JP2005501097A - Inflatable gastric retention device - Google Patents

Abstract

The present application relates to an intragastric stomach formed from a composition containing a polymeric material, such as a polysaccharide, and selective additional materials, including excipients, therapeutic agents and diagnostic agents, which remains in the stomach for a controlled duration. It relates to a retention device.

Description

【００７３】
異なるサイズおよび形状に切り出されたフィルムを、水または胃液中で水和させた。水和研究はまた、比較のために希釈した胃液中で（1部のSGFおよび3部の水）実行した。円形、星形、立方体、長方形、三角形などの形状が研究された。
【００７４】
研究されたすべての形状のうちで、いくぶん平らに、一般的には長方形のフィルムに乾燥させた、高さ、幅、および奥行きは一様でなくかつ不均一な立方体形状のゲルが、最も速い膨潤および最大容積を有することが見い出され、またより大きいゲル強度を有した。しかし、カプセルに最も容易に組み込まれるサイズの研究に基づくと、好ましい形状は、乾燥前で約4cm×4cm×1cmの次元を有する長方形ゲル形状であった。
【００７５】
キサンタンガム対イナゴマメガムの種々の固体比率のゲルを表1に示すように作製し、フィルムに乾燥した。水または人工胃液中での24時間のフィルムの完全な水和を、それぞれ図1および図2に示す。水または人工胃液中の初期のフィルムの水和を、それぞれ図3および図4に示す。カプセルまたは錠剤を空の胃で消化した場合、胃から腸へ通る時間の長さは、MMC（移動性強収縮運動）の到達時間に依存して、数分から2時間までの範囲にわたり得る。カプセル中に取り込まれたGRDは理想的にはカプセルが溶解するとすぐに水和を開始するべきであり、かつ幽門括約筋を経由しての通過を避けるために15〜20分間以内十分に大きなサイズを保持するべきである。水和ゲルの構造的な統合性はMMCに抵抗するに十分であるべきである。従って、初期の水和速度および構造的な統合性は非常に重要である。
【００７６】
（表１）XG／LBGフィルムの組成

水和研究プロファイルおよびゲル強度に基づいて、50：50比率を有するゲルをさらなる修飾のために考慮した。ゲル強度は、水和の間のフィルムの視覚的な観察に基づき、およびフィルムの水和後に形成されたゲルの物理的試験によった。
【００７７】
図1〜図4に示されるように、SGF中のフィルムの水和は広範であるが、水中でのそれよりも比較的小さいものである。水中での水和はSGF中よりも約10倍大きい。それゆえに、SGF中でフィルムをより速くかつより大きなサイズにまで膨潤させるために、緩衝剤リン酸二ナトリウムまたはリン酸ナトリウムの添加が試験された。リン酸二ナトリウムまたはリン酸ナトリウムを含む（ガム固体の2倍量）フィルムは、約12時間でSGF中で完全に膨潤する。12時間後、水和研究のために使用されるSGF（約500ml容量）は、pH 6.8を有することが見い出された。インビボでは、一次プロセスにおいて胃から除去された液体とともに、胃酸の連続的な分泌が存在する。それゆえに、胃におけるpHはインビトロ（ここでは酸の量が固定されている）におけるように6.8には到達しない。しかし、フィルムが水和するときのフィルム内部の微小環境のpHは、アルカリまたは中性にとどまり得、かつ胃のpHを有意に変化させることなく胃液中での迅速な膨潤を促進し得る。アルカリ化剤の添加に対する1つの制限は、アルカリ化剤の量とフィルムを圧縮してカプセルに組み込む能力との間の相関が存在することである。25％の人工胃液および75％の水を含む媒体中でのフィルムの水和は、胃液単独と比較して顕著に改善した。医薬品は水とともに取り込まれる。従って、3：1の水：SGF媒体において行われた水和研究は、GRDが8〜10オンスの水とともに取り込まれた場合に予測された状態を模倣する。
【００７８】
ポリエチレンオキシド、カルボキシメチルセルロース（CM）、および／またはウォーター/ロック（Water/Loc)（登録商標）のような他の添加物の、ゲル形成の間のゲルへの添加は、SGF中のフィルムの初期の水和を改善するために使用した。表2は、異なる添加物を含む種々の製剤を示す。上記に言及したすべての研究は、規則的な時間間隔の後にフィルムの水和の視覚的検査によって評価した。
【００７９】
ゲルはもろくなり過ぎてカプセル中に配置するために成形または圧縮することができなくなり得る。ゲルへのポリエチレングリコール（PEG）の添加は、ゲル乾燥後によりしなやかなフィルムを生成する。
【００８０】
B．他の実施例において、水和研究は以下の方法に従って実行した。
実施例1Bの方法に従って、XG、LBG、PVP、SLS、およびPEG400から作製された4つの異なる形状の乾燥ゲル（フィルム）での水和研究を、37℃の人工胃液中で行った。乾燥ゲルは、成分を水中に溶解することによって調製した。次いで、混合物を85℃で加熱し、この熱い粘性溶液10mlを異なる形状の型に流し込み、所望の形状を作製した。これら4つの形状は、立方体、長方形、短い円筒形、および長い円筒形であった。次いで、ゲルを乾燥させ、水和研究に供した。
【００８１】
（表２）GRDの開発の間に水和について研究した種々の製剤の例（全体のパーセント）

【００８２】
4つの異なる形状を人工胃液中で水和させた。試験したGRDの次元および形状を図5に示す。水和フィルムの重量％の増加は、15分、30分、45分、60分、120分、および180分後に測定し、12時間および24時間後に再度測定した。
【００８３】
水和フィルムは人工胃液中で24時間までそれらの統合性を保持していた。研究したすべての形状のうちで、ほぼ平らな長方形フィルムに乾燥させた長方形形状のゲルが、最も速い膨潤および最大体積を有することが見い出された。この研究に基づいて、長方形形状がさらなるインビトロおよびインビボでの研究のために選択された。
【００８４】
人工胃液（SGI）中のフィルムの24時間までの完全な水和を図6に示す。SGF中でのフィルムの初期の水和を図7に示す。初期の水和は、GRDの開発への非常に重要な因子である。理想的には、容易な嚥下のためのカプセルを組み込むために十分に小さいが、胃液との接触に際して幽門を通過するには大きすぎるサイズまで膨張する装置を作製することが最もよい。特定の適用のために、この大きなサイズへの膨潤は、約5〜15分間続く、ハウスキーパー波（housekeeper wave）の強力な収縮による胃内容排出を避けるために、速く（例えば、約15〜約30分間）あるべきである。従って、放出された乾燥ゲルの迅速な膨潤および膨潤したゲルの統合性は、非常に重要である。
【００８５】
実施例5
この節は、診断剤または治療剤のGRDへの取り込みのための方法に関する。
【００８６】
A．アモキシシリンを、カプレット形状を有する錠剤の形態で、実施例1A、IV節からのGRDに取り込んだ。アモキシシリンは、モデル薬物として選択した。なぜなら、これが「吸収の窓」を有するからである。
【００８７】
実施例1A、IV節において記載された方法によって調製されたガムの熱い粘性溶液を適切な型に流し込み、その結果ゲルに取り込まれた錠剤はゲルに懸濁されたままになる。次いで、この錠剤含有ゲルを、所望のサイズに切り分けた。12〜18時間の乾燥の後に、錠剤を含有するこれらの乾燥フィルムを、液圧プレスを用いてパンチおよびダイスで圧縮し、「000」号カプセルに組み込んだ。
【００８８】
B．リボフラビンを、粉末、ビーズ、または固体分散物の形態で、実施例1BからのGRDに取り込んだ。ゲルへの冷却の直前に熱い、粘性の混合物に攪拌することによってゲル中に取り込まれたリボフラビンは、ゲル中に懸濁されたままであった。薬物のビーズ、粉末、または固体分散物を含む乾燥したゲル（フィルム）は、容易にロールされ、適切なサイズのカプセルに組み込まれた。次いで、薬物のビーズ、粉末、または固体分散物を含むGRDは、インビトロ溶解および／またはインビボ研究に供せられた。
【００８９】
実施例6
この節は、GRDとの使用のためのアモキシシリンカプレットおよび「コア」カプレットの調製に関する。
【００９０】
アモキシシリンカプレットを、表3に列挙した成分と合わせることによって調製し、直接的な圧縮によって形成させた。
【００９１】
（表３）アモキシシリンカプレットのための製剤

【００９２】
アモキシシリン「コア」カプレットを形成するために、アモキシシリンカプレットを、より大きなダイスおよびパンチ中に、微結晶セルロースとともに中心に置き、アモキシシリンカプレットが微結晶セルロースによって形成されるシェルの内側にあるように再度圧縮する。このように形成された新しいカプレットは、コアとしてアモキシシリンカプレットを有し、これは、「コア錠剤」または「錠剤内錠剤」として一般に知られるものである。
【００９３】
実施例7
この節は、GRDを伴う使用のためのリボフラビン製剤の調製に関する。
【００９４】
リボフラビンは、粉末、ビーズ、または固体分散物の形態でGRD中に取り込まれた。リボフラビンビーズは、既知の量のリボフラビン、アビセルPH−101、およびポリエチレンオキシド200，000を水と混合して湿った塊を産生することによって調製した。次いで、実験室用押し出し機（モデル10/25）および球状成形機（モデル120、Caleva Process LTD、England）を使用して、この塊を押し出しかつ球状に成形し、薬物ビーズを作製した（直径1.5〜2.0nm）。このビーズを、50℃のオーブン中で一晩乾燥させたままにした。ゲルへの冷却の直前に、熱く粘性の混合物に攪拌することによってゲルに取り込まれたビーズは、ゲルに懸濁されたままであった。
【００９５】
リボフラビンビーズを、表4に示した製剤を用いて押しだしおよび球状成形によって調製した。粉末形態で使用される場合、湿気を除去するためにリボフラビンを2時間120℃で乾燥させ、その後ゲルに取り込んだ。
【００９６】
（表４）リボフラビンビーズの製剤

【００９７】
リボフラビン固体分散物を、秤量した量のPEG3500を蒸発皿中で融解することによって調製した。次いで、秤量した量の薬物を、薬物：PEGの所望の比率（1：3）を生じるように添加した。この系を、薬物の完全な溶解が達成されるまで加熱した。次いで、蒸発皿をアイスバスに移し、材料が冷却されるまで攪拌した。最終的な固形の塊を破壊し、粉砕し、ふるいにかけて、微細な粉末を生成した。調製された固体分散物を、真空オーブン中で一晩、室温で乾燥させ、その後ゲルに取り込んだ。
【００９８】
実施例8
この節は、診断剤および／または治療剤を含むGRDで実行される溶解研究に関する。
【００９９】
A．この実施例は、錠剤の形態の治療剤がポリサッカリドから形成された胃内滞留装置に取り込まれ得ること、およびこの装置が被験体への投与のために適切なサイズに形成され得、胃液によって浸食される接種可能なカプセル中に入れられることを実証する。溶解研究は、実施例1A、IV節の方法に従って作製されたGRDを用いて実行され、モデル薬物アモキシシリンまたはラニチジンHClを含み、USP XXIIパドル法を、37℃、75rpm、20時間で使用した。溶解媒体は、900mlの人工胃液（酵素を含まない）からなった。試料は、等量の媒体と置き換えて、0.5時間、1時間、2時間、3時間、4時間、6時間、8時間、12時間、および20時間に収集した。試料を、アモキシシリンの場合には、HPダイオードアレイ分光光度計を使用して280nmで、ラニチジンHCl（ザンタック（Zantac）（登録商標））の場合には、219nmで、アッセイした。
【０１００】
GRDに含まれるa）アモキシシリンまたはb）ラニチジンHClの錠剤の溶解研究を、製剤単独を使用した場合と比較した。アモキシシリンカプレットを実施例6に概説したように作製した。GRDにおける同じ製剤と比較した、アモキシシリン即時放出（IR）錠剤の溶解パターンを図8に示す。アモキシシリンIRは1時間以内に80％の薬物を放出したが、10％のみの薬物放出がGRDから1時間で生じ、80％放出は12時間まで到達しなかった。GRDに取り込まれたIR錠剤からの薬物の放出パターンは0次であった。
【０１０１】
コア錠剤を含むGRDからの溶解に対する、コア錠剤（微結晶セルロースシェル中に埋め込まれたアモキシシリンカプレット）からのアモキシシリンの溶解を、図9に提示される。アモキシシリンのコア錠剤は1時間以内で80％の薬物を放出するのに対して、GRD内部のコア錠剤からの薬物の放出は24時間0次であり、薬物の80％放出は約20時間にわたった。
【０１０２】
即時放出の市販のラニチジンHCl（ザンタック（登録商標）150）の錠剤からの溶解の、GRDに取り込まれた同一の錠剤の溶解に対する比較を図10に提示する。GRD中ではないザンタック（登録商標）150からの完全な薬物の溶解は1時間を要したが、GRD中の錠剤からの80％薬物放出は最初の7時間で観察されたのみであった。
【０１０３】
B．溶解研究は、モデル薬物リボフラビンを含み、米国薬局方（USP）XXIIパドル法を37℃、50rpm、24時間で使用した実施例1Bの方法に従って調整したGRDで実行した。溶解媒体は、900mlの人工胃液（酵素を含まない）からなった。試料は、1、2、4、6、8、10、12、16、20、および24時間に収集した。試料を、HPダイオードアレイ分光光度計を使用して446nmで、リボフラビンについてアッセイした。
【０１０４】
GRD（通常または修飾）に含まれるリボフラビンのビーズ、粉末、および固体分散物の溶解研究を、等量のビタミンを含む即時放出カプセルと比較した。すべての研究において、リボフラビンの量は50mgと等価であり、使用されるGRDは長方形形状であった（3^＊1.5^＊1）。サイズ「0」号カプセルは即時放出製剤とGRD製剤の両方を取り込むために使用した。
【０１０５】
通常のGRDからの溶解：
長方形形状の通常のGRDに含まれるリボフラビンビーズの溶解と比較した、カプセル中に含まれるリボフラビンビーズ溶解のパターンを図11に示す。リボフラビンビーズは9時間以内に100％の薬物を放出したが、しかし、5時間で8％のみの薬物放出が通常のGRDから生じ、24時間で約30％の放出が生じた。通常のGRDからの薬物のこの放出パターンは、ほぼ0次であった。
【０１０６】
即時放出カプセル（50mgリボフラビン＋200mg乳糖）からのリボフラビン粉末の溶解を、同じ量のリボフラビン粉末を含む通常のGRDからの溶解と比較した。リボフラビンの即時放出カプセルは約1時間で100％の薬物を放出したのに対して、カプセル中のGRDは24時間で約50％の薬物を放出した。通常のGRDからのリボフラビン粉末の放出はまた、ほぼ0次であった。
【０１０７】
修飾GRDからの溶解：
調製された修飾GRDを使用して、薬物放出の速度および量を変化させた。修飾GRDは、PVPおよびSLSを含む点で通常のGRDとは異なる。修飾GRDからのリボフラビン粉末の溶解を図12に示す。修飾GRDは24時間で約65％の薬物を放出した。放出のパターンはまた0次に見えた。修飾GRDからの溶解の増加は、疎水性ポリマーPVPおよび界面活性剤SLSの存在に起因し得る。PVPとSLSの両方が、ハイドロゲルからのビタミンの拡散を補助した可能性がある。製剤中のPVPおよびSLSの存在はまた、PVPおよびSLSを有しない製剤からの通常のフィルムと比較した場合に、より容易にカプセルに組み込まれた、より可撓性の乾燥フィルムを生成した。この可撓性の増加はカプセル中でのより大きなGRDの組み込みを容易にする。
【０１０８】
修飾GRDからのリボフラビンおよびPEG3500（比率1：3）の固体分散物の溶解を図13に示す。薬物の100％がこの製剤から24時間で放出されたが、しかしGRDは約6時間でその統合性を喪失したことが観察された。
【０１０９】
リボフラビンおよびPEG3500の固体分散物が熱い粘性ガム溶液に添加される場合に、ゲルを乾燥させたときに柔らかいフィルムが生成した。時折、GF中では水和後に、このゲルは崩壊して断片化した。
【０１１０】
実施例9
この節は、イヌにおけるGRDのインビボ試験のための被験体に関する。
【０１１１】
A．実施例1A、IV節に従って作製したGRDのインビボ試験のための被験体
2匹の雑種のイヌ（2.5才および5才）を、異なるサイズおよび形状のGRDの胃の滞留時間を研究するために使用した。この動物は、オレゴン州立大学獣医学部の動物研究実験室に置かれ、2週間、缶入りのタンパク質食餌（d/d Hills）で飼育した。この動物を個別のおりに入れ、これは、イヌの自由な動きおよび通常の活動を合理的に許容し、従って通常の胃腸の運動性が予想された。
【０１１２】
B．実施例1Bに従って作製されたGRDのインビボ試験のための被験体
この研究は、2匹の成犬のジャーマンシェパード犬（8〜9才）で行った。これらは、市販の餌で飼育され、オレゴン州立大学獣医学部の動物研究実験室に置かれた。これらは、清掃を容易にするためのスロープを付したコンクリートの床を覆う、ラバー製の金網のある、小さな隣接する個別のおりに入れられた。この動物のおりは、イヌの自由な動きおよび通常の活動のための妥当な空間を許容し、従って、通常の胃腸の動きが存在する。この飼育領域は、日中には光が当たった状態に、夜間は暗く保たれた。
【０１１３】
実施例10
この節は、イヌにおけるGRDのインビボ試験のための被験体の剤形および用量に関する。
【０１１４】
A．実施例1A、IV節に従って作製したGRDのインビボ試験のための剤形
GRDを、実施例9Aに記載されるように被験体に投与した。サイズ「0」号のカプセルに取り込まれた4つの異なる形態のGRDを使用した。「000」号カプセルに取り込まれた7×1.5×1cmの長方形形状のGRDもまた、これらの研究において試験した。すべての剤形はX線による可視化のために放射線不透過性のスレッドを含んだ。
【０１１５】
サイズ「0」号のカプセルに取り込まれた4つの異なる形状のGRDをイヌで試験して、胃に滞留する時間を測定した。これらの4つの形状の次元を図8に列挙する。すべてのGRDは、放射線不透過性のスレッドの10個未満の小さな断片を含んだ。これらのスレッドは、X線による胃腸管中のGDRの可視化を補助した。これらはまた、ゲルの水和および崩壊を確認する際に補助した。
【０１１６】
イヌを一晩絶食させた。放射性不透過性のスレッドを充填した剤形を、4オンスの水とともに早朝に経口的に投与した。
【０１１７】
胃から食物を空にすることに対するGRDの効果を研究するために、食餌をまた、BIPSと混合し、2時間後に与えた。2つの異なるサイズのGRDを試験した。1つはサイズ「0」号のカプセルに取り込まれ、他はサイズ「000」号のカプセルに取り込まれた。これらの2つのサイズは、それぞれ、3×1.5×1および7×1.5×1cmに対応する。
【０１１８】
B．実施例1Bに従って作製したGRDのインビボ試験のための剤形
GRDを、実施例9Bに記載した被験体に投与した。「000」号カプセルに封入され、硫酸バリウムカプレット、放射線不透過性スレッド、またはビスマス含浸ポリエチレン球（BIPS）を含む胃内滞留装置を使用した。この系では次にX線を使用した。
【０１１９】
イヌを一晩絶食させ、剤形を10オンスの水とともに早朝に経口的に投与した。食餌を投薬の3時間後に供給した。胃が空になったことを確認するために投薬の直前にX線写真を撮影した。この胃内滞留装置は、次にX線を使用し、イヌに投薬の3時間後に餌を与えた。食物の存在は、胃の中のより暗い領域としてX線で容易に認識され得る。
【０１２０】
異なる型の放射線不透過剤（例えば、硫酸バリウム錠剤、放射線不透過性スレッド、および放射線不透過性BIPS）を含む製剤を用いる研究を、同じイヌで違う日に実行した。絶食条件下でのイヌにおいて放射線不透過性マーカーで正常な胃が空であることは、放射線不透過性スレッドを含むカプセルを摂取することによって決定した。
【０１２１】
BaSO₄錠剤を、カプレットの形状で、Carver pressにおいて作製した。錠剤を取り込むための種々の方法が開発された。基本的に、この方法は、ゲルの層を型に流し込む工程、所望の距離でその型の中に錠剤を配置する工程、および別のゲル層をすぐに付加する工程を含んだ。これらのゲルは真空下で乾燥させた。乾燥フィルムを「000」号カプセルに圧縮した。これらのフィルムを水和研究に供する際に、これらのフィルムは、水和後に2つの層に分けられ、かつ早発的に錠剤を放出することが見い出された。
【０１２２】
カプレットを、これらが型の内部側の中間にあるような様式で、スレッドの補助で懸濁した。注ぎ込まれたときに、熱いゲルがカプレットを包み込んだ。BaSO₄は、ゲル伸長研究の間にゲルまたは錠剤から漏れ出すことが見い出された。このことは、GRDの位置を決定することを困難にする。この制限を考慮して、イヌのインビボ研究を実行した。予測されたように、イヌの胃においてこの系を追跡することは困難であった。なぜなら、BaSO₄錠剤は、胃腸管全体にわたって溶解し、拡散したからである。
【０１２３】
実施例11
この節は、イヌにおけるGRDのインビボ試験のためのX線撮影法に関する。
【０１２４】
A．実施例1A、IV節に従って作製されたGRDのインビボ試験のためのX線撮影法
GRDを、実施例10Aに記載されるように投与した。X線撮影試験を、トランスワールド360 V（Transworld 360 V） X線発生装置を使用して実行した。使用したX線カセットは、スリーエムウルトラディーテイル（3M ultradetail） (1416) フィルムと組み合わせたスリーエムトリマックス12（3M Trimax 12）であった。X線撮影を使用して、胃腸管でのGRDの通過を追跡した。イヌについてのX線撮影は、0分（空の胃を確認するために投薬の直前）、5分（装置が胃にあることを確認するために投薬の直後）、2時間（GRDがハウスキーパー波によって除去されていないか確認するため）、および9時間に、曝露された。イヌにX線撮影2時間後、餌を与えた。餌には時折BIPS（バリウム含浸ポリエチレン球）を混合して、胃から食物が空になることに対する剤形の効果を研究した。BIPSは食物と類似の密度を有するが十分な放射線密度であり、腹部のX線撮影で明確に示されるものである。使用される小さなBIPS（1.5mm）は、食物の通過を模倣し、それらの胃腸管を通しての通過は、胃が空になる速度および食物の腸の通過時間の正確な見積もりを提供する。Hills d/d食餌はBIPSを懸濁することが知られ、これは、BIPSにより空になることと食物により空になることとの間の相関が研究され、証明された唯一の食餌である。BIPSはX線撮影中の放射線不透過性のスレッドから区別され得る。各動物について、X線撮影試験を、2つの角度（側面視界および背腹側視界）から実行した。
【０１２５】
長方形形状は、少なくとも9時間、1匹のイヌの胃にとどまることが見い出された。他の3つの形状は、2時間未満で、胃から空になった。24時間でのX線撮影は、長方形形状GRDについて、胃における放射線不透過性スレッドの非存在、および結腸でのスレッドの拡散によって示されるように、4つの異なる形状のGRDの崩壊を示した。全体で4つの研究を、長方形形状GRDを使用して行った。4つすべての研究において、GRDは同じイヌの胃にとどまったが、他のイヌではそうではなかった。これらの研究の結果を図14〜17に示す。
【０１２６】
BIPSと混合した食物との混合後2時間に撮影されたX線写真は、その食物が胃から空になったがGRDはそうではないことを示した。この研究の結果を図18に示す。このことは、GRDが、胃から腸へ食物を排出することに影響していなかったことを示す。より大きなサイズのGRDからの結果もまた、幽門がGRDによってブロックされていなかったことを示す。このインビボ研究の結果に基づいて、「000」号カプセルに取り込まれた大きなサイズのGRDを、ヒトにおいて試験するために選択した。
【０１２７】
B．実施例1Bに従って作製したGRDのインビボ試験のためのX線撮影
GRDを、実施例10Bに記載するように投与した。X線撮影を、イヌの胃腸管中で胃内滞留装置の通過を追跡するために使用した。X線写真を、空の胃を確認するために投薬の直前および投薬の直後に撮影した。引き続くX線写真を、0.5時間、1時間、2時間、3時間、6時間、9時間、および24時間に撮影した。すべてのX線写真は側面視界であり、いくつかの前後（腹背、VD）X線写真もまた、イヌの胃における剤形の位置を確認するために撮影した。
【０１２８】
X線写真検査をトランスワールド 360 V X線発生装置を使用して実行した（360ミリアンペア数および125キロボルト電位）。使用したX線カセットは、スリーエムウルトラディーテイル(1416) フィルムと組み合わせたスリーエムトリマックス12であった。曝露の設定を表5に示す。
【０１２９】
（表５）2匹のイヌについてのX線装置の曝露設定

【０１３０】
ビスマス含浸ポリエチレン球（BIPS）は、その名称が意味するように、ビスマスを含むポリエチレンの球であり、このことはこれを放射線不透過性にする。これらの球は、イヌにおける研究のためにGRDに取り込まれた。2つの大きなBIPSを含む系を、X線を用いて、異なる時点において（0時間、0.5時間、1時間、2時間、3時間、6時間、8時間、9時間、および24時間を含む）追跡した。この系は、実験の9時間目で、1匹のイヌの胃に滞留していた。次のX線写真は、24時間まで撮影しなかった。2つのBIPSのうち、1つがなお胃に滞留したのに対して、他の1つは腸において見い出された。このことは、この系が、1つのBIPSの放出を伴って破壊されたに違いないことを示す。2番目のイヌの場合には、両方のBIPSが9時間で小腸に見い出された。
【０１３１】
放射線不透過性スレッドは、獣医学的な医薬および外科手術において使用されてきた。また、これらのスレッドの断片はGRDに取り込まれた。これらのスレッドは、フィルムを追跡する際に役立つだけでなく、ゲルの水和を観察するためにも役立つ。
【０１３２】
偽薬研究を両方のイヌにおいて実行した。放射線不透過性スレッドおよび乳糖を有するカプセルを、GRD中にはない場合の、スレッドの胃を空にする局面を研究するための絶食の条件下でイヌに投与した。X線写真を定期的な間隔で撮影した。これらのスレッドは、2〜3時間の間にイヌの胃から小腸に除去された。
【０１３３】
放射線不透過性スレッドを含む胃内滞留装置のイヌへの投与もまた、X線で追跡した。この系は、少なくとも10時間、イヌの胃にとどまった。24時間で撮影されたX線写真は、胃または小腸のいずれにおいても放射線不透過性スレッドの非存在を実証した。イヌにおける、放射線非透過性スレッドを含有するGRDの投与の結果を図19および20に示す。総計5つの研究を、放射線非透過性材料を含有するGRDを使用して実行した。本発明者らの3つの研究から観察されたように、この系は、少なくとも9時間、イヌの胃にとどまることが見い出された。
【０１３４】
投薬の7時間以後に撮影したX線写真は、胃における食物の非存在を示し、食物は腸において見い出された。しかし、GRDは胃には見い出されなかった。このことは、GRDが、食物の腸への通過に影響を与えなかったこと、およびGRDによって幽門をブロックしなかったことを示す。
【０１３５】
実施例12
この節は、イヌにおけるGRDのインビボ試験のための内視鏡検査に関する。
【０１３６】
内視鏡検査を、実施例1A、IV節に従って作製されたGRDの胃における膨潤の視覚的な観察を可能にするために使用した。1匹のイヌをこの研究のために使用した。この動物を、投薬の14〜16時間前から絶食させた。覚醒している間にこのイヌに投薬した。この動物を、ジアゼパム（7.5mg）と組み合わせて静脈内投与されたケタミン（259mg）で誘導した。この動物を、袖口のついた気管内チューブとともに挿管し、イソフルランガスおよび酸素を用いる一般的な麻酔下に維持した。適切な麻酔水準への到達後、可撓性の光ファイバー内視鏡（135cm長；9mm o.d.）を口および食道に導入し、胃に導いた。GRDを内視鏡に装着したカメラによってモニターし、膨張プロセスを45分間の時間にわたってビデオテープに記録した。
【０１３７】
この動物は内視鏡検査のために予定に入れており、この内視鏡手順は十分に許容性であった。全体の手順の時間は、麻酔の導入から抜管までの時間として定義されるように、約1時間であった。この内視鏡は、動物の胃に指向されていた。内視鏡の視界は、胃の中のGRDの位置を示した。次いで、GRDを45分間の時間にわたって内視鏡のカメラによって連続的にモニターした。カプセルのシェルは数分間で溶解しGRDが放出された。GRDの膨潤は30分間の時間にわたって次第に生じた。45分後、膨潤したゲルを胃から回収し、その次元を調べてそれをインビトロの結果と比較した。イヌの胃から回収した膨潤したゲルは、37℃で人工胃液に浸漬した類似のGRD（3^＊1.5^＊1）と比較してほぼ同じ次元（2.8^＊1.3^＊0.8）に達した。調製したGRDは胃液中で30分間未満で顕著なサイズにまで膨潤し、それゆえにハウスキーパー波による絶食した胃からの除去を回避する良好な機会を有する。
【０１３８】
実施例13
この節はヒトへのGRDの投与に関する。
【０１３９】
A．実施例1A、IV節の方法に従って作製されたGRDを使用するヒト被験体へのGRDの投与
絶食した条件下および食物を与える条件下での横断的な生物的研究を、200mgのアモキシシリンを含む胃内滞留装置またはこの装置を有しない200mgのアモキシシリン錠剤のみについて、1名の被験体中で行った。この被験体には、両方の研究において一晩絶食することが求められた。この研究の間、絶食の条件下で、朝食を投薬の2時間後に供給した。食物を与えた状態の研究において、被験体は、朝食とともに剤形を受けた。標準的な朝食は、プレーンベーグル、1オンスのクリームチーズおよび125mlのフルーツジュースであった。48時間の洗浄時間の後、他の用量を与えた。尿を、0時間、1時間、2、3、4、5、6、8、12、および24時間で収集した。尿試料を直ちにHPLCによって分析した。
【０１４０】
B．実施例1Bの方法に従って作製したGRDを用いるヒト被験体へのGRDの投与
第I期：
6名の健康な被験体（男性4名および女性2名）は、無作為横断的設計で、少なくとも1週間の洗浄期間を伴って、（IR）カプセル（処置A）または（LGRD）カプセル（処置B）のいずれかを接種した。このカプセルは、200mlの水とともに摂取された。すべての被験体は、研究の前少なくとも10時間の絶食を要求され、投薬後3時間は食物が許されなかった。
【０１４１】
第II期：
この研究は、絶食条件下で1つの処置からなり、ここで6名の被験体各々が（IGRD）カプセルを摂取した（処置C）。
【０１４２】
第III期：
この研究もまた、絶食条件下で1つの処置からなり、ここで6名の被験体各々が（SGRD）カプセルを摂取した（処置D）。
【０１４３】
製剤成分
リボフラビン（Sigma Chemicals、St. Louis、MO）を治療剤として選択した。すべての試験製剤は、GRDの形態、または粉末形態の100mgのリボフラビンを含む即時放出のいずれにおいても、オレゴン州立大学薬学部（Corvallis、OR）で作製された。GRD製剤は以前に記載されたように調製した。
【０１４４】
生物的研究において使用されるカプセル
1．即時放出（IR）カプセルは、主要な賦形剤としての乳糖（200mg）、およびあらかじめ乾燥させた100mgのリボフラビンを含む、サイズ「1」カプセルであった。
2．大型GRD（LGRD）カプセルは、100mgのリボフラビンを含む乾燥GRDで満たしたサイズ「000」号カプセルであった。乾燥前に取り込まれたGRDの次元は、7^＊1.5^＊1cmであった。
3．中間型GRDカプセル（IGRD）は、100mgのリボフラビンを含む乾燥GRDで満たしたサイズ「00」号カプセルであった。乾燥前に取り込まれたGRDの次元は、5^＊1.5^＊1cmであった。
小型GRDカプセル（SGRD）は、100mgのリボフラビンを含む乾燥GRDで満たしたサイズ「0」号カプセルであった。乾燥前に取り込まれたGRDの次元は、3^＊1.5^＊1cmであった。
【０１４５】
実施例14
この節は、ヒト被験体へのGRDの投与後の薬物排出のHPLC分析に関する。
【０１４６】
A．実施例13Aの被験体からの尿試料のHPLC分析
内部標準：アセトアミノフェンUSP（1mcg／ml）
この溶液は、冷所に保存し、直射光から十分に保護した場合には比較的安定である。
【０１４７】
緩衝溶液：
緩衝液を、350mlの脱イオン水に100mlの0.5M リン酸水素二ナトリウムを添加することによって調製した。pHを、1M クエン酸で6に調整する。得られる溶液を脱イオン水で500ml容量にする。
【０１４８】
移動相の調製：
0.26gのリン酸二水素カリウムを3800mlの脱イオン水に添加した。200mlのHPLC等級メタノールを添加した。この溶液を濾過していかなる粒子をも取り除き、約20分間真空下で攪拌して気泡を取り除いた。
【０１４９】
HPLC装置：
ウォーターズ インテリジェントサンプルプロセッサー（Waters Intelligent Sample Processor） (WISP（商標）) 712、カラムへの注入のための48試料バイアルまでの自動試料注入モジュール。
【０１５０】
カラム：
逆相C₁₈、25cm、5μ、100A レイニン マイクロソーブ-MV（100A Rainin Microsorb-MV）（登録商標）。
【０１５１】
検出器：
UV吸収検出器、モデル440（固定波長を有する）。
【０１５２】
緩衝化試料：
各尿試料からの2mlを2mlのpH6緩衝液に添加する。この溶液をボルテックスにて混合し、適切な混合を確実にする。
【０１５３】
HPLC試料：
1mlの緩衝化した尿を5mlの脱イオン水で希釈した。小さなプラスチック製の遠心分離チューブ中で、この希釈試料50μlに50μlの内部標準溶液を添加した。得られる溶液をボルテックスにて混合し、適切な混合を確実にした。HPLC試料バイアルを集め、キャップをし、HPLC分析のためのWISP（商標）オートインジェクター中に配置した。20μlの試料を注入した。HPLCのための他のすべてのパラメーターを以下に列挙する：
移動相の流速：1.3ml／分
検出波長：229nm
実行時間：約23分間
【０１５４】
標準曲線の作製
アモキシシリン較正曲線を以下の方法によって生成した：0.03gのアモキシシリン三水和物を100mlメスフラスコに入れ、薬物を含まない尿（ブランク）：脱イオン水の1：10混合物で溶解し、100mlにした。これを、約40分間室温で攪拌し、完全な溶解を確実にした。段階的な1：1希釈を脱イオン水で作製し、6つの試料を得る。この段階希釈のプロセスは、較正曲線を作製するために使用された濃度の範囲内の一連の試料を生じた。HPLC分析のための試料調製の方法は以前に示したものと同じであった。各試料の計20μlを注入した。
【０１５５】
B．13Bの被験体からの尿試料のHPLC分析
1）HPLCアッセイ法のための試薬
メタノール（HPLC等級、Fisher Chemicals、NT）、リン酸一塩基カリウム（Fisher Chemicals、NT）、水酸化ナトリウム（Mallinckrodt）。この手順において使用した水は、ミリQ試薬用ウォーターシステム（Milli-Q Reagent Water System）（Millipore、Bedford、MA、USA）を使用して脱イオン化した。
【０１５６】
2）薬物アッセイ方法：
カラムは逆相微粒子C₁₈（□Bondapak C₁₈、粒子サイズ10μm、30cm×4mm、Water Assoc.、Milford、MA、USA）であった。これは、前にC₁₈ガードカートリッジ（ODS、4×3mm、Phenomenax、CA、USA）が取り付けてあった。
【０１５７】
アッセイ手順は、Smithによって記載されたものに従った。溶出液は0.01M KH₂PO₄（pH5）：メタノール（65：35）で、流速1.2ml／分であった。移動相を、正確な容量のメタノール、および1N水酸化ナトリウムでpH5に調整した0.01リン酸一塩基カリウム溶液を混合することによって調製し、次いで、真空下で0.2μmフィルターを通して濾過した。この移動相を使用前に脱気した。検出器は固定波長の分光蛍光光度計（Gilson Spectra/GloFluorometer、Middleton、WI）であった。励起波長は450nmであった。放射フィルターの波長範囲は520〜650nmであった。ピーク面積をシマズ積分器（Schimadzu integrator） (C-R3A Chromatopac、Schimadzu Corp、Kyoto、Japan) を用いて測定した。
【０１５８】
HPLCシステムにおける他の装置には、送液ポンプ（Waters 550 Solvent Delivery System、Waters Associates、Milford、MA）、自動試料注入装置（Waters WISP Model 712B、Waters Associates、Milford、MA）が含まれた。
【０１５９】
3）尿試料の収集：
一晩絶食した被験体が、投薬の前の0時間の尿試料を提供し、次いで、製剤を摂取した。尿試料を、投薬後1時間、2時間、3時間、4時間、6時間、8時間、10時間、12時間、および24時間に、16オンス容器中に収集した。容量およびビタミン摂取から経過した時間を各尿試料について記録し、一部をビタミン濃度測定のために保存した。
【０１６０】
4）標準溶液：
リボフラビン標準保存溶液を、あらかじめ105℃で2時間乾燥させた100mgのリボフラビン、750mlの水、および1.2mlの氷酢酸の、1リッターフラスコへの添加、熱による溶解、および水での容量への希釈によって、100μg／mlの参照標準を含むように調製した。この保存溶液を、1μg／ml、2μg／ml、4μg／ml、6μg／ml、8μg／ml、10μg／ml、および15μg／mlのリボフラビンを含むようにブランクの尿で希釈した。すべての溶液を遮光した。これらの標準をカラムに注入し、クロマトグラムを記録し、ピーク面積を測定した。リボフラビンの保持時間は約6分であった。
【０１６１】
標準曲線を、尿中のリボフラビン濃度に対してピーク面積をプロットすることによって構築した。アッセイ法の感度は1μg／mlであり、ピーク面積と1〜10μg／mlのリボフラビン濃度との間に直線関係を伴った（R²＝0.9971）。尿中のリボフラビンについての代表的な標準曲線を図29に示す。内因性のリボフラビンは、ブランクの尿またはすべてのアッセイされた標準および試料のからの0時間の尿試料の分析から得られた面積を減算することによって考慮した。
【０１６２】
5）試料分析：
約10mlの尿を、10分間、4000rpmで遠心分離した。上清の一部（150μl）をHPLCチューブに移し、50μlをHPLCカラムに注入した。リボフラビンは注入後6分で溶出した。
【０１６３】
実施例15
この節はHPLCデータの薬物動態学的分析に関する。
【０１６４】
リボフラビン排出データを、実施例14B、1−5節に概説したように得た。異なる処置を、投与後最初の24時間の間のリボフラビンのそれらの尿中での回収（回収_{0 − 24}）、最大尿排出速度（R_max）、およびR_maxに到達するために必要な時間（T_max）について比較した。すべてのパラメーターを、個々の尿排出速度−時間曲線、尿収集間隔の中間点に対する尿排出速度のプロットから決定した。回収_{0 − 24h}を、個々の累積尿薬物排出−時間曲線、排出された累積の薬物を収集時間間隔に関連付けるプロットから決定した。
【０１６５】
実施例16
この節は、HPLCデータの統計学的分析に関する。
【０１６６】
リボフラビン排出データを、実施例14B、1−5節に概説したように得た。処置間での薬物動態学的なパラメーターの違いを、両側スチューデントt検定を用いて調べた。α＝0.05、帰無仮説Ho：μ_T−μ_R＝0での両側スチューデントt検定を、尿回収データについての回収_{0 − 24h}、R_max、およびT_maxで実行した。帰無仮説（Ho）の受容は、GRD製剤のパラメーター平均と中間の放出製剤の対応するパラメーター平均との間に有意な差異が存在すると結論付けるための十分な証拠が存在しないこと：すなわち、これらのパラメーターは等価であることを示す。帰無仮説の拒絶は、2つの製剤の試験したパラメーターは有意に異なることを強力に示す。
【０１６７】
実施例17
この節は、尿排出速度データの逆重畳に関する。
【０１６８】
生物研究データからの逆重畳入力関数は、Williams GillespieによるコンピューターソフトウェアPCDCONを用いて決定した。逆重畳は、入力応答および薬物の特徴的なインパルス応答関数から入力関数（インビボで溶解した累積量対時間）を生成する。逆重畳によって予測された、時間に対する累積薬物入力を使用して、異なるサイズのGRDの胃内滞留時間を決定した。胃内滞留時間を、吸収が停止したときに観察された時間として逆重畳曲線から計算した。使用した入力応答は、異なる製剤からのリボフラビンの尿排出速度（dU／dt）であったが、使用したインパルス応答は、リボフラビンの静脈内ボーラス用量から決定した、文献由来の除去速度定数であった。
【０１６９】
実施例18
この節は、ヒト被験体によるGRDからの薬物吸収に関する。
【０１７０】
A．実施例13Aにおいて概説したような、被験体へのGRDの投与後のアモキシシリン排出および実施例14において概説したような分析
カプレットの形態でGRDに取り込まれたアモキシシリン（β−ラクタム系抗生物質の一種）を、その生物学的利用能について試験した。β−ラクタム濃度の上昇は、最小阻害濃度（MIC）（これは治療濃度と呼ばれ得る）の約4倍である傾向がある有限点までのみ、細菌の殺傷の増加を実証する。さらなる上昇は、殺菌的な効力の増加とは関連しない（18、例えば、ストレプト・ニューモコッシ（Strep. pneumococci）についてのMICは0.02mcg／mlであり、治療濃度は0.08mcg／mlである）。β−ラクタム抗生物質濃度が上記の治療濃度より上に維持されている時間と臨床的な作用との間には直接的な相関が存在する。細菌の再増殖は、これらの濃度が細菌MICより下に下がった後に急速に生じる。従って、各々の個別のβ−ラクタムについての投与計画は、投薬間の薬物のない間隔を、細菌病原体にとって増殖が再開するのに十分に大きくしないようにすべきである。
【０１７１】
アモキシシリンは約1時間の非常に短い半減期および経口投与後に限られた「吸収ウィンドウ」を有する。薬物は十二指腸および空腸で十分に吸収されるが、吸収は回腸で減少し、かつ速度依存的である。吸収は、すべての腸の領域においては非常に乏しい。従って、β−ラクタム抗生物質（例えば、アモキシシリン）を送達するためにGRDを使用することは、通常のIR製剤に関して、インビボでのMICにわたって時間を伸長する。生物学的利用能はまた、吸収の部位に到達する薬物の量が時間にわたって延長され、従ってその部位での飽和を妨げるに従って向上する。
【０１７２】
アモキシシリンを絶食条件下で実施例13Aの被験体に投与し、実施例14Aの方法に従って分析した場合、GRDに取り込まれた薬物についての排出速度曲線（AUC）の下の面積は、GRDの非存在と比較して30％の増加が見い出された。最大排出速度（C_max）は、GRD非存在下では34.2ml／hrであり、GRD存在下では29.0mg／hrであった。これらの値は有意には異なっていはいなかった。T_maxの値は両方で同一であった。2つの製剤の比較できる生物学的利用能を図21に示す。
【０１７３】
食物を与える条件下で実行した研究は、AUCまたはC_maxにおいていかなる有意な差も示さなかった。しかし、GRDについてのT_maxは、GRDの非存在下と比較して右側にシフトした。GRDについてのT_maxは4時間であると見い出され、ここで、GRDの非存在下ではそれは2時間であった。食物を与える条件下での両方の製剤についての生物学的利用能を図22に示す。
【０１７４】
アモキシシリンを用いるこれらの結果は、被験体が食物を与えられた場合に胃から腸への薬物送達を遅くする食物と一致しており、GRDは、被験体が絶食させられた場合に腸への薬物の送達を遅くする。さらに、その食物は、GRDからの薬物放出に有害な影響を与えなかった。
【０１７５】
B．実施例13Bに概説するような被験体へのGRDの投与後のリボフラビン排出、ならびに実施例14B、1−5節ならびに実施例15、16、および17に概説するような分析
尿の薬物排出データは、生物学的利用能を見積もるために使用され得る。なぜなら、尿に排出された薬物の累積量は、吸収され、次いで、一次除去プロセスを通して排出された薬物の総量と直接的に関連するからである。妥当な見積もりを得るために、薬物は、尿中で有意な量排出されなければならないし、完全な尿の試料が収集されなければならない。
【０１７６】
絶食条件下で胃を空にすることのためのGRDのカットオフサイズの決定は、この生物研究の1つの目的であった。異なる製剤からのリボフラビンの相対的分画的な吸収を、尿排出データから評価した。異なる処置についての平均薬物動態学的パラメーターを以下の表に示す。
【０１７７】
（表６）絶食したボランティアへの即時放出またはGRDのカプセル中の100mgのリボフラビンの経口投与後の薬物動態学的パラメーター

データは平均値±SEである
【０１７８】
4つの処置についての各被験体の個々の薬物動態学的パラメーターもまた、以下の表7〜12に示す。
【０１７９】
図23は、回収_{0 − 24 時間}についての最大の平均値がLGRDカプセルで観察され、続いてIGRDカプセル、IRカプセル、およびSGRDカプセルで観察されたことを示す。LGRDカプセルからの平均回収_{0 − 24 時間}見積もり（17.3mg）は、IRカプセルからの平均（5.33mg）と比較して、225％大きく、かつ統計学的に有意に（P＜0.05）異なると決定された。SGRDカプセルからの平均回収_{0 − 24 時間}見積もり（4.09mg）はより小さいが、IRカプセルからの平均（5.33mg）と比較して、統計学的に有意に（P＜0.05）異なっていなかった。IGRDカプセルからの平均回収_{0 − 24 時間}見積もり（9.3mg）はより高かったがIRカプセルとは有意に異なっていなかった。このことは、何人かのボランティアのみにおいては、この装置の胃内滞留時間の延長に起因し得る（被験体1および2は、IRカプセルと比較した場合、有意に高いIGRDカプセルからの尿の回収_{0 − 24 時間}を有した）。
【０１８０】
R_maxパラメーターおよびT_maxパラメーターの統計学的比較もまた、LGRDカプセルからの結果（それぞれ2.5±0.98mg／hおよび5.08±2.4hr）とIRカプセル（それぞれ1.36±0.4mg／hおよび2.5±0.63hr）からの結果との間の有意な差（P＜0.05）を示した。IGRDカプセルおよびSGRDカプセルからのR_maxパラメーターおよびT_maxパラメーターは、（IR）カプセルとは有意に異ならなかった。これらの結果を図24に示す。
【０１８１】
この研究で得られたLGRDカプセルからのリボフラビンの改善された生物学的利用能（IRカプセルの投与後に測定された尿の回収は3倍より高かった）は、この装置が胃の中で保持されたことを示唆する。LGRDは、そのビタミン内容物をゆっくりと放出するのに十分な時間、胃の中にとどまり、結果として放出されたビタミンは徐々に吸収ウィンドウを介して通過し、より効率的に吸収された。
【０１８２】
他方、SGRDカプセルの投与は、IRカプセルと比較した場合に、リボフラビン吸収の減少を生じた。このことは、比較的少ない薬物放出を伴う、第III期筋電性移動収縮活性により胃から排出された小さいサイズの装置に起因し得る。一旦装置が吸収ウィンドウを通過すると、吸収は起こらない。
【０１８３】
図25は、IR、SGRD、IGRD、およびLGRDのカプセルについての生物研究データから逆重畳した薬物吸収対時間の累積量を示す。LGRDカプセルについては吸収は15時間まで継続しその後停止した。このことは、LGRDが胃の中にとどまり約15時間ゆっくりと薬物を放出することを示し得る。他方、IGRDカプセルからの吸収は、約9時間継続し、その後一定になった。このことは、この装置がその薬物内容物のすべてを放出するために胃の中に十分に長くとどまらなかったことを示す。SGRDカプセルからの吸収は、3時間のみ継続し、このことは、この装置が、IRの投薬と同じくらい迅速に（その小さなサイズに起因して）ハウスキーパー波によって胃から排出されたことを示す。
【０１８４】
これらの結果は、制限された吸収部位を有する異なる薬剤を含む膨潤可能な系（例えばGRD）の胃での滞留時間が、同じ量の薬物を含む膨潤可能な系および即時放出系の投与後にAUCの測定または尿回収によって測定されるような、薬物の生物学的利用能を比較することによって評価され得ることを示す。
【０１８５】
（表７）被験体1への即時放出カプセルまたはGRDカプセル中の100mgの経口投与後のリボフラビンの薬物動態学的パラメーター

【０１８６】
（表８）被験体2への即時放出カプセルまたはGRDカプセル中の100mgの経口投与後のリボフラビンの薬物動態学的パラメーター

【０１８７】
（表９）被験体3への即時放出カプセルまたはGRDカプセル中の100mgの経口投与後のリボフラビンの薬物動態学的パラメーター

【０１８８】
（表１０）被験体4への即時放出カプセルまたはGRDカプセル中の100mgの経口投与後のリボフラビンの薬物動態学的パラメーター

【０１８９】
（表１１）被験体5への即時放出カプセルまたはGRDカプセル中の100mgの経口投与後のリボフラビンの薬物動態学的パラメーター

【０１９０】
（表１２）被験体6への即時放出カプセルまたはGRDカプセル中の100mgの経口投与後のリボフラビンの薬物動態学的パラメーター

【０１９１】
実施例19
この節は、ヒドロクロロチアジドを含む胃内滞留装置の作製に関する。
【０１９２】
すべての成分および型を調製した（熱い溶液に耐え得る1^＊1.5^＊7.5の長方形形状の容器を使用した）。XG（キサンタンガム）およびLBG（イナゴマメガム）をそれぞれ0.75gまで秤量し、十分に互いに混合し、その後この混合物を100mlの脱イオン水（DIW）に溶解した。次いで、これらをDIW中で十分に分散させ、3〜4時間膨潤させるために放置した。
【０１９３】
別個の泡溶液を調製した：
・25mlの脱イオン水（蒸発分を補填するために約26ml）を暖め、0.125gのSLS（ラウリル硫酸ナトリウム）を溶解し、次いで、マグネチックスターラーで攪拌しながら0.075gのカルボポールを懸濁させた。攪拌を約3時間継続した。
・3時間後、ニュートラル（Neutral）（非常にわずかな量）を用いてpHを7〜7.5に調製した（pH試験紙の変化：カーキ色から暗い緑色）。次いで、泡をセットするために泡溶液のビーカーを氷水バスに置いた（ニュートラルはカルボポール溶液のpHを調整するために使用される賦形剤または成分であり、溶液を非常に濁らせる。他のアルカリ中和剤が使用され得る）。
・上記の工程1からのガム溶液を加熱し、攪拌を断続的に行い、その間に上記の工程3からの泡溶液を、マグネチックスターラーを用いて、最大速度で攪拌した。
・このガム溶液を80℃に達するまで加熱し、次いで5.5mlのPEG400を添加し、10秒間攪拌した。
・ガム溶液からマグネチックスターラーを取り除き、泡溶液をガム溶液にスパチュラを用いて注ぎ込んだ。これらをスパチュラで一緒に混合した。
・ガム／泡混合物を各々の型に流し込み、約半分を型に入れて、次いで薬物ビーズを添加し、型の残りをガム／泡混合物で満たした。次いで、これらをすばやく混合し、薬物ビーズが均一に分配されるように冷却およびゲル化を行った。
・室温に約2〜4時間置いた。
・冷却したゲルを冷蔵庫に入れ、放置した（通常10時間より長く（一晩）、しかし利便性のために変更した時間も可能である）。
・各々のゲルを容器から出し、ワックス処理してあるかまたはプラスチックのシーツ上に置いた。
・実験室の真空オーブン中で、53℃、4.5〜5時間にてゲルを乾燥させた。正確な真空度、温度、および乾燥時間は、利用可能な器具に依存してすべて変更可能である。これらの条件は、水流の減圧を使用しても良好な結果が得られた。
【０１９４】
実施例20
この節は、ヒドロクロロチアジドの徐放性製剤の作製に関する。
【０１９５】
1．18−20メッシュサイズの糖の球にヒドロクロロチアジド懸濁液を層状化した。この懸濁液は、9gのPVP（ポビドンK-30（Povidone K-30））、3gのクルセル（Klucel）（登録商標）（HPC）（両方は結合剤として）、40gのHCTZを100mlの脱イオン水中で室温で一晩懸濁することによって調製した。
2．層状化を、ボトムスプレーイング、ワースター（Wurster）カラム、スプレーコーティングチャンバー中で行った。
【０１９６】
（表１３）スプレーコーティングのための条件

【０１９７】
3．HCTZ層状化球を、シュアリース（Surelease）およびオパドライ混合物の懸濁液でコートした。薬物層状化球100gを、10mlの脱イオン水中の1gのオパドライおよび8.06gのシュアリースの懸濁液でコートした。HCTZ層状化球に適用したコーティングの全体の％は3％であり、これは、66.6％のシュアリースおよび33.3％のオパドライからなった。
4．層状化が完了した後、球を約30分間チャンバー中で乾燥させた。
【０１９８】
実施例21
この節は、ヒドロクロロチアジドを含有するGRDのヒトへの投与に関する。
【０１９９】
徐放性製剤（SR）を含有する、ヒドロクロロチアジドのための2つの製剤（即時放出製剤（IR）および胃内滞留装置（GRD））を、生物研究（生物学的利用能研究）において投与した。50mgのHCTZを含有する市販の錠剤をIR対照として使用し、50mgのHCTZに等価であるスプレーコートビーズを実験室でSRのために製剤化した。SR製剤のプロセスは上記に記載する。生物研究を、IRからのものと比較して、GRDからのHCTZの生物学的利用能ならびに薬物動態学を評価するために実行した。
【０２００】
健康な大人のボランティアの尿中におけるヒドロクロロチアジドの濃度のモニタリングは、GRD製剤からのおよび従来の錠剤からのヒドロクロロチアジドの相対的な生物学的利用能の比較を可能にした。参加には、各処置について少なくとも2日間が含まれ、これは、投薬間の少なくとも72時間の洗い出し期間を伴った。一度IRを与え、GRDを、新規な剤形であるGRDの再現性を試験するために2回反復した。50mgの用量を研究のために選択した。なぜなら、これは、PDR（Physician's Desk References）からの推奨用量の範囲内にあったからであり、これは、HPLC分析を効率的にするために十分に高い濃度を生成したからである。6名の被験体がこの研究に参加し、そのうち4名が健康な男性、および2名が健康な女性であった。彼らはカフェインを含むいかなる食物または飲料も許可されず、また、アルコールもしくは他の医薬も許可されなかった。喫煙者および菜食主義者は含まれていなかった。被験体は、一晩および投薬後少なくとも2時間絶食させられた。彼らは、各研究においてヒドロクロロチアジドの単回用量を受ける前に彼らの膀胱を空にし、12オンスの水とともに用量を摂取した。投薬後、被験体は、彼らの尿を収集する容器のセットおよび排尿の時間を記録するタイムシートを受け取った。被験体は、製剤の経口投与後24時間以内にすべての尿を収集した。尿試料を、0−1時間、1−2時間、2−3時間、3−4時間、4−6時間、6−8時間、8−10時間、10−12時間、12−24時間、24−36時間、および36−48時間の間に収集した。尿試料は、研究者に渡すまでは冷蔵した。収集した尿の容量を、回収した薬物の総量を計算するために測定した。Papadoyannisら（1988）のHPLC（高速液体クロマトグラフィー）アッセイ法の改良方法を使用して、薬物含量についての尿試料の一部を分析した。
【０２０１】
実施例22
この節は、ヒドロクロロチアジドを含むGRDの投与後の薬物動態学的パラメーターおよび尿の排出データの分析に関する。
【０２０２】
薬物ヒドロクロロチアジドを含むGRDを、実施例21に概説したようにヒト被験体に投与した。絶食条件下での各処置についての平均薬物動態学的パラメーターを、以下の表14に提供する。図26は、排出した薬物の累積量対時間を示す。排泄の半減期（t_{1 ／ 2}）は約7時間であった。A_{0 − 36}の値を、統計学的分析のために比較した。なぜなら、短い半減期に起因して、1名の被験体からのIRについて48時間での値を得ることは不可能であったからである。
【０２０３】
実施例23
この節は、絶食した被験体へのヒドロクロロチアジドのGRD投与の効果に関する。
【０２０４】
薬物ヒドロクロロチアジドを含むGRDを、実施例21に概説したようにヒト被験体に投与した。各処置についての平均薬物動態学的パラメーターを、実施例23に概説したように分析した。IRからの平均A_{0 − 36h}（33.3mg、66.6％）は、絶食条件で、GRD（37mg、75.4％）からのそれと比較した場合に有意に異なることが見い出されたが（P＜0.05）、その差は10％未満である。20％未満の差は、一般的に、FDA BA／BEガイダンスから有意でないとみなされる。図26および表14から、吸収された薬物および尿中で収集された薬物の総量の平均値は等価であった。（A_{0 − 48}）は、絶食条件で、IRおよびGRDについて、それぞれ、38.12mg（76.2％）および38.95mg（77.9％）であった。A_{0 − 48}は、吸収された用量の50％が尿中でインタクトであるらしいと仮定することに基づいていた。従って、GRDは、絶食した被験体中で48時間まではIRから吸収されたのと本質的に同じ量の薬物を生じた。しかし、尿排出に対する効果は驚異的に全く異なっていた。
【０２０５】
（表１４）IRについて薬物動態学的パラメーターおよび尿の排出データ

【０２０６】
図27は、予測されるように、薬物のより高い最大排出速度（R_max）が、新規製剤（GRD）からのものよりも即時放出（IR）カプセルから、より早い時間（t_max）に生じたことを示す（2.5時間で4.84mg／時間対、5時間で2.5mg／時間）。
【０２０７】
実施例24
この実施例は、絶食被験体において48時間にわたるHCTZ−50mgについてのプロファイルに関する。
【０２０８】
薬物ヒドロクロロチアジドを含むGRDを、実施例21に概説したようにヒト被験体に投与した。また、各処置についての平均薬物動態学的パラメーターを、実施例23に概説したように分析した。HCTZ−50mgの累積量対時間を、実施例23に概説したように分析した。
・CmaxおよびTmaxは、IRおよびGRDについて、それぞれ、4.84（mg／ml）および2.46（mg／ml）、ならびに2.5（時間）および5（時間）であった。
・T_{1 ／ 2}は7時間である。
【０２０９】
尿の生成の速度は、投薬後10時間まで、IRとGRDの両方において同様であった。このことは全く予期していないことであった。なぜなら、吸収された薬物の量および体内の薬物濃度は、市販のIRカプセルと比較して、本明細書中に示されるGRDからは、より少ないからである。IRカプセルについては10時間から後は利尿が減少し始めたのに対して、GRDについては、より長い時間の期間、大量の利尿が維持された。
【０２１０】
最初の等量の利尿は驚くべきことである。なぜなら、より少ない薬物がGRDから最初に吸収されるからである（絶食条件で、IRおよびGRDについて、それぞれ、t_max2.5時間でR_max4.8（μg／ml）およびt_max5時間でR_max2.5（μg／ml））。このことは、今、より少ない薬物がより有効であり得ることを教示する。このことは薬物では一般的なことではない。実際、より少ない量の薬物が摂取される場合、より少ない効果が予想されるが、この新規なGRDおよび利尿剤では逆の効果が生じた。
【０２１１】
GRDからの薬物の尿生成への効果は約15時間まで継続的であることもまた、明確に観察された（上記の表に提供されるデータを参照されたい）。図28から、尿の生成と水の摂取との間の比較、および尿の生成と水の摂取の比率の間の比較を研究した。IRとGRDの両方におけるヒドロクロロチアジドからの尿の排出の累積量は、水の摂取と一致する。
【０２１２】
健康な、正常な被験体における体液排出の増加は、水の摂取を刺激した。IRと比較してGRDにおける同じ用量からの尿生成の総量はより高かった。これは、GRDからの延長された薬物摂取、続いて、予期せぬ薬物効果の増加を補償するためのフィードバックの水摂取の増加量に起因し得る。
【０２１３】
この全体の増加効果もまた、（上記で議論したより小さな薬物摂取での最初のより大きな効果に加えて）驚くべきものである。なぜなら、利尿効果を増加させるために、薬物用量を増加させることが必要であることは周知であるからである。実際、大部分の薬物応答曲線は、log直線であって、これは、通常、最初の応答閾値を通過する後では、用量の増加よりも効果の増加はより少ない（より小さな％）ことを意味する。しかし、今回の場合では、絶食条件下での薬物の生物学的利用能は実質的に等しいが、利尿効果は図38および上記に提供する表に示すように27％増加した。
【０２１４】
ヒドロクロロチアジドのこの生物学的利用能研究の結果は、この装置が、胃の中のすべてまたは大部分の薬物を放出するに十分長く保持されることを確立するが、また、剤形が薬物の効果を延長するために薬物の徐放も確立する。従ってGRDは、腸の上の方の部分において制限された吸収部位を示す、ヒドロクロロチアジドならびに他の利尿剤を投与するための優秀な装置である。この剤形は、所望されない副作用（副作用の情報については以下を参照されたい）を誘導し得る薬物の高いピーク濃度を回避すること、投与される用量あたりの薬物の効果を増加させること、および薬物効果の延長を達成することによって患者の介護を改善し得る。
【０２１５】
実施例25
この節は、GRDにおけるヒドロクロロチアジドの投与後のヒト被験体における副作用に関する。
【０２１６】
薬物ヒドロクロロチアジドを含むGRDを、実施例21に概説したようにヒト被験体に投与し、以下の副作用が報告された。
・7被験体のうちの3被験体が、投薬後4〜6時間の間でIR剤形からの副作用を報告した。
・報告された有害な反応は、重篤または中程度の頭痛、脱水症状、および疲労であった。
・1被験体が重篤な頭痛、脱水症状、および疲労のために研究を継続しなかった。
・GRDにおいて同じ用量のヒドロクロロチアジドからは有害な反応の報告はなかった。
・1回目の研究後、IRの場合に被験体はより多くの水を飲むことを奨励された。これは、HCTZからの脱水症状の結果を認識していることによる。
【０２１７】
記載された方法の正確な詳細が、記載された発明の精神から逸脱することなく変更または改変され得ることは明らかである。本発明者らは、以下の特許請求の範囲の範囲および精神に含まれるすべてのこのような改変および変更を主張する。
【図面の簡単な説明】
【０２１８】
【図１】種々の固体比率のキサンタンガム/イナゴマメガムフィルムの水中における水和率のグラフである。
【図２】種々の固体比率のキサンタンガム/イナゴマメガムフィルムの人工胃液中における水和率のグラフである。
【図３】種々の固体比率のキサンタンガム/イナゴマメガムフィルムの水中における初期水和率のグラフである。
【図４】0時間〜3時間の間の、種々の固体比率のキサンタンガム/イナゴマメガムフィルムの人工胃液中における水和率のグラフである。
【図５】試験した4つのGRDの形とサイズが示されている。
【図６】3時間〜24時間の間の、人工胃液中におけるGRDの水和のグラフである。
【図７】0時間〜3時間の間の、人工胃液中におけるGRDの水和のグラフである。
【図８】アモキシシリンカプレットから20時間に渡って放出されたアモキシシリン(mg)を、GRD内アモキシシリンカプレットの場合と比較したグラフである。
【図９】アモキシシリンコアカプレットから20時間に渡って放出されたアモキシシリン(mg)を、GRD内アモキシシリンコアカプレットの場合と比較したグラフである。
【図１０】ザンタック(登録商標)錠から20時間に渡って放出された塩酸ラニチジン(mg)を、GRD内ザンタック(登録商標)錠の場合と比較したグラフである。
【図１１】リボフラビンビーズから長時間に渡って放出された有効なリボフラビンの割合を、GRD内リボフラビンビーズの場合と比較したグラフである。
【図１２】改変型GRD内リボフラビンビーズから長時間に渡って放出された有効なリボフラビンの割合のグラフである。
【図１３】改変型GRD内リボフラビン固体分散体から長時間に渡って放出された有効なリボフラビンの割合のグラフである。
【図１４】投与直後の胃内のGRDを示す、絶食犬の胃のX線図のデジタル画像である。
【図１５】投与から2時間後の胃内のGRDを示す、犬の胃のX線図のデジタル画像である。
【図１６】投与から9時間後の胃内のGRDを示す、犬の胃のX線図のデジタル画像である。
【図１７】投与から24時間後の、結腸内で崩壊したGRDを示す、犬のX線図のデジタル画像である。
【図１８】投与から2時間後の胃内のGRDを示す、犬のX線図のデジタル画像である。GRD投与後に投与された食物は、胃から排出されたが、GRDは排出されなかった。
【図１９】放射線不透過性糸剤を含有するGRDを示す、犬の胃のX線デジタル画像である。X線像により、投与前、投与直後(0時間)、投与から1時間後および投与から2時間後、犬の胃が空であることが示される。
【図２０】放射線不透過性糸剤を含有するGRDを示す、犬の胃のX線デジタル画像である。X線像により、投与から3時間、7時間および9時間後にはGRDが犬の胃内に存在しており、24時間後にはGRDが存在していないことが示される。
【図２１】アモキシシリンカプレットを投与後のアモキシシリンの排泄率を、GRD内アモキシシリンカプレットの場合と比較して示したグラフ(両者とも絶食状態下)である。
【図２２】アモキシシリン単独投与後のアモキシシリンの排泄率を、GRD内アモキシシリンの場合と比較して示したグラフ(絶食状態下)である。
【図２３】リボフラビンを即時放出製剤として、または小型GRD、中型GRDおよび大型GRD内で輸送した際に、長時間に渡って排泄されたその累積量を示すグラフである。
【図２４】リボフラビンを即時放出製剤として、または小型GRD、中型GRDおよび大型GRD内で輸送した際の、その尿排泄率を示すグラフである。
【図２５】リボフラビンの即時放出およびGRD製剤に関する生物研究(biostudy)データからデコンボリューション処理された投入関数を示すグラフである。
【図２６】ヒドロクロロチアジドの即時放出製剤の投与後に排泄されたヒドロクロロチアジドの累積量 対 時間を、GRD内ヒドロクロロチアジドの場合と比較したグラフである。
【図２７】即時放出(IR)カプセルに関するおよび新規製剤(GRD)に関するヒドロクロロチアジドの排泄率 対 時間のグラフである。
【図２８】IRおよびGRDの双方における、尿産生量と水分摂取量との比較ならびにヒドロクロロチアジド由来の累積尿排出量である。【Technical field】
[0001]
Field
The present application relates to an intragastric stomach formed from a composition containing a polymeric material, such as a polysaccharide, and selective additional materials, including excipients, therapeutic agents and diagnostic agents, which remains in the stomach for a controlled duration. It relates to a retention device.
[Background]
[0002]
background
Recent oral drug delivery systems allow drug release to be controlled in a predetermined manner for periods ranging from several hours to over 24 hours. However, the effect of drug treatment depends not only on the drug release mode of the formulation but also on the rate of drug absorption in the gastrointestinal tract. Some drugs are absorbed only in specific areas of the small intestine called “windows of absorption”. Once such a drug passes through this area, only a small amount of drug is absorbed or no drug is absorbed. Accordingly, there is great interest in developing a gastric retention device (GRD) that retains a drug in the stomach for a long and predictable period.
[0003]
The need for such a device is well discussed both in the literature and in the scientific literature, including US Pat. No. 5,651,985 and references therein. In treatment, the timing of drug administration relative to food intake is very important. When sustained-release drugs are administered after meals, food interferes with the migrating myoelectric complex, allowing the dosage form to remain in the stomach for 12 hours or longer, This provides an opportunity for the drug to be absorbed. However, if the product is administered on an empty stomach, it can drain into the small intestine in less than 20 minutes and be transferred from the small intestine in less than 3-5 hours. This can dramatically reduce drug absorption for drugs that use an absorption window or drugs that are not absorbed if not sufficiently dissolved in gastric juice prior to transfer to the small intestine. Thus, even if the same medicine is used, it seems that the result is completely different depending on whether the medicine is taken after meals or on an empty stomach.
[0004]
Three major approaches have been used in an attempt to make a gastric retention device, including a review by U.S. Pat.No. 5,651,985 and Hwang et al. 15 (3): 243-284 (1998)], all have suffered from serious obstacles or failures. The most common approach is known as the Hydrodynamic Balance (HBS) system (U.S. Pat.No. 4,140,755 and U.S. Pat.No. 4,167,558), which floats in the stomach contents and injects into the intestine the stomach Designed to stay away from the part. However, these devices can only float in the stomach if the stomach contains food. In fasting patients, HBS-type drug dosage forms exit the stomach in a short time. They are swept away from the stomach by “housekeeping waves”, also called fasting strong contractions (IMC) or mobile strong contractions (MMC). The contraction wave has the ability to remove undigested material from the stomach, which is swallowed by 5 cents, 25 cents, and children (and adults) once all the food in the stomach has been digested and removed. It is the action of flushing other solids from the stomach.
[0005]
A second approach to the gastric retention device includes tablets that expand in gastric juice, as described in US Pat. No. 3,574,820 and US Pat. No. 4,434,153. Unfortunately, these tablets fall apart when hydrated. The dimensional stability of the materials used to make expandable tablets decreases significantly with expansion, which can cause premature erosion or gel layer dissolution. Furthermore, both expandable tablets and hydrodynamic balancing systems require that the formulation be formulated overall. That is, it is impossible to incorporate existing tablets into the GRD.
[0006]
A third approach to the gastric retention device involves mechanical manipulation such that, after swallowing, the polymer membrane is expanded by the release of gas (see, eg, US Pat. No. 4,207,890). Alternatively, the device can be opened by opening a “flower-like” structure (US Pat. No. 4,767,627), unfolding a folded sheet (US Pat. No. 4,308,250 for veterinary use), or on a propellant and balloon. It can function by a self-actuating valve with a changing collapsible bag. Balloon inflation causes the device to remain in the stomach (US Pat. No. 3,797,492). Unfortunately, these approaches have not worked well in humans. In particular, GRD stays in the hungry stomach during MMC, needs to disintegrate or break down in the stomach after a predetermined time, and while the device is in place and food is present, the food is pylorus Do not prevent it from passing through the stomach. No device met all these criteria.
[0007]
In addition to the approach outlined above, GRD is made from a new class of synthetic acrylamide / sulfopropyl acrylate / acrylic acid polymers containing croscarmellose sodium, also known as “superporous hydrogel composites” (Chen et al., “Gastric retention properties of superporous hydrogel composites”, Journal of Controlled Release 64, 39-51 (2000); Hwang et al.). Dry hydrogels usually swell, especially at sizes that can be swallowed by humans (tablet and capsule sizes made from 1.36 g of the starting material), which takes several hours and does not work well before reaching full swelling There is a possibility of getting out of the stomach. Furthermore, even after inflation, hydrogels are not large enough to prevent long-term inflation devices from passing through the pylorus; Chen et al.'S GRD is only slightly administered when administered to fasting dogs. Moved to colon in less than 3 hours. In addition, these new polymers have not been approved by the FDA or other government regulators.
[0008]
A further problem with existing GRDs is that if they stay in the stomach, they interfere with food transport from the stomach to the intestines. Obviously, no device is known that stays in the stomach but still allows normal food transport.
DISCLOSURE OF THE INVENTION
[0009]
wrap up
Disclosed herein is a GRD that avoids many problems of the prior art because an expandable material formed from a mixture containing polysaccharides allows for sufficient dimensional stability and flexibility at the same time. . This mixture can be processed to produce an expandable polymer gel that remains in the stomach when administered with or without food. Surprisingly, this composition does not prevent food from passing through the stomach; the device normally stays in the stomach whether the stomach is full or empty. The device can be adjusted to fully decompose in the gastric juice and exit the stomach within a predetermined time, usually 12-24 hours, but if necessary, the residence time can be made shorter or longer Is also possible. Further, the gastric retention device is suitable for administration into a lumen other than the stomach, i.e. oral cavity, rectal cavity, vaginal cavity, nasal cavity or intestinal cavity. Further, the device includes, but is not limited to, products that are already formulated and / or commercially available, such as solutions, suspensions, emulsions, powders, tablets, capsules, Alternatively, diagnostic and / or therapeutic agents, including beads, can be incorporated, and the product can be retained in the stomach to control the release of the agent in the stomach.
[0010]
The GRDs disclosed herein typically include gels formed from polysaccharides or mixtures of polysaccharides. The device is shaped to a size suitable for administration to subjects including humans and animals, for example, by removing at least a portion of the liquid fraction (ie, dehydration) prior to compression. Usually, though not necessarily, the molded device has a gastric erodible coating applied to its outer surface or stored in an ingestible gastric erodible capsule. Optionally, the molded device may be enteric coated or stored in an enteric capsule. In some embodiments, the polysaccharide includes a carbohydrate gum, and in some embodiments, the GRD is formed from a mixture that includes a sugar, a polysaccharide, or a combination thereof. Although GRD may be processed to form a gel as desired, the described embodiments typically relate to heat-induced gels. The GRD may be substantially dehydrated, and in a more specific embodiment, it is lyophilized. Xanthan gum and locust bean gum are examples of materials used to make embodiments. The weight ratio of xanthan gum to locust bean gum typically varies from about 1 to 4 to about 4 to 1, and in a more specific aspect, GRD has a weight ratio of xanthan gum to locust bean megam of about 1.5 to 1 to about 1 to 1 1. GRD is selected from the group consisting of plasticizers, pH adjusters, GI motility adjusters, viscosity modifiers, therapeutic agents, diagnostic agents, contrast agents, swelling agents, surfactants, and mixtures thereof. Further substances may be included.
[0011]
The diagnostic or therapeutic agent can be used as a solution, suspension, emulsion, tablet, capsule, powder, bead, small pill, granule, solid dispersion, or a combination thereof. Diagnostic or therapeutic agents are more soluble in gastric juice than intestinal fluid; more soluble in intestinal fluid than gastric fluid; more easily absorbed in the small intestine than in the large intestine; more easily absorbed in the stomach than in the intestine Well; and in yet other embodiments, the diagnostic or therapeutic agent can be more easily absorbed in the intestine than in the stomach.
[0012]
In some embodiments, GRD allows food to pass through, but the device is tested for a predetermined period of time up to 24 hours (e.g. 2 hours, 6 hours, 9 hours, 12 hours, or 24 hours or more). A compression device is included that is fully inflated after ingestion and sufficiently strong to inflate so that it is prevented from passing through the pylorus of the person. The device can be designed to substantially form any geometric shape after expansion, such as a cube, cone, cylinder, pyramid, sphere, column, or parallelepiped. Usually, GRD has an expansion coefficient of at least 3.0, preferably not necessarily, but the gel is within 2 hours in an aqueous environment or, optionally, 2 hours after ingestion by the subject. Within substantially expands to 80% of its final size. Without being limited to a single theory of operation, the expanding gel may be at least one dimension larger than the diameter of the pylorus.
[0013]
GRD is usually eroded in the presence of gastric juice and passes through the pylorus after a predetermined time. The GRD may include an enzyme that aids in the erosion of the coating or capsule after ingestion of the device, such as a hydrolase, protease, cellulase, or gluconase.
[0014]
A specific embodiment of GRD is about 0.1% to about 2.0% xanthan gum, about 0.1% to about 2.0% locust bean gum, about 5% polyethylene glycol, about 1% sodium lauryl sulfate by weight, The gel was prepared from a mixture containing 1% carbopol and a biologically effective amount of the therapeutic agent, diagnostic agent, or combination thereof, others including liquids such as water. The device was sufficiently dried and compressed to a size suitable for administration to a subject and to a shape suitable for insertion into a gastroerodible capsule.
[0015]
Embodiments disclosed as a method for making a gastric retention device include the steps of forming a mixture comprising a polymeric material, processing the mixture to form a dry gel, and optionally, subjecting the dry gel to gastric juice. The steps included coating with an erodible substance or placing the gel in a gastric erodible capsule. The processing step may include heating the mixture and lyophilizing the gel to effectively form a heat-induced gel. The dried gel may be compressed to a size and shape suitable for administration to a subject prior to coating the gel or placing it in a capsule.
[0016]
Also disclosed herein is a method for using a gastric retention device. Embodiments of the method include providing a gastric retention device and administering the gastric retention device to a subject as outlined herein. Also disclosed is an aspect for appetite suppression comprising providing a gastric retention device that expands sufficiently in the stomach of a subject to at least partially suppress the subject's appetite. is there. The gastric retention device is regularly administered to the subject. In some embodiments, the device further includes an effective amount of a fatty acid, an appetite suppressant, a weight loss drug, or a combination thereof. Also disclosed herein is a method of altering the pharmacological response without changing the total dose, eg, increasing urine output while keeping the oral dose of diuretic constant.
[0017]
The foregoing and other features and advantages will become apparent from the following detailed description of several embodiments, which proceeds with reference to the accompanying drawings.
[0018]
Detailed description
I. Introduction
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified by context, the singular terms “a”, “an”, and “the” include plural subjects. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. The described materials, methods, and examples are illustrative only and not intended to be limiting.
[0019]
II. Terminology
The term definitions are provided solely for the benefit of the reader and should not be construed to limit the defined terms to any particular example provided, or are narrower definitions than would be accepted by one skilled in the art. Should not be interpreted.
[0020]
By active agent is meant any therapeutic or diagnostic agent that is now known or that will become apparent below that it can be formulated as described herein. Examples of therapeutic agents are listed in, but not limited to, US Pat. No. 4,649,043, which is hereby incorporated by reference. Further examples are listed in American Druggist, p. 21-24 (February 1995).
[0021]
Administration to a subject can be performed by any known method including, but not limited to, oral, vaginal, rectal, nasal, or buccal.
[0022]
Controlled release includes all terms describing modes of release other than sustained release, sustained release (sustained release), vibrational release, delayed release and immediate release.
[0023]
Diagnostic means, but is not limited to, imaging of a substance and / or tissue or cavity useful for testing whether a substance or disease is present or absent Means a substance that improves
[0024]
An effective amount is the amount of a diagnostic or therapeutic agent that is useful to cause the desired effect.
[0025]
By erodible is meant a combination of digestibility, solubility, solubility, enzyme removal, etc., and such erosion processes. While not meant to be limiting, one method of measuring erodibility is to use a coating, capsule, or GRD in a suitable aqueous environment, such as in a paddle stirred dissolver (operated at 50 rpm) by the United States Pharmacopeia, such as By measuring the degree of cohesive loss of the coating, capsule, or GRD within a predetermined time, such as 1 hour, 3 hours, 6 hours, 9 hours, 12 hours or 24 hours, when exposed to artificial gastric juice is there. Suitable aqueous environments can include one or more aqueous media, including media exchange during research, and usually depend on the specific intended use of the GRD, as is well known to those skilled in the art It is thought that there are many cases.
[0026]
The expansion coefficient is calculated by dividing the volume of the fully expanded device by the volume of the GRD before expansion.
[0027]
A gastric retention device (GRD) is a device that can be administered to a subject with or without added substances. The GRD device can be adjusted for various body cavities including the abdominal (gastric) cavity, intestinal cavity, oral cavity, rectal cavity, vaginal cavity or nasal cavity. Usually, for intragastric transport, the device is shaped to a size suitable for administration to a subject, and after administration, the device absorbs fluid and expands to a size larger than the administered size. Adjusted to prevent passage through the pylorus. For other body cavities, the device is shaped to a size suitable for that cavity. For example, for the intestinal cavity, the device is usually administered orally into the gastric cavity and adjusted to form a size suitable for the intestine. Usually, a dehydrated polysaccharide gel is used to make the device. For routes of administration other than oral administration, GRD usually absorbs liquids, although this is not always the case.
[0028]
A hydrophilic gel-forming substance or agent, also called a hydrogel, is a substance that exhibits the ability to hydrate in water and retain a significant water fraction within its structure. Hydrogels can be non-crosslinkable or they may be cross-linked by covalent or ionic bonds. Hydrogels can be plant-derived or animal-derived, hydrogels prepared by modifying naturally occurring structures, and synthetic polymer hydrogels.
[0029]
A monosaccharide is an aldehyde or ketone derivative of a linear polyhydroxy alcohol containing at least 3 carbon atoms.
[0030]
A polysaccharide consists of monosaccharides linked together by glycosidic bonds.
[0031]
Tablet is a well-known term in the art and is used herein as a compressed material, molded material, or otherwise molded without limitation in size or shape, and any method of preparation. Used to contain all the substances. Thus, one common example includes a compressed or molded shape known as a caplet.
[0032]
III. Composition
Typically, a GRD is made by selecting one or more materials useful for forming an expandable gel matrix, generally a monomeric or polymeric material, such as a polysaccharide. Thus, additional excipients, diagnostic agents, therapeutic agents, contrast agents or combinations thereof may be selected and used depending on the situation to form the GRD. The selected polymeric material, excipient, and / or diagnostic or therapeutic agent and / or contrast agent are combined with the liquid to form a mixture, and the mixture is further processed to form a liquid-containing gel. Then, to make a dried gel film, some liquid is removed from the gel, and optionally the dried gel film may be compressed to a size suitable for administration. The dried gel film may be coated with or encapsulated with a gastric erodible coating and / or an enteric coating. After administration, the dry gel absorbs the liquid. Thus, in various aspects, the gel may include a liquid or may be a dry gel. Each of these steps is discussed in more detail below.
[0033]
A. Monomers or polymeric materials useful for forming GRD
Disclosed herein is a GRD formed generally from a mixture comprising a polymeric material. However, as long as the monomeric materials form the same polymeric material, eg, such polymeric materials are formed in situ, they may be used as well. The polymeric material may be a hydrophilic gel former. Examples of hydrophilic gel formers include, but are not limited to, acacia, tragacanth, gar gum, pectin, xanthan gum, locust bean gum, Carbopol® acidic carboxy polymer, hydroxypropyl methylcellulose , Polycarbophil, polyethylene oxide, polyhydroxyalkyl methacrylate, poly (electrolyte complexes), poly (vinyl acetate) cross-linked with hydrolyzable bonds , Water-swellable N-vinyl lactam polysaccharide, natural rubber, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, ibarnea (hypnea), giraffe (eucheuma), Arabic gum, Gatch rubber, Karaya gum, Ara Alginic gum, crosslinkable alginate gum (crosslinkable alginate gum is a divalent or trivalent ion) containing both arbinoglactan, amylopectin, gelatin, carboxymethylcellulose gum or non-crosslinkable and crosslinkable alginate gum Hydrophilic colloids (such as can be crosslinked), polyols such as propylene glycol, or other crosslinking agents, Cyanamer (R) polyacrylamide, Good-rite (R) polyacrylic Materials such as acids, starch graft copolymers, Aqua-Keeps® acrylate polymers, ester cross-linked polyglucans are included. Some of these hydrogels are discussed in U.S. Patent 3,640,741, U.S. Patent 3,865,108, U.S. Patent 3,992,562, U.S. Patent 4,002,173, U.S. Patent 4,014,335 and U.S. Patent 4,207,893. Yes. Similarly, hydrogels are discussed in "Handbook of Common Polymers" by Scott and Roff, published by Chemical Rubber Company, Cleveland, Ohio.
[0034]
For the GRD embodiment, polysaccharides were used. Optionally, the GRD may include a carbohydrate gum or may be formed from a mixture including one or more sugars, one or more polysaccharides, or a combination thereof. In an embodiment for forming GRD, xanthan gum and locust bean gum were used, and the weight ratio of xanthan gum to locust bean megam was about 1 to 4 to about 4 to 1. In a specific embodiment of GRD, the weight ratio of xanthan gum to locust bean megam was from about 1.5 to 1 to about 1 to 1. Generally, the polysaccharide comprises about 0.1% to 5% of the starting material, more usually about 1% to 4%, and even more typically about 1% to 3%, Most commonly, it contains about 1% of the starting components. Percentage is the ratio of all components, including the liquid portion.
[0035]
B. Excipient
Optionally, the GRD may also include excipients such as plasticizers, pH modifiers, gastrointestinal motility modifiers, viscosity modifiers, swelling agents, surfactants, or mixtures thereof.
[0036]
A plasticizer can be added to the composition to increase the plasticity of the mixture to a level suitable for administration to a subject. The plasticizer may be a hydroxylated compound, especially a polyhydroxylated organic compound. For example, polyethylene glycol (PEG) is a poly-aliphatic hydroxylated organic compound used in the examples. One skilled in the art would be able to substitute other plasticizers such as glycerin or surfactants. Typically, embodiments included about 1% to 8% plasticizer.
[0037]
A pH adjuster can be added to adjust the pH of the GRD to a desired pH level. For example, it is now believed that increasing the pH in the GRD region will increase swelling in the acidic environment of the stomach. pH adjusting agents may also be used to modify the viscosity of some polymer excipients such as carbopol. Suitable pH adjusting agents include buffers, inorganic acids or inorganic bases, or organic acids or organic bases. The pH adjuster is optionally a buffer solution, and disodium phosphate and sodium phosphate were used in the examples. Other pH adjusting agents are known to those skilled in the art and include, but are not limited to, hydrochloric acid, sodium hydroxide, potassium hydroxide, organic acids such as acetic acid, and organic amines, especially more Lower alkyl amines (10 carbon atoms or less) such as triethylamine may be included.
[0038]
Viscosity modifiers can be added to adjust the viscosity to a viscosity level that allows the retention of GRD in the stomach over a predetermined time. Viscosity modifiers include, but are not limited to, carbopol, polyvinyl pyrrolidone, alginate, cellulose, gum (thickener) and hydrogel. In an embodiment, carbopol and polyvinylpyrrolidone were included as viscosity modifiers. Other viscosity modifiers can be selected by those skilled in the art. Typically, embodiments contained about 0.25% to 1% carbopol and / or polyvinyl pyrrolidone.
[0039]
C. Diagnostic and therapeutic agents
The GRD may also incorporate a diagnostic or therapeutic agent selected from the group consisting of nucleic acids, proteins, naturally occurring organic compounds, synthetic and semi-synthetic compounds, and combinations thereof. More specifically, diagnostic or therapeutic agents include AIDS adjunct agents, alcohol abuse preparations, Alzheimer's disease management agents, muscle atrophic lateral cords. Amyotrophic lateral sclerosis therapeutic agent, analgesic, anesthetic, antacid, antiarythmic, antibiotic, anticonvulsant ), Antidepressant, antidiabetic agent, antiemetic, antidote, antifibrosis therapeutic agent, antifungal, antihistamine Antihypertensive, antiinfective agent, antimicrobial, antineoplastic, antipsychotic, antiparkinsonian agent, antirheumatic drug ( antirheumatic agent), appetite stimulant stimulant, appetite suppressant, biological response modifier, biological blood modifier, bone metabolism regulator, cardioprotective agent Cardiovascular agents, central nervous system stimulants, cholinesterase inhibitors, contraceptives, cystic fibrosis management agents, deodorants (deodorant), diagnostic, dietary supplement, diuretic, dopamine receptor agonist, endometriosis management agent, enzyme ), Erectile dysfunction therapeutic, fatty acid, gastrointestinal agent, Gaucher's disease management agent, gout preparation, homeopathic medicine (homeopathic remedy), hormone (hormone), hypercalcemia management agent, hypnotic, hypocalcemia management agent, immunomodulator, immunosuppressant ( immunosuppressive), ion exchange resin, levocarnitine deficiency management agent, mast cell stabilizer, migraine preparation, motion sickness sickness product), multiple sclerosis management agent, muscle relaxant, narcotic detoxification agent, narcotic, nucleoside analog, non Non-steroidal anti-inflammatory drug, obesity management agent, osteoporosis preparation, oxytocic, parasympathetic blockade (parasympatholytic), parasympathomimetic, phosphate binder, porphyria agent, psychotherapeutic agent, radio-opaque agent, psychotropic Psychotropic, sclerosing agent, sedative, sickle cell anemia management agent, smoking cessation aid, steroid, stimulant (stimulant), sympatholytic, sympathomimetic, Tourette's syndrome agent, tremor preparation, urinary tract agent, It may be a vaginal preparation, a vasodilator, a vertigo agent, a weight loss agent, a Wilson's disease management agent, and mixtures thereof . Specific examples of such therapeutic and diagnostic agents include, but are not limited to, abacavir sulfate, abacavir sulfate / lamivudine / zidovudine, acetazolamide (acetazolamide), acyclovir, albendazole, albuterol, aldactone, allopurinol BP, amoxicillin, amoxicillin / clavulanate potassium, amoxicillin / clavulanate potassium Amprenavir, atovaquone, atoxiqulin and proguanil hydrochloride, atracurium besylate, beclomethasone dipropionate, bererate betamethasone valerate betamethasone valerate ), View propiyl chloride Bupropion hydrochloride, bupropion hydrochloride SR, carvedilol, caspofungin acetate, cefazolin, cefazolin, ceftazidime, cefuroxime (no sulfate) sulfate)), chlorambucil, chlorpromazine, cimetidine, cimetidine hydrochloride, cisatracurium besilate, clobetasol propionate, cotrimoxazole (co -trimoxazole), colfosceril palmitate, dextroamphetamine sulfate, digoxin, enalapril maleate, epoprostenol, esomepraxole magnesium, The Fluticasone propionate, furosemide, hydrochlorothiazide / triamterene, lamivudine, lamotrigine, lithium carbonate, losartan potassium, melphalan ), Mercaptopurine, mesalazine, mupirocin calcium cream, nabumetone, naratriptan, omeprazole, ondansetron hydrochloride, ovine ), Oxiconazole nitrate, paroxetine hydrochloride, prochlorperazine, procyclidine hydrochloride, pyrimethamine, ranitidine bismut citrate h citrate), ranitidine hydrochloride, rofecoxib, ropinirole hydrochloride, rosiglitazone maleate, salmeterol xinafoate, salmeterol, salmeterolone, fluticone propionate propionate), sterile ticarcillin disodium / clavulanate potassium, simvastatin, spironolactone, succinylcholine chloride, sumatriptan, thioguanine, thioguanine, thioguanine Hydrochloride (tirofiban HCl), topotecan hydrochloride, tranylcypromine sulfate, trifluoperazine hydrochloride, valacyclovir hydrochloride, vinoler Down (vinorelbine), zanamivir (zanamivir), zidovudine (zidovudine), include lamivudine (lamivudine) or mixtures thereof.
[0040]
An effective amount of a diagnostic or therapeutic agent is incorporated within the GRD as a solution, suspension, emulsion, tablet, capsule, powder, bead, small pill, granule, solid dispersion, or a combination thereof Also good. Optionally, diagnostic or therapeutic agents are more soluble in gastric juice than intestinal fluid, more soluble in intestinal fluid than gastric fluid, more easily absorbed in the small intestine than in the large intestine, and more absorbed in the stomach than in the intestine. Or may be more easily absorbed in the intestine than in the stomach.
[0041]
D. Liquid
The polymeric materials, excipients, and / or diagnostic or therapeutic agents can be dissolved and / or suspended in any liquid in which they are at least partially soluble. A preferred liquid is water. Other liquids include polar organic compounds such as alcohols. Usually, the liquid constitutes the remainder of the mixture after the polymeric material, diagnostic and / or therapeutic agent, and excipients have been added.
[0042]
IV. GRD formation
Typically, GRD mixes and mixes selected ingredients, induces gelation, drys the resulting gel, and selectively encapsulates the resulting dry, formed gel with a gastroerodible coating. Produced. Each of these steps is described in more detail below.
[0043]
A. Mixing
Methods for forming the gel mixture include mixing an appropriate amount of the selected polymer material (s) with a desired amount of liquid and mixing with agitation. One or more excipients and / or one or more diagnostic or therapeutic agents may be mixed directly with the polymeric material, or optionally they are mixed separately and later mixed with the polymeric material May be mixed with. Existing dosage forms such as capsules or tablets may be added into the polymer material just prior to gelation, or inserted into it after the gel is formed.
[0044]
B. Gelation
Gelation of the gel can be induced by any method well known to those skilled in the art, such as a chemical gelling method or a thermal gelling method. In the examples, a heat-induced gelation method was mainly used to avoid the use of chemically acting gelling agents. For example, as a specific example, gelling involves heating the mixture sufficiently to dissolve at least some solid components, such as from about 50 ° C to about 100 ° C, typically about 80 ° C. It was included to heat the temperature and maintain the mixture at that temperature until it was sufficiently dissolved to allow subsequent gelation. Typical heating times ranged from about 10 minutes to about 30 minutes for small batches, but the heating time can vary depending on the batch size. After heating, the gel is formed by slowly cooling the mixture to induce gelation. In the working process, the mixture was allowed to cool to about room temperature.
[0045]
C. Drying
To form a dry film, the liquid is formed from the gel formed by any method known to those skilled in the art including air drying, freeze drying, vacuum drying, or other drying or dehydration methods known to those skilled in the art. Can be removed. In one embodiment, dehydration was achieved by vacuum drying at room temperature. In another embodiment, it was dehydrated by oven drying at a temperature of about 35 ° C to about 75 ° C. In another embodiment, the gel was dehydrated by lyophilization.
[0046]
Drying or dehydrating means that a total of more than 50% of the liquid solvent is removed, and 90% or more of any liquid that is normally present is removed. The liquid used in the formulation helps the “dry” gel film maintain some flexibility and strength, or because it does not need to be removed completely to facilitate swelling or If desired, it may be left in the apparatus.
[0047]
D. Compression
Optionally, the dry film may be compressed to a size and shape suitable for administration to a subject prior to coating the GRD or placing it in a capsule. In an embodiment, the dry film was compressed with a compression mold, but to fit a capsule size of size 2, 1, 0, 00 or 000, by rolling the dry film or making it Any compression method known to those skilled in the art by squeezing or folding may be used. Smaller size capsules may be suitable for transporting the device through the stomach and into the intestine. In other examples, the dried film was compressed in a punch mold at a pressure of about 500 to 3000 pounds per square inch.
[0048]
E. Encapsulation
A gastric erodible coating can be applied to the outer surface of the dehydrated GRD by any method known to those skilled in the art, such as by spray coating or dip coating, or by insertion into a capsule. Additionally or alternatively, the GRD can be coated with an enteric coating, such as Eudragit® or Opadry®, on the outer surface, or the GRD can be inserted into the capsule it can. In the GRD embodiment, it was inserted into capsules of size 2, 1, 0, 00 or 000. One skilled in the art can select any known method of coating or encapsulating GRD.
[0049]
V. Administration
Usually, GRD is administered orally. However, in some embodiments, GRD may be administered into a lumen other than the stomach, i.e., oral cavity, rectal cavity, vaginal cavity, nasal cavity or intestinal cavity. The device may be used as an imaging aid by including a dye or other contrast material and expanding to fill the cavity. Alternatively, for local or systemic effects, the device may be used to deliver a therapeutic or diagnostic agent to a cavity wall by expanding and releasing the substance into the cavity. For example, the device may be placed in a capsule and the capsule may be enteric coated such that the device expands into contact with the intestinal wall without being released into the stomach. GRD inflation can also help to keep the GRD position within the desired cavity. In one aspect, the preferred dimensions of the inflated device can be different from devices designed to be retained in the stomach and are often much smaller. For example, the presence of a device in the intestine can be used to reduce hunger and suppress appetite. In this embodiment, the desired GRD size is usually smaller than the gastric GRD, especially when administered multiple times over an extended period of time. Smaller dimensions are preferred for the nasal cavity.
[0050]
Hereinafter, although an example of the present invention is given and explained, the present invention is not limited to this.
[0051]
Example
Example 1
This example relates to a method for making a GRD. The listed materials were obtained and processed as described.
[0052]
I. Dry powders of xanthan gum (XG, Spectrum Chemical Mfg. Corp., Gardena, Calif.) And locust bean megame (LBG, Sigma Chemicals, St. Louis, Mo.) were mixed well and compressed into round tablets.
II. XG and LBG were dissolved in 80 ° C. water, gelled, dried and crushed. A viscous gel was formed, poured into a petri dish and dried in an oven. The thick dry mass was then crushed to a powder and then compressed into tablets.
III. Accurately weighed LBG (0 g to 1 g) was added to 100 ml of water maintained at 70-75 ° C. with constant stirring. The resulting solution was heated to a temperature of 80-85 ° C. for the addition of XG and XG was added slowly with constant stirring. The highly viscous solution thus prepared was poured into an appropriately shaped mold. Upon cooling, the resulting gel was cut into the desired size. These gels were dried and subjected to hydration studies.
IV. Accurately weighed LBG (0g-1g) was added to 100ml water at 70-75 ° C with constant stirring. XG was added to the resulting solution at 80-85 ° C. with constant stirring. 10 ml of polyethylene glycol (PEG) 400 was added to the resulting mixture, which was cooled (gelled), cut to the desired size and dried.
V. Various drugs (0.5 to 4 g) (sodium bicarbonate (Mallinckrodt, Paris KY), tartaric acid, Water-Loc® (Grain Processing Corp., Muscatine IA), hydroxypropyl methylcellulose, polyethylene oxide N-80 (Union Carbide Corp. Danbury, CT) were incorporated into gels prior to drying to film in separate experiments to assess the effect of the ingredients on the rate of hydration in artificial gastric fluid (SGF) .
[0053]
Tablets made by direct compression of XG powder mixed with LBG did not produce a sticky hydrated gel in either water or gastric fluid when received from the supplier. In fact, the tablets broke apart when placed in water or gastric juice.
[0054]
Dissolution of both gums in water results in the generation of interactions that cause gelation. Dissolution of XG and LBG in water at 80 ° C. produced a solution that, upon cooling, produced a gel that dried to form a film. The gel strength was dependent on the temperature at which the interaction between the two gums occurred, ie the temperature at which the gel was made. Interaction above the Tm of XG results in a gel with better gel strength. Dissolution of the gum at 70-75 ° C (first LBG followed by XG) gives a gel with good gel strength.
[0055]
The gel thus produced was dried in an oven to produce a gel film that was then pulverized and the powder was compressed into tablets. Such tablets broke apart when contacted with water or artificial gastric juice. However, the individual particles were extensively hydrated when they were contacted with the medium.
[0056]
B. In another example, GRD was made according to the following method.
material
The following chemicals were obtained from standard suppliers as indicated. All chemicals were used as received.
[0057]
Xanthan gum (XG; spectrum Chemical Mfg. Corp., Gardena, CA), locust bean megame (galactomannan polysaccharide from Ceratonia Siliqua seeds, Sigma catalog number G-0753, Sigma Chemicals, St. Louis, MO), polyvinylpyrrolidone ( PVP) and riboflavin (Sigma Chemicals, St. Louis, MO), sodium lauryl sulfate (SLS; Matheson Coleman & Bell, Cincinnati OH), polyethylene glycol 400 (PEG 400) and polyethylene oxide, molecular weight 200,000 (Union Carbide Corp. Danburg , CT), microcrystalline cellulose [Avicel, PH101] (FMC Corp, Newwark, DE). Barium penetrating polyethylene sphere, 1.5 mm diameter (BIPS) (Chemstock Animal Health LTD, New Zealand), radiopaque thread (provided by Oregon State University Veterinary School).
[0058]
Two types of GRD were prepared: normal GRD and modified GPD. Regular GPD was prepared by dissolving LBG (0.5 gm) and XG (0.75 gm) in 100 ml water. The modified GRD was prepared by dissolving PVP (0.5 gm), LBG (0.5 gm), SLS (0.15 gm), and XG (0.75 gm) in 100 ml water with constant stirring (in this order). . Both solutions were heated to a temperature of 85 ° C. 6 ml of PEG400 was then added to each of the hot viscous solutions. A precisely weighed riboflavin in the form of a powder, bead, or solid dispersion was then added to the hot viscous solution with constant stirring to produce a uniform mass.
[0059]
This viscous solution was then poured into a suitably shaped mold and the resulting gel was allowed to cool at room temperature for 4 hours and cut into the desired size. The cut gel was dried in a vacuum oven for about 16 hours at 50 ° C. This drying process could be easily shaped manually and produced a flexible film that fits into the capsule. In this case, GRD consisting of capsules containing a dry gel (film) with drug was suitable for use.
[0060]
Three different size capsules (“0”, “0”, and “000” size) were filled with different sizes of GRD containing riboflavin.
[0061]
The two main components of GRD described are XG and LBG. XG and LBG were used in a ratio of 1.5: 1, respectively. By increasing the ratio of XG above 1.5, a very viscous and harder film was produced after drying. It is difficult to prepare a solution containing more than 3% gum. This is because both XG and LBG are highly viscous colloids. XG was used at a higher ratio than LBG since better pH stability is obtained when the colloid ratio is closer to XG. XG is stable over the entire pH spectrum, whereas LBG has low acid stability. Some GRDs are intended to remain in the acidic environment of the stomach for longer than 9 hours, so a higher XG ratio produces a stronger gel after hydration in gastric juice and the resulting gel is rapidly Do not disassemble. Solutions containing less than 1% gum are less viscous, dry films are thinner, and lose their overall hardness and integrity in less than 6 hours when hydrated in artificial gastric juice To do. When adding PVP and SLS in an attempt to increase the rate and amount of riboflavin released from GRD, a surprisingly more elastic film was formed when the gel was dried. A further increase in the amount of PVP and SLS added to the gum solution produced a very soft film after drying. These soft films, when immersed in SGF, produced weak gels that lost SGF integrity in about 4 hours.
[0062]
The gum solution was heated to 85 ° C. The viscosity of the solution drops sharply at this temperature, which allows the viscous solution to be poured into the mold. The viscosity rises again rapidly around 40-50 ° C when the solution is cooled from 85 ° C. Addition of therapeutic, diagnostic, or visualization agents as solutions, suspensions, powders, tablets, capsules, beads, pellets, granules, emulsions, solid dispersions, or combinations thereof, the gel is completely formed by cooling Can be done before being done.
[0063]
Example 2
This section relates to a method for drying a gel into a film.
[0064]
A. Using the method of gel preparation as outlined in Example 1A, Section IV, films with different hydration times were made using different methods of drying the gel into films. Methods used include oven drying at 45 ° C., vacuum drying at 35-60 ° C., and freeze drying at −20 ° C.
[0065]
Gels dried to film at temperatures in an oven higher than 40 ° C. tended to lose PEG (because the boiling point of liquid PEG was around 45 ° C. as expected). Drying at lower temperatures (eg, 30-35 ° C.) required more than 24 hours for the gel to dry into a film.
[0066]
When the gel was dried in an oven under vacuum at 30 ° C., the loss of PEG was negligible. The drying time was about 12-18 hours.
[0067]
There was no loss of PEG when the gel was freeze-dried to film. These films were easy to compress and incorporate into capsules. Freeze-drying included first freezing the gel at −20 ° C. for 2 hours and then subjecting it to freeze-drying at −46 ° C.
[0068]
B. The GRD produced according to Example 1B was dried by the following method.
A flexible soft film was obtained when the gel was dried in a vacuum oven at 50-55 ° C. for about 16-17 hours. A flexible soft film promotes easy rolling and incorporation into capsules and rapid swelling when immersed in SGF. When higher temperatures (60-70 ° C) are attempted for shorter times (12-15 hours), they break more easily when rolled into capsules and do not swell on it when immersed in SGF, A harder film was obtained. When lower temperatures (30-40 ° C) are attempted, it takes about 48 hours to obtain a dry film, and this dry film swells at the same rate as a film made at 50-55 ° C. There wasn't.
[0069]
Example 3
This section relates to the compression of dry film to a size suitable for administration.
[0070]
To form the dry film of Example 2A, the gel of Example 1A, Section IV was dried and the dry film was compressed with the aid of a specially made punch and die. A series of dies with progressively narrow inner diameters were used. The punch pushed the film from one soybean to the next die, followed by another punch to push the film to the next die. This process was continued until the film reached a point that was small enough to achieve the desired capsule size (eg, “000” capsules). Other size capsules may be used with other size films or caplets.
[0071]
Example 4
This section relates to hydration studies performed at GRD.
[0072]
A. In some examples, hydration studies were performed as follows.
Prepare a gel according to Example 1A, Section IV, dry the gel to form a dry film as outlined in Example 2A, compress the dry film as shown in Example 3, and use different shapes as well as various Hydration studies of films made with xanthan gum and locust bean megame ratios were performed in both water and artificial gastric juice. Hydration studies in artificial gastric juice were performed at 37 ° C. Hydration% was calculated as follows:

[0073]
Films cut to different sizes and shapes were hydrated in water or gastric fluid. Hydration studies were also performed in diluted gastric fluid (1 part SGF and 3 parts water) for comparison. Shapes such as circles, stars, cubes, rectangles and triangles were studied.
[0074]
Of all the shapes studied, cubes that are somewhat flat, generally non-uniform in height, width, and depth, and dried in a generally rectangular film, are the fastest It was found to have swelling and maximum volume and had greater gel strength. However, based on a study of the size that is most easily incorporated into the capsule, the preferred shape was a rectangular gel shape with dimensions of about 4 cm × 4 cm × 1 cm before drying.
[0075]
Gels with various solid ratios of xanthan gum to locust bean gum were made as shown in Table 1 and dried into films. Complete hydration of the film for 24 hours in water or artificial gastric fluid is shown in FIGS. 1 and 2, respectively. The initial film hydration in water or artificial gastric juice is shown in FIGS. 3 and 4, respectively. When a capsule or tablet is digested with an empty stomach, the length of time it passes from the stomach to the intestine can range from a few minutes to 2 hours, depending on the arrival time of the MMC (Mobility Strong Contraction Movement). The GRD incorporated in the capsule should ideally begin hydration as soon as the capsule dissolves, and be sufficiently large within 15-20 minutes to avoid passage through the pyloric sphincter Should be retained. The structural integrity of the hydrated gel should be sufficient to resist MMC. Thus, the initial hydration rate and structural integrity are very important.
[0076]
(Table 1) XG / LBG film composition

Based on the hydration study profile and gel strength, a gel with a 50:50 ratio was considered for further modification. Gel strength was based on visual observation of the film during hydration and by physical testing of the gel formed after film hydration.
[0077]
As shown in FIGS. 1-4, the hydration of the film in SGF is extensive but relatively less than that in water. Hydration in water is about 10 times greater than in SGF. Therefore, the addition of the buffering disodium phosphate or sodium phosphate was tested to swell the film faster and to a larger size in SGF. Films containing disodium phosphate or sodium phosphate (2 times the amount of gum solid) swell completely in SGF in about 12 hours. After 12 hours, the SGF used for hydration studies (approximately 500 ml volume) was found to have a pH of 6.8. In vivo, there is a continuous secretion of gastric acid with fluid removed from the stomach in the primary process. Therefore, the pH in the stomach does not reach 6.8 as in vitro (here the amount of acid is fixed). However, the pH of the microenvironment inside the film when the film is hydrated can remain alkaline or neutral and can promote rapid swelling in gastric juice without significantly changing the pH of the stomach. One limitation to the addition of the alkalinizing agent is that there is a correlation between the amount of alkalinizing agent and the ability to compress the film and incorporate it into the capsule. Hydration of the film in a medium containing 25% artificial gastric juice and 75% water was significantly improved compared to gastric juice alone. Drugs are taken up with water. Thus, hydration studies conducted in 3: 1 water: SGF media mimic the state expected when GRD is incorporated with 8-10 ounces of water.
[0078]
The addition of other additives, such as polyethylene oxide, carboxymethylcellulose (CM), and / or Water / Loc® to the gel during gel formation, is the initial stage of the film in SGF. Used to improve the hydration of. Table 2 shows various formulations containing different additives. All studies mentioned above were evaluated by visual inspection of film hydration after regular time intervals.
[0079]
The gel may become too brittle and cannot be molded or compressed for placement in the capsule. Addition of polyethylene glycol (PEG) to the gel produces a more supple film after gel drying.
[0080]
B. In other examples, hydration studies were performed according to the following method.
According to the method of Example 1B, hydration studies on four different shaped dry gels (films) made from XG, LBG, PVP, SLS, and PEG400 were performed in artificial gastric fluid at 37 ° C. A dry gel was prepared by dissolving the ingredients in water. The mixture was then heated at 85 ° C. and 10 ml of this hot viscous solution was poured into differently shaped molds to create the desired shape. These four shapes were cubes, rectangles, short cylinders, and long cylinders. The gel was then dried and subjected to hydration studies.
[0081]
Table 2 Examples of various formulations studied for hydration during GRD development (percent of total)

[0082]
Four different shapes were hydrated in artificial gastric juice. The dimensions and shape of the tested GRD are shown in FIG. The weight percent increase in hydrated film was measured after 15 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, and 180 minutes, and again after 12 hours and 24 hours.
[0083]
Hydrated films retained their integrity in artificial gastric juice for up to 24 hours. Of all the shapes studied, it was found that the rectangular gel dried to a nearly flat rectangular film had the fastest swelling and maximum volume. Based on this study, a rectangular shape was selected for further in vitro and in vivo studies.
[0084]
The complete hydration of the film in artificial gastric juice (SGI) up to 24 hours is shown in FIG. The initial hydration of the film in SGF is shown in FIG. Early hydration is a very important factor in the development of GRD. Ideally, it would be best to create a device that is small enough to incorporate a capsule for easy swallowing but expands to a size that is too large to pass through the pylorus upon contact with gastric juice. For certain applications, this large size swelling lasts about 5-15 minutes, to avoid gastric emptying due to the strong contraction of the housekeeper wave (eg, about 15 to about Should be 30 minutes). Thus, the rapid swelling of the released dry gel and the integrity of the swollen gel are very important.
[0085]
Example 5
This section relates to methods for incorporation of diagnostic or therapeutic agents into GRD.
[0086]
A. Amoxicillin was incorporated into the GRD from Example 1A, Section IV in the form of a tablet having a caplet shape. Amoxicillin was selected as a model drug. This is because it has an “absorption window”.
[0087]
A hot viscous solution of gum prepared by the method described in Example 1A, Section IV is poured into a suitable mold so that the tablets incorporated in the gel remain suspended in the gel. The tablet-containing gel was then cut into the desired size. After drying for 18-18 hours, these dry films containing tablets were compressed with a punch and die using a hydraulic press and incorporated into "000" capsules.
[0088]
B. Riboflavin was incorporated into the GRD from Example 1B in the form of a powder, beads, or solid dispersion. Riboflavin incorporated into the gel by stirring into a hot, viscous mixture just prior to cooling to the gel remained suspended in the gel. Dry gels (films) containing drug beads, powders or solid dispersions were easily rolled and incorporated into appropriately sized capsules. The GRD containing drug beads, powders, or solid dispersions were then subjected to in vitro lysis and / or in vivo studies.
[0089]
Example 6
This section relates to the preparation of amoxicillin and “core” couplets for use with GRD.
[0090]
Amoxicillin caplets were prepared by combining with the ingredients listed in Table 3 and formed by direct compression.
[0091]
Table 3 Formulations for amoxicillin caplets

[0092]
To form an amoxicillin “core” couplet, the amoxicillin caplet is centered with the microcrystalline cellulose in a larger die and punch and recompressed so that the amoxicillin caplet is inside the shell formed by the microcrystalline cellulose To do. The new caplet thus formed has an amoxicillin caplet as the core, which is commonly known as a “core tablet” or “in-tablet tablet”.
[0093]
Example 7
This section relates to the preparation of riboflavin formulations for use with GRD.
[0094]
Riboflavin was incorporated into GRD in the form of powder, beads, or solid dispersion. Riboflavin beads were prepared by mixing known amounts of riboflavin, Avicel PH-101, and polyethylene oxide 200,000 with water to produce a wet mass. The mass was then extruded and spherically formed using a laboratory extruder (model 10/25) and a spherical molding machine (model 120, Caleva Process LTD, England) to produce drug beads (diameter 1.5). ~ 2.0nm). The beads were left to dry overnight in a 50 ° C. oven. Immediately prior to cooling to the gel, the beads incorporated into the gel by stirring into the hot viscous mixture remained suspended in the gel.
[0095]
Riboflavin beads were prepared by extrusion and spherical molding using the formulations shown in Table 4. When used in powder form, riboflavin was dried at 120 ° C. for 2 hours to remove moisture and then incorporated into a gel.
[0096]
(Table 4) Preparation of riboflavin beads

[0097]
A riboflavin solid dispersion was prepared by melting a weighed amount of PEG3500 in an evaporating dish. A weighed amount of drug was then added to produce the desired ratio of drug: PEG (1: 3). The system was heated until complete dissolution of the drug was achieved. The evaporating dish was then transferred to an ice bath and stirred until the material was cooled. The final solid mass was broken, crushed and sieved to produce a fine powder. The prepared solid dispersion was dried in a vacuum oven overnight at room temperature and then incorporated into a gel.
[0098]
Example 8
This section relates to dissolution studies performed with GRD containing diagnostic and / or therapeutic agents.
[0099]
A. This example illustrates that a therapeutic agent in the form of a tablet can be incorporated into a gastric retention device formed from a polysaccharide, and that the device can be formed to an appropriate size for administration to a subject, depending on gastric juice. Demonstrate that it is placed in an inoculated capsule that is eroded. Dissolution studies were performed using GRDs made according to the method of Example 1A, Section IV, containing the model drugs amoxicillin or ranitidine HCl, and USP XXII paddle method was used at 37 ° C., 75 rpm, 20 hours. The dissolution medium consisted of 900 ml artificial gastric juice (without enzyme). Samples were collected at 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 20 hours replacing an equal volume of media. Samples were assayed at 280 nm using an HP diode array spectrophotometer in the case of amoxicillin and 219 nm in the case of ranitidine HCl (Zantac®).
[0100]
Dissolution studies of a) amoxicillin or b) ranitidine HCl tablets contained in GRD were compared to those using the formulation alone. Amoxicillin couplets were made as outlined in Example 6. The dissolution pattern of amoxicillin immediate release (IR) tablets compared to the same formulation in GRD is shown in FIG. Amoxicillin IR released 80% drug within 1 hour, but only 10% drug release occurred in 1 hour from GRD and 80% release did not reach until 12 hours. The release pattern of drug from IR tablets incorporated into GRD was zero order.
[0101]
The dissolution of amoxicillin from the core tablet (amoxicillin caplet embedded in a microcrystalline cellulose shell) versus dissolution from GRD containing the core tablet is presented in FIG. Amoxicillin core tablets release 80% of the drug within 1 hour, while the release of drug from the core tablet inside GRD is zero order for 24 hours, and 80% release of the drug over about 20 hours. It was.
[0102]
A comparison of dissolution from a tablet of immediate release commercial ranitidine HCl (Zantac® 150) versus dissolution of the same tablet incorporated in GRD is presented in FIG. Complete drug dissolution from Zantac® 150 not in GRD took 1 hour, but 80% drug release from tablets in GRD was only observed in the first 7 hours.
[0103]
B. Dissolution studies were performed with GRD containing the model drug riboflavin and adjusted according to the method of Example 1B using the United States Pharmacopeia (USP) XXII paddle method at 37 ° C., 50 rpm, 24 hours. The dissolution medium consisted of 900 ml artificial gastric juice (without enzyme). Samples were collected at 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. Samples were assayed for riboflavin at 446 nm using an HP diode array spectrophotometer.
[0104]
Dissolution studies of riboflavin beads, powders and solid dispersions contained in GRD (normal or modified) were compared to immediate release capsules containing equal amounts of vitamins. In all studies, the amount of riboflavin was equivalent to 50 mg and the GRD used was rectangular (3^*1.5^*1). Size “0” capsules were used to incorporate both immediate release and GRD formulations.
[0105]
Dissolution from normal GRD:
FIG. 11 shows a dissolution pattern of riboflavin beads contained in a capsule as compared to dissolution of riboflavin beads contained in a normal GRD having a rectangular shape. Riboflavin beads released 100% drug within 9 hours, but only 8% drug release from normal GRD in 5 hours and about 30% release in 24 hours. This release pattern of drug from normal GRD was almost zero order.
[0106]
The dissolution of riboflavin powder from an immediate release capsule (50 mg riboflavin + 200 mg lactose) was compared to the dissolution from normal GRD containing the same amount of riboflavin powder. Riboflavin immediate release capsules released 100% drug in about 1 hour, whereas GRD in the capsules released about 50% drug in 24 hours. Release of riboflavin powder from normal GRD was also nearly zero order.
[0107]
Dissolution from modified GRD:
The prepared modified GRD was used to vary the rate and amount of drug release. Modified GRDs differ from normal GRDs in that they contain PVP and SLS. The dissolution of riboflavin powder from the modified GRD is shown in FIG. The modified GRD released about 65% drug in 24 hours. The emission pattern also appeared at zero order. The increase in dissolution from the modified GRD can be attributed to the presence of the hydrophobic polymer PVP and the surfactant SLS. Both PVP and SLS may have helped the diffusion of vitamins from the hydrogel. The presence of PVP and SLS in the formulation also produced a more flexible dry film that was more easily incorporated into the capsule when compared to a regular film from a formulation without PVP and SLS. This increased flexibility facilitates the incorporation of larger GRDs in the capsule.
[0108]
The dissolution of a solid dispersion of riboflavin and PEG3500 (ratio 1: 3) from the modified GRD is shown in FIG. It was observed that 100% of the drug was released from this formulation in 24 hours, but GRD lost its integrity in about 6 hours.
[0109]
When a solid dispersion of riboflavin and PEG3500 was added to the hot viscous gum solution, a soft film formed when the gel was dried. Occasionally, after hydration in GF, the gel collapsed and fragmented.
[0110]
Example 9
This section relates to subjects for in vivo testing of GRD in dogs.
[0111]
A. Subjects for in vivo testing of GRD made according to Example 1A, section IV
Two crossbreed dogs (2.5 and 5 years old) were used to study the gastric residence time of GRDs of different sizes and shapes. The animals were placed in an animal research laboratory at the University of Oregon Veterinary Medicine and were kept on a canned protein diet (d / d Hills) for 2 weeks. This animal was placed in a separate cage, which reasonably tolerated free movement and normal activity of the dog, and therefore normal gastrointestinal motility was expected.
[0112]
B. Subjects for in vivo testing of GRD made according to Example 1B
The study was conducted on two adult German Shepherd dogs (8-9 years old). They were bred on commercial food and placed in the animal research laboratory at the University of Oregon Veterinary Medicine. These were placed in small adjacent individual cages with rubber wire mesh covering a concrete floor with a slope to facilitate cleaning. This animal cage allows for free movement of the dog and reasonable space for normal activity, and therefore normal gastrointestinal movement exists. This rearing area was kept lit during the day and dark at night.
[0113]
Example 10
This section relates to subject dosage forms and doses for in vivo testing of GRD in dogs.
[0114]
A. Dosage form for in vivo testing of GRD made according to Example 1A, section IV
GRD was administered to the subject as described in Example 9A. Four different forms of GRD encapsulated in size “0” capsules were used. A 7 × 1.5 × 1 cm rectangular GRD encapsulated in a “000” capsule was also tested in these studies. All dosage forms included a radiopaque thread for X-ray visualization.
[0115]
Four different shapes of GRD encapsulated in size “0” capsules were tested in dogs to determine the residence time in the stomach. The dimensions of these four shapes are listed in FIG. All GRDs contained less than 10 small pieces of radiopaque threads. These threads helped visualize the GDR in the gastrointestinal tract by X-rays. These also aided in confirming gel hydration and disintegration.
[0116]
The dog was fasted overnight. A dosage form filled with radiopaque threads was orally administered early in the morning with 4 ounces of water.
[0117]
To study the effect of GRD on emptying food from the stomach, the diet was also mixed with BIPS and given 2 hours later. Two different sizes of GRD were tested. One was encapsulated in size “0” capsules and the other was encapsulated in size “000” capsules. These two sizes correspond to 3 × 1.5 × 1 and 7 × 1.5 × 1 cm, respectively.
[0118]
B. Dosage form for in vivo testing of GRD made according to Example 1B
GRD was administered to the subject described in Example 9B. A gastric retention device encapsulated in a “000” capsule and containing barium sulfate couplets, radiopaque threads, or bismuth-impregnated polyethylene spheres (BIPS) was used. The system then used X-rays.
[0119]
The dogs were fasted overnight and the dosage form was orally administered early in the morning with 10 ounces of water. Diet was fed 3 hours after dosing. An X-ray was taken just before medication to confirm that the stomach was empty. The gastric retention device then used X-rays and fed the dogs 3 hours after dosing. The presence of food can be easily recognized with x-rays as darker areas in the stomach.
[0120]
Studies with formulations containing different types of radiopaque agents (eg, barium sulfate tablets, radiopaque threads, and radiopaque BIPS) were performed on the same dog on different days. The normal stomach emptying with radiopaque markers in dogs under fasting conditions was determined by ingesting capsules containing radiopaque threads.
[0121]
BaSO_FourTablets were made on a Carver press in the form of a caplet. Various methods have been developed for taking tablets. Basically, the method involved casting a layer of gel into a mold, placing a tablet in the mold at the desired distance, and immediately adding another gel layer. These gels were dried under vacuum. The dried film was compressed into “000” capsules. In subjecting these films to hydration studies, they were found to divide into two layers after hydration and release the tablets prematurely.
[0122]
The couplets were suspended with the aid of threads in such a way that they were in the middle of the interior side of the mold. When poured, the hot gel wrapped the caplet. BaSO_FourWas found to leak from gels or tablets during gel extension studies. This makes it difficult to determine the location of the GRD. In view of this limitation, an in vivo study of dogs was performed. As expected, it was difficult to follow this system in the dog stomach. Because BaSO_FourThis is because the tablet dissolved and spread throughout the gastrointestinal tract.
[0123]
Example 11
This section relates to radiography for in vivo testing of GRD in dogs.
[0124]
A. Radiography for in vivo testing of GRDs made according to Example 1A, section IV
GRD was administered as described in Example 10A. X-ray imaging tests were performed using a Transworld 360 V X-ray generator. The X-ray cassette used was 3M Trimax 12 in combination with 3M ultradetail (1416) film. Radiography was used to follow the passage of GRD in the gastrointestinal tract. X-rays for dogs are: 0 minutes (immediately before dosing to confirm empty stomach), 5 minutes (immediately after dosing to confirm device is in stomach), 2 hours (GRD is housekeeper) To see if it was removed by waves) and at 9 hours. The dogs were fed 2 hours after radiography. The diet was occasionally mixed with BIPS (barium impregnated polyethylene spheres) to study the effect of the dosage form on emptying food from the stomach. BIPS has a density similar to that of food but sufficient radiation density and is clearly shown by radiography of the abdomen. The small BIPS used (1.5 mm) mimics the passage of food, and their passage through the gastrointestinal tract provides an accurate estimate of the rate at which the stomach is empty and the transit time of the food intestine. Hills d / d diet is known to suspend BIPS, which is the only diet that has been studied and proven to correlate between emptying with BIPS and emptying with food. BIPS can be distinguished from radiopaque threads during radiography. For each animal, a radiographic study was performed from two angles (side view and dorsal ventral view).
[0125]
The rectangular shape was found to remain in the stomach of one dog for at least 9 hours. The other three shapes emptied from the stomach in less than 2 hours. Radiographs at 24 hours showed the collapse of four different shapes of GRD for the rectangular shape GRD, as indicated by the absence of radiopaque threads in the stomach and the spread of threads in the colon. A total of four studies were performed using rectangular GRD. In all four studies, GRD remained in the same dog stomach, but not in other dogs. The results of these studies are shown in FIGS.
[0126]
Radiographs taken 2 hours after mixing with food mixed with BIPS showed that the food was emptied from the stomach but GRD was not. The results of this study are shown in FIG. This indicates that GRD did not affect the excretion of food from the stomach to the intestine. Results from the larger size GRD also indicate that the pylorus was not blocked by GRD. Based on the results of this in vivo study, large size GRDs incorporated into “000” capsules were selected for testing in humans.
[0127]
B. X-ray imaging for in vivo testing of GRD made according to Example 1B
GRD was administered as described in Example 10B. X-rays were used to follow the passage of the gastric retention device in the dog's gastrointestinal tract. Radiographs were taken immediately before and immediately after dosing to confirm an empty stomach. Subsequent radiographs were taken at 0.5 hours, 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, and 24 hours. All radiographs were in side view, and several anteroposterior (abdominal dorsal, VD) radiographs were also taken to confirm the location of the dosage form in the dog's stomach.
[0128]
Radiographic examinations were performed using a Transworld 360 V X-ray generator (360 mA and 125 kV potential). The X-ray cassette used was 3M Trimax 12 in combination with 3M Ultra Detail (1416) film. Table 5 shows the exposure settings.
[0129]
(Table 5) X-ray exposure settings for two dogs

[0130]
Bismuth-impregnated polyethylene spheres (BIPS), as the name implies, are polyethylene spheres containing bismuth, which makes it radiopaque. These spheres were incorporated into GRD for study in dogs. Track two large BIPS-containing systems at different time points (including 0, 0.5, 1, 2, 3, 6, 8, 8, 9 and 24 hours) using X-rays did. This system was retained in the stomach of one dog at the 9th hour of the experiment. The next radiograph was not taken until 24 hours. Of the two BIPS, one was still retained in the stomach, while the other was found in the intestine. This indicates that this system must have been destroyed with the release of one BIPS. In the second dog, both BIPS were found in the small intestine at 9 hours.
[0131]
Radiopaque threads have been used in veterinary medicine and surgery. In addition, fragments of these threads were incorporated into GRD. These threads not only help in tracking the film, but also help to observe gel hydration.
[0132]
A placebo study was performed in both dogs. Capsules with radiopaque threads and lactose were administered to dogs under fasting conditions to study the aspect of emptying the stomach of the threads when not in GRD. Radiographs were taken at regular intervals. These threads were removed from the dog's stomach to the small intestine between 2-3 hours.
[0133]
Administration of a gastric retention device containing a radiopaque thread to a dog was also followed by X-ray. This system remained in the dog's stomach for at least 10 hours. Radiographs taken at 24 hours demonstrated the absence of radiopaque threads in either the stomach or small intestine. The results of administration of GRD containing radiopaque threads in dogs are shown in FIGS. 19 and 20. A total of 5 studies were performed using GRD containing radiopaque material. As observed from our three studies, this system was found to remain in the dog's stomach for at least 9 hours.
[0134]
Radiographs taken 7 hours after dosing showed the absence of food in the stomach and food was found in the intestine. However, GRD was not found in the stomach. This indicates that GRD did not affect the passage of food into the intestine and did not block the pylorus by GRD.
[0135]
Example 12
This section relates to endoscopy for in vivo testing of GRD in dogs.
[0136]
Endoscopy was used to allow visual observation of swelling in the stomach of GRD made according to Example 1A, section IV. One dog was used for this study. The animals were fasted 14-16 hours prior to dosing. The dog was dosed while awake. The animals were induced with ketamine (259 mg) administered intravenously in combination with diazepam (7.5 mg). The animal was intubated with an endotracheal tube with a cuff and maintained under general anesthesia with isoflurane gas and oxygen. After reaching the appropriate level of anesthesia, a flexible fiber optic endoscope (135 cm long; 9 mm o.d.) was introduced into the mouth and esophagus and led to the stomach. The GRD was monitored by a camera attached to the endoscope and the inflation process was recorded on videotape over a 45 minute period.
[0137]
The animal was scheduled for endoscopy and the endoscopic procedure was well tolerated. The overall procedure time was approximately 1 hour, as defined as the time from the introduction of anesthesia to extubation. This endoscope was aimed at the animal's stomach. The field of view of the endoscope showed the position of the GRD in the stomach. The GRD was then continuously monitored by an endoscopic camera over a period of 45 minutes. The capsule shell dissolved in a few minutes and the GRD was released. GRD swelling occurred gradually over a period of 30 minutes. After 45 minutes, the swollen gel was collected from the stomach and its dimensions were examined and compared to in vitro results. The swollen gel recovered from the dog's stomach is a similar GRD (3^*1.5^*1) almost the same dimension (2.8^*1.3^*0.8). The prepared GRD swells to a significant size in gastric juice in less than 30 minutes and therefore has a good opportunity to avoid removal from the fasted stomach by housekeeper waves.
[0138]
Example 13
This section relates to administration of GRD to humans.
[0139]
A. Administration of GRD to human subjects using GRD made according to the method of Example 1A, Section IV
Cross-sectional biological studies under fasted and food-fed conditions were conducted in a single subject on a gastric retention device containing 200 mg amoxicillin or only 200 mg amoxicillin tablets without this device. It was. This subject was required to fast overnight in both studies. During this study, breakfast was served 2 hours after dosing under fasting conditions. In the food fed study, subjects received the dosage form with breakfast. The standard breakfast was plain bagels, 1 ounce cream cheese and 125 ml fruit juice. Other doses were given after a 48 hour wash time. Urine was collected at 0 hours, 1 hour, 2, 3, 4, 5, 6, 8, 12, and 24 hours. Urine samples were immediately analyzed by HPLC.
[0140]
B. Administration of GRD to human subjects using GRD prepared according to the method of Example 1B
Phase I:
Six healthy subjects (4 males and 2 females) were randomized and designed with (IR) capsule (treatment A) or (LGRD) capsule (treatment) with at least one week washout period. B) Inoculated either. This capsule was taken with 200 ml of water. All subjects were required to fast for at least 10 hours prior to the study and no food was allowed for 3 hours after dosing.
[0141]
Phase II:
The study consisted of one treatment under fasting conditions, where each of six subjects took (IGRD) capsules (treatment C).
[0142]
Phase III:
This study also consisted of one treatment under fasting conditions, where each of six subjects took (SGRD) capsules (treatment D).
[0143]
Formulation ingredients
Riboflavin (Sigma Chemicals, St. Louis, MO) was selected as the therapeutic agent. All test formulations were made at the Oregon State University School of Pharmacy (Corvallis, OR) in either GRD form or immediate release containing 100 mg riboflavin in powder form. The GRD formulation was prepared as previously described.
[0144]
Capsules used in biological research
1． Immediate release (IR) capsules were size “1” capsules containing lactose (200 mg) as the main excipient and 100 mg riboflavin previously dried.
2． Large GRD (LGRD) capsules were size “000” capsules filled with dry GRD containing 100 mg riboflavin. The dimension of GRD captured before drying is 7^*1.5^*It was 1cm.
3． The intermediate GRD capsule (IGRD) was a size “00” capsule filled with dry GRD containing 100 mg of riboflavin. The dimension of GRD captured before drying is 5^*1.5^*It was 1cm.
The small GRD capsule (SGRD) was a size “0” capsule filled with dry GRD containing 100 mg riboflavin. The dimension of GRD captured before drying is 3^*1.5^*It was 1cm.
[0145]
Example 14
This section relates to HPLC analysis of drug excretion after administration of GRD to human subjects.
[0146]
A. HPLC analysis of urine samples from the subject of Example 13A
Internal standard: Acetaminophen USP (1mcg / ml)
This solution is relatively stable when stored in a cool place and well protected from direct light.
[0147]
Buffer solution:
The buffer was prepared by adding 100 ml 0.5 M disodium hydrogen phosphate to 350 ml deionized water. The pH is adjusted to 6 with 1M citric acid. The resulting solution is made up to 500 ml volume with deionized water.
[0148]
Mobile phase preparation:
0.26 g potassium dihydrogen phosphate was added to 3800 ml deionized water. 200 ml of HPLC grade methanol was added. The solution was filtered to remove any particles and stirred for about 20 minutes under vacuum to remove bubbles.
[0149]
HPLC system:
Waters Intelligent Sample Processor (WISP ™) 712, automatic sample injection module up to 48 sample vials for column injection.
[0150]
column:
Reverse phase C₁₈25cm, 5μ, 100A Rainin Microsorb-MV (registered trademark).
[0151]
Detector:
UV absorption detector, model 440 (with fixed wavelength).
[0152]
Buffered sample:
Add 2 ml from each urine sample to 2 ml of pH 6 buffer. This solution is vortexed to ensure proper mixing.
[0153]
HPLC sample:
1 ml of buffered urine was diluted with 5 ml of deionized water. In a small plastic centrifuge tube, 50 μl of internal standard solution was added to 50 μl of this diluted sample. The resulting solution was vortexed to ensure proper mixing. HPLC sample vials were collected, capped and placed in a WISP ™ autoinjector for HPLC analysis. 20 μl of sample was injected. All other parameters for HPLC are listed below:
Mobile phase flow rate: 1.3 ml / min
Detection wavelength: 229nm
Execution time: about 23 minutes
[0154]
Creating a standard curve
An amoxicillin calibration curve was generated by the following method: 0.03 g of amoxicillin trihydrate was placed in a 100 ml volumetric flask and dissolved in a 1:10 mixture of drug-free urine (blank): deionized water to make 100 ml . This was stirred for about 40 minutes at room temperature to ensure complete dissolution. Make serial 1: 1 dilution with deionized water to obtain 6 samples. This serial dilution process yielded a series of samples within the concentration range used to generate the calibration curve. The method of sample preparation for HPLC analysis was the same as previously shown. A total of 20 μl of each sample was injected.
[0155]
B. HPLC analysis of urine samples from 13B subjects
1) Reagent for HPLC assay
Methanol (HPLC grade, Fisher Chemicals, NT), monobasic potassium phosphate (Fisher Chemicals, NT), sodium hydroxide (Mallinckrodt). The water used in this procedure was deionized using a Milli-Q Reagent Water System (Millipore, Bedford, MA, USA).
[0156]
2) Drug assay method:
Column is reversed phase fine particle C₁₈(□ Bondapak C₁₈Particle size 10 μm, 30 cm × 4 mm, Water Assoc., Milford, MA, USA). This is before C₁₈A guard cartridge (ODS, 4x3mm, Phenomenax, CA, USA) was attached.
[0157]
The assay procedure followed that described by Smith. Eluent is 0.01M KH₂PO_Four(PH 5): Methanol (65:35), flow rate was 1.2 ml / min. The mobile phase was prepared by mixing the correct volume of methanol and 0.01 phosphate monobasic potassium phosphate solution adjusted to pH 5 with 1N sodium hydroxide and then filtered through a 0.2 μm filter under vacuum. This mobile phase was degassed before use. The detector was a fixed wavelength spectrofluorometer (Gilson Spectra / GloFluorometer, Middleton, WI). The excitation wavelength was 450 nm. The wavelength range of the radiation filter was 520-650 nm. The peak area was measured using a Shimadzu integrator (C-R3A Chromatopac, Schimadzu Corp, Kyoto, Japan).
[0158]
Other equipment in the HPLC system included a liquid delivery pump (Waters 550 Solvent Delivery System, Waters Associates, Milford, Mass.) And an automatic sample injector (Waters WISP Model 712B, Waters Associates, Milford, Mass.).
[0159]
3) Collection of urine samples:
Subjects fasted overnight provided a 0 hour urine sample prior to dosing and then ingested the formulation. Urine samples were collected in 16 ounce containers at 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, and 24 hours after dosing. Volume and time elapsed since vitamin intake was recorded for each urine sample and a portion was saved for vitamin concentration measurements.
[0160]
4) Standard solution:
Add 100 mg riboflavin, 750 ml water, and 1.2 ml glacial acetic acid, previously dried at 105 ° C for 2 hours, to a 1 liter flask, dissolve by heat, and dilute to volume with water. Prepared to contain a reference standard of 100 μg / ml. This stock solution was diluted with blank urine to contain 1 μg / ml, 2 μg / ml, 4 μg / ml, 6 μg / ml, 8 μg / ml, 10 μg / ml, and 15 μg / ml riboflavin. All solutions were protected from light. These standards were injected into the column, chromatograms were recorded, and peak areas were measured. The retention time of riboflavin was about 6 minutes.
[0161]
A standard curve was constructed by plotting peak area against urinary riboflavin concentration. The sensitivity of the assay was 1 μg / ml, with a linear relationship between peak area and riboflavin concentration of 1-10 μg / ml (R²= 0.9971). A typical standard curve for urinary riboflavin is shown in FIG. Endogenous riboflavin was considered by subtracting the area obtained from analysis of blank urine or 0 hour urine samples from all assayed standards and samples.
[0162]
5) Sample analysis:
Approximately 10 ml of urine was centrifuged at 4000 rpm for 10 minutes. A portion of the supernatant (150 μl) was transferred to an HPLC tube and 50 μl was injected onto the HPLC column. Riboflavin eluted at 6 minutes after injection.
[0163]
Example 15
This section relates to pharmacokinetic analysis of HPLC data.
[0164]
Riboflavin excretion data was obtained as outlined in Example 14B, sections 1-5. Different treatments were used to collect riboflavin in their urine during the first 24 hours after administration (recovery_{0 − twenty four}), Maximum urine output rate (R_max), And R_maxTime required to reach (T_max). All parameters were determined from individual urine output rate-time curves, a plot of urine output rate against the midpoint of the urine collection interval. Recovery_{0 − 24h}Was determined from the individual cumulative urine drug excretion-time curve, a plot relating the excreted cumulative drug to the collection time interval.
[0165]
Example 16
This section relates to statistical analysis of HPLC data.
[0166]
Riboflavin excretion data was obtained as outlined in Example 14B, sections 1-5. Differences in pharmacokinetic parameters between treatments were examined using a two-sided student t-test. α = 0.05, null hypothesis Ho: μ_T−μ_RTwo-sided student t-test with = 0, recovery for urine recovery data_{0 − 24h}, R_max, And T_maxExecuted with. The acceptance of the null hypothesis (Ho) is that there is not enough evidence to conclude that there is a significant difference between the parameter average of the GRD formulation and the corresponding parameter average of the intermediate release formulation: Indicates that the parameters are equivalent. The null hypothesis rejection strongly indicates that the tested parameters of the two formulations are significantly different.
[0167]
Example 17
This section relates to the deconvolution of urine output rate data.
[0168]
The deconvolution input function from biological research data was determined using the computer software PCDCON by Williams Gillespie. Deconvolution generates an input function (accumulated volume vs time dissolved in vivo) from the input response and the characteristic impulse response function of the drug. The cumulative drug input over time predicted by deconvolution was used to determine the gastric residence time of different sizes of GRD. Gastric residence time was calculated from the deconvolution curve as the time observed when absorption stopped. The input response used was the urinary excretion rate of riboflavin (dU / dt) from different formulations, but the impulse response used was a literature-derived elimination rate constant determined from the intravenous bolus dose of riboflavin .
[0169]
Example 18
This section relates to drug absorption from GRD by human subjects.
[0170]
A. Amoxicillin excretion after administration of GRD to subjects as outlined in Example 13A and analysis as outlined in Example 14
Amoxicillin (a type of β-lactam antibiotic) incorporated into GRD in the form of a caplet was tested for its bioavailability. An increase in β-lactam concentration demonstrates an increase in bacterial killing only to a finite point that tends to be about 4 times the minimum inhibitory concentration (MIC), which can be referred to as a therapeutic concentration. Further increases are not associated with increased bactericidal efficacy (18, eg, MIC for Strep. Pneumococci is 0.02 mcg / ml and therapeutic concentration is 0.08 mcg / ml). There is a direct correlation between the time that the β-lactam antibiotic concentration is maintained above the therapeutic concentration and clinical effects. Bacterial regrowth occurs rapidly after these concentrations fall below the bacterial MIC. Therefore, the dosage regimen for each individual β-lactam should not make the drug-free interval between doses large enough for bacterial pathogens to resume growth.
[0171]
Amoxicillin has a very short half-life of about 1 hour and a limited “absorption window” after oral administration. The drug is well absorbed in the duodenum and jejunum, but absorption is reduced in the ileum and is rate dependent. Absorption is very poor in all intestinal regions. Thus, using GRD to deliver β-lactam antibiotics (eg, amoxicillin) extends time over MIC in vivo for normal IR formulations. Bioavailability also improves as the amount of drug reaching the site of absorption is prolonged over time, thus preventing saturation at that site.
[0172]
When amoxicillin is administered to subjects in Example 13A under fasting conditions and analyzed according to the method of Example 14A, the area under the elimination rate curve (AUC) for drugs incorporated into GRD is the absence of GRD An increase of 30% was found. Maximum discharge speed (C_max) Was 34.2 ml / hr in the absence of GRD and 29.0 mg / hr in the presence of GRD. These values were not significantly different. T_maxThe value of was the same in both. The comparable bioavailability of the two formulations is shown in FIG.
[0173]
Studies performed under food-fed conditions are AUC or C_maxDid not show any significant difference. But T about GRD_maxShifted to the right compared to the absence of GRD. T about GRD_maxWas found to be 4 hours, where in the absence of GRD it was 2 hours. The bioavailability for both formulations under food-fed conditions is shown in FIG.
[0174]
These results with amoxicillin are consistent with food that slows drug delivery from the stomach to the intestine when the subject is fed, and GRD is intestinal when the subject is fasted. Slow drug delivery. Furthermore, the food did not adversely affect drug release from GRD.
[0175]
B. Riboflavin excretion after administration of GRD to subjects as outlined in Example 13B and analysis as outlined in Example 14B, Sections 1-5 and Examples 15, 16, and 17.
Urine drug excretion data can be used to estimate bioavailability. This is because the cumulative amount of drug excreted in the urine is directly related to the total amount of drug absorbed and then excreted through the primary removal process. In order to obtain a reasonable estimate, the drug must be excreted in significant amounts in urine and a complete urine sample must be collected.
[0176]
The determination of the GRD cutoff size for emptying the stomach under fasting conditions was one objective of this biological study. The relative fractional absorption of riboflavin from different formulations was evaluated from urine output data. The average pharmacokinetic parameters for the different treatments are shown in the table below.
[0177]
Table 6: Pharmacokinetic parameters after immediate release to fasted volunteers or oral administration of 100 mg riboflavin in capsules of GRD

Data are mean ± SE
[0178]
The individual pharmacokinetic parameters for each subject for the four treatments are also shown in Tables 7-12 below.
[0179]
Figure 23 shows the recovery_{0 − twenty four time}It is shown that the maximum mean value for was observed with LGRD capsules, followed by IGRD capsules, IR capsules, and SGRD capsules. Average recovery from LGRD capsules_{0 − twenty four time}The estimate (17.3 mg) was determined to be 225% larger and statistically significantly (P <0.05) different from the average from IR capsules (5.33 mg). Average recovery from SGRD capsules_{0 − twenty four time}Although the estimate (4.09 mg) was smaller, it was not statistically significantly different (P <0.05) compared to the average from IR capsules (5.33 mg). Average recovery from IGRD capsules_{0 − twenty four time}The estimate (9.3 mg) was higher but not significantly different from IR capsules. This can be attributed to prolonged gastric residence time of this device in some volunteers only (subjects 1 and 2 have significantly higher urine recovery from IGRD capsules when compared to IR capsules._{0 − twenty four time}Had).
[0180]
R_maxParameters and T_maxA statistical comparison of parameters was also made between the results from LGRD capsules (2.5 ± 0.98 mg / h and 5.08 ± 2.4 hr, respectively) and the results from IR capsules (1.36 ± 0.4 mg / h and 2.5 ± 0.63 hr, respectively). A significant difference (P <0.05) was shown. R from IGRD and SGRD capsules_maxParameters and T_maxThe parameters were not significantly different from (IR) capsules. These results are shown in FIG.
[0181]
The improved bioavailability of riboflavin from the LGRD capsules obtained in this study (urine recovery measured after administration of IR capsules was more than 3 times), this device is retained in the stomach I suggest that. LGRD stayed in the stomach for a time sufficient to release its vitamin content slowly, and the resulting released vitamin gradually passed through the absorption window and was absorbed more efficiently.
[0182]
On the other hand, administration of SGRD capsules resulted in a decrease in riboflavin absorption when compared to IR capsules. This may be due to the small size of the device expelled from the stomach by stage III myoelectric migration contractile activity with relatively little drug release. Once the device passes the absorption window, no absorption occurs.
[0183]
FIG. 25 shows the cumulative amount of drug absorption versus time de-superposed from biological study data for IR, SGRD, IGRD, and LGRD capsules. For LGRD capsules, absorption continued for up to 15 hours and then stopped. This may indicate that LGRD stays in the stomach and slowly releases the drug for about 15 hours. On the other hand, the absorption from the IGRD capsule continued for about 9 hours and then became constant. This indicates that the device did not stay long enough in the stomach to release all of its drug content. Absorption from SGRD capsules lasted only 3 hours, indicating that the device was expelled from the stomach by housekeeper waves as quickly as the IR medication (due to its small size) .
[0184]
These results indicate that the residence time in the stomach of a swellable system containing different drugs with limited absorption sites (eg GRD) is AUC after administration of a swellable system containing the same amount of drug and an immediate release system It can be assessed by comparing the bioavailability of a drug as measured by measurement of or by urine collection.
[0185]
Table 7: Pharmacokinetic parameters of riboflavin after oral administration of 100 mg in immediate release capsules or GRD capsules to subject 1

[0186]
Table 8: Pharmacokinetic parameters of riboflavin after oral administration of 100 mg in immediate release capsules or GRD capsules to subject 2

[0187]
Table 9: Pharmacokinetic parameters of riboflavin after oral administration of 100 mg in immediate release capsules or GRD capsules to subject 3

[0188]
TABLE 10 Riboflavin pharmacokinetic parameters after oral administration of 100 mg in immediate release capsules or GRD capsules to subject 4

[0189]
Table 11: Pharmacokinetic parameters of riboflavin after oral administration of 100 mg in immediate release capsules or GRD capsules to subject 5

[0190]
Table 12: Pharmacokinetic parameters of riboflavin after oral administration of 100 mg in immediate release capsules or GRD capsules to subject 6

[0191]
Example 19
This section relates to making a gastric retention device containing hydrochlorothiazide.
[0192]
All ingredients and molds prepared (one that can withstand hot solutions^*1.5^*7.5 rectangular container was used). XG (xanthan gum) and LBG (locust bean gum) were weighed to 0.75 g each and mixed well with each other, after which the mixture was dissolved in 100 ml deionized water (DIW). They were then fully dispersed in DIW and left to swell for 3-4 hours.
[0193]
A separate foam solution was prepared:
・ Warm 25 ml of deionized water (about 26 ml to compensate for evaporation), dissolve 0.125 g of SLS (sodium lauryl sulfate), and then suspend 0.075 g of carbopol while stirring with a magnetic stirrer. I let you. Stirring was continued for about 3 hours.
After 3 hours, the pH was adjusted to 7-7.5 using Neutral (very small amount) (pH test paper change: khaki to dark green). The foam solution beaker was then placed in an ice water bath to set the foam (neutral is an excipient or ingredient used to adjust the pH of the carbopol solution, making the solution very turbid. Can be used).
The gum solution from step 1 above was heated and stirred intermittently while the foam solution from step 3 above was stirred at maximum speed using a magnetic stirrer.
• The gum solution was heated to reach 80 ° C., then 5.5 ml of PEG400 was added and stirred for 10 seconds.
• The magnetic stirrer was removed from the gum solution and the foam solution was poured into the gum solution using a spatula. These were mixed together with a spatula.
• The gum / foam mixture was poured into each mold, about half was placed in the mold, then drug beads were added and the rest of the mold was filled with the gum / foam mixture. They were then quickly mixed and cooled and gelled so that the drug beads were evenly distributed.
• Placed at room temperature for about 2-4 hours.
• The cooled gel was placed in the refrigerator and left (usually longer than 10 hours (overnight), but times changed for convenience are possible).
• Each gel was removed from the container and placed on a waxed or plastic sheet.
-The gel was dried in a laboratory vacuum oven at 53 ° C for 4.5-5 hours. The exact vacuum, temperature, and drying time can all vary depending on the equipment available. These conditions gave good results even when using reduced pressure in the water stream.
[0194]
Example 20
This section relates to making sustained release formulations of hydrochlorothiazide.
[0195]
1. Hydrochlorothiazide suspension was layered on sugar spheres of 18-20 mesh size. This suspension consists of 9 g PVP (Povidone K-30), 3 g Klucel® (HPC) (both as binders), 40 g HCTZ, 100 ml Prepared by suspending in ionic water overnight at room temperature.
2． Layering was performed in a bottom spraying, Wurster column, spray coating chamber.
[0196]
Table 13: Conditions for spray coating

[0197]
3． HCTZ layered spheres were coated with a suspension of Surelease and Opadry mixture. 100 g of drug stratified spheres were coated with a suspension of 1 g Opadry and 8.06 g Surely in 10 ml deionized water. The total percentage of coating applied to HCTZ layered spheres was 3%, which consisted of 66.6% Ssure and 33.3% Opadry.
Four. After layering was complete, the spheres were dried in the chamber for about 30 minutes.
[0198]
Example 21
This section relates to the administration of GRD containing hydrochlorothiazide to humans.
[0199]
Two formulations for hydrochlorothiazide containing an extended release formulation (SR), an immediate release formulation (IR) and a gastric retention device (GRD), were administered in a biological study (bioavailability study). A commercial tablet containing 50 mg HCTZ was used as an IR control and spray coated beads equivalent to 50 mg HCTZ were formulated for SR in the laboratory. The SR formulation process is described above. Biological studies were performed to evaluate the bioavailability and pharmacokinetics of HCTZ from GRD compared to those from IR.
[0200]
Monitoring the concentration of hydrochlorothiazide in the urine of healthy adult volunteers allowed a comparison of the relative bioavailability of hydrochlorothiazide from GRD formulations and from conventional tablets. Participation included at least 2 days for each treatment, which was accompanied by a washout period of at least 72 hours between doses. Once IR was given, GRD was repeated twice to test the reproducibility of the new dosage form GRD. A dose of 50 mg was selected for the study. This was because it was within the recommended dose range from PDR (Physician's Desk References) because it produced a high enough concentration to make HPLC analysis efficient. Six subjects participated in the study, of which 4 were healthy men and 2 were healthy women. They were not allowed any food or beverage containing caffeine, nor were any alcohol or other medications allowed. Smokers and vegetarians were not included. Subjects were fasted overnight and at least 2 hours after dosing. They emptied their bladder before taking a single dose of hydrochlorothiazide in each study and took the dose with 12 ounces of water. After dosing, subjects received a set of containers to collect their urine and a timesheet recording the time of urination. Subjects collected all urine within 24 hours after oral administration of the formulation. Urine samples can be collected for 0-1 hours, 1-2 hours, 2-3 hours, 3-4 hours, 4-6 hours, 6-8 hours, 8-10 hours, 10-12 hours, 12-24 hours, 24 Collected between -36 hours and 36-48 hours. Urine samples were refrigerated until handed over to researchers. The volume of collected urine was measured to calculate the total amount of drug collected. A portion of the urine sample was analyzed for drug content using a modified method of Papadoyannis et al. (1988) HPLC (High Performance Liquid Chromatography) assay.
[0201]
Example 22
This section relates to analysis of pharmacokinetic parameters and urinary excretion data after administration of GRD containing hydrochlorothiazide.
[0202]
GRD containing the drug hydrochlorothiazide was administered to human subjects as outlined in Example 21. Mean pharmacokinetic parameters for each treatment under fasting conditions are provided in Table 14 below. FIG. 26 shows the cumulative amount of drug excreted versus time. Elimination half-life (t_{1 / 2}) Was about 7 hours. A_{0 − 36}The values of were compared for statistical analysis. Because, due to the short half-life, it was impossible to obtain a value at 48 hours for IR from one subject.
[0203]
Example 23
This section relates to the effect of hydrochlorothiazide GRD administration on fasted subjects.
[0204]
GRD containing the drug hydrochlorothiazide was administered to human subjects as outlined in Example 21. Average pharmacokinetic parameters for each treatment were analyzed as outlined in Example 23. Average A from IR_{0 − 36h}(33.3 mg, 66.6%) was found to be significantly different in fasting conditions when compared to that from GRD (37 mg, 75.4%) (P <0.05), but the difference is less than 10% . Differences less than 20% are generally considered insignificant from the FDA BA / BE guidance. From FIG. 26 and Table 14, the average value of the total amount of drug absorbed and drug collected in urine was equivalent. (A_{0 − 48}) Were 38.12 mg (76.2%) and 38.95 mg (77.9%) for IR and GRD, respectively, under fasting conditions. A_{0 − 48}Was based on the assumption that 50% of the absorbed dose appeared to be intact in the urine. Thus, GRD produced essentially the same amount of drug absorbed from IR up to 48 hours in fasted subjects. However, the effect on urine output was surprisingly completely different.
[0205]
Table 14: Pharmacokinetic parameters and urine excretion data for IR

[0206]
Figure 27 shows that the higher maximum elimination rate of the drug (R_max) From an immediate release (IR) capsule faster than that from a new formulation (GRD)_max) (4.84 mg / hour at 2.5 hours vs. 2.5 mg / hour at 5 hours).
[0207]
Example 24
This example relates to a profile for HCTZ-50 mg over 48 hours in a fasted subject.
[0208]
GRD containing the drug hydrochlorothiazide was administered to human subjects as outlined in Example 21. Also, the average pharmacokinetic parameters for each treatment were analyzed as outlined in Example 23. The cumulative amount of HCTZ-50 mg versus time was analyzed as outlined in Example 23.
Cmax and Tmax were 4.84 (mg / ml) and 2.46 (mg / ml), and 2.5 (hours) and 5 (hours) for IR and GRD, respectively.
・ T_{1 / 2}Is 7 hours.
[0209]
The rate of urine production was similar in both IR and GRD up to 10 hours after dosing. This was completely unexpected. This is because the amount of drug absorbed and the drug concentration in the body is less than the GRD shown here compared to the commercially available IR capsules. For IR capsules, diuresis began to decrease after 10 hours, whereas for GRD, a large amount of diuresis was maintained for a longer period of time.
[0210]
The first equivalent diuresis is surprising. This is because less drug is first absorbed from GRD (under fasting conditions, for IR and GRD, respectively, t_maxR in 2.5 hours_max4.8 (μg / ml) and t_maxR in 5 hours_max2.5 (μg / ml)). This now teaches that fewer drugs may be more effective. This is not common for drugs. In fact, if a smaller amount of drug is taken, a lesser effect is expected, but this new GRD and diuretic produced the opposite effect.
[0211]
It was also clearly observed that the effect of drugs from GRD on urine production lasted up to about 15 hours (see data provided in the table above). From FIG. 28, a comparison between urine production and water intake and a comparison between urine production and water intake ratio was studied. The cumulative amount of urinary excretion from hydrochlorothiazide in both IR and GRD is consistent with water intake.
[0212]
Increased fluid output in healthy normal subjects stimulated water intake. Compared with IR, the total amount of urine production from the same dose in GRD was higher. This may be due to prolonged drug intake from GRD followed by an increased amount of feedback water intake to compensate for an unexpected increase in drug effect.
[0213]
This overall increasing effect is also surprising (in addition to the first larger effect with smaller drug intake discussed above). This is because it is well known that it is necessary to increase the drug dose in order to increase the diuretic effect. In fact, most drug response curves are log straight lines, which usually means that after passing the first response threshold, there is less increase in efficacy (smaller%) than increase in dose. To do. However, in this case, the bioavailability of the drug under fasting conditions was substantially equal, but the diuretic effect increased by 27% as shown in FIG. 38 and the table provided above.
[0214]
The results of this bioavailability study of hydrochlorothiazide establish that this device is held long enough to release all or most of the drug in the stomach, but also the dosage form Establish sustained release of the drug to prolong the drug. GRD is therefore an excellent device for administering hydrochlorothiazide as well as other diuretics that exhibit a limited absorption site in the upper part of the intestine. This dosage form avoids high peak concentrations of the drug that can induce unwanted side effects (see below for side effect information), increases the effect of the drug per dose administered, and Patient care can be improved by achieving extended efficacy.
[0215]
Example 25
This section relates to side effects in human subjects after administration of hydrochlorothiazide in GRD.
[0216]
GRD containing the drug hydrochlorothiazide was administered to human subjects as outlined in Example 21, and the following side effects were reported.
• 3 of 7 subjects reported side effects from the IR dosage form between 4 and 6 hours after dosing.
The reported adverse reactions were severe or moderate headache, dehydration, and fatigue.
• One subject did not continue the study due to severe headache, dehydration, and fatigue.
• No adverse reactions were reported from the same dose of hydrochlorothiazide in GRD.
• After the first study, subjects were encouraged to drink more water in the case of IR. This is due to recognizing the consequences of dehydration from HCTZ.
[0217]
It will be apparent that the precise details of the methods described may be changed or modified without departing from the spirit of the described invention. We claim all such modifications and changes that fall within the scope and spirit of the following claims.
[Brief description of the drawings]
[0218]
FIG. 1 is a graph of hydration rate in water of xanthan gum / Locusta megam films of various solid ratios.
FIG. 2 is a graph of the hydration rate in artificial gastric juice of xanthan gum / locust megamum films of various solid ratios.
FIG. 3 is a graph of the initial hydration rate in water of various solid ratio xanthan gum / Locusta megam films.
FIG. 4 is a graph of the hydration rate in artificial gastric juice of xanthan gum / locust megamum films of various solid ratios between 0 and 3 hours.
FIG. 5 shows the shape and size of the four GRDs tested.
FIG. 6 is a graph of GRD hydration in artificial gastric juice between 3 and 24 hours.
FIG. 7 is a graph of GRD hydration in artificial gastric fluid between 0 and 3 hours.
FIG. 8 is a graph comparing amoxicillin (mg) released from an amoxicillin caplet over 20 hours compared to the amoxicillin caplet in GRD.
FIG. 9 is a graph comparing amoxicillin (mg) released from amoxicillin core caplets over 20 hours compared to the case of amoxicillin core caplets in GRD.
FIG. 10 is a graph comparing ranitidine hydrochloride (mg) released over 20 hours from Zantac® tablets compared to Zantac® tablets in GRD.
FIG. 11 is a graph comparing the ratio of effective riboflavin released from riboflavin beads over a long period of time with that of riboflavin beads in GRD.
FIG. 12 is a graph showing the ratio of effective riboflavin released from riboflavin beads in modified GRD over a long period of time.
FIG. 13 is a graph showing the ratio of effective riboflavin released from a modified riboflavin solid dispersion in GRD over a long period of time.
FIG. 14 is an X-ray digital image of a fasted dog stomach showing GRD in the stomach immediately after administration.
FIG. 15 is an X-ray digital image of a dog stomach showing GRD in the stomach 2 hours after administration.
FIG. 16 is an X-ray digital image of a dog stomach showing GRD in the stomach 9 hours after administration.
FIG. 17 is a digital image of a dog X-ray showing a GRD collapsed in the colon 24 hours after administration.
FIG. 18 is a digital image of a dog X-ray showing the GRD in the stomach 2 hours after administration. Food administered after GRD was excreted from the stomach, but GRD was not excreted.
FIG. 19 is an X-ray digital image of a dog stomach showing a GRD containing a radiopaque thread. X-ray images indicate that the dog's stomach is empty before administration, immediately after administration (0 hours), 1 hour after administration, and 2 hours after administration.
FIG. 20 is an X-ray digital image of a dog stomach showing a GRD containing a radiopaque thread. X-ray images show that GRD is present in the dog's stomach at 3, 7, and 9 hours after administration and no GRD is present at 24 hours.
FIG. 21 is a graph showing the excretion rate of amoxicillin after administration of amoxicillin caplets in comparison with the case of amoxicillin caplets in GRD (both under fasting conditions).
FIG. 22 is a graph (under fasting condition) showing the excretion rate of amoxicillin after administration of amoxicillin alone, compared with the case of amoxicillin in GRD.
FIG. 23 is a graph showing the cumulative amount of riboflavin excreted over time when transported as an immediate release formulation or within small GRDs, medium GRDs and large GRDs.
FIG. 24 is a graph showing the urinary excretion rate when riboflavin is transported as an immediate release formulation or in small GRD, medium GRD and large GRD.
FIG. 25 is a graph showing the input function deconvolved from immediate release of riboflavin and biostudy data for GRD formulations.
FIG. 26 is a graph comparing the cumulative amount of hydrochlorothiazide excreted after administration of an immediate release formulation of hydrochlorothiazide versus time for GRD hydrochlorothiazide.
FIG. 27 is a graph of hydrochlorothiazide excretion rate versus time for immediate release (IR) capsules and for new formulations (GRD).
FIG. 28 shows comparison between urine production and water intake and cumulative urine output derived from hydrochlorothiazide in both IR and GRD.

Claims (109)

A gastric retention device comprising a gel formed from a polysaccharide and having a size suitable for administration to a subject. 2. A gastric retention device according to claim 1, wherein the outer surface is coated or stored in an ingestible capsule. 3. A gastric retention device according to claim 2, wherein the coating or capsule is eroded by gastric juice. 3. A gastric retention device according to claim 2, wherein the coating or capsule is an enteric coating. 2. The gastric retention device according to claim 1, wherein the polysaccharide contains xanthan gum. 2. The gastric retention device according to claim 1, wherein the polysaccharide contains locust bean megam. The gastric retention device according to claim 1, wherein the polysaccharide contains a mixture of xanthan gum and locust bean gum. The composition further comprises a substance selected from the group consisting of a plasticizer, a pH adjuster, a gastrointestinal motility adjuster, a viscosity adjuster, a therapeutic agent, a diagnostic agent, a contrast agent, a swelling agent, a surfactant, and mixtures thereof. The gastric retention device described. 2. The gastric retention device of claim 1 compressed to a size suitable for oral administration. The gastric retention device according to claim 1, wherein the administration includes oral administration, rectal administration, vaginal administration, nasal administration, or buccal administration. 2. The gastric retention device according to claim 1, which expands after administration, and after expansion, the device is a cube, a cone, a cylinder, a pyramid, a sphere, a column, or a parallelepiped. 9. The gastric retention device of claim 8, wherein the diagnostic or therapeutic agent is selected from the group consisting of nucleic acids, proteins, and combinations thereof. AIDS adjuvants, alcoholics, Alzheimer's disease management, amyotrophic lateral sclerosis, analgesics, anesthetics, antacids, antiarrhythmics, antibiotics, anticonvulsants, antidepressants Antidiabetic, antiemetic, antidote, antifibrotic, antifungal, antihistamine, antihypertensive, antiinfective, antibacterial, antineoplastic, antipsychotic, antiparkinsonian, antirheumatic Medicine, appetite stimulant, appetite suppressant, biological response modifier, biological blood preparation agent, bone metabolism regulator, cardioprotectant, cardiovascular agent, central nervous system stimulant, cholinesterase inhibitor, contraceptive, cystic Fibrosis control agent, deodorant, diagnostic agent, dietary supplement, diuretic, dopamine receptor agonist, endometriosis control agent, enzyme, erectile dysfunction drug, fatty acid, gastrointestinal drug, Gaucher disease control drug, gout Formulations, homeopathic drugs, hormones, high calcium Antihypertensive, Hypnotic, Hypocalcemia, Immunomodulator, Immunosuppressant, Ion exchange resin, Levocarnitine deficiency, Mast cell stabilizer, Migraine formulation, Motion sickness, Multiple Management drug for sclerosis, muscle relaxant, narcotic antidote, narcotic drug, nucleoside analog, nonsteroidal anti-inflammatory drug, obesity management drug, formulation for osteoporosis, delivery promoting drug, parasympathetic blockade, parasympathetic nerve Stimulant, phosphorus adsorbent, porphyria, psychotherapeutic, radiopaque, psychotropic, sclerosing, sedative, sickle cell anemia, smoking cessation, steroid, stimulant, sympathy Containing neuroleptics, sympathomimetics, Tourette syndrome drugs, tremor preparations, urinary tract drugs, vaginal preparations, vasodilators, dizziness drugs, weight loss drugs, Wilson disease control drugs, and mixtures thereof Things selected from the group Further comprising a gastric retention device of claim 1, wherein. 9. The gastric retention device of claim 8, wherein the diagnostic or therapeutic agent is provided by a tablet, capsule, powder, bead, small pill, granule, solid dispersion, or a combination thereof. 9. The gastric retention device according to claim 8, wherein the diagnostic or therapeutic agent is more easily dissolved in the gastric fluid than the intestinal fluid. 9. The gastric retention device according to claim 8, wherein the diagnostic or therapeutic agent is more easily dissolved in the intestinal fluid than the gastric fluid. 9. The gastric retention device according to claim 8, wherein the diagnostic or therapeutic agent is more easily absorbed in the small intestine than in the large intestine. 9. The gastric retention device according to claim 8, wherein the diagnostic or therapeutic agent is more easily absorbed in the stomach than in the intestine. 9. The gastric retention device of claim 8, wherein the diagnostic or therapeutic agent is more easily absorbed in the intestine than in the stomach. Diagnostic or therapeutic agents include abacavir sulfate, abacavir sulfate / lamivudine / zidovudine, acetazolamide, acyclovir, albendazole, albuterol, alducton, allopurinol BP, amoxicillin, amoxicillin / potassium clavulanate, amprenavir, atovaquon, atovaquon・ Proguanil hydrochloride, atracurium besylate, beclomethasone dipropionate, betamethasone valerate lactone, buepropion hydrochloride, buepropion hydrochloride sustained release tablets, carvedilol, caspofungin acetate, cefazolin, ceftazidime, cefuroxime (not sulfate), chlorambucil, chlorpromazine , Cimetidine, cimetidine hydrochloride, cis-atracurium besylate, clobetasol propionate, cotrimoxazole, palmi Colfoseryl tinate, dextroamphetamine sulfate, digoxin, enalapril maleate, epoprostenol, esomeprazole magnesium, fluticasone propionate, furosemide, hydrochlorothiazide / triamterene, lamivudine, lamotrigine, lithium carbonate, losartan potassium, melphalan, mercaptopurine, Mesalazine, mupirocin calcium cream, nabumetone, naratriptan, omeprazole, ondansetron hydrochloride, obine, oxyconazole nitrate, paroxetine hydrochloride, prochlorperazine, procyclidine hydrochloride, pyrimethamine, ranitidine bismuth citrate, ranitidine hydrochloride, rofecoxib, Ropinirole hydrochloride, rosiglitazone maleate, salmeterol xinafoate, salmeterol, Fluticasone lopionate, sterile disodium ticarcillin / potassium clavulanate, simvastatin, spironolactone, succinylcholine chloride, sumatriptan, thioguanine, tirofiban hydrochloride, topotecan hydrochloride, tranylcypromine sulfate, trifloperazine hydrochloride, valaciclovir hydrochloride, vinorelbine, zanamivir, 9. The gastric retention device according to claim 8, which is zidovudine, lamivudine or a mixture thereof. The food is allowed to pass, but it will swell sufficiently after ingestion by the subject so that the device will not pass the subject's pylorus for a pre-determined period of up to 24 hours. A gastric retention device including a compression device that is rigid. 24. The gastric retention device of claim 21, further comprising a therapeutic or diagnostic agent that is more readily absorbed in the stomach than in the intestine. 24. The gastric retention device of claim 21, having an expansion coefficient of at least 3.0. 24. The gastric retention device of claim 21, having an expansion coefficient of at least 6.0. 24. The gastric retention device of claim 21, having an expansion coefficient of at least 8.0. A gastric retention device formed from a mixture comprising a sugar, a polysaccharide, or a combination thereof. 2. The gastric retention device according to claim 1, wherein the gel is a heat-induced gel. 2. The gastric retention device of claim 1, wherein the gel is a chemically induced gel. The gastric retention device according to claim 1, further comprising hydrochlorothiazide, ranitidine hydrochloride, or amoxicillin. 24. The gastric retention device of claim 21, further comprising hydrochlorothiazide, ranitidine hydrochloride, or amoxicillin. 23. The gastric retention device of claim 21, further comprising an enzyme that aids in erosion of the coating, capsule or device after ingestion of the device. Gastric retention device, including:
The food is allowed to pass, but it will swell sufficiently after ingestion by the subject so that the device will not pass the subject's pylorus for a pre-determined period of up to 24 hours. A strong compression device comprising a substance selected from the group consisting of plasticizers, pH adjusters, gastrointestinal motility adjusters, viscosity adjusters, therapeutic agents, diagnostic agents, swelling agents, surfactants, and mixtures thereof A gastric erodible capsule containing a gastric erodible coating or a compressed gel applied to the outer surface of the compression device. An inflatable gastric retention device prepared from a mixture containing xanthan gum and locust bean gum, compressed to form a compression device, the compression device having a coating applied to its outer surface or gastric erosion An inflatable gastric retention device housed in a capsule. 34. The gastric retention device of claim 33, wherein the device is substantially dehydrated. 34. The gastric retention device of claim 33, wherein the device is lyophilized. 34. The gastric retention device of claim 33, having an expansion coefficient of at least 3.0. 34. The gastric retention device of claim 33, wherein the weight ratio of xanthan gum to locust bean megam is from about 1: 4 to about 4: 1. 34. The gastric retention device of claim 33, wherein the weight ratio of xanthan gum to locust bean megam is about 1: 1. 34. The stomach of claim 33, further comprising a substance selected from the group consisting of a plasticizer, a pH adjuster, a gastrointestinal motility adjuster, a viscosity adjuster, a therapeutic agent, a diagnostic agent, a swelling agent, a surfactant, and mixtures thereof. Internal retention device. 40. The gastric retention device of claim 39, wherein the plasticizer is polyethylene glycol. 40. The gastric retention device according to claim 39, wherein the pH adjusting agent is sodium phosphate or disodium phosphate. 40. The gastric retention device of claim 39, wherein the swelling agent is sodium lauryl sulfate. 40. A gastric retention device according to claim 39, wherein the viscosity modifier is carbopol. 40. The gastric retention device according to claim 39, wherein the viscosity modifier is polyvinylpyrrolidone. 34. A gastric retention device according to claim 33, wherein after expansion, the device is a cube, cone, cylinder, pyramid, sphere, column, or parallelepiped. 34. The weight ratio of xanthan gum to locust bean megam is about 1 to 4 to about 4 to 1 and further comprises a material selected from the group consisting of carbopol, sodium lauryl sulfate, PEG 400, and mixtures thereof. Stomach retention device. 48. The gastric retention device of claim 46, wherein the weight ratio of xanthan gum to locust bean megam is about 1: 1. 34. The gastric retention device of claim 33, further comprising a substance selected from the group consisting of diagnostic agents, therapeutic agents, and mixtures thereof. Drugs include nucleic acids, proteins, AIDS adjuvants, alcoholics, Alzheimer's disease management, amyotrophic lateral sclerosis, analgesics, anesthetics, antacids, antiarrhythmic drugs, antibiotics, Anticonvulsant, antidepressant, antidiabetic, antiemetic, antidote, antifibrotic treatment, antifungal, antihistamine, antihypertensive, antiinfective, antibacterial, antineoplastic, antipsychotic, anti Parkinson's disease drug, anti-rheumatic drug, appetite stimulant, appetite suppressant, biological response regulator, biological blood preparation agent, bone metabolism regulator, cardioprotectant, cardiovascular drug, central nervous system stimulant, cholinesterase inhibitor , Contraceptives, cystic fibrosis control, deodorant, diagnostics, dietary supplements, diuretics, dopamine receptor agonists, endometriosis control, enzymes, erectile dysfunction, fatty acids, gastrointestinal, Gaucher Disease control drugs, gout preparations, homeopathic drugs , Hormone, hypercalcemia management drug, sleeping pill, hypocalcemia management drug, immunomodulator, immunosuppressant, ion exchange resin, levocarnitine deficiency control drug, mast cell stabilizer, migraine preparation, vehicle Sickness drug, multiple sclerosis management drug, muscle relaxant, narcotic antidote, narcotic drug, nucleoside analog, nonsteroidal anti-inflammatory drug, obesity management drug, osteoporosis preparation, delivery promoting drug, sympathetic nerve Blockade, parasympathomimetic, phosphorus adsorbent, porphyria, psychotherapeutic, radiopaque, psychotropic, sclerosing, sedative, sickle cell anemia control, smoking cessation aid, steroid , Stimulant, sympathetic blocker, sympathomimetic, Tourette syndrome drug, tremor drug, urinary tract, vaginal drug, vasodilator, dizziness drug, weight loss drug, Wilson disease control drug, And from its mixture That is selected from the group, gastric retention device of claim 48. 49. The gastric retention device of claim 48, wherein the medicament is provided by tablets, capsules, powders, beads, small pills, granules, solid dispersions, or combinations thereof. 49. The gastric retention device of claim 48, wherein the drug is more soluble in gastric juice than intestinal fluid. 49. The gastric retention device of claim 48, wherein the drug is more readily absorbed in the small intestine than in the large intestine. 49. The gastric retention device of claim 48, wherein the drug is hydrochlorothiazide, amoxicillin, or ranitidine hydrochloride. 34. The gastric retention device of claim 33, wherein the gel substantially swells to its final size within 2 hours in an aqueous environment. 34. The gastric retention device of claim 33, wherein the gel swells to 60% of its final size within 2 hours in an aqueous environment. 34. The gastric retention device of claim 33, wherein the gel swells to 80% of its final size within 2 hours in an aqueous environment. 34. The gastric retention device of claim 33, wherein the gel substantially expands to its final size to form an expanded gel within 2 hours of ingestion by the subject. 58. The gastric retention device of claim 57, wherein the swelling gel prevents the gastric retention device from passing through the pylorus for a predetermined period of time. 58. The gastric retention device of claim 57, wherein the expandable gel is at least one dimension greater than the diameter of the pylorus. 59. The gastric retention device of claim 58, wherein the device allows food to pass through the pylorus. 59. The gastric retention device of claim 58, wherein the gel is eroded in the presence of gastric juice and passes through the pylorus after a predetermined time. 34. The gastric retention device of claim 33, wherein the device substantially remains in the subject's stomach for at least 2 hours. 34. The gastric retention device of claim 33, wherein the device substantially remains in the subject's stomach for at least 9 hours. 34. The gastric retention device of claim 33, wherein the device substantially remains in the subject's stomach for at least 24 hours. 34. The gastric retention device of claim 33, further comprising an enzyme for promoting gastric erosion of the gel. Can stay in the stomach for at least 24 hours, (a) carbohydrate gums, and (b) therapeutic agents, diagnostic agents, plasticizers, pH modifiers, gastrointestinal motility modifiers, viscosity modifiers, swelling agents, surfactants A stomach that compresses into a form that is sufficiently expandable and suitable for insertion into a gastroerosable capsule, comprising an inflatable device prepared from a mixture containing an agent and a substance selected from the group consisting of the mixture Internal retention device. Can stay in the stomach for at least 9 hours, (a) xanthan gum and locust bean gum, and (b) therapeutic agents, diagnostic agents, plasticizers, pH adjusters, gastrointestinal motility adjusters, viscosity modifiers, swelling agents, A swellable device prepared from a mixture containing a surfactant and a substance selected from the group consisting of mixtures thereof, in a form suitable for insertion into a fully and gastroerodible capsule A gastric retention device that compresses. Can stay in the stomach for at least 9 hours, and by weight, about 0.1% to about 2.0% xanthan gum, about 0.1% to about 2.0% locust bean gum, less than 5% polyethylene glycol, less than 1% lauryl sulfate Full and gastric erosion can include an inflatable device prepared from a mixture containing sodium, less than 1% carbopol by weight, and a biologically effective amount of a therapeutic, diagnostic, or combination thereof Gastric retention device that compresses into a shape suitable for insertion into a sex capsule. A method for making a gastric retention device comprising the following steps:
Forming a mixture containing polysaccharides;
Processing the mixture to form a dry gel in a form suitable for administration to a subject; and coating the dry gel with a gastric erodible substance or placing the gel in a liquid erodible capsule . 70. The method of claim 69, wherein the mixture includes locust bean megam. 70. The method of claim 69, wherein the mixture includes xanthan gum. 70. The method of claim 69, wherein the mixture comprises a polysaccharide, locust bean gum and water. 70. The method of claim 69, wherein the xanthan gum and locust bean gum comprise from about 0.1% to about 5% of the mixture by weight. The mixture further comprises a substance selected from the group consisting of therapeutic agents, diagnostic agents, plasticizers, pH adjusters, gastrointestinal motility adjusters, viscosity modifiers, swelling agents, surfactants, and mixtures thereof. 72. The method according to 72. Drugs include nucleic acids, proteins, AIDS adjuvants, alcoholics, Alzheimer's disease management, amyotrophic lateral sclerosis, analgesics, anesthetics, antacids, antiarrhythmic drugs, antibiotics, Anticonvulsant, antidepressant, antidiabetic, antiemetic, antidote, antifibrotic treatment, antifungal, antihistamine, antihypertensive, antiinfective, antibacterial, antineoplastic, antipsychotic, anti Parkinson's disease drug, anti-rheumatic drug, appetite stimulant, appetite suppressant, biological response regulator, biological blood preparation agent, bone metabolism regulator, cardioprotectant, cardiovascular drug, central nervous system stimulant, cholinesterase inhibitor , Contraceptives, cystic fibrosis control, deodorant, diagnostics, dietary supplements, diuretics, dopamine receptor agonists, endometriosis control, enzymes, erectile dysfunction, fatty acids, gastrointestinal, Gaucher Disease control drugs, gout preparations, homeopathic drugs , Hormone, hypercalcemia management drug, sleeping pill, hypocalcemia management drug, immunomodulator, immunosuppressant, ion exchange resin, levocarnitine deficiency control drug, mast cell stabilizer, migraine preparation, vehicle Sickness drug, multiple sclerosis management drug, muscle relaxant, narcotic antidote, narcotic drug, nucleoside analog, nonsteroidal anti-inflammatory drug, obesity management drug, osteoporosis preparation, delivery promoting drug, sympathetic nerve Blockade, parasympathomimetic, phosphorus adsorbent, porphyria, psychotherapeutic, radiopaque, psychotropic, sclerosing, sedative, sickle cell anemia control, smoking cessation aid, steroid , Stimulant, sympathetic blocker, sympathomimetic, Tourette syndrome drug, tremor drug, urinary tract, vaginal drug, vasodilator, dizziness drug, weight loss drug, Wilson disease control drug, And from its mixture That is selected from the group The method of claim 74. 75. The method of claim 74, wherein the mixture further comprises hydrochlorothiazide. 75. The method of claim 74, wherein the processing comprises lyophilizing the gel. 70. The method of claim 69, wherein processing the mixture includes effectively heating the mixture to thermally induce gelation of the mixture to form a gel. 70. The method of claim 69, further comprising compressing the dried gel to a size and shape suitable for administration to a subject prior to coating the gel or placing it in a capsule. 75. The method of claim 74, wherein the medicament is provided by tablets, capsules, powders, beads, pills, granules, solid dispersions, or combinations thereof. A method for making a gastric retention device comprising the following steps:
Forming a mixture comprising a polysaccharide and a substance selected from the group consisting of plasticizers, pH adjusters, gastrointestinal motility adjusters, viscosity adjusters, therapeutic agents, diagnostic agents, swelling agents, surfactants, and mixtures thereof;
Heating the mixture to a temperature sufficient to induce gelation of the mixture to form a gel;
Drying the gel to form a dry film;
Compressing the dried film to form a compressed film; and coating the compressed film with a gastric erodible substance or placing the gel in a gastric erodible capsule. Abacavir sulfate, Abacavir sulfate / lamivudine / zidovudine, Acetazolamide, Acyclovir, Albendazole, Albuterol, Arductone, Allopurinol BP, Amoxicillin, Amoxicillin / potassium clavulanate, Amprenavir, Atovaquon, Atovaquon / Proguanil hydrochloride, Atracurium Besylate, beclomethasone dipropionate, betamethasone valerate lactone, buepropion hydrochloride, buepropion hydrochloride sustained release tablets, carvedilol, caspofungin acetate, cefazoline, ceftazidime, cefuroxime (not sulfate), chlorambucil, chlorpromazine, cimetidine, cimetidine hydrochloride, cis Atracurium besylate, clobetasol propionate, cotrimoxazole, colfoceryl palmitate, Dextroamphetamine sulfate, digoxin, enalapril maleate, epoprostenol, esomeprazole magnesium, fluticasone propionate, furosemide, hydrochlorothiazide / triamterene, lamivudine, lamotrigine, lithium carbonate, losartan potassium, melphalan, mercaptopurine, mesalazine, mupirocin calcium Cream, nabumetone, naratriptan, omeprazole, ondansetron hydrochloride, obine, oxyconazole nitrate, paroxetine hydrochloride, prochlorperazine, procyclidine hydrochloride, pyrimethamine, ranitidine bismuth citrate, ranitidine hydrochloride, rofecoxib, ropinirole hydrochloride, malein Rosiglitazone acid, salmeterol xinafoate, salmeterol, fluticasone propionate , Sterile ticarcillin disodium / potassium clavulanate, simvastatin, spironolactone, succinylcholine chloride, sumatriptan, thioguanine, tirofiban hydrochloride, topotecan hydrochloride, tranylcypromine sulfate, trifloperazine hydrochloride, valaciclovir hydrochloride, vinorelbine, zanamivir, zidovudine or lamivudine 84. The method of claim 81, further comprising the step of incorporating the or a mixture thereof into the gel. A method for using a gastric retention device comprising the following steps;
Providing a gastric retention device; and administering the gastric retention device to a subject. 84. The method of claim 83, wherein the gastric retention device further comprises a therapeutic agent, a diagnostic agent, or a mixture thereof. Therapeutic or diagnostic agents are abacavir sulfate, abacavir sulfate / lamivudine / zidovudine, acetazolamide, acyclovir, albendazole, albuterol, alducton, allopurinol BP, amoxicillin, amoxicillin / potassium clavulanate, amprenavir, atovaquon, atovaquon・ Proguanil hydrochloride, atracurium besylate, beclomethasone dipropionate, betamethasone valerate lactone, buepropion hydrochloride, buepropion hydrochloride sustained release tablets, carvedilol, caspofungin acetate, cefazolin, ceftazidime, cefuroxime (not sulfate), chlorambucil, chlorpromazine , Cimetidine, cimetidine hydrochloride, cis-atracurium besylate, clobetasol propionate, cotrimoxazole, palmi Colfoseryl tinate, dextroamphetamine sulfate, digoxin, enalapril maleate, epoprostenol, esomeprazole magnesium, fluticasone propionate, furosemide, hydrochlorothiazide / triamterene, lamivudine, lamotrigine, lithium carbonate, losartan potassium, melphalan, mercaptopurine, Mesalazine, mupirocin calcium cream, nabumetone, naratriptan, omeprazole, ondansetron hydrochloride, obine, oxyconazole nitrate, paroxetine hydrochloride, prochlorperazine, procyclidine hydrochloride, pyrimethamine, ranitidine bismuth citrate, ranitidine hydrochloride, rofecoxib, Ropinirole hydrochloride, rosiglitazone maleate, salmeterol xinafoate, salmeterol, Fluticasone lopionate, sterile disodium ticarcillin / potassium clavulanate, simvastatin, spironolactone, succinylcholine chloride, sumatriptan, thioguanine, tirofiban hydrochloride, topotecan hydrochloride, tranylcypromine sulfate, trifloperazine hydrochloride, valaciclovir hydrochloride, vinorelbine, zanamivir, 84. The method of claim 83, wherein the method is zidovudine or lamivudine, or a mixture thereof. The gastric retention device includes an inflatable device prepared from a mixture comprising a polysaccharide and locust bean gum, which is compressed to form a compression device of a size suitable for swallowing, the compression device being 84. The method of claim 83, wherein a gastric erodible coating is applied to the outer surface or stored in a gastric erodible ingestible capsule. The gastroretentive device allows food to pass through but is fully inflated and inflated after ingestion to prevent the device from passing through the subject's pylorus for at least a predetermined period of time up to 24 hours. A compression device that is also sufficiently robust to include a therapeutic agent, a diagnostic agent, a plasticizer, a pH adjuster, a gastrointestinal motility adjuster, a viscosity modifier, a swelling agent, a surfactant, and mixtures thereof 90. The method of claim 86, further comprising a substance selected from the group, wherein the compression device is coated with a gastric erodible coating on its outer surface or stored in a gastric erodible capsule. The gastric retention device includes an inflatable device prepared from a mixture containing xanthan gum and locust bean gum, which is compressed to form a compression device, and the compression device has a coating applied to its outer surface. 84. The method of claim 83, wherein the method is stored in a gastric erodible capsule. 85. The method of claim 84, wherein the GRD is of sufficient size to pass through the pylorus and transports diagnostic and / or therapeutic agents to the colon. 85. The method of claim 84, wherein the GRD further comprises an enteric coating and transports the diagnostic and / or therapeutic agent to the colon. An appetite suppression method that includes the following steps:
Providing a gastric retention device that expands sufficiently in the subject's stomach to at least partially suppress the subject's appetite; and administering the gastric retention device to the subject. 92. The method of claim 91, wherein the device further comprises an effective amount of a fatty acid, an appetite suppressant, a weight loss drug, or a combination thereof. A method of appetite suppression that includes the following steps:
Providing a gastric retention device that expands sufficiently in the intestine of the subject to at least partially suppress the subject's appetite; and administering the gastric retention device to the subject. 94. The method of claim 93, wherein the device further comprises an effective amount of a fatty acid, an appetite suppressant, a weight loss drug, or a combination thereof. An oral dosage form comprising a dehydrated polymer gel shaped to a size suitable for swallowing and with excipients, the dehydrated polymer weighing 1 gram or less. 96. The oral dosage form of claim 95, shaped to a size suitable for nasal administration. 96. The oral dosage form of claim 95, shaped to a size suitable for vaginal administration. 96. The oral dosage form of claim 95, shaped to a size suitable for rectal administration. 96. The oral dosage form of claim 95, shaped to a size suitable for enteral administration. 96. The oral dosage form of claim 95, shaped to a size suitable for oral administration. Further comprising a diagnostic or therapeutic agent, wherein the transport of the drug in 2 hours ranges from about 2% to about 70% of the total transportable drug and the transport of the drug in 24 hours is transportable 94. The method of claim 83, wherein the method ranges from about 35% to about 100% of the total therapeutic agent. Contain ranitidine hydrochloride, transported in a suitable aqueous medium in a paddle stirrer by the United States Pharmacopeia (USP), measured in vitro at 37 ° C, and transported ranitidine hydrochloride in 2 hours 84. The method of claim 83, wherein the amount is about 70% of the total amount of ranitidine hydrochloride, and transport of ranitidine hydrochloride in about 24 hours is about 100% of the total amount of ranitidine hydrochloride that can be transported. Further comprising riboflavin, the transport of which can be transported when measured in vitro in a suitable aqueous medium in a paddle stirring and dissolving apparatus by the United States Pharmacopeia (USP) at 37 ° C. and in 2 hours 84. The method of claim 83, wherein the amount is about 2% of the total amount of riboflavin and the transport of riboflavin in about 24 hours is about 35% of the total amount of riboflavin that can be transported. If the diagnostic or therapeutic agent is riboflavin and its transport is measured in vivo as urinary excretion of riboflavin, riboflavin transport is about 15% of the total transportable riboflavin in 2 hours and riboflavin in 24 hours 84. The method of claim 83, wherein the transport of is about 100% of the total transportable riboflavin. If the diagnostic or therapeutic agent is hydrochlorothiazide and the transport of hydrochlorothiazide is assessed by determining urine output, and urine output at 2 hours is about 10% of the total urine output at 42 hours; 84. The method of claim 83, wherein the urine output at 24 hours is about 75% of the 42 hour total urine output. Administration of a diagnostic or therapeutic agent in a gastric retention device provides a first result, whereby a second result obtained by administering the diagnostic or therapeutic agent without a gastric retention device and 84. A method of using a gastric retention device according to claim 83, wherein when compared, a desired biological benefit is produced. 107. The method of claim 106, wherein the diagnostic or therapeutic agent is hydrochlorothiazide and the desired biological benefit is an increase in total urine output. Administration includes administering a GRD of a size sufficient to prevent GRD from passing through the pylorus and further comprising determining a GI absorption site for the diagnostic or therapeutic agent 84. A method according to claim 83 for determining a GI absorption site of a therapeutic agent. Administration includes administering a GRD of sufficient size to pass through the pylorus and further comprising determining a GI absorption site for the diagnostic or therapeutic agent, wherein the GI absorption site for the diagnostic or therapeutic agent is further included. 84. A method according to claim 83 for determining.

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