JP4847437B2 - アルカロイド製剤 - Google Patents
アルカロイド製剤 Download PDFInfo
- Publication number
- JP4847437B2 JP4847437B2 JP2007501066A JP2007501066A JP4847437B2 JP 4847437 B2 JP4847437 B2 JP 4847437B2 JP 2007501066 A JP2007501066 A JP 2007501066A JP 2007501066 A JP2007501066 A JP 2007501066A JP 4847437 B2 JP4847437 B2 JP 4847437B2
- Authority
- JP
- Japan
- Prior art keywords
- alkaloid
- phosphate
- group
- electron transfer
- morphine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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Description
本出願は、1又は複数のアルカロイドを含む製剤に関する。さらに特に、しかし限定的でなく、1又は複数のアルカロイド、及び1又は複数の電子伝達剤のリン酸塩誘導体を含む製剤に関する。
本明細書中、知見の文書、認識行為又は項目が言及又は議論される際、この言及又は議論は、認識行為又は項目又はそれらのいずれかの混合が、優先日において、技術常識又は本明細書に関連するいくつかの課題を解決するための試みに関連すると知られた事項の一部であることを承認するわけではない。
薬物としてのアルカロイドの使用には長い歴史がある。これらの化合物は、最初、植物から抽出され、そして薬物及び毒物として人間における生理的作用を有する窒素化合物を含む。本明細書、及び特許請求の範囲中において使用される用語「アルカロイド」は、第1級、2級又は3級アミン置換基を含む全ての天然の及び合成の活性化合物を含む。当該アミンは、1又は2つの環に含まれ得るが、しかし非環状構造もまた含まれ得る。例えば、それは、以下の:
第3級アミンであって:
3つの環の共通の構成員として窒素原子を有する脂環式のもの(例えば、モルヒネ、アトロピン、キニーネ);又は
窒素原子が単一の環に組み入れられるか又はアルキル化される環状のもの(例えば、ニコチン、フェンスピリド);又は
窒素原子を組み入れる環状構造を有さないもの(例えば、フルラゼパム);
第2級アミンであって、窒素原子が脂環式構造に組み入れられるもの(例えば、Conline、フェンジリン)又は直鎖状構造に組み入れられるもの(例えば、エピネフリン);
第1級アミン(例えば、エフィドリン);
ピリジン(ニコチン);
メタミジン(methamidine)誘導体;
キノリン(例えば、シンコニン);及び
グアニヂン(例えば、アルギニン)、
を含む。
局所性投与は、身体の一部に直接薬剤を適用することをいい、そして経皮投与(皮膚に適用)及び口腔投与(口の中に適用)を含む。
多くの薬物が経口投与されるが、しかし潜在的に有用な薬物の多くは拒絶される、なぜならば、それらは腸壁を通過できないからである。脂肪の如き基質は腸を通過して効果的に輸送されるが、しかし、トコフェロールの如き他の多くは、ほとんど輸送されないことが理解される。それ故、アルカロイドの経口投与を改良し得るシステムの必要性がある。
アルカロイド化合物が電子伝達剤のリン酸塩誘導体と直接に複合体を形成する際の投与に関して、重要な改良点が存在することがわかっている。例えば、トコフェリルホスフェイトと直接複合体を形成されたとき、モルヒネの投与は改良される。
この実施例は、本発明に関する製剤におけるアトロピンのブタへの経皮デリバリーを調査する。この実施例は、ブタの心拍数に関して、ゲル形態で投与したときのアトロピンの皮膚透過の効果を調査した。
アトロピン(20mg/kg)を、以下の試験用基礎クリーム中に配合した。以下に特定された成分に加えて、当該全クリームは、以下:12%のUltrez−10カルボマー−3%溶液、0.25%のトリエタノールアミン、0.1%のSurcide DMDMH、及び100%までの脱イオン水を含んだ。
当該データは、アトロピンの経皮適用は当該ブタの心拍数の増大を提示し、適用後約60分で生ずるピークを有する。当該データは、基礎クリームのみでは心拍数を増大しないこと、及び当該製剤の影響はアトロピン自体に起因することをも提示する。
この実施例は、モルヒネのブタに対する経皮デリバリーの効果を調査した。当該ブタの皮膚は人間の皮膚と似たような特性を有し、そしてそれ故、当該ブタは、薬物の経皮デリバリーを試験するための優れたモデルである。
この実施例は、ラットに対するモルヒネの経皮デリバリーに関して、複合体トコフェリルホスフェイトを使用して、対照と比較したときの本発明における異なる製剤の効果を調査する。
動物:知覚反応のあるSprague Dawleyラット(〜280g)、グループあたりn=6.
経皮製剤製造:塩酸モルヒネ、Glaxo オーストラリア Pty Ltd(カタログ番号22284)。モルヒネ遊離塩基を、炭酸カリウムの添加により水溶液中のHCL形態から得た。この過程は、Monash大学で完成された(塩酸モルヒネはクリームと共に使用され得なかった、それ故、遊離塩基を使用した。)。
足の裏の無痛覚計を、小実験動物における痛覚欠如レベルの素早く及び効果的なスクリーニングのために設計した。当該装置を、当該動物の後足に熱源(赤外線により〜45℃)を適用するために使用し、そして当該足を引っ込めるまでにかかる時間を測定した(足を引く待ち時間)。当該熱板は、0.1℃の精度を有する組み込みデジタル温度計、及び0.1秒の精度を有するタイマーを伴い、一定の表面温度を提供する。当該動物を熱版上に置き、それを当該板を囲む透明なアクリルの檻により確認し、そして足の僅かな反応を観察する。足の僅かな反応前の増大時間は、痛覚の欠如を示す。
図6は、当該各製剤で得られた結果を示す。当該結果は、用量依存的に、痛覚欠如を示す反応時間の増大を表す。モルヒネを有するがTPMを有さないゲルの対照試験は、経皮経路が働くためにはTPMが本質的に必要であることを示す。結果は対照と比較される後退する時間の変化を示す、ここで、対照の値は不十分な製剤(すなわち、モルヒネなし、またはTPMなし)で処理されたラットに由来し、並びにゼロ時間の値は十分な製剤であるTPM−01/Mで処理されたラットに由来する。
本試験において使用される当該製剤は、TP/T2Pの混合(又はTPM)、塩酸モルヒネ、及び表5に載せられたような他の賦形剤を含む。当該製剤は、いずれのラウリルジアミノプロピオン酸を含まなかった。
Claims (7)
- (i)第3級アミン基を有するアルカロイドと、
(ii)モノ−トコフェリルホスフェイト、ジ−トコフェリルホスフェイト、及びそれらの混合体からなる群より選択される、1又は複数の電子伝達剤の1又は複数のリン酸塩誘導体
との反応生成物を含む、局所用アルカロイド製剤。 - 前記1又は複数の電子伝達剤の1又は複数のリン酸塩誘導体が、モノ−トコフェリルホスフェイト及びジ−トコフェリルホスフェイトの混合体である、請求項1に記載のアルカロイド製剤。
- 前記アルカロイドが、アトロピン、キニーネ、第3級アミン基を有するオピオイド、フェンタニル、ニコチン、フェンスピリド、フルラゼパム、及びコデインからなる群より選択される、請求項1又は2に記載のアルカロイド製剤。
- 前記アルカロイドがアトロピン又はモルヒネである、請求項1〜3のいずれか1項に記載のアルカロイド製剤。
- 皮膚デリバリー形態及び経皮デリバリー形態からなる群より選択される形態である、請求項1〜4のいずれか1項に記載のアルカロイド製剤。
- 局所用アルカロイド製剤において第3級アミン基を有するアルカロイドの効果を改良する方法であって、前記アルカロイドを、モノ−トコフェリルホスフェイト、ジ−トコフェリルホスフェイト、及びそれらの混合体からなる群より選択される、1又は複数の電子伝達剤の1又は複数のリン酸塩誘導体と反応させるステップを含む方法。
- 請求項1〜5のいずれか1項に記載のアルカロイド製剤を含む、医薬組成物。
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AU2004904367A AU2004904367A0 (en) | 2004-08-03 | Alkaloid formulations | |
PCT/AU2005/000307 WO2005084678A1 (en) | 2004-03-03 | 2005-03-03 | Alkaloid formulations |
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JP2007526256A JP2007526256A (ja) | 2007-09-13 |
JP2007526256A5 JP2007526256A5 (ja) | 2008-05-15 |
JP4847437B2 true JP4847437B2 (ja) | 2011-12-28 |
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AUPR549901A0 (en) * | 2001-06-06 | 2001-07-12 | Vital Health Sciences Pty Ltd | Topical formulation containing tocopheryl phosphates |
BR0211673A (pt) * | 2001-07-27 | 2004-07-13 | Vital Health Sciences Pty Ltd | Terapia dermal utilizando derivados de fosfato de agentes de transferência de elétrons |
JP4624673B2 (ja) * | 2001-12-13 | 2011-02-02 | バイタル ヘルス サイエンシズ プロプライアタリー リミティド | 化合物の経皮輸送 |
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US20060241085A1 (en) * | 2003-01-17 | 2006-10-26 | West Simon M | Compounds having anti-proliferative properties |
AU2003901815A0 (en) * | 2003-04-15 | 2003-05-01 | Vital Health Sciences Pty Ltd | Phosphate derivatives |
DE602005025979D1 (de) | 2004-03-03 | 2011-03-03 | Vital Health Sciences Pty Ltd | Alkaloid-formulierungen |
DE602005025883D1 (de) * | 2004-08-03 | 2011-02-24 | Vital Health Sciences Pty Ltd | Träger für die enterale verabreichung |
MX2007010492A (es) * | 2005-03-03 | 2007-11-08 | Vital Health Sciences Pty Ltd | Compuestos que tienen propiedades anticancer. |
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EP1720551A4 (en) | 2007-04-04 |
CA2557354C (en) | 2013-05-07 |
RU2477136C2 (ru) | 2013-03-10 |
WO2005084678A1 (en) | 2005-09-15 |
EP1720551A1 (en) | 2006-11-15 |
EP1720551B1 (en) | 2011-01-19 |
IL177781A (en) | 2015-03-31 |
AU2005202477A1 (en) | 2005-09-22 |
ATE495730T1 (de) | 2011-02-15 |
KR20060130195A (ko) | 2006-12-18 |
BRPI0508125A (pt) | 2007-07-17 |
RU2006131997A (ru) | 2008-04-10 |
NZ549567A (en) | 2009-10-30 |
US20060281716A1 (en) | 2006-12-14 |
DK1720551T3 (da) | 2011-05-16 |
EP1720551B9 (en) | 2011-09-21 |
IL177781A0 (en) | 2006-12-31 |
JP2007526256A (ja) | 2007-09-13 |
AU2005202477B2 (en) | 2005-12-15 |
KR101173159B1 (ko) | 2012-08-16 |
CA2557354A1 (en) | 2005-09-15 |
HK1098684A1 (en) | 2007-07-27 |
DE602005025979D1 (de) | 2011-03-03 |
US8529947B2 (en) | 2013-09-10 |
US20100209459A1 (en) | 2010-08-19 |
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