。
また、前記外容器の端板に形成した内容器の軸貫通用の開口は媒質の注入及び溶出媒質の採取部位を兼ねていることを特徴とする薬物溶出試験装置である。
また、前記駆動装置は前記内容器を固定するための軸を支持する軸支持部を有するとともに、外容器を回転するローラを備え、前記ローラには外容器の横移動を防ぐ位置決め手段を有することを特徴とする薬物溶出試験装置である。
また、前記内容器および外容器はアクリル、プラスチックまたはガラスから構成されることを特徴とする薬物溶出試験装置である。
また、溶出試験を受ける経皮適用型製剤を固定できる開口を有する半円筒状の内容器と、前記円筒状の内容器を収納し前記内容器の開口と適当な隙間を保持しながら内容器の周りを回転でき媒質を保持攪拌することができる円筒状の外容器と、前記外容器を回転させる駆動装置とを備え、前記内容器の開口は半円筒状の下部に形成され、また前記内容器は前記円筒状の外容器よりも小さい径からなり、前記外容器と同軸となるように配置され、さらに前記外容器の両端板から突出し内容器を固定する軸を備えている薬物溶出試験装置を用い、前記内容器の下部に形成した開口に経皮適用型製剤を固定した薬物透過性膜を固定し、この内容器を外容器内に収納し、外容器内に保持した媒質中に前記内容器の開口を浸漬し、製剤が媒質と直接に接することが無いようにして経皮適用型製剤の溶出試験を行うことを特徴とする薬物溶出試験方法である。
また、前記外容器を内容器の周りに回転させ、媒質を攪拌しながら、経皮適用型製剤の溶出試験を行うことを特徴とする薬物溶出試験方法である。
また、前記外容器には外容器に形成した開口から媒質を注入し、さらに前記開口から溶出媒質の採取を行うことを特徴とする薬物溶出試験方法である。
【０００６】
【実施の形態】
本発明の薬物溶出試験装置に係る実施形態を図面を参照して説明すると、図１は本薬物溶出試験装置の全体図、図２は装置組立後の内容器と外容器部の側面図、図３は本薬物溶出試験装置を構成する内容器の斜視図、図４は同内容器の正面図、平面図、側面図、図５は同内容器下部の平面図、側断面図、図６は同内容器上部の平面図、側面図、図７は内容器に薬物透過性膜を固定する固定板の平面図、図８は本薬物溶出試験装置を構成する外容器の斜視図、図９は同外容器の平面図、側面図、図１０は本薬物溶出試験装置の内の駆動装置正面図、平面図、側面図である。
【０００７】
図１において、本薬物溶出試験装置は、経皮適用型製剤を固定することができる内容器１と、試験容器と攪拌装置を兼ねる外容器２と、内容器１の固定と外容器２を回転駆動させるための駆動装置３を備えている。
【０００８】
以下各構成要素毎の詳細を説明すると、内容器１は、図３、図４に示すように、製剤適用部としての下部１ａ、容器固定部としての上部１ｈの２つの部分から構成され、下部１ａは図５に示すように半円筒形状として構成され、中央部には薬物透過性膜を装着するための開口１ｂと、膜装着後、同じ大きさの開口を有する固定板１ｆ（後述する）を着脱固定するための係止突起１ｃおよび上部１ｈを下部１ａに固定できる固定部１ｄが形成されている。
【０００９】
内容器１に薬物透過性膜を固定する固定板１ｆは図７に示すように平板で形成され中央部に下部１ａに形成した開口１ｂと同じ大きさの開口１ｇが形成されている。固定板１ｆは薬物透過性膜を内容器の開口１ｂに固定できるものであれば、材料、形状等は自由に選択することができる。
内容器の上部１ｈは、図３、図４に示すように前記下部１ａの上方に組付けられ、内容器の下部１ａを支持する機能を有しており、図６に示すように下部１ａの上方形状に合った四角形状をしており、四隅には下部１ａに形成された固定部１ｄと着脱係合する係止爪１ｉが形成され、さらに、内容器１を後述する駆動装置側に固定するための軸１ｊが形成されており、軸１ｊは内容器の回転を防止するために断面が四角形に形成されている。
【００１０】
外容器２は、内容器１の外径よりも大きい径を有し、内容器のとの間に適当な隙間を形成し、媒質を保持攪拌できるようにした図８、図９に示すような円筒状に形成され、一方側の端板２ａは開閉可能に、また他方側の端板２ｂは円筒状容器と一体に構成されており、さらに両端板２ａ、２ｂの中央部には前記内容器１に設けた軸１ｊを貫通させることができるとともに、媒質を外容器２内に注入したり溶出媒質の採取を行うための開口２ｃが形成されている。前記開閉可能な端板２ａは、外容器２に対して液密となるようにシール部材（Ｏリング）２ｄで封止可能に構成されており、外容器２内に収納した媒質が外に漏れださぬようになっている。また外容器は後述するローラ３ｂ上に載置され独立して回転し、試験容器と撹拌装置を兼ねることができる構成となっている。
【００１１】
前記内容器１、外容器２、固定板１ｆの材質は、特に限定されないが、内部が観察でき、加工が容易で耐水性、耐酸性、塩基性のアクリル、プラスチック又はガラスが好ましい。また、内容器の下部１ａに形成する開口１ｂの面積は特に限定されないが、薬物透過性膜を直接に固定し、長時間溶出試験を実施でき、製剤を固定できる程度の大きさがあればよい。
【００１２】
駆動装置は、図１０に示すようにモータ（不図示）と、モータによって回転される一対の回転部材３ａ、３ａを備えており、回転部材３ａには前記外容器２を載置しながら外容器２を回転させるためのローラ３ｂが設けられている。前記ローラ３ｂには外容器２の軸方向の位置決めをする位置決めストッパ（位置決め手段）３ｃが形成されている。また駆動装置３には内容器に形成した軸１ｊを保持固定する軸支持部３ｄが形成され、この軸支持部３ｄに、内容器に形成した軸１ｊをネジ３ｅ等によって保持固定することできるようになっている。モータは、操作スイッチ３ｆ等によって駆動することができ、さらに回転数は可変とすることができる構成となっている。
【００１３】
前記のように構成された各構成要素は、外容器２の内部に、内容器１を収納し、外容器２の両側から突出した内容器１の軸１ｊを駆動装置側の軸支持部３ｄに固定し、また外容器２の外周を駆動装置３側のローラ３ｂ上に載置し、図１、図２に示すように組み立てられる。
【００１４】
前記薬物溶出試験装置の作動を説明する。
図２において、内容器１の下部１ａに形成された開口１ｂに薬物透過膜を装着し、同じ大きさに開口された固定板１ｆで固定する。この時固定板１ｆは、内容器の下部１ａの内部に形成された係止突起１ｃに係止される。薬物透過膜に製剤を適用後、内容器の上部１ｈの四隅に形成された係止爪１ｉを内容器の下部１ａの固定部１ｄに係合し、上部１ｈと下部１ａを一体とする。なお、製剤は通気性のサージカルテープで被覆する。また、薬物透過性膜としては、媒質が透過せず、薬物を透過する膜であれば特に限定されない。製剤からの薬物の放出あるいは皮膚を経由して透過する薬物量を測定するので、例えば、前者には疎水分離膜等、後者にはラット等の動物の皮膚、又はこれらに類似する構造をもつシリコン膜などが好ましい。
【００１５】
外容器２の開閉可能な端板２ａを開いて前記内容器１を挿入収納後、端板にＯリング２ｄを装着し外容器２から媒質が漏れぬように端板２ａを固定する。外容器２の両端板２ａ、２ｂの開口２ｃから突出している内容器１の軸１ｊを駆動装置側の軸支持部３ｄにネジ３ｅ等で固定し、また外容器２の外周を駆動装置３側のローラ３ｂ上にセットする。このとき、外容器２はローラ３ｂに形成した位置決めストッパ３ｃにより軸方向への移動が禁止された状態となっている。
【００１６】
外容器２の端板２ａまたは２ｂに形成した開口２ｃから媒質を注入し、駆動装置３のスイッチ３ｆを入れモータを作動して回転部材３ａを回転し、回転部材３ａに設けられているローラ３ｂ上に載置された外容器２を回転させる。試料の採取は外容器２の開口２ｃより、経時的に行い、放出薬物量を測定する。経皮適用型製剤は薬物透過性膜を装着した半円筒形の内容器に固定されており、直接、媒質と接触することなく、空気に十分に触れ、製剤の使用状況を反映できる。また、媒質は試験容器となる外容器が回転することで撹拌されるため、パドルなどの撹拌手段を用いずに薬物溶出試験を行うことができる。なお媒質の液量、回転数は可変である。媒質は内容器１と外容器２の間に存在するため、製剤と接することはなく、外容器２のみが回転することで媒質の緩やかな撹拌を得ることができる。また、試験中は外容器の回転数は一定であるが、必要に応じて可変とすることも可能である。
【００１７】
以上のように本発明の薬物溶出試験装置では、経皮適用型製剤の生体適用時の状態を反映した試験を行うことができる。つまり、媒質中に製剤が存在しないこと、種々の透過性膜及び製剤を簡単に固定でき、膜は媒質に直接に接すること、全身型（吸収型）製剤を評価する場合では媒質の撹拌が血流を反映するものであり、この結果、放出または透過する薬物量を正確に予測することができる。
【００１８】
〔実施例〕次に、本発明の実施例を貼付剤の場合で説明する。
（実施例１）市販製剤ホクナリンテープ３サイズ（北陸製薬株式会社；ツロブテロール：含量０．５，１，２ｍｇ、貼付面積２．５，５，１０ｃｍ２）を用いて本装置により薬物溶出試験を行った。内容器１に液相分離濾紙１ＰＳ（Ｗｈａｔｍａｎ、ＵＫ）を７．５×７．５ｃｍに裁断、装着し、固定板で固定した。液相分離濾紙１ＰＳに製剤を貼付し、サージカルテープ（通気性）で被覆した。内容器１を組み立て、外容器２に挿入し、閉じた。恒温器内（３２±０．５℃）に設置した駆動装置３のローラ３ｂ上に外容器２を置き、内容器１の軸１ｊを駆動装置側に固定した。媒質（生理食塩液）１００ｍＬを外容器２の開口２ｃから注入し、外容器２を回転させた（１０ｒｐｍ）。経時的に開口２ｃより試料を採取し、放出された薬物量を測定した。結果を図１１に示す。ホクナリンテープは膏体（粘着剤）に薬物（ツロブテロール）の一部を結晶状態で共存させる結晶レジポアシステムが採用されている。本試験器で測定した結果、０次の放出を示し、また各種サイズのテープを貼付した実験から単位面積当りの放出量（図１２）が一定であり、製剤の特徴を十分に捉えることができた。また、放出量は各サイズとも８時間で４０％、２４時間で９０％であり、製剤からの薬物放出挙動を評価できた。
【００１９】
（実施例２）ニコチネルＴＴＳ（ノバルティスファーマ株式会社；ニコチン：含量１７．５ｍｇ，放出有効面積１０ ｃｍ２，製剤直径３６ｍｍ）からのニコチンの放出性を同様の方法で検討、８時間で約５５％，２４時間では９０％のニコチンの放出を観察した。本剤はマトリックス型製剤で放出挙動（図１３）からその特徴を評価できた。また、膜としてラット腹部剥離皮膚を用いた皮膚透過実験では約１００分のラグタイム後、０次の放出を観察した（図１４）。２４時間では約４０％と生体での報告と良好な一致を見ており、皮膚を経由して放出される薬物量（吸収量）も評価できることが示された。
【００２０】
以上、本発明の実施の形態について説明してきたが、内容器１は必ずしも２分割する必要はなく、半円筒状の下部１ａ側に軸１ｊを一体に形成することも可能である。また、外容器２への内容器１の挿入方法は、必ずしも外容器２の開閉自在な端板２ａ側からに限定することなく、外容器２を上下に２分割し、内容器１を外容器２内に入れることができるようにしてもよい。ただし、分割部は媒質の漏れが無いようにシールしておく必要がある。内容器１に固定板を固定する手段、内容器の下部１ａと上部１ｈとを固定する手段も実施形態のものに限定することはなく、同様の機能を達成できるものであれば、他の固定手段を使用することもできる。また外容器２を回転する手段もローラに限定することなく、外容器２を回転できる機構、例えばギヤ、ベルト等の伝導手段を使用することも可能である。さらに本発明はその精神または主要な特徴から逸脱することなく、他のいかなる形でも実施できる。そのため、前述の実施形態はあらゆる点で単なる例示にすぎず限定的に解釈してはならない。
【００２１】
【発明の効果】
これまで詳述してきたように本発明の薬物溶出試験装置および方法によれば、経皮適用型製剤の生体適用時の状態を反映できること、つまり、媒質中に製剤が存在しないこと、種々の透過性膜及び製剤を簡単に固定でき、膜は媒質に直接に接すること、全身型（吸収型）製剤を評価する場合では媒質の撹拌が血流を反映することができ、放出または透過する薬物量を正確に予測することができる。そのため製剤設計を効率的に行うことができるという優れた効果を奏することができる。
【図面の簡単な説明】
【図１】本薬物溶出試験装置の全体図である。
【図２】同装置組立後の内容器と外容器部の側面図である。
【図３】本薬物溶出試験装置を構成する内容器の斜視図である。
【図４】同内容器の正面図、平面図、側面図である。
【図５】同内容器下部の平面図、側断面図である。
【図６】同内容器上部の平面図、側面図である。
【図７】内容器に薬物透過性膜を固定する固定板の平面図である。
【図８】本薬物溶出試験装置を構成する外容器の斜視図である。
【図９】同外容器の平面図、側面図である。
【図１０】本薬物溶出試験装置の内の駆動装置正面図、平面図、側面図である。
【図１１】本発明の実施例１の実験結果であり、各種サイズのテープ剤を貼付した実験から、薬物放出量を測定した図である。
【図１２】同実施例１の実験結果であり、各種サイズのテープ剤を貼付した実験から単位面積当りの薬物放出量を求めた図である。
【図１３】本発明の実施例２の実験結果であり、マトリックス型製剤で薬物放出挙動を求めた図である。
【図１４】同実施例２の実験結果であり、膜としてラット腹部剥離皮膚を用いた薬物皮膚透過実験結果である。
【符号の説明】
１ 内容器
１ａ 下部
１ｂ 開口
１ｃ 係止突起
１ｄ 固定部
１ｆ 固定板
１ｇ 開口
１ｈ 上部
１ｉ 係止爪
１ｊ 軸
２ 外容器
２ａ 開閉可能な端板
２ｂ 端板
２ｃ 開口
２ｄ シール部材
３ 駆動装置
３ａ 回転部材
３ｂ ローラ部
３ｃ 位置決めストッパ[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a drug dissolution test apparatus and a test method capable of accurately predicting a drug release behavior when designing or evaluating a transdermally applied preparation.
[0002]
[Prior art]
Currently, the Japanese Pharmacopoeia has no description of the test method for measuring the drug release properties and evaluating the quality of a transdermal preparation, and it is being conducted by the USP XXIV Paddle over Disk method. .
[0003]
[Problems to be solved by the invention]
However, in this method, since the preparation is submerged in the medium, the state in which the preparation is applied to the skin cannot be reflected. Moreover, the stirring of the medium is performed at a paddle rotation speed of 50 to 100 rpm, so that the drug is excessively released during stirring and elution and the drug is also released from the support part. The problem of being different is pointed out. Japanese Patent Application Laid-Open No. 8-114587 discloses that the direct contact between the preparation and the medium is prevented and the drawbacks related to the drug release from the support are improved, but the preparation is placed in the medium. The condition applied to the skin is not fully reflected.
[0004]
[Problems to be solved by the invention]
Therefore, the present invention has been made in view of the above-described drawbacks, and an object of the present invention is to provide a drug dissolution test apparatus and a test method that can reflect the state of a transdermal application-type preparation during biological application. Specifically, there are no preparations in the medium, various permeable membranes and preparations can be easily fixed, the membrane is in direct contact with the medium, and when evaluating a whole body (absorption) preparation, It is to provide a drug elution test apparatus and method that can satisfy the conditions such that agitation can reflect the blood flow, and this apparatus and method can accurately predict the amount of drug released or permeated.
[0005]
[Means for Solving the Problems]
For this reason, the technical solution means adopted by the present invention is:
A semi-cylindrical inner container having an opening capable of fixing a transdermal preparation to be subjected to a dissolution test, and a medium capable of rotating around the inner container while holding the inner container and maintaining an appropriate gap with the opening of the inner container A cylindrical outer container capable of holding and stirring, and a driving device for rotating the outer container, the opening of the inner container is formed in a semi-cylindrical lower part, and the inner container is formed in the cylindrical shape. A drug elution test apparatus characterized in that it has a smaller diameter than the outer container, is arranged so as to be coaxial with the outer container, and further includes a shaft that protrudes from both end plates of the outer container and fixes the inner container. is there.
The drug dissolution test apparatus is characterized in that a fixing plate for fixing the drug permeable membrane can be detachably attached to the opening of the inner container.
Further, the drug elution test apparatus is characterized in that a drug-permeable membrane is fixed to the opening of the inner container, and a transdermal preparation is affixed to the inside thereof.
The inner container is divided into two parts, a lower part as a preparation application part and an upper part as a container fixing part, and the lower part has a protruding part for mounting a fixing plate for fixing a drug permeable membrane. The drug dissolution test apparatus further includes a shaft for fixing the inner container at the upper part.
In addition, the medium to be injected into the outer container exists between the inner and outer containers, does not come into direct contact with the preparation, and the outer container rotates independently and serves as a test container and a stirring device. Is a drug dissolution test apparatus characterized by
In addition, the drug dissolution test apparatus is characterized in that one of the end plates is configured to be openable and the openable portion is configured to be hermetically sealed so that the outer container is inserted into the inner container.
In addition, the drug elution test apparatus is characterized in that the opening for shaft penetration of the inner container formed in the end plate of the outer container also serves as the medium injection and elution medium collection site.
In addition, the drive device includes a shaft support portion that supports a shaft for fixing the inner container, and includes a roller that rotates the outer container, and the roller includes positioning means that prevents lateral movement of the outer container. Is a drug dissolution test apparatus characterized by
The inner container and the outer container may be made of acrylic, plastic, or glass.
In addition, a semi-cylindrical inner container having an opening capable of fixing a transdermally applied preparation to be subjected to a dissolution test, and the inner container having a suitable gap between the opening of the inner container and holding the cylindrical inner container. A cylindrical outer container capable of rotating around and capable of holding and stirring the medium; and a driving device for rotating the outer container, wherein the opening of the inner container is formed in a semi-cylindrical lower portion, and the inner container Is a drug elution test apparatus that has a smaller diameter than the cylindrical outer container, is arranged so as to be coaxial with the outer container, and further includes a shaft that protrudes from both end plates of the outer container and fixes the inner container. Used, a drug permeable membrane having a transdermal preparation fixed thereto is fixed in an opening formed in the lower part of the inner container, the inner container is accommodated in the outer container, and the contents are contained in a medium held in the outer container. Immerse the vessel opening so that the formulation is in direct contact with the medium. It is the drug dissolution test method and performing the dissolution test transdermal application formulations as no Rukoto.
The drug dissolution test method is characterized in that the dissolution test of a transdermal preparation is performed while rotating the outer container around the inner container and stirring the medium.
The drug dissolution test method is characterized in that a medium is injected into the outer container from an opening formed in the outer container, and further, the elution medium is collected from the opening.
[0006]
Embodiment
An embodiment of a drug dissolution test apparatus according to the present invention will be described with reference to the drawings. FIG. 1 is an overall view of the drug dissolution test apparatus, FIG. 2 is a side view of an inner container and an outer container after assembly of the apparatus, and FIG. 3 is a perspective view of an inner container constituting the drug dissolution test apparatus, FIG. 4 is a front view, a plan view and a side view of the inner container, FIG. 5 is a plan view of the lower part of the inner container, a side sectional view, and FIG. FIG. 7 is a plan view of a fixing plate for fixing a drug permeable membrane to the inner container, FIG. 8 is a perspective view of an outer container constituting the drug dissolution test apparatus, and FIG. FIG. 10 is a front view, a plan view, and a side view of a driving device in the drug dissolution test apparatus.
[0007]
In FIG. 1, the drug dissolution test apparatus includes an inner container 1 that can fix a transdermal preparation, an outer container 2 that also serves as a test container and a stirrer, and fixing the inner container 1 and rotating the outer container 2. A driving device 3 for driving is provided.
[0008]
The details of each component will be described below. As shown in FIGS. 3 and 4, the inner container 1 is composed of two parts, a lower part 1a as a preparation application part and an upper part 1h as a container fixing part. As shown in FIG. 5, 1a is formed in a semi-cylindrical shape, and an opening 1b for mounting a drug permeable membrane at the center and a fixing plate 1f having an opening of the same size after mounting the membrane (described later) A locking projection 1c for attaching / detaching and fixing and a fixing portion 1d capable of fixing the upper portion 1h to the lower portion 1a are formed.
[0009]
The fixing plate 1f for fixing the drug permeable membrane to the inner container 1 is formed as a flat plate as shown in FIG. 7, and an opening 1g having the same size as the opening 1b formed in the lower portion 1a is formed at the center. As long as the fixing plate 1f can fix the drug-permeable membrane to the opening 1b of the inner container, the material, shape, etc. can be freely selected.
The upper part 1h of the inner container is assembled above the lower part 1a as shown in FIGS. 3 and 4, and has a function of supporting the lower part 1a of the inner container, and as shown in FIG. It has a quadrilateral shape that matches the upper shape. Locking claws 1i that are detachably engaged with fixing portions 1d formed in the lower portion 1a are formed at the four corners. Further, the inner container 1 is fixed to the drive device side described later. A shaft 1j is formed, and the shaft 1j has a quadrangular cross section to prevent the inner container from rotating.
[0010]
The outer container 2 has a diameter larger than the outer diameter of the inner container 1, and forms an appropriate gap with the inner container so that the medium can be held and stirred as shown in FIGS. It is formed in a cylindrical shape, one end plate 2a is openable and closable, and the other end plate 2b is formed integrally with the cylindrical container, and the inner container is disposed at the center of both end plates 2a and 2b. 1 is formed, and an opening 2c for injecting the medium into the outer container 2 or collecting the elution medium is formed. The openable / closable end plate 2a is configured to be sealed with a sealing member (O-ring) 2d so as to be liquid-tight with respect to the outer container 2, and the medium stored in the outer container 2 leaks outside. It's getting rid of. In addition, the outer container is placed on a roller 3b, which will be described later, and rotates independently, so that it can serve as a test container and a stirring device.
[0011]
The materials of the inner container 1, the outer container 2, and the fixing plate 1f are not particularly limited, but water-resistant, acid-resistant, basic acrylic, plastic, or glass is preferable because the inside can be observed and processing is easy. Moreover, the area of the opening 1b formed in the lower part 1a of the inner container is not particularly limited as long as the drug-permeable membrane can be directly fixed, a long-time dissolution test can be performed, and the preparation can be fixed. .
[0012]
As shown in FIG. 10, the drive device includes a motor (not shown) and a pair of rotating members 3a and 3a rotated by the motor, and the outer container 2 is placed on the rotating member 3a while the outer container 2 is placed thereon. A roller 3b for rotating 2 is provided. The roller 3b is formed with a positioning stopper (positioning means) 3c for positioning the outer container 2 in the axial direction. Further, the driving device 3 is formed with a shaft support portion 3d for holding and fixing the shaft 1j formed on the inner container, and the shaft 1j formed on the inner container can be held and fixed to the shaft support portion 3d by a screw 3e or the like. It has become. The motor can be driven by the operation switch 3f and the like, and the rotation speed can be made variable.
[0013]
Each component configured as described above houses the inner container 1 inside the outer container 2, and the shaft 1j of the inner container 1 protruding from both sides of the outer container 2 serves as a shaft support portion 3d on the drive device side. The outer periphery of the outer container 2 is mounted on the roller 3b on the drive device 3 side, and assembled as shown in FIGS.
[0014]
The operation of the drug dissolution test apparatus will be described.
In FIG. 2, a drug permeable membrane is attached to the opening 1b formed in the lower portion 1a of the inner container 1, and fixed with a fixing plate 1f opened to the same size. At this time, the fixing plate 1f is locked to a locking projection 1c formed inside the lower portion 1a of the inner container. After the formulation is applied to the drug permeable membrane, the locking claws 1i formed at the four corners of the upper part 1h of the inner container are engaged with the fixing parts 1d of the lower part 1a of the inner container, so that the upper part 1h and the lower part 1a are integrated. The preparation is covered with a breathable surgical tape. Further, the drug permeable membrane is not particularly limited as long as it is a membrane that does not allow the medium to permeate and permeates the drug. Since the amount of drug released from the preparation or the amount of drug permeating through the skin is measured, for example, the former is a hydrophobic separation membrane, the latter is the skin of an animal such as a rat, or silicon having a structure similar to these. A membrane or the like is preferred.
[0015]
After opening and closing the end plate 2a that can be opened and closed of the outer container 2 and inserting and storing the inner container 1, an O-ring 2d is attached to the end plate and the end plate 2a is fixed so that the medium does not leak from the outer container 2. The shaft 1j of the inner container 1 protruding from the openings 2c of the both end plates 2a and 2b of the outer container 2 is fixed to the shaft support portion 3d on the driving device side with screws 3e and the outer periphery of the outer container 2 is connected to the driving device 3 side. Set on the roller 3b. At this time, the outer container 2 is in a state where movement in the axial direction is prohibited by the positioning stopper 3c formed on the roller 3b.
[0016]
A medium is injected from an opening 2c formed in the end plate 2a or 2b of the outer container 2, a switch 3f of the driving device 3 is turned on, a motor is operated to rotate the rotating member 3a, and a roller 3b provided on the rotating member 3a The outer container 2 placed on the top is rotated. The sample is collected from the opening 2c of the outer container 2 over time, and the amount of released drug is measured. The transdermal preparation is fixed to a semi-cylindrical inner container equipped with a drug permeable membrane, and can directly touch the air without direct contact with the medium and reflect the use state of the preparation. Further, since the medium is stirred by the rotation of the outer container serving as the test container, the drug elution test can be performed without using a stirring means such as a paddle. Note that the amount of liquid and the number of rotations of the medium are variable. Since the medium exists between the inner container 1 and the outer container 2, it does not come into contact with the preparation, and only the outer container 2 rotates, so that the medium can be gently stirred. Further, the rotational speed of the outer container is constant during the test, but it can be varied as necessary.
[0017]
As described above, in the drug dissolution test apparatus of the present invention, it is possible to perform a test reflecting the state at the time of application of the transdermal preparation to the living body. In other words, the absence of the preparation in the medium, various permeable membranes and preparations can be easily fixed, the membrane is in direct contact with the medium, and when the whole body (absorption) preparation is evaluated, the agitation of the medium is blood. As a result, the amount of drug released or permeated can be accurately predicted.
[0018]
[Example] Next, an example of the present invention will be described in the case of a patch.
(Example 1) A drug dissolution test was conducted with this apparatus using commercially available formulation Hokunarin tape 3 size (Hokuriku Pharmaceutical Co., Ltd .; Tulobuterol: content 0.5, 1, 2 mg, application area 2.5, 5, 10 cm 2 ). It was. Liquid phase separation filter paper 1PS (Whatman, UK) was cut into 7.5 × 7.5 cm and attached to the inner container 1 and fixed with a fixing plate. The preparation was affixed to the liquid phase separation filter paper 1PS and covered with surgical tape (breathability). The inner container 1 was assembled, inserted into the outer container 2, and closed. The outer container 2 was placed on the roller 3b of the driving device 3 installed in the thermostat (32 ± 0.5 ° C.), and the shaft 1j of the inner container 1 was fixed to the driving device side. 100 mL of a medium (saline solution) was injected from the opening 2c of the outer container 2, and the outer container 2 was rotated (10 rpm). A sample was taken from the opening 2c over time, and the amount of drug released was measured. The results are shown in FIG. Hokunarin tape employs a crystal repore system in which a part of a drug (tulobuterol) coexists in a crystalline state in a plaster (adhesive). As a result of measuring with this tester, it shows zero-order release, and the amount of release per unit area (Figure 12) is constant from the experiment with tapes of various sizes, and the characteristics of the preparation can be fully understood. It was. The release amount was 40% for 8 hours and 90% for 24 hours for each size, and the drug release behavior from the preparation could be evaluated.
[0019]
Example 2 Nicotine release from Nicotinel TTS (Novatis Pharma Inc .; Nicotine: content 17.5 mg, effective release area 10 cm 2 , formulation diameter 36 mm) was examined in the same manner, about 55% in 8 hours. , 90% nicotine release was observed at 24 hours. This drug was a matrix-type preparation and its characteristics could be evaluated from the release behavior (FIG. 13). Further, in a skin permeation experiment using rat abdomen exfoliated skin as a membrane, zero-order release was observed after a lag time of about 100 minutes (FIG. 14). In 24 hours, about 40% was found to be in good agreement with the report in vivo, and it was shown that the amount of drug released through the skin (absorption amount) can also be evaluated.
[0020]
Although the embodiment of the present invention has been described above, the inner container 1 is not necessarily divided into two, and the shaft 1j can be integrally formed on the semi-cylindrical lower portion 1a side. Further, the method of inserting the inner container 1 into the outer container 2 is not necessarily limited to the side of the end plate 2a that can be freely opened and closed. 2 may be included. However, it is necessary to seal the dividing portion so that there is no leakage of the medium. The means for fixing the fixing plate to the inner container 1 and the means for fixing the lower part 1a and the upper part 1h of the inner container are not limited to those of the embodiment, and other fixings are possible as long as the same function can be achieved. Means can also be used. Further, the means for rotating the outer container 2 is not limited to a roller, and a mechanism capable of rotating the outer container 2 such as a transmission means such as a gear or a belt can be used. Furthermore, the present invention may be implemented in any other form without departing from the spirit or main features thereof. Therefore, the above-described embodiment is merely an example in all respects and should not be interpreted in a limited manner.
[0021]
【The invention's effect】
As described in detail so far, according to the drug dissolution test apparatus and method of the present invention, it is possible to reflect the state of the transdermal preparation at the time of biological application, that is, the absence of the preparation in the medium, Drug membranes and formulations can be easily fixed, the membrane can be in direct contact with the medium, and when evaluating whole body (absorption) formulations, the agitation of the medium can reflect blood flow, and the amount of drug released or permeated Can be accurately predicted. Therefore, the outstanding effect that a formulation design can be performed efficiently can be produced.
[Brief description of the drawings]
FIG. 1 is an overall view of the drug dissolution test apparatus.
FIG. 2 is a side view of the inner container and the outer container after assembly of the apparatus.
FIG. 3 is a perspective view of an inner container constituting the drug dissolution test apparatus.
FIG. 4 is a front view, a plan view, and a side view of the inner container.
FIG. 5 is a plan view and a side sectional view of the lower part of the inner container.
FIG. 6 is a plan view and a side view of the upper part of the inner container.
FIG. 7 is a plan view of a fixing plate for fixing a drug permeable membrane to the inner container.
FIG. 8 is a perspective view of an outer container constituting the drug dissolution test apparatus.
FIG. 9 is a plan view and a side view of the outer container.
FIG. 10 is a front view, a plan view, and a side view of a driving device in the drug dissolution test apparatus.
FIG. 11 shows the experimental results of Example 1 of the present invention, in which the amount of drug released was measured from an experiment in which tapes of various sizes were affixed.
FIG. 12 shows the experimental results of Example 1, in which the amount of drug released per unit area was obtained from an experiment in which tapes of various sizes were affixed.
FIG. 13 shows the experimental results of Example 2 of the present invention, and shows the drug release behavior obtained with a matrix-type preparation.
FIG. 14 shows the experimental results of Example 2, which are drug skin permeation experimental results using rat abdomen exfoliated skin as a membrane.
[Explanation of symbols]
DESCRIPTION OF SYMBOLS 1 Inner container 1a Lower part 1b Opening 1c Locking protrusion 1d Fixing part 1f Fixing plate 1g Opening 1h Upper part 1i Locking claw 1j Shaft 2 Outer container 2a End plate 2b which can be opened and closed End plate 2c Opening 2d Seal member 3 Drive device 3a Rotating member 3b Roller part 3c Positioning stopper

Claims (12)

溶出試験を受ける経皮適用型製剤を固定できる開口を有する半円筒状の内容器と、前記内容器を収納し前記内容器の開口と適当な隙間を保持しながら内容器の周りを回転でき媒質を保持攪拌することができる円筒状の外容器と、前記外容器を回転させる駆動装置とを備え、前記内容器の開口は半円筒状の下部に形成され、また前記内容器は前記円筒状の外容器よりも小さい径からなり、前記外容器と同軸となるように配置され、さらに前記外容器の両端板から突出し内容器を固定する軸を備えていることを特徴とする薬物溶出試験装置。A semi-cylindrical inner container having an opening capable of fixing a transdermally applied preparation to be subjected to a dissolution test, and a medium capable of rotating around the inner container while holding the inner container and maintaining an appropriate gap from the opening of the inner container A cylindrical outer container capable of holding and stirring, and a driving device for rotating the outer container, the opening of the inner container is formed in a semi-cylindrical lower part, and the inner container is formed in the cylindrical shape. A drug elution test apparatus characterized in that it has a smaller diameter than the outer container, is arranged so as to be coaxial with the outer container, and further includes a shaft that protrudes from both end plates of the outer container and fixes the inner container. 前記内容器の開口には薬物透過性膜を固定する固定板を着脱自在に取り付けることができるようにしたことを特徴とする請求項１に記載の薬物溶出試験装置。The inner container fixing plate removably attached to a drug dissolution test apparatus mounting serial to claim 1 you, characterized in that to allow to fix the drug permeable membrane in the opening of. 前記内容器の開口には薬物透過性膜を固定し、その内側に経皮適用型製剤を貼付したことを特徴とする請求項１または請求項２に記載の薬物溶出試験装置。The drug elution test apparatus according to claim 1 or 2 , wherein a drug-permeable membrane is fixed to the opening of the inner container, and a transdermally applied preparation is affixed to the inside thereof. 前記内容器は製剤適用部としての下部と、容器固定部としての上部とに２分割して構成され、前記下部には薬物透過性膜を固定する固定板を装着する突出部を有し、さらに上部には内容器を固定する軸を有することを特徴とする請求項１〜請求項３のいずれかに記載の薬物溶出試験装置。The inner container is divided into two parts, a lower part as a preparation application part and an upper part as a container fixing part, and the lower part has a protruding part to which a fixing plate for fixing a drug permeable membrane is attached, The drug dissolution test apparatus according to any one of claims 1 to 3 , further comprising a shaft for fixing the inner container at an upper part. 前記外容器内に注入する媒質は内・外容器の間に存在し、製剤と直接に接することはなく、また外容器が独立して回転し、試験容器と撹拌装置を兼ねていることを特徴とする請求項１〜請求項４のいずれかに記載の薬物溶出試験装置。The medium to be injected into the outer container exists between the inner and outer containers, does not come into direct contact with the preparation, and the outer container rotates independently and serves as a test container and a stirring device. The drug dissolution test apparatus according to any one of claims 1 to 4 . 前記外容器は内容器挿入のため、一方の端板は開閉式として構成され、且つ開閉部は密封可能に構成されていることを特徴とする請求項１〜請求項５のいずれかに記載の薬物溶出試験装置。The said outer container is an inner container insertion, and one end plate is comprised as an openable type, and the opening-and-closing part is comprised so that sealing is possible, The any one of Claims 1-5 characterized by the above-mentioned. Drug dissolution test equipment. 前記外容器の端板に形成した内容器の軸貫通用の開口は媒質の注入及び溶出媒質の採取部位を兼ねていることを特徴とする請求項１〜請求項６のいずれかに記載の薬物溶出試験装置。7. The drug according to claim 1, wherein the inner container opening formed in the end plate of the outer container also serves as a medium injection and elution medium collection site. Dissolution test equipment. 前記駆動装置は前記内容器を固定するための軸を支持する軸支持部を有するとともに、外容器を回転するローラを備え、前記ローラには外容器の横移動を防ぐ位置決め手段を有することを特徴とする請求項１〜請求項７のいずれかに記載の薬物溶出試験装置。The drive device includes a shaft support portion that supports a shaft for fixing the inner container, and includes a roller that rotates the outer container, and the roller includes positioning means that prevents lateral movement of the outer container. The drug dissolution test apparatus according to any one of claims 1 to 7 . 前記内容器および外容器はアクリル、プラスチックまたはガラスから構成されることを特徴とする請求項１〜請求項８のいずれかに記載の薬物溶出試験装置。The drug dissolution test apparatus according to any one of claims 1 to 8 , wherein the inner container and the outer container are made of acrylic, plastic, or glass. 溶出試験を受ける経皮適用型製剤を固定できる開口を有する半円筒状の内容器と、前記円筒状の内容器を収納し前記内容器の開口と適当な隙間を保持しながら内容器の周りを回転でき媒質を保持攪拌することができる円筒状の外容器と、前記外容器を回転させる駆動装置とを備え、前記内容器の開口は半円筒状の下部に形成され、また前記内容器は前記円筒状の外容器よりも小さい径からなり、前記外容器と同軸となるように配置され、さらに前記外容器の両端板から突出し内容器を固定する軸を備えている薬物溶出試験装置を用い、前記内容器の下部に形成した開口に経皮適用型製剤を固定した薬物透過性膜を固定し、この内容器を外容器内に収納し、外容器内に保持した媒質中に前記内容器の開口を浸漬し、製剤が媒質と直接に接することが無いようにして経皮適用型製剤の溶出試験を行うことを特徴とする薬物溶出試験方法。A semi-cylindrical inner container having an opening capable of fixing a transdermal preparation for undergoing a dissolution test, and a space around the inner container while holding the cylindrical inner container and maintaining an appropriate clearance from the opening of the inner container A cylindrical outer container capable of rotating and holding and stirring the medium; and a driving device for rotating the outer container, wherein the opening of the inner container is formed in a semi-cylindrical lower portion, and the inner container is Using a drug elution test apparatus that has a smaller diameter than the cylindrical outer container, is arranged to be coaxial with the outer container, and further includes shafts that protrude from both end plates of the outer container and fix the inner container, A drug permeable membrane having a transdermally applied formulation fixed thereto is fixed to an opening formed in a lower portion of the inner container, the inner container is accommodated in the outer container, and the inner container is placed in a medium held in the outer container. Immerse the openings so that the product is in direct contact with the medium. Drug dissolution test method and performing the dissolution test transdermal application formulations as no. 前記外容器を内容器の周りに回転させ、媒質を攪拌しながら、経皮適用型製剤の溶出試験を行うことを特徴とする請求項１０に記載の薬物溶出試験方法。The drug dissolution test method according to claim 10 , wherein the dissolution test of a transdermal preparation is performed while rotating the outer container around the inner container and stirring the medium. 前記外容器には外容器に形成した開口から媒質を注入し、さらに前記開口から溶出媒質の採取を行うことを特徴とする請求項１０または請求項１１のいずれかに記載の薬物溶出試験方法。12. The drug elution test method according to claim 10 , wherein a medium is injected into the outer container from an opening formed in the outer container, and further, the elution medium is collected from the opening.
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