JP2007503399A - 生物活性化合物の粒子サイズの低減 - Google Patents
生物活性化合物の粒子サイズの低減 Download PDFInfo
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- JP2007503399A JP2007503399A JP2006524181A JP2006524181A JP2007503399A JP 2007503399 A JP2007503399 A JP 2007503399A JP 2006524181 A JP2006524181 A JP 2006524181A JP 2006524181 A JP2006524181 A JP 2006524181A JP 2007503399 A JP2007503399 A JP 2007503399A
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Abstract
Description
本明細書で使用する用語「生物活性化合物」は、ヒト、動物もしくは植物の生体機能に作用する、もしくは影響を及ぼす化学物質であって、この化学物質が金属イオンおよび1つ以上の原子または例えばイオン結合および/またはイオン錯体の形態をとっている原子のグループを含んでいない限りにおける化学物質、好ましくは有機物質を意味する。
くは1nm〜約450nmの範囲内の平均サイズを有する集団の一部である粒子を意味する。
も250mLの水性媒体中で溶解性である場合は高度に可溶性であると分類すべきである。特に、本発明の方法を用いてこの化合物を調製することによってそのバイオアベイラビリティを向上させることのできる生物活性化合物には次のものが含まれる:アセチルサリチル酸、アンプレナビル、アニパミル、ベンタゾン、ベンゾカイン、ベンザフィブレート、ベキサロテン、ビペリデン、ブタゾリジン、カプトプリル、カルバマゼピン、クロラムフェニコール、クロファジミン、クロモグリク酸、クロトリマゾール、カフェイン、シクロスポリン、ジアゼパム、ジクロフェナク、ジゴキシン、ジリアゾン、ジルチアゼム、ジメトリダゾール、ジフェンヒドラミン、5,5−ジフェニルヒダントイン、ドロナビノール、デュタステライド、エトポシド、ステアリン酸エリスロマイシン、エスプロン、フェノフィブレート、フレカイニド、フロセミド、フルコナゾール、ガロパミル、グリベンクラミド、グリセオフルビン、ヒドロクロロチアジド、イブプロフェン、インドメタシン、(イソ)トレチノイン、イトラコナゾール、ケトコナゾール、ケトプロフェン、ロペラミド、ロピナビル、メルペロン、メタザクロル、ナリキシジン酸、ナフチドロフリル、ネキソパミル、ニフェジピン、ニモジピン、ニトレンジピン、ニトロフラントイン、オキシブチニン、パラセタモール、ペントキシフィリン、パロキセチン、プラゾシン、プロパフェノン、プロゲステロン、プソイドエフェドリン、ラニチジン、リボフラビン、リスペリドン、リトナビル、サキナビル、シロリムス、セレギリン、スルファメタジン、スルファメトキサゾール、スルファチアゾール、スピリノラクトン、タクロリムス、テオフィリン、トルブタミド、トリアムテレン、トリメトプリム、バルプロ酸およびゾテピン。本発明によって処理し得る薬物もしくは生物活性化合物は、好ましくは約2.5mg/mL未満、0.1〜1mg/mL(すなわち、米国薬局方に規定されているように「極めて溶けにくい」)と同等の、さらに0.1mg/mL(すなわち、米国薬局方において規定されているように「ほとんど溶けない」)未満と同等の、さらにいっそう約5μg/mL未満と同等のの水溶性を有していてよく、さらに室温および生理的pHで約0.2μg/mLと同等という低い水溶性を有していてよい。そのような薬物の非限定的例には、例えば、クロロチアジド、ヒドロクロロチアジド、ニモジピン、フルフェナム酸、フロセミド、メフェナム酸、ベンドロフルメチアジド、ベンズチアジド、エタクリン酸、ニトレンジピン、イトラコナゾール、サペルコナゾール、トログリタゾン、プラゾシン、アトバコン、ダナゾール、グリベンクラミド、グリセオフルビン、ケトコナゾール、カルバマゼピン、スルファジアジン、フロルフェニコール、アセトヘキサミド、アジャマリン、ベンズブロマロン、安息香酸ベンジル、ベタメタゾン、クロラムフェニコール、クロルプロパミド、クロルサリドン、クロフィブレート、ジアゼパム、ジクマロール、ジギトキシン、エトトイン、グルテチミド、ヒドロコルチゾン、ヒドロフルメチアジド、ヒドロキニン、インドメタシン、イブプロフェン、ケトプロフェン、ナプロキセン、ケリン、ニトラゼパム、ニトロフラントイン、ノバルギン、オキサゼパム、パパベリン、フェニルブタゾン、フェニントイン、プレドニゾロン、プレドニゾン、レセルピン、スピロノラクトン、スルファベンズアミド、スルファジメトキシン、スルファメラジン、スルファメタジン、スルファメトキシピリダジン、スクシニルスルファチアゾール、スルファメチゾール、スルファメトキサゾール(トリメトプリムとの混合物中でも)、スルファフェナゾール、スルファチアゾール、スルフィソキサゾール、スルピリド、テストステロンおよびジアミノピリミジン類が含まれる。ジアミノピリミジン類の適切な例には、制限なく、2,4−ジアミノ−5−(3,4,5−トリメトキシベンジル)ピリミジン(トリメトプリムとして知られる)、2,4−ジアミノ−5−(3,4−ジメトキシベンジル)ピリミジン(ジアベリジンとして知られる)、2,4−ジアミノ−5−(3,4,6−トリメトキシベンジル)ピリミジン、2,4−ジアミノ−5−(2−メチル−4,5−ジメトキシベンジル)ピリミジン(オルメトプリムとして知られる)、2,4−ジアミノ−5−(3,4−ジメトキシ−5−ブロモベンジル)ピリミジン、および2,4−ジアミノ−5−(4−クロロ−フェニル)−6−エチルピリミジン(ピリメタミンとして知られる)が含まれる。当業者には理解されるように、これらの薬物は、利尿薬、降圧薬、抗ウイルス薬、抗菌薬、抗真菌薬などの様々な治療薬クラスに属しており、ヒトまたは獣医学的使用のみには限定されない。生物活性
化合物は、さらにまた化粧品、診断薬、除草剤、殺虫剤、殺生物剤もしくは殺菌剤であってもよい。特により近年に開発された薬物、タンパク質およびペプチドは重要な部分を表している。これらの化合物は、インビボにおける迅速な薬物代謝および不都合な薬物動態とともに、難透過性、難溶性であり、生理的流体中で不安定であることが多い。このため、本発明の方法は、タンパク質およびペプチド薬を投与するための送達形を調製するために有用であることも実証することができる。
る流体は、ガスもしくは超臨界流体(例、二酸化炭素)であってもよい。このガスもしくは臨界流体の性質は、この生物活性化合物の化学組成および反応性に広範に依存する可能性がある。
ある。好ましくは、各この磁場を通るこの流体の線形流量は約0.25〜25m/秒である。磁場の長さを考慮に入れると、各この磁場を通過するこの流体の滞留時間は、回数もしくは再循環時間に依存して、約60マイクロ秒間〜10秒間であると計算することができる。
酸ナトリウムなど)のアルカリもしくはアルカリ土類金属塩から入手された脂肪アルコール硫酸塩の混合物が含まれる。アルキルアリールスルホネートの例は、ドデシルベンゼンスルホン酸もしくはジブチル−ナフタレンスルホン酸またはナフタレンースルホン酸/ホルムアルデヒド縮合生成物のナトリウム、カルシウム、もしくはアルカノールアミン塩である。同様に適合するのはこれに対応するリン酸塩であり、例えばリン酸エステルの塩およびp−ノニルフェノールの酸化エチレンおよび/または酸化プロピレンとの付加物などである。
ールエステル由来の部分の両方を有する物質が含まれる。例えば、本発明における両親媒性物質賦形剤としてポリグリコシル化グリセリドを使用することが適合する。本明細書で使用する表現「ポリグリコシル化グリセリド」は、モノ−、ジ−およびトリグリセリドと好ましくは約200〜約600の分子量を備えるC8−C18脂肪酸のポリエチレングリコール(PEG)モノエステルおよびジエステルとの混合物を意味しており、任意でさらにグリセロールおよび/または遊離PEGを含む。ここで、PEGの親水性−親油性バランス(HLB)価はPEGの鎖長によって調節され、PEGの融点は脂肪酸の鎖長、PEGの鎖長および脂肪酸、したがって出発油の飽和度によって調節される。同様に、本明細書で使用する表現「C8−C18脂肪酸」は、様々な比率のこれらの酸が飽和している場合はカプリル酸、カプリン酸、ラウリン酸、ミリスチン酸、パルミチン酸およびステアリン酸およびこれらの対応する不飽和酸の混合物を意味する。当業者には既知のように、これらの脂肪酸の比率は、出発油の関数として変動する可能性がある。後者の例には、商標名LabrasolとしてGattefosse Corporationによって販売されているPEG−8カプリル酸塩−カプリン酸グリセリドエステルなどの飽和ポリグリコール化C8−C10グリセリド;商標名Softigen 767としてHuls Aktiengesellschaftによって販売されているPEG−6カプリル酸/カプリン酸グリセリド;商標名Crovol M−70としてCroda社によって販売されているPEG−60コーングリセリド;商標名Eumulgin B2としてHenkel Corporation社によって販売されているCeteareth−20;商標名TranscutolとしてGattefosse Corporationによって販売されているジエチレングリコールモノエチルエーテル;たとえば商標名Gelucire 48/09、Gelucire 44/14およびGelucire 42/12としてGattefosse Corporation社によって販売されているような約42〜48℃の範囲内の融点および約8〜16の範囲内のHLBを有するC8−C18飽和ポリグリコシル化グリセリドの混合物;および様々な比率にあるそれらの混合物が含まれるが、それらに限定されない。
するサイズ低減の程度を微調整するための多数の方法と結び付けることができる。第2に、これは極めて多数の生物活性化合物、特に双極子を含む生物活性化合物の粒子および凝集体の実質的なサイズ低減を達成する。
R1/4D)、(3)三方向水平ボール弁(スイス国Schaffhausenに所在するGeorg Fischer Rohrleitungssysteme AG製の343 DN10/15型)、および(4)ポンプ(米国イリノイ州に所在するCole−Parmer Instrument Company製のMasterflexI/P)から構成される図2に示した閉鎖システム内で実施した。ポンプは、11m/秒の磁場通過速度に等しい4.7L/分の流量および装置の通過1回に付き136μsの磁場滞留時間で作動させた。一部のジアゼパム懸濁液を閉鎖システム内に導入し、磁場に通して再循環させた。
、結果として生じた濾液についてDLS測定を実施し、図4において未処理分散体の濾液と粒子サイズ分布を比較した。磁気処理懸濁液の粒子サイズ分布は、濾過を実施した場合(図4)および濾過を実施していない場合(図3)と類似であった。未処理懸濁液の濾液は、Tweenミセル(ピークは11nm)および200nmのジアゼパム粒子を含有している(図4)。これらの観察は、それらの存在が1μmより大きな粒子が富裕であることによって遮蔽されたために、未濾過、未処理懸濁液を分析したときには明らかにならなかった(図3)。そこで、未処理分散体中のマイクロメーターサイズの粒子は、本発明の磁気処理によってナノメーターサイズの粒子に破砕されたと結論することができる。
って調製した。この懸濁液を、磁気装置を備えた100mLの閉鎖システム(図2A)内で4.7L/分で1時間にわたり磁気処理したが、これは11m/秒の速度で磁場に通過させる2,820回の再循環(通過)に相当する。粉末サンプルは、液体窒素中での即時の凝固および凍結乾燥後に入手した(X線回折パターンは図8に示した)。
、大きな粒子の結晶面は明確な形状である。これらの大きな粒子の上には、サイズ約1μmの少量の粒子が散乱している。これらの小さな粒子は、大きな粒子の極めて平滑な結晶面上の凹凸として観察される。
Company社、米国イリノイ州)、(4)Al−Ni−Coタイプの内蔵磁石(商標名W SAN R1/4Dとしてベルギー国Borgerhoutに所在するCEPI−CO社から市販されている)、および(5)液体窒素中に維持した予冷ボールから構成される一連の9個の連結磁気装置を通してポンプで送出した。磁場を通る11m/秒の速度に相当する4.7L/minの流速および磁場内での9×136μsの滞留時間を使用した。システムの出口では、この懸濁液は液体窒素中に維持した予冷ボール中で凝固させ、その後に凍結乾燥を実施した。これらの未処理および磁気処理サンプルの溶解プロファイルは図11に示されている。
ンプルを採取し、直ちに10、20、30、45、60および120分後に各々新鮮溶解媒体と取り替え、その後0.45μmのPVDFフィルタ(米国ニューヨーク州に所在するPall Corporationから市販されている)を用いてHPLCバイアル(1.5mL、ドイツ国ダルムシュタットに所在するMerck社から市販されている)内へ濾過した。対応する濃度は、HPLCを用いた検量線から決定した。
Claims (33)
- 流体中に懸濁させた生物活性化合物粒子もしくは凝集体の平均サイズを、その中に懸濁させた生物活性化合物粒子もしくは凝集体を有する前記流体を1つ以上の磁場に通して1回以上流動させることによって低減させるための方法であって、前記生物活性化合物粒子もしくは凝集体の実質的部分の平均サイズを少なくとも25%、好ましくは少なくとも50%、より好ましくは少なくとも80%低減させる方法。
- 各前記磁場の強さが少なくとも約2,000ガウスである、請求項1に記載の方法。
- 前記方法を実施する前の前記生物活性化合物凝集体の平均サイズが約10μm〜約100μmの範囲内にある、請求項1または請求項2に記載の方法。
- 前記方法を実施した後の前記生物活性化合物凝集体の実質的部分の平均サイズが約0.45μm〜5μmの範囲内にある、請求項1〜3のいずれか一項に記載の方法。
- 前記実質的部分が前記懸濁させた凝集体の少なくとも50重量%である、請求項1〜4のいずれか一項に記載の方法。
- 前記方法を実施する前の前記生物活性化合物粒子の平均粒子サイズが約0.5μm〜約10μmの範囲内にある、請求項1〜5のいずれか一項に記載の方法。
- 実施後の前記生物活性化合物粒子の平均粒子サイズが約0.5nm〜約500nmの範囲まで低減される、請求項1〜6のいずれか一項に記載の方法。
- 前記流体が液体である、請求項1〜7のいずれか一項に記載の方法。
- 前記流体が水である、請求項1〜8のいずれか一項に記載の方法。
- 前記流体が有機溶媒またはそれと水との組み合わせである、請求項1〜8のいずれか一項に記載の方法。
- 前記生物活性化合物粒子もしくは凝集体がスラリーの形態で前記流体中に懸濁され、かつ前記流体中の前記生物活性化合物粒子もしくは凝集体の濃度が、前記スラリーを前記磁場に通して流動させる間に優勢である物理的(温度、圧力)および化学的(pH)条件下で前記流体中の前記生物活性化合物の溶解限度の少なくとも2倍である、請求項1〜10のいずれか一項に記載の方法。
- 前記流体が液体であり、前記液体を前記磁場に通して流動させるステップが、前記流体を前記磁場に通して流動させる間に優勢である圧力下で前記流体の凝固点と沸点との間の温度で実施される、請求項1〜11のいずれか一項に記載の方法。
- 前記流体が水であり、前記液体を前記1つ以上の磁場に通して流動させるステップが大気圧下の約2℃〜95℃の温度で実施される、請求項1〜12のいずれか一項に記載の方法。
- 前記流体がガスもしくは超臨界流体である、請求項1〜7のいずれか一項に記載の方法。
- 前記流体が1種以上の安定剤を含む、請求項1〜14のいずれか一項に記載の方法。
- 前記安定剤が、界面活性剤、ポリマー、ケイ酸塩、親水性物質もしくはそれらの組み合わせである、請求項15に記載の方法。
- 前記安定剤が、界面活性剤でキャップされたナノ粒子を生成できるような量で界面活性剤を含有する、請求項15または16に記載の方法。
- 前記流体が前記1つ以上の磁場に通して2回以上再循環される、請求項1〜17のいずれか一項に記載の方法。
- 各前記磁場を通る前記流体の線流速が0.25〜25m/秒である、請求項1〜18のいずれか一項に記載の方法。
- 各前記磁場を通る5種の前記流体の滞留時間が60マイクロ秒間〜10秒間である、請求項1〜19のいずれか一項に記載の方法。
- 前記生物活性化合物が結晶形である、請求項1〜20のいずれか一項に記載の方法。
- 前記生物活性化合物が無定形である、請求項1〜20のいずれか一項に記載の方法。
- 前記生物活性化合物が生物薬剤分類系のクラスIIまたはクラスIVであると分類できる薬物である、請求項1〜22のいずれか一項に記載の方法。
- 前記生物活性化合物が約2mg/mL未満の水溶性を有する薬物である、請求項1〜23のいずれか一項に記載の方法。
- 前記生物活性化合物が約5μg/mL未満の水溶性を有する薬物である、請求項1〜24のいずれか一項に記載の方法。
- 前記生物活性化合物が、化粧品、診断薬、除草剤、殺虫剤、殺生物剤もしくは殺菌剤である、請求項1〜25のいずれか一項に記載の方法。
- 生物活性化合物調製物を製造するための工程であって、前記工程が生物活性化合物粒子もしくは凝集体の使用を含み、前記生物活性化合物粒子もしくは凝集体の実質的部分の平均サイズを少なくとも25%低減させるステップを含み、このとき前記ステップが請求項1〜26のいずれか一項に記載の方法を含む工程。
- 前記工程が、前記サイズを低減させるステップの後に実施される1つ以上の後処理ステップをさらに含む、請求項27に記載の工程。
- 前記後処理ステップが、前記サイズを低減させるステップ中にその中に生物活性化合物粒子もしくは凝集体が懸濁されている流体を実質的に除去するための乾燥させるステップである、請求項27または28に記載の工程。
- 前記乾燥させるステップが凍結乾燥法を含む、請求項29に記載の工程。
- 前記乾燥させるステップが噴霧乾燥法を含む、請求項29に記載の工程。
- 前記後処理ステップが、アジュバントを任意的に乾燥させた低減されたサイズを備える粒子もしくは凝集体と一緒に混合するステップである、請求項27〜31のいずれか一項
に記載の工程。 - 請求項1〜26のいずれか一項に記載の方法または請求項27〜32のいずれか一項に記載の工程によって入手される生物活性化合物粒子の集団。
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GBGB0319797.7A GB0319797D0 (en) | 2003-08-26 | 2003-08-26 | Particle size reduction of poorly soluble drugs |
GB0319797.7 | 2003-08-26 | ||
PCT/BE2004/000121 WO2005018611A1 (en) | 2003-08-26 | 2004-08-25 | Particle size reduction of bioactive compounds |
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JP2006524181A Pending JP2007503399A (ja) | 2003-08-26 | 2004-08-25 | 生物活性化合物の粒子サイズの低減 |
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US (1) | US7666307B2 (ja) |
EP (1) | EP1658052B1 (ja) |
JP (1) | JP2007503399A (ja) |
AT (1) | ATE359765T1 (ja) |
DE (1) | DE602004006000T2 (ja) |
ES (1) | ES2286655T3 (ja) |
GB (1) | GB0319797D0 (ja) |
WO (1) | WO2005018611A1 (ja) |
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JP2014528486A (ja) * | 2011-10-13 | 2014-10-27 | ケース ウエスタン リザーブ ユニバーシティ | Rxrアゴニスト化合物および方法 |
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US8486423B2 (en) | 2007-08-21 | 2013-07-16 | Board Of Regents, The University Of Texas System | Thermo-kinetic mixing for pharmaceutical applications |
WO2009026647A1 (en) * | 2007-08-30 | 2009-03-05 | The University Of Queensland | Method and apparatus for breaking solid materials |
GB0818403D0 (en) * | 2008-10-08 | 2008-11-12 | Univ Leuven Kath | Aqueous electrophoretic deposition |
EP2334845A2 (en) * | 2008-10-06 | 2011-06-22 | Katholieke Universiteit Leuven K.U. Leuven R&D | Functional layers of biomolecules and living cells, and a novel system to produce such |
US9441019B2 (en) | 2011-09-23 | 2016-09-13 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Influenza hemagglutinin protein-based vaccines |
EP3906939A1 (en) | 2013-10-11 | 2021-11-10 | The United States of America, represented by the Secretary, Department of Health and Human Services | Epstein-barr virus vaccines |
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DE602004006000T2 (de) | 2008-01-17 |
DE602004006000D1 (de) | 2007-05-31 |
GB0319797D0 (en) | 2003-09-24 |
EP1658052B1 (en) | 2007-04-18 |
US7666307B2 (en) | 2010-02-23 |
US20070082054A1 (en) | 2007-04-12 |
WO2005018611A1 (en) | 2005-03-03 |
EP1658052A1 (en) | 2006-05-24 |
ES2286655T3 (es) | 2007-12-01 |
ATE359765T1 (de) | 2007-05-15 |
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