JP2005507393A - Water-soluble nanoparticles of hydrophilic and hydrophobic active substances - Google Patents

Abstract

The present invention provides soluble nano-sized particles formed from a core (water-insoluble lipophilic) compound or hydrophilic compound and an amphiphilic polymer, which exhibit improved solubility and / or stability. It was. The lipophilic compounds within the soluble nanosized particles (“soluble nanoparticles”) can consist of pharmaceutical compounds, food additives, cosmetics, agricultural products and veterinary products. The present invention also provides a novel chemical reactor for producing inclusion complexes comprising these nanosize soluble particles as well as a novel method of preparing nanosize soluble particles.

Description

ここで：
Ｎ_ｃ−「両親媒性重合体と親油性化合物との」重量比。
【００４３】
Ｍ_ｆ−重合体断片の分子量。
【００４４】
Ｍ_ｌ−親油性化合物の分子量。
【００４５】
Ｍ_ｐ−重合体の分子量
Ｎ_ｆ−複合体形成に関与できる重合体断片の量。
【００４６】
次に、この重合体の水溶媒の物理的パラメータが評価される。この段階で、この複合体を作成するのに必要なｐＨ、必要なイオン力およびその親油性化合物に必要な担体の決定が行われる。上記成分を使用すると、その重合体鎖の可動性を制御するのに最適な条件が得られる。
【００４７】
次いで、担体非水性溶媒が選択される。この溶媒の目的は、溶解した化合物の分子が実際に互いに反応しないように、この活性化合物を非常に弱い（低濃度の）溶液に移動させることにある。この溶液は、次いで、ナノ分散体（例えば、ナノ乳濁液（これは、液状コア物質を有する）またはナノ懸濁液（これは、固形コア物質を有する））を作成するための化学反応器（これは、以下で詳細に述べる）にある反応ゾーンに送達される。
【００４８】
本明細書中で使用する「懸濁液」との用語は、一般に、液体中の微粒子の分散体を意味する。
【００４９】
本明細書中で使用する「乳濁液」との用語は、一方が他方（これは、分散相を規定する）にコロイド状で懸濁された二種類の通常混合できない液体の混合物を意味する。乳濁液中の分散相の粒径は、一般に、数百ナノメーターと数十マイクロメーターとの間にある。
【００５０】
形成された分散体を安定化するために重合体を使用する既知のナノサイズ粒子調製方法とは異なり、これらの分散体安定化では、前記両親媒性重合体（これは、先に計算した親水性−親油性バランスＨＬＢを有する）の一部だけが使用される。さらに、この分散体中の両親媒性重合体の動的三次元立体配置のために、特定の条件が選択され、これは、粘度付与剤（すなわち、粘度を高めるもの）として作用するのではなく、その複合体を作り出すものおよびコア活性化合物を固定するものとして働く。先に計算したＨＬＢは、この活性化合物に必要な可溶化を与える。
【００５１】
この「ナノ分散体」形成において両親媒性重合体を作成する特定の条件により、以下の２つの要素が得られる：（１）その化学結合の周りでの重合体鎖の運動セグメントの自由回転（従って、これらのセグメントは、結合している）という規定、および（２）両親媒性重合体の親油性官能基と可溶化が意図される化合物の親水性基との間の非原子価相互作用という規定。これらの特定の条件には、以下が挙げられる：分散性媒体のｐＨパラメータ、分散性媒体のイオン力、分散性媒体の成分組成、複合体処方の温度、プロセスの持続時間およびプロセスの機械要素。これらの特定の条件の各々は、以下でさらに詳細に述べる。
【００５２】
（分散性媒体のｐＨパラメータ）
この両親媒性重合体の組成がイオン性官能基を含むなら、その重合体は、これらの基の極性に依存して、等電点よりも高い（ポリ酸）か、等電点よりも低い（ポリ塩基）ｐＨで、溶解性であり得る。これらの場合の両方では、この等電点は、「重合体溶液の粘度−重合体溶液のｐＨ」の曲線について、高い精度で決定できる。これらの２種の重合体は、その複合体作成において、それらの溶液が粘稠な液体であるｐＨ範囲内でのみ、沈殿できる。非イオン性官能基を有する重合体については、明確に規定される等電点は存在せず、この理由のために、これらの重合体は、広いｐＨ範囲で、この複合体作成に関与できる。
【００５３】
（分散性媒体のイオン力）
この重合体溶液内の水溶性塩のイオンの影響下にて、この両親媒性重合体の形状は、変わる。この因子は、その重合体の親油性基と親油性化合物それ自体との間の非共有結合相互作用の立体特異的条件の作成に使用される。それにもかかわらず、多くの重合体は、これらの塩の出現時（その重合体の「塩析」プロセス）にて、非常に活発に反応するので、この因子を複合体作成反応に常に利用するのが可能な訳ではない。
【００５４】
水分子に対して、これらのイオンと重合体との間には、競争が存在しており、それらのイオンは、その重合体の水和物殻から水を獲得する。水和物殻が減少する結果として、この重合体は、小球に巻き付けられる。イオン活性が高い程、その重合体が小球に巻き付けられるようになる。
【００５５】
（分散性媒体の成分組成）
溶媒の組成の助けを借りて、これらの高分子の形状を柔軟に制御することが可能である。しかしながら、医薬品、食品添加物および化粧品化合物を溶解性（可溶化）にする目的のために、生物学的に安全な溶媒（例えば、グリセロール、エチレングリコール、およびそれより頻繁ではないが、エチルアルコール、イソブタノールおよびジメチルスルホキシド）だけが使用できる。溶媒を追加すると、水の溶解性能を低下させる。これは、塩（すなわち、緩いまたは密な小球に変換する非コイル状重合体鎖）の添加と類似している。それゆえ、この方法の選択肢は、限られている。
【００５６】
（複合体形成の温度）
この重合体溶液の温度変化に伴って、その重合体分子の水和状態、従って、この溶液中でのその立体配置は、大幅に変化する。その温度を上げると、この重合体分子を取り囲む水和殻は、脱着し始め、その直鎖高分子は、小球形状をとり始める。同時に、この高分子の可動性が高まる。結果として、複合体作成のための別の肯定的な条件が生まれる。
【００５７】
（プロセス持続時間）
その包接を作成中の非原子価相互作用のために、このプロセスの限定段階は、これらの親油性化合物および高分子の互いに対する拡散から成り、これは、各反応系について、複合体作成のための最小時間で、存在している。それより短い時間が許容されるなら、この系は、２相のままである。この２相ナノ分散体は、熱力学的に不安定である。その担体を蒸発させる次の段階では、この分散相の粒子を１〜１０００ｎｍの範囲のサイズにする。次いで、その溶液中の重合体分子は、これらの活性化合物を覆い、取り込んで、粒子を作り出す。この担体は、蒸発されて、安定なナノ粒子を形成する。
【００５８】
（プロセスの機械的要素）
ミキサー、分散機、ホモジナイザーおよび他の設備により、この活性化合物は、その水−重合体溶液中にて、最大に分散され、ナノ寸法サイズの粒子が分散相にある乳濁液または懸濁液の形成が加速される。本発明のナノ乳濁液またはナノ懸濁液とナノ可溶粒子とを形成するのに有利な新規化学反応器は、以下で詳細に述べる。
【００５９】
上記条件を組み合わせた効果は、複合体形成中において、この複合体の具体的に選択した寸法および割合、活性化合物の最大の分散ならびにそれらの化合物と重合体との非原子価相互作用に最適な条件を達成するのを助ける。
【００６０】
上で列挙したように、本発明に従ってこの複合体を調製するには、その複合体を調製する方法を開始する前に、多数の計算および手順を実行する必要がある。一部の計算および手順（これらは、コンピューターシステムでのアルゴリズムを使用して決定される）は、以下の工程を包含する：
（ａ）複合体（これは、活性化合物、両親媒性重合体および担体溶媒を含有する）を調製する成分の組成および特性を計算する工程；
（ｂ）両親媒性重合体と活性化合物との重量比を計算する工程；
（ｃ）両親媒性重合体に対する水溶媒の物理的パラメータを評価する工程；
（ｄ）正しい非水性溶媒を決定する工程；
（ｅ）複合体の幾何学モデルを作成する工程。
【００６１】
このアルゴリズムは、これらの計算には限定されず、製造する複合体の性質および特性に依存して、必要に応じて、計算および決定を追加するようにプログラム化され得る。
【００６２】
列挙したように、本発明の活性化合物および両親媒性重合体からなる分子複合体の製造には、その活性化合物をナノ粒子サイズまで分散する必要がある。これらのナノサイズ粒子は、この活性化合物の分散したナノサイズ粒子と重合体分子との間の殆ど即座の相互作用を保証する。本発明の方法に従って、また、これらのナノサイズ粒子の逆凝集（コアセルベーション）を防止して、この活性化合物の分散したナノサイズ粒子と重合体分子との間の即座の相互作用を保証する必要がある。これにより、アンテナ複合体（包接または他のもの）の形成が保証される。この活性化合物のサイズは、（その結合の長さと結合間の角度とを考慮して）その幾何学モデルを作成することにより、その後、その化合物を球形のまたは他の幾何学形状に変換することにより、決定される。この球の直径は、その活性化合物を決定する測定サイズである。長鎖構造を備えた親油性物質は、原則として、小球構成を有する形状を呈するということを考慮する必要がある。
【００６３】
本発明に従って、この可溶性ナノサイズ粒子または「可溶ナノ粒子」を形成する処理中にて、重合体は、水性溶媒（好ましくは、水）に加えられて、化学反応器の第一容器にて、重合体溶液を形成する。それに加えて、この活性化合物および重合体を選択するのに必要なアルゴリズムによって決定されるパラメータに基づいて、必要に応じて、この溶液のｐＨおよびイオン力レベルを調節する成分が加えられ得る。この化学反応器の第二容器には、活性化合物（これは、有利には、不溶性親油性物質である）が入れられる。この活性化合物（またはコア）は、任意のサイズ、寸法または重量であり得、種々の官能基のいずれかを含有し得る。この不溶性親油性または親水性化合物の非水性溶媒（または溶媒混合物）溶液は、「担体」と呼ばれている。この担体を重合体溶液に注ぐか加える速度は、１個またはそれ以上の調整タップ（これらは、その重合体溶液に加えられる親油性溶液が０．１％未満の濃度を有することを保証する）により、調節される。
【００６４】
この親油性溶液は、その重合体溶液を加熱したときに形成され、加熱した重合体溶液からの蒸気は、凝縮して、第二容器に存在している親油性物質を溶解する。（担体中の）親油性溶液は、次いで、この重合体溶液と混合されて、乳濁液または懸濁液中で、分散相を形成する。この化学反応器内では、この乳濁液は、分散機（さらに正確には、ナノ分散機）により引き起こされる乱流領域に給送され、これは、この乳濁液または懸濁液内にて、ナノサイズ親油性分子の形成を引き起こす。この乱流領域は、「作用ゾーン」または「相互作用ゾーン」と呼ばれている。この乱流領域に給送される乳濁液または懸濁液は、Ｒｅ＞１０，０００のレイノルズ数を有する。この乳濁液は、それゆえ、約１〜約１０００ｎｍの範囲の粒子を有する「ナノ乳濁液」または「ナノ懸濁液」となる。この粒子製造はまた、小さいミクロンサイズの粒子を含むように広げることができる。このナノ乳濁液またはナノ懸濁液内には、分散媒体（これは、この重合体溶液から構成される）および分散相（これは、この親油性物質の担体溶液を含有する）が存在している。しかしながら、この二相ナノ乳濁液またはナノ懸濁液は、不安定である。その担体を蒸発させると、約１〜約１０００ナノメートルの範囲のサイズの分散相粒子が残る。次いで、この重合体溶液内の重合体分子は、この担体の蒸発後に分散相の粒子内に残っていた活性化合物を取り囲むか包み、さらに適当には、包んで、それにより、包接複合体中で親水性重合体により包まれた水不溶性親油性化合物の均一なナノサイズ分散体を形成する。次いで、残りの担体は、蒸着または他の適当な乾燥技術（例えば、凍結乾燥、減圧蒸留）により、脱気される。この乳濁液または懸濁液および得られる複合体の形成に最適な活性化合物および重合体を選択するのに使用されるアルゴリズムの結果として、一般に、その担体の蒸発後には、遊離の重合体は残らない。この担体の蒸発に続いて、安定な包接複合体は、無定形および／または部分結晶化または結晶化活性要素から構成される。薬剤送達には、バイオアベイラビリティを実際に高め得るので、この非晶質状態が好ましいことは、当業者に知られている。
【００６５】
本発明の有利で好ましい実施態様では、この重合体溶液内の重合体分子は、その重合体と活性化合物との間の非原子価相互作用（例えば、静電力、ファンデルワールス力、水素結合）により、その非原子価相互作用が活性化合物を重合体内に固定してそれにより活性化合物および重合体の分子可動性を減らすように、この活性化合物を「包む」。
【００６６】
本発明は、さらに、本発明に従ってナノ可溶粒子を製造するように設計された新規化学反応器を包含する。図１で図示しているように、化学反応器１０は、第一容器１２および第二容器１４を含む。本発明に従って、先に決定したパラメータに従った濃度、ｐＨおよびイオン特性を有する重合体溶液１６（これは、水中にて、選択重合体から構成される）が調製される。蒸留水容器５２は、「Ｗ」で表示される蒸留水を含有し、そしてカバー１８に位置している。蒸留水容器５２内の蒸留水は、重合体容器５４に移され、これに、推定量の選択重合体が加えられる。重合体容器５４内で形成された重合体溶液は、方向矢印「Ｘ」で示されるように、蠕動ポンプ４２の作用によって、第一容器１２に移される。重合体溶液１６は、蠕動ポンプ４２の助けを借りて、カバー１８にある開口部を経由して、第一容器１２に加えられる。第一容器１２内の重合体溶液１６には、非水性溶媒（「担体」）が加えられる。
【００６７】
この活性化合物は、第二容器１４に加えられるが、これは、第二容器１４と第一容器１２との間で流体連絡を可能にするために、逆チューブ２０を経由して、第一容器１２に連結されている。押圧低減弁５８を備えた二酸化炭素（ＣＯ_２）バルーン５６は、第二容器１４にＣＯ_２ガスを供給し得る。有機溶液中に二酸化炭素酸性ガスＣＯ_２を給送すると、以下の操作特性が改善される：
（ａ）溶媒の沸点の低下；
（ｂ）溶媒の密度の低下；
（ｃ）溶媒の熱容量の低下；および
（ｄ）重合体溶液に衝突する有機溶液のマイクロドリップの「爆発」効果の開始（空洞化）。
【００６８】
因子（ａ）〜（ｄ）は、水−重合体溶液からの有機溶媒の迅速かつ完全な除去を促進する。因子（ｄ）は、有機溶液のマイクロドリップのさらに完全な分割を促進する。
【００６９】
この溶液内で高い剪断および乱流を作り出すために、また、逆チューブ２０を経由して第二容器１４から第一容器１２に入る溶液を（この担体中）に分散するために、ナノ分散機２２は、第一容器１２内に位置付けられる。ナノ分散機２２は、第一容器１２にある重合体溶液１６内で、ナノサイズ親油性粒子を作り出す。ナノ分散機２２はまた、通例、ディスパーゲターまたはホモジナイザーとも呼ばれている。真空ポンプ２６に連結された第一冷却器２４は、第一容器１２に伸長している。第二容器１４には、第二冷却器２８が連結されている。第一および第二冷却器２４、２８を制御し、そして該第一容器１２と該第二容器１４との間の溶液および蒸気の流れを調節するために、この化学反応器上の種々の一には、タップ３０Ａ、３０Ｂおよび３０Ｃが設けられている。
【００７０】
第一容器１２の下には、その中の溶液１６を加熱するために、電気ヒーター３２が位置付けられている。第一容器１２は、その担体の沸点より高いが重合体溶液１６の沸点より低い温度まで加熱される。第一容器１２内の溶液１６の温度を制御してモニターするために、第一容器１２には、電気温度計３４が伸長している。第二容器１４の下には、この親油性化合物を加熱してそれを第二容器１４内の担体溶媒と混合するために、磁気ミキサーおよびヒーター３６が位置付けられている。
【００７１】
この加熱の結果として、第二容器１２内の非水性溶媒（担体）の蒸気は、蒸気パイプ３８を通って上昇し、第二容器１４に入り、その中で凝縮する。第二容器１４では、この活性化合物は、この非水性溶媒にゆっくりと溶解し、得られた親油性溶液は、逆チューブ２０を経由して、第一容器１２に還流する。逆チューブ２０の開口部４０は、この親油性溶液がナノ分散機２２に近い領域（これは、「作用ゾーン」または「反応ゾーン」と呼ばれている）にある第一容器１２に入ってＲｅ＞１０，０００のレイノルズ数の乱流を有するような様式で、配列されている。このレイノルズ数は、流体流れの滑らかさの測定値である。高いレイノルズ数は、その流れが乱流であることを意味しているのに対して、低いレイノルズ数は、その流れが層流であることを意味している。この乳濁液または懸濁液は、ここで形成される。この作用ゾーンでは、このナノ分散機は、１分間あたり約１０，０００以上の回転数範囲で作動する。
【００７２】
スクリーン４４は、この乱流がその液相の上にある第一容器１２の空隙４６に入るのを阻止する。このプロセスは、活性化合物全体が重合体溶液１６に移るまで、継続される。この非水溶媒は、容器１２、１４の両方から、クーラー４８を経由して、凝縮液容器５０へと除去される。この非水溶媒の除去は、「Ｃ」の文字で表示される矢印により、図示されている。第一容器１２内の残りの非水溶媒は、真空ポンプ２６の助けを借りて、除去される。その結果、包接複合体内で親水性重合体に包まれた水不溶性親油性化合物の均一なナノサイズ分散体が得られる。
【００７３】
所定の反応系レジメンに対して先に決定したプロトコルに依存して、その回転速度をゼロに減速しつつ、同時に、その温度は、次いで、室温まで低下される。
【００７４】
本発明の代表的な実施態様では、マクロライド薬剤であるエリスロマイシンおよびクラリスロマイシンのナノサイズ可溶粒子は、本発明に従って、包接複合体として調製され、本明細書中で、実施例にて、さらに詳細に記述されている。しかしながら、本発明は、エリスロマイシンおよびクラリスロマイシンのナノサイズ可溶粒子の形成には限定されない。他の種類の医薬品および薬剤は、本発明で考慮され、例えば、以下がある：鎮痛薬、抗炎症薬、駆虫薬、抗狭心薬、抗不整脈薬、抗生物質（ペニシリン系抗生物質を含めて）、抗凝血薬、抗うつ薬、抗糖尿病薬、抗てんかん薬、抗性腺刺激ホルモン薬、抗ヒスタミン剤、降圧薬、抗ムスカリン薬、抗放線菌薬、抗悪性腫瘍薬、免疫抑制薬、抗甲状腺薬、抗ウイルス薬、抗悪性腫瘍薬および化学療法薬、抗不安鎮静薬（催眠薬および神経遮断薬）、収斂薬、βアドレナリンレセプタ遮断薬、血液産物および代替物、心臓変力薬（ｃａｒｄｉａｃｉｎｏｔｒｏｐｉｃ ａｇｅｎｔ）、造影剤、コルチコステロイド、咳止め薬（去痰薬およびムコ溶解薬）、診断薬、画像診断薬、利尿薬、ドーパミン作動薬（抗パーキンソン病薬）、止血薬、免疫抑制性環状オリゴペプチド、免疫薬、脂質調節薬、筋肉弛緩薬、副交感神経作動薬、副甲状腺カルシトニンおよびビホスホネート、プロスタグランジン、放射性医薬品、性ホルモン（ステロイドを含めて）、抗アレルギー薬、刺激薬および食欲抑制薬、交感神経模倣薬、甲状腺薬、血管拡張薬およびキサンチン。好ましい薬剤物質には、経口投与、静脈投与、粘膜投与および肺投与向けのものが挙げられる。これらの種類の薬剤の説明および各種類の入る種のリストは、Ｍａｒｔｉｎｄａｌｅ，Ｔｈｅ Ｅｘｔｒａ Ｐｈａｒｍａｃｏｐｏｅｉａ，Ｔｗｅｎｔｙ−Ｎｉｎｔｈ Ｅｄｉｔｉｏｎ，Ｔｈｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｐｒｅｓｓ，Ｌｏｎｄｏｎ，１９８９で見られる。
【００７５】
本発明は、人体で使用することに関連して記述されているものの、本発明は、この点には限定されず、包接複合体は、本発明に従って、獣医学用の医薬品および他の製品でも使用するように使用できる。
【実施例】
【００７６】
（実施例１、包接複合体を生成する実験手順）
Ａ．重合体溶液の調製
蒸留水５００ｍｌを、蒸留水容器５２から重合体容器５４へと移す。重合体容器５４には、推定量の重合体を加え、これを、親油性化合物との包接複合体を作成するために選択した。２０〜２５℃の温度で、重合体容器５４の内容物を、３０〜６０分^−１（回転／分）の速度で、その重合体が完全に溶解して透明または不透明な溶液が形成されるまで、混合する。
【００７７】
Ｂ．反応器での化合物の装填
重合体容器５４で調製した重合体溶液を、ポンプ４２により、第一容器１２に移す。同じ容器にて、その担体溶媒を装填する。第二容器１４には、親油性化合物を入れる。
【００７８】
Ｃ．反応器の開始
ナノ分散機２２を、５００〜８００分^−１の速度で起動する。第一および第二冷却器２４および２８に、冷却水を入れる。担体溶媒の沸点より５〜１０℃高い温度となるように、ヒーター（サーモスタット）３２を起動する。５〜１０分^−１の速度で、磁気ミキサー３６を起動する。
【００７９】
Ｄ．複合体の合成
指定温度に達した後、この担体溶媒は、第一容器１２から蒸発し始める。その蒸気は、蒸気管３８を通って、第二容器１４に達する。この瞬間、ナノ分散機２２を、８，０００〜１０，０００分^−１の速度に加速する。次いで、活性化合物の担体溶媒溶液を、第二容器１４から、逆チューブ２０を通って、第一容器１２へと移動させる。この溶液は、開口部４０を通って出ていき、ナノ分散機２２の活動が最も活発なゾーンに達する。ヒーター３２の温度を、さらに５〜１０℃上げ、この担体溶媒中の活性化合物の濃度を０．０２〜０．１％の範囲内にとどめる。このプロセスは、全ての親油性化合物が第二容器１４から第一容器１２へと通るまで、続ける。
【００８０】
Ｅ．担体溶媒の除去
このナノ分散機の速度を、２００〜３００分^−１まで下げた。第一容器１２を冷却器４８および凝縮容器５０と連結する導管にあるタップ３０Ａを開く。この担体溶媒を留去して、容器５０を凝縮する。その溶媒が移った後、タップ３０Ａを、クーラー２８にあるタップ３０Ｂと共に閉じる。次いで、タップ３０Ｃ（これは、第一容器１２を真空ポンプ２６と連結する導管に位置している）を開く。次いで、ヒーター３２の温度を３０〜３５℃まで下げ、真空ポンプ２６を起動して、この溶媒の残遺物を１〜２時間で脱気する。次いで、真空ポンプ２６を止め、全てのタップ３０Ａ、３０Ｂおよび３０Ｃを開き、このナノ分散機の速度を３０〜６０分^−１に下げる。
【００８１】
Ｆ．実験の完了
この包接複合体の溶液を第一容器１２から取り出し、分析した。その結果を、表１に示す。
【００８２】
表１−水相、重合体、活性化合物、処理温度（これは、選択したナノ乳濁液およびナノ懸濁液を調製するのに使用される）、およびそれらの安定性（処方前レベル−これは、時間長（日）によって決定される）の組合せ
【００８３】
【表１】

（実施例２、多糖類の修飾）
種々の量で多糖類を有する蒸留水を容器に入れた。その後、混合時に指定したｐＨ２に達するまで、クエン酸を加えた。Ｘ１は、水中の多糖類の量を意味し、Ｘ２は、多糖類水溶液のｐＨ値を意味する。
【００８４】
得られた懸濁液を、均一な不透明塊が得られるまで、７０〜９５℃まで、室温で連続的に混合しつつ、約１０〜２０分間加熱する。得られた塊を、時間Ｘ３で、オートクレーブに入れ、そしてオートクレーブ中にて、１６０〜１８０℃の温度に晒す。これらの条件下にて、多糖類のネットワーク構造は、部分的または完全に、直鎖で弱く分枝した高分子に変換し、これを、水に溶解する。このオートクレーブ時間が終了すると、１００℃未満の冷却が起こり、重合体の溶液が得られる。ポリエチレングリコール−４００（ＰＥＧ−４００）の溶液を、量Ｘ４（多糖類との％関係）を加える。得られた混合物をオートクレーブに入れ、そして時間Ｘ５の間に、１６０〜１８０℃の温度まで加熱する。このオートクレーブ時間が終わると、１００℃未満の冷却を行い、修飾された重合体を得る。その溶液の濁度および粘度を測定した。観察されたデータを表２で示す。
【００８５】
表２−ジャガイモデンプンをベースにした修飾デンプン
【００８６】
【表２】

（実施例３、修飾多糖類に包まれた可溶ナノ粒子の作成（重量部））
蒸留水中にて、多糖類を溶解し、最初に、１６０〜１８０℃で、分子量（５〜１０）×１０（４）で加熱し、そしてポリエチレングリコールＰＥＧ−４００により修飾した。修飾条件：比率２：１〜４：１の「多糖類−ポリエチレングリコールＰＥＧ−４００」比、クエン酸で作り出されるｐＨ２〜５の酸性環境、１６０〜１８０℃の温度、６０〜１８０分間の修飾時間。修飾多糖類の溶液を反応容器に入れ、１０，０００以上の回転／分の速度でホモジナイザーにより混合しつつ、６０℃まで加熱する。
【００８７】
同時に、マクロライドの有機溶媒溶液を調製する。この多糖類溶液を所定温度６０℃に到達させると、次いで、約１ｍｌ／秒の速度で、マクロライドの溶液を加え始める。ホモジナイザーの速度を１００００回転／分以上に上げる。このマクロライドは、この重合体と相互作用して、ナノ粒子を形成し、その有機溶媒を蒸発させる。この有機溶媒を、直接冷却器にて、凝縮させる。全てのマクロライドが重合体との相互作用に入って包接複合体「マクロライド−重合体」として可溶化した後、この有機溶媒を、連続混合しつつ、減圧蒸発させ、その複合体の溶液を３０〜３５℃まで冷却した。
【００８８】
冷却した溶液の濁度（表３）および粘度を測定する。結晶相の存在およびその複合体の粒径を測定した。
【００８９】
表３−クラリスロマイシンとの複合体
【００９０】
【表３】

安定な濁度＝安定なナノ分散体。
【００９１】
（実施例４、ナノ粒子複合体でクラリスロマイシンを使うインビトロ微生物結果）
種々の濃度で実施例５にて調製した複合体化クラリスロマイシンの微生物活性を試験し、そして同じ濃度の非複合体化クラリスロマイシンと直接比較した。使用した試験方法は、一般に認められた寒天充填ペトリ皿試験の方法であった。使用した試験微生物は、Ｍｉｃｒｏｃｏｃｃｏｕｓ ｌｕｔｅｕｓであり、これは、マクロライド抗生物質に感受性である。小さい濾紙を切断した円板に、特定溶液濃度の試験抗生物質を含浸した。静菌活性ゾーンの直径を、時間に対して測定した。コントロールおよび複合体化試験物質の両方に対する濃度は、著しく変わり、適用の２１６時間後まで観察した。これらの結果を図２で図示する。
【００９２】
この試験から、さらに、複合体化クラリスロマイシンが、その量（濃度）の１／１０を使用して、市販のクラリスロマイシンと同じ微生物活性を有することが立証された。さらに、同じ薬剤濃度について、このクラリスロマイシンの微生物活性は、約４８時間で消えたのに対して、複合体化クラリスロマイシンの微生物活性は、現在の測定の約２１６時間まで有意に持続し、本発明者は、測定を継続している。異なる桁の濃度差を有する複合体化クラリスロマイシンの微生物活性の差は、クラリスロマイシンだけで認められる対応した差よりも非常に大きいこともまた、認められた。
【００９３】
（実施例５、クラリスロマイシン包接複合体を使うインビボ研究）
ラットに、胃管栄養法により、１５０ｍｇ／ｋｇで、本発明によるナノ粒子複合体で、クラリスロマイシンを与えた。頸静脈カテーテルを介して、時間間隔を置いて、血液試料を集めた。
【００９４】
０時間の値は、各動物に対するコントロールベースラインであった。ナノ粒子複合体でのクラリスロマイシンの経口投与に続いて、その薬剤が、投与の４時間後に、その最大血漿値に達したことを確認した。最初の吸収段階は、１時間まで急速であり、最大で４時間継続した。そのクリアランスは、市販のクラリスロマイシンを使った公開データと比較して、著しく遅かった。その循環半減期は、２時間の範囲であった。本発明によるクラリスロマイシン複合体のＡｒｅａ Ｕｎｄｅｒ ｔｈｅ Ｃｕｒｖｅ（ＡＵＣ_{０〜２４時間}）は、ラットにおける同用量の市販クラリスロマイシンを使った公開データ（同じ１５０ｍｇ／ｋｇの経口投薬量で、ＡＵＣ_{０〜２４時間}＝３２．５４ｍｉｃｒｏｇ^＊ｈ／ｍｌ）と比較して、著しく高い５４．２ｍｉｃｒｏｇ^＊ｈ／ｍｌであった。それゆえ、以下のことが考えられる：本発明による複合体化クラリスロマイシンは、経口投与に続いて、高い生体利用能または腸での遅延放出を示す。
【００９５】
このクラリスロマイシン複合体は、ＩＶ巨丸剤投与に続いて、市販薬剤と比較して、同じ範囲の循環半減期、すなわち、２時間を示した。それは、経口投与後に著しく高いＡＵＣを有し、生体利用能向上または徐放特性という仮定を裏付けている。
【００９６】
ナノ粒子複合体中の試験クラリスロマイシンの薬物動態定数の市販クラリスロマイシン公開データとの比較は、図３で図示している。ナノ粒子複合体中のクラリスロマイシンのＰＫ定数は、市販クラリスロマイシンの公開研究と比較され、図４で示される。
【００９７】
（実施例６、ナノ粒子複合体中のクラリスロマイシンおよびエリスロマイシンの物理的測定値および特性）
１．粒径および分布
水溶液中のエリスロマイシンまたはクラリスロマイシン＋重合体の複合体ついて、本発明の技術により、非常に均一な粒径分布で、制御可能なナノ粒径（これは、１ナノメートルから１０００ｎｍまでの範囲である）を有する薬剤−重合体分散体の作成が可能となることが明らかとなった。
【００９８】
本発明の方法に従って調製したクラリスロマイシンの複合体は、５週間後、同じ分散スペクトルを示した。図５は、約１９０ｎｍのサイズを有する複合体化クラリスロマイシン粒子を図示している。エリスロマイシンおよびクラリスロマイシン複合体のサイズ測定は、「ＡＬＶ−Ｐａｒｔｉｃｌｅ Ｓｉｚｅｒ」（これは、３〜３０００ｎｍの解像度を有する）を使用して、実施した。図６は、ＳＥＭ顕微鏡写真であり、これは、本発明の方法に従って調製された一貫した球形の複合体化クラリスロマイシン粒子を図示している。
【００９９】
２．溶解性
エリスロマイシン（水に事実上不溶な抗生物質）を、分散相での粒子の制御可能な粒径分布で、熱力学的に安定なナノ分散体に再処方した。得られた新規処方物は、８％（ｗ／ｖ）活性薬剤を有し、これは、最初の薬剤の水溶解度（０．２％）よりも４０倍高かった。さらに、薬剤粒子は、非常に均一なサイズの複合体（９５％以上）で、得られた。このエリスロマイシンは、生理的条件下にて、十分な濃度で、この包接複合体から放出された。既存の可溶化技術（例えば、界面活性剤、リポソーム、カプセル化など）を使用しなかった。エリスロマイシン単独およびクラリスロマイシン単独と本発明の包接複合体の一部としてのエリスロマイシンおよびクラリスロマイシンとの比較は、図７で図示している。
【０１００】
３．安定性
相分離が起こらないことと粒径および粒径分布の維持とについて、包接複合体の透明水溶液の観察を行った。以下の所見および結果が得られた：
（ａ）７５日間にわたって、再処方した８％エリスロマイシンの試験により、相分離がないことと、粒径および粒径分布の維持が明らかとなった。
【０１０１】
（ｂ）本発明による複合体化クラリスロマイシンの安定性は、室温で１２週間および３５℃で４週間観察したところ、それらは、安定であることが分かった。
【０１０２】
（ｃ）複合体化クラリスロマイシンを凍結乾燥し、引き続いて、再水和しても、その薬剤−重合体複合体の粒径が保持されていた。３０日以上にわたって、凝集がなく、このナノ分散体は、安定であった。
【０１０３】
４．Ｘ線回折結果および特性
Ｘ線回折測定から、この結晶性薬剤エリスロマイシンをナノ分散体に再処方することに伴って、それが非晶質形状物質に変換されることが分かった。
【０１０４】
図８および９は、本発明によるエリスロマイシンおよびクラリスロマイシンの包接複合体とそれぞれ比べたインタクトなエリスロマイシンおよびインタクトなクラリスロマイシンのＸ線回折比較を図示している。
【０１０５】
エリスロマイシン（図８）およびクラリスロマイシン（図９）の既知スペクトルと本発明の包接複合体との比較を行った。乾燥粉末としてのエリスロマイシン（図８）の既知スペクトルは、明確な結晶パターンを示した。
【０１０６】
対照的に、このエリスロマイシン包接複合体（図８）は、結晶性エリスロマイシンに由来のピークの大部分が存在せず、残っている少数のピークは高さが大幅に低くなったことを示している。このスペクトルは、既知エリスロマイシンのものと関連していることは疑う余地はないが、しかしながら、複合体化後に、別の「形状」が存在していることを暗示している。
【０１０７】
複合体化エリスロマイシンおよびクラリスロマイシンの両方のスペクトルにおける平均散乱角を観察すると、明らかに、特定のピークが「平坦になった」ことが分かり得、このことは、事実上、ベースラインピークが広がったことを示している。この現象は、非晶質状態を暗示している。
【０１０８】
これらの結果から、本発明の技術を使用するエリスロマイシンおよびクラリスロマイシンの複合体化により、ファンデルワールス力および水素結合に基づいた包接重合体内に薬剤が固定化されることが原因で、その結晶格子を形成し得ないので、非複合体化薬剤の結晶度を低くすることが明らかである。この非晶質状態は、実際に生体利用能を高め得るので、薬剤送達に好ましいことが知られている。
【０１０９】
図１０のＸ線スペクトルは、市販のクラリスロマイシン（上部トレース）と比較した６ヶ月のクラリスロマイシン複合体化試料（下部トレース）を描写している。この特定の複合体化試料は、図９で見えるものおよび実施例６で述べた微生物試験で見えるものと同じである。このことは、本発明による独特の複合体化薬剤抱合体（これは、著しく安定化した非晶質状態を示す）を調製する技術的な性能を確証している。
【０１１０】
本発明者は、この包接複合体内の非晶質または部分非晶質の薬剤状態をこのように安定化することにより、文献で実証されているように、より高い生体利用能の機会が高められ得ると考えている。本発明の方法および装置を使用して達成された他のパラメータ（例えば、非常に正確なサイズ制御）と一緒に考えると、この方法は、それ自体、著しく高めた生体利用能に簡単に適合する。
【０１１１】
（実施例７、エリスロマイシン包接複合体からの徐放）
これらの薬物の再処方は、特定の速度およびパターンで薬剤を送達する徐放系を達成する新しい手段に相当している。この包接複合体からのエリスロマイシンの実験的な徐放パターンを調べるために、透析方法を実行した。この方法では、それらの薬剤−重合体ナノ分散体を透析膜バッグ内に入れた。このような膜により、それらのナノ分散体を維持しつつ、３０００Ｄａ未満のサイズの分子およびイオンだけを拡散することが可能となる。透析は、室温で、絶えず攪拌しつつ、２４時間実施した。薬剤放出を分析するために、その外部緩衝液から、試料を定期的に取り出した。この包接複合体から放出されたエリスロマイシンの濃度を、そのＯ．Ｄ．（光学密度）を測定することにより、検出した。２４時間インキュベーションした後、外部流体中のエリスロマイシンの濃度は、この包接複合体中の初期エリスロマイシン濃度の２５％であった（初期濃度は、４ｍｇ／ｍｌ（８％ｗ／ｖ）である）。放出された濃度はまた、血清モデル化した溶液でのエリスロマイシンの最大溶解度を反映している。それゆえ、この結果は、このナノ分散体がエリスロマイシンの放出を持続する性能を有することを示している。
【０１１２】
（実施例８、インビトロヒト細胞適合性研究）
新たなドナーのＷＢＣから赤血球を分離し、そして等張性緩衝液に懸濁した。水および溶解緩衝液中にて、処理する赤血球を指定緩衝液に懸濁した。１ｍｌの全容量で、振盪（４０ｒｐｍ）しつつ、３７℃で、溶血反応を実行した。４時間で、２５０μｌのアリコートを除去し、１８時間でその残りを集めた。アリコートを、２５０ｇで、５分間遠心分離し、上澄み液を５４０ｎｍで読み取った。この試験の結果から、複合体化クラリスロマイシンがヒト血液と相溶性であることが分かった。
【０１１３】
（実施例９、ナノ可溶粒子での懸濁重合）
図１で図示した本発明の化学反応器を使用して、カプロラクタムをエチルエーテルに溶解した。アミロースを、１０％のアミド化度まで尿素で修飾し、その後、修飾アミロース溶液を調製した。この重合体溶液を第一容器１２に移し、このカプロラクタム溶液を第二容器１４に移した。ナノ分散機２２およびヒーター３２を起動した。ヒーター（サーモスタット）３２を、５０〜５５℃に起動した。次いで、カプロラクタム溶液を、第二容器１４から、逆チューブ２０を通って、第一容器１２に移した。逆チューブ２０を通って全ての逆カプロラクタム溶液を給送した後、その反応混合物の温度を２５〜３５℃に下げて、この反応器から蒸発させた。
【０１１４】
ポリカプロラクタム（ナイロン−６，６）の重合時にて、得られた「溶液」を、真空カラムにて、２６０〜２８０℃の温度で噴霧した。その糸の下部から、（均一な粒径で）細かい均一な粉末として、重合体を取り出した。重合体の分子量は、粘度法で決定した。それらの結果を、表４に示す。
【０１１５】
表４
【０１１６】
【表４】

（均等論）
それゆえ、本発明の基本的な新規特徴は、その好ましい実施態様に適用されるように、示され、記述され、そして指摘されているものの、開示した発明の形態または詳細で、種々の省略および置換および変更が、本発明の精神から逸脱することなく、当業者によりなされ得ることが分かる。従って、本発明は、本明細書に添付の特許請求の範囲によってのみ限定されることが、意図される。
【０１１７】
図面は、必ずしも同一縮尺では描かれておらず、単に、概念的なものにすぎないことが理解できるはずである。
【図面の簡単な説明】
【０１１８】
【図１】図１は、本発明に従ってナノサイズ可溶粒子を製造する化学反応器の概略図である。
【図２】図２は、適用の２１６時間後までに観察されたコントロールと複合体化クラリスロマイシン試験物質の濃度を図示している。
【図３】図３は、ナノ粒子複合体中の試験クラリスロマイシンの薬物動態定数と市販クラリスロマイシンの公開データとを比較しているチャートである。
【図４】図４は、ナノ粒子複合体中のクラリスロマイシンのＰＫ定数と市販クラリスロマイシンを使った公開研究とを比較しているチャートである。
【図５】図５は、約１９０ｎｍのサイズを有する複合体化クラリスロマイシン粒子を図示している。
【図６】図６は、ＳＥＭ顕微鏡写真であり、これは、本発明の方法に従って調製された一貫した球形の複合体化クラリスロマイシン粒子を図示している。
【図７】図７は、エリスロマイシンおよびクラリスロマイシン単独と本発明の包接複合体の一部としてのエリスロマイシンおよびクラリスロマイシンとの溶解度の比較を図示している。
【図８】図８は、本発明によるエリスロマイシンの包接複合体とそれぞれ比べたインタクトなエリスロマイシンのＸ線回折比較を図示している。
【図９】図９は、本発明によるクラリスロマイシンの包接複合体とそれぞれ比べたインタクトなクラリスロマイシンのＸ線回折比較を図示している。
【図１０】図１０は、市販のクラリスロマイシン（上部トレース）と比較した６月齢のクラリスロマイシン複合体化試料（下部トレース）のＸ線スペクトルである。【Technical field】
[0001]
(Field of Invention)
The present invention is in the field of nanoparticles. More particularly, the present invention relates to methods for producing soluble nano-sized particles (“soluble nanoparticles”) and soluble nanoparticles, which solubilize insoluble compounds in a non-soluble medium.
[Background]
[0002]
(Background of the Invention)
Two overwhelming obstacles in effective drug delivery and hence treatment of disease are solubility and stability. In order to be absorbed by the body, the compound must be soluble in both water and fat (lipid). However, water solubility is often associated with poor fat solubility and vice versa.
[0003]
More than one third of the drugs described in the US Pharmacopoeia and about 50% of the new chemical element (NCE) are water insoluble or poorly water soluble. More than 40% of drug molecules and drug compounds are insoluble in the body. Despite this, lipophilic drug substances with low water solubility are drugs in growing fields with increasing applications in various therapeutic areas and in various pathologies. Today, over 2500 large molecules are in various stages of development, and over 5500 small molecules are under development (see Drug Delivery Companies Report 2001, p. 2, www.pharmaventures.com). Each of the existing companies that focus on these large and small molecules have their own limitations and restrictions with respect to both the large and small molecules of interest.
[0004]
Solubility and stability issues are major prescription barriers that hinder the development of therapeutics. Water solubility is an essential but often difficult property to formulate complex organic structures found in pharmaceuticals. Traditional formulation systems for highly insoluble drugs involved a combination of organic solvents, surfactants and extreme pH conditions. These formulations are often irritating to the patient and can cause adverse responses. Sometimes these methods are insufficient to sufficiently solubilize a certain amount of drug for parenteral formulation. In such cases, the physician may administer an “overdose”, for example, for poorly soluble vitamins. In most cases, this overdose is not harmful because the unabsorbed amount is excreted out of the body with the urine. However, overdose wastes a large amount of active compound.
[0005]
The size of these drug molecules also plays a major role in bioavailability as well as their solubility and stability. Bioavailability means the extent to which a drug becomes available to a target tissue or any alternative in vivo target (ie, receptor, tumor, etc.) after administration into the body. Poor bioavailability is a major problem encountered in developing pharmaceutical compositions, particularly those containing active ingredients that are poorly water soluble. Drugs with poor water solubility tend to be excreted from the digestive tract before being absorbed into the blood circulation. It is known that the dissolution rate of a particulate drug can be increased with increasing surface area (ie, decreasing particle size).
[0006]
Recently, there has been a surge in interest in nanotechnology, ie nanoscale operation. Nanotechnology is not a whole new field; colloidal sols and platinum-supported catalysts are nanoparticles. Nevertheless, recent interest in the nanoscale is particularly directed to materials used for drug delivery. Nanoparticles are generally considered to be solids whose diameter varies between 1-1000 nm.
[0007]
Although many solubilization techniques exist (eg, liposomes, cyclodextrins, microencapsulation and dendrimers), each of these techniques has many significant drawbacks.
[0008]
Phospholipids exposed to an aqueous environment form a bilayer structure called liposomes. Liposomes are microscopic spherical structures composed of phospholipids, which were first discovered in the early 1960s (Bangham et al., J. Mol. Biol. 13: 238 (1965)). In aqueous media, phospholipid molecules are amphiphilic, but spontaneously constitute self-closed bilayers as a result of hydrophilic and hydrophobic interactions. The resulting vesicles, called liposomes, are therefore encapsulated inside the aqueous medium in which they are suspended, making them a potential carrier for bioactive hydrophilic molecules and drugs in vivo. There is a nature. Lipophilic drugs can also be transported and embedded in liposome membranes. Liposomes are similar to biological membranes and have been used as a means to solubilize water-insoluble bioactive molecules for many years. They are non-toxic and biodegradable and can be used for specific target organs.
[0009]
Liposome technology makes it possible to prepare small to large vesicles using unilamellar (ULV) and multilamellar (MLV) vesicles. The MLV is generated by mechanical stirring. Large ULVs are prepared from MLVs by extruding under pressure through membranes of known pore size. These sizes are usually less than 200 nm in diameter, but liposomes can be custom designed for almost any requirement by changing lipid content, surface charge and preparation method.
[0010]
Numerous companies (eg, Elan, Corp., Dublin, Ireland; Endorex Corp., Lake Forest, IL; Subsidiary); and Michelle AG, Buchs, Switzerland) provide contract research and manufacturing facilities for the industry to prepare liposome inclusion complexes or inclusion moieties.
[0011]
Liposomes have several potential advantages as drug carriers, including the ability to carry significant amounts of drug, relatively easy to prepare, and low toxicity when using natural lipids. Can be mentioned. However, common problems encountered with liposomes include: low stability, short lifetime, poor tissue specificity, and toxicity associated with unnatural lipids. In addition, uptake by phagocytic cells shortens the circulation time. Furthermore, preparing liposome formulations with a narrow size distribution is not only a considerable challenge, but also expensive under the required conditions. Also, membranes are often clogged during mass production required for pharmaceutical manufacture of specific drugs.
[0012]
Cyclodextrins are crystalline, water-soluble, cyclic non-reducing oligosaccharides that contain 6, 7 or 8 glycopyranose units (which are α cyclodextrin, β cyclodextrin and γ cyclodextrin, respectively. It has long been known as a product that can be formed into an inclusion complex. The structure of cyclodextrin results in a molecule shaped like a segment of a hollow cone, which has an external hydrophilic surface and an internal hydrophilic cavity.
[0013]
The hydrophilic surface creates good water solubility for cyclodextrins and the hydrophobic cavity provides a favorable environment for trapping, encapsulating or entrap the drug molecule. This association allows the drug to be isolated from the aqueous solvent, thereby increasing the water solubility and stability of the drug. Over time, most cyclodextrins have not been more than scientific interest due to limited availability and high cost.
[0014]
As a result of in-depth research and advances in enzyme technology, cyclodextrins and their chemically modified derivatives are now commercially available, creating a new technology of packaging at the molecular level. For the development and production of cyclodextrins, Cyclolab Ltd. , Budapest, Hungary; Cydex, Inc. , Overland Park, Kansas; and Cyclops, Inc. , Companies such as Reykjavik, Iceland are involved.
[0015]
However, cyclodextrins have drawbacks. The ideal cyclodextrin shows both oral safety and systemic safety. It has a higher water solubility than the parent cyclodextrins retain or exceed their complexing properties. However, the disadvantages of cyclodextrins include the following: limited space available for incorporating active molecules into the core, lack of pure stability of the complex, and commercial availability. Limited and high price.
[0016]
Microencapsulation is active from the environment in which a very small parcel of gas, liquid or solid active ingredient (also referred to herein as used interchangeably with “core material”). A process that is packaged in a second material for the purpose of shielding the ingredients. These capsules range in size from 1 micron (thousandth of a millimeter) to about 7 millimeters, but later release their contents by means appropriate to the application.
[0017]
There are four typical mechanisms by which this core material is released from the microcapsules: (1) mechanical rupture of the capsule wall, (2) dissolution of the wall, (3) melting of the wall, and (4) Diffusion through. Less common release mechanisms include ablation (slow erosion of the shell) and biodegradation.
[0018]
Microencapsulation covers several techniques, in which case a specific substance is coated to obtain a micropackage of the active compound. This coating is performed to stabilize the material for taste masking, to prepare a free-flowing material for the otherwise packed drug, and for many other purposes. This technology has been successfully applied in the food additive industry and agriculture. However, the relatively high manufacturing costs of many of these formulations are a major drawback.
[0019]
In the case of nanoencapsulation and nanoparticles, which are advantageously spherical and are therefore nanospheres, the following two types of systems with different internal structures are possible:
a) a matrix-type system, which consists of entanglement of oligomeric or polymeric units and is defined as nanoparticles or nanospheres; and
b) A reservoir-type system, which consists of an oily core surrounded by a polymer wall and is defined as a nanocapsule.
[0020]
Depending on the nature of the materials used to prepare these nanospheres, the following classifications exist:
a) an amphiphilic polymer, which undergoes a crosslinking reaction during the preparation of the nanospheres;
b) a monomer, which polymerizes during the preparation of the nanoparticles;
c) a hydrophobic polymer, which is first dissolved in an organic solvent and then precipitated under controlled conditions to produce nanoparticles.
[0021]
Problems associated with the use of polymers in microencapsulation and nanoencapsulation include the following: use of toxic emulgators in emulsions or dispersions, high shear during the emulsification process Polymerization or application of force, poor biocompatibility and biodegradability, balance between hydrophilic and hydrophobic parts. These features result in insufficient drug release.
[0022]
Dendrimers are a type of polymer that is distinguished by their highly branched tree-like structure. They are synthesized in an iterative fashion from ABn monomers, each iteration adding a layer or “generation” to the growing polymer. Dendrimers up to 10 generations have been synthesized with molecular weights exceeding 106 kDa. One important feature of dendrimer polymers is their narrow molecular weight distribution. Indeed, depending on the synthetic strategy used, dendrimers with a molecular weight above 20 kDa can be produced as a single compound.
[0023]
Dendrimers, like liposomes, exhibit encapsulation properties; they can sequester molecules within the interior space. Because they are single molecules rather than aggregates, drug-dendrimer complexes are expected to be significantly more stable than liposomal drugs. Dendrimers are therefore regarded as one of the most promising vesicles for drug delivery systems. However, dendrimer technology is still in the research stage and it is estimated that it will take several years for the industry to adopt this technology as a safe and efficient drug delivery system.
DISCLOSURE OF THE INVENTION
[Problems to be solved by the invention]
[0024]
There is a need for a safe, biocompatible, stable and efficient drug delivery system that includes nano-sized particles of active ingredients for high bioavailability and overcomes problems inherent in the prior art .
[Means for Solving the Problems]
[0025]
(Summary of the Invention)
Nano-sized particles, ie lipophilic compounds and hydrophilic compounds solubilized in the form of “nanoparticles”, especially in pharmacology and not only in food additives, cosmetics and agricultural products, but also in pet food and veterinary products Can be used in the manufacture of
[0026]
The present invention provides nanoparticles and methods for producing soluble nanoparticles, particularly inclusion complexes of water-insoluble lipophilic materials and water-soluble hydrophilic organic materials. The present invention also provides an apparatus for producing these soluble nanoparticles using a novel manufacturing method.
[0027]
Soluble nanoparticles according to the present invention (referred to as “soluble nanoparticles”) are soluble amphiphiles that can form molecular complexes with lipophilic active compounds and hydrophilic active compounds or molecules (especially drugs and pharmaceuticals). A distinction is made by using polymers. Soluble nanoparticles formed according to the present invention render insoluble compounds soluble in water and readily bioavailable in the body.
[0028]
In accordance with the present invention, these soluble nanoparticles are composed of a polymer in which the active compound or molecule is encapsulated, immobilized or secured within the polymer. These soluble nanoparticles contain active compounds or molecules that are linked to the polymer by non-valent bonds and form polymer-active compounds as separate molecular elements. The outer surface of these soluble nanoparticles is composed of a polymer that carries drug molecules to the target destination. The complex can be nano-sized in size, and advantageously, the drug molecule itself does not change when encapsulated in the polymer. The soluble nanoparticles can remain stable for extended periods of time, can be manufactured at low cost, and can improve the overall bioavailability of the active compound.
[0029]
The polymers used in forming these complexes are from a group of amphiphilic polymers that exhibit a hydrophilic-lipophilic balance (HLB), and the total HLB of the complex is nanoemulsion or nanosuspension. It is selected so that it can be made water-soluble with a stable solution of a suspension. The amphiphilic polymer is selected using an algorithm that takes into account the molecular weight, size (three-dimensional), surface polarity and solubility in non-aqueous solvents of the lipophilic or hydrophilic compound. Unlike the prior art inclusion complex, the inclusion complex of the present invention is not limited in the size of the core compound that can be used. Conditions in the method of forming these nanosoluble particles are such that they do not cause disruption of the molecular composition of the core active lipophilic compound or hydrophilic compound or loss of its bioactivity or bioactivity. With respect to the method of preparing the inclusion complex of the present invention, the process temperature is always lower than the temperature at which the lipophilic compound loses its bioactivity or bioactivity or the temperature at which the hydrophilic compound changes its chemical composition.
[0030]
Depending on the polymer used in forming these soluble nanoparticles, drugs and pharmaceuticals as active compounds in the complex can easily and quickly reach specific areas within the body. The polymer and active compound selected also provide soluble nanoparticles that can be released at multiple levels, multiple steps and / or controlled within the body to release the drug or pharmaceutical agent.
[0031]
Significantly advantageous and unique features of the complex (inclusion complex or others) of the present invention are that during the formation of this inclusion complex no new bonds are formed and existing bonds are not destroyed. There is. In addition, the existing conditions during the addition of the active compound to the composite formulation ensure the formation of soluble nanoparticles. Furthermore, the components used in preparing this complex are inexpensive, abundant, non-toxic and safe for use in the surrounding environment.
[0032]
In another aspect of the present invention, a novel chemical reactor is provided that implements a method of forming these soluble nanoparticles in accordance with the present invention. The chemical reactor of the present invention provides a continuous circulation of the “carrier” between the polymer solution and the active compound during the production of the complex of the present invention. This ensures a high uniformity of the emulsion or suspension formed in this way. This chemical reactor design allows all of these processes to be performed in the same vessel, thereby ensuring high purity of the final product, simplifying the process, and reducing the effort required. decrease.
[0033]
The foregoing has outlined rather important features of the invention in order that the detailed description that follows may be better understood, and so that the contribution of the invention to the art may be better understood. Other objects and features of the present invention will become apparent from the following detailed description considered in conjunction with the accompanying drawings. These drawings, however, are designed for illustrative purposes only and are not intended to limit the invention, which is defined by the appended claims.
[0034]
The invention can be better understood with reference to the following drawings.
[0035]
(Detailed description of the invention)
The nanoparticles of the present invention comprise an insoluble or soluble active compound or core that is encapsulated in a moderately soluble amphiphilic polymer. A variety of different polymers can be used for any selected active (lipophilic or hydrophilic) compound. This polymer or group of polymers takes into account the various physical properties of both this active lipophilic or hydrophilic compound and the interaction of this compound within the resulting active compound / polymer nanosoluble particles. Selected according to algorithm.
[0036]
As used herein, the terms “lipophilic”, “lipophilic molecule” and “lipophilic compound” are used interchangeably and are all taken to refer to the same thing. Molecules and compounds referred to herein as lipophilic molecules and lipophilic compounds have a hydrophilic-lipophilic balance (HLB) of less than 6, and the HLB international scale (which ranges from 0 to 20) Get inside. Hydrophilic molecules have a hydrophilic-lipophilic balance (HLB) higher than 6. HLB is described in further detail herein below.
[0037]
More particularly, the components of the composition of the present invention contain an active (lipophilic or hydrophilic) compound (preferably lipophilic) and a polymer (which provides a molecular element). The lipophilic compound is any organic molecule or compound that is not required for water, preferably a drug or pharmaceutical composition. The lipophilic compounds can be small or large, single or complex, heavy or light, and contain various functional groups. The polymer used to make up this complex may be selected from the group of polymers that have been approved for use in humans (ie, biocompatible and FDA approved). Such polymers include, for example, but are not limited to: natural polysaccharides, polyacrylic acid and derivatives thereof, polyethyleneimine and derivatives thereof, polymethacrylic acid and derivatives thereof, polyethylene oxide and derivatives thereof. , Polyvinyl alcohol and derivatives thereof, polyacetylene derivatives, polyisoprene derivatives and polybutadiene derivatives.
[0038]
As listed, the polymer or group of polymers used in forming the nanosoluble particles of the present invention is not only the various physical properties of the active compound and polymer, but also the resulting complex. Selected according to an algorithm that takes into account their future interactions. This algorithm is thus utilized in such a way as to select the optimal polymer and to evaluate properties such as pH, ionic strength, temperature and various solvent parameters. More specifically, the amphiphilic polymer is selected using an algorithm that takes into account the molecular weight, dimensions (three-dimensional) and solubility in non-aqueous solvents of the lipophilic or hydrophilic compound. The algorithm also considers the following properties of the polymer itself when selecting the polymer for active molecule / polymer interactions during the formation of the complex: molecular weight, basic polymer chain length, motion Unit length, solubility of the polymer in water, overall solubility, degree of polymer chain mobility, hydrophilic-lipophilic balance, and polarity of the hydrophilic group of the polymer.
[0039]
The system includes a selected polymer, which is soluble in water and has a hydrophilic-lipophilic balance that ensures the solubility of a lipophilic compound or a complex containing a hydrophilic compound and a polymer ( HLB). The carrier is a non-aqueous solvent (or group of solvents) of a water-insoluble lipophilic compound or a water-soluble hydrophilic compound, which has a boiling temperature below the boiling point of water, more specifically (the complex formation process). Has a boiling point lower than the temperature at which the non-valent bonds that create the complex break down. The creation of this complex does not involve the formation of any valence bonds, which can change the properties or properties of the active compound. In the complex of the present invention, weak non-valent bonds (eg, H-bonds and van der Waals forces) are formed during the formation of the inclusion complex. Formation of non-valent bonds maintains the structure and properties of the lipophilic compound, which is particularly important when the active compound is a pharmaceutical. “Non-valent” as used herein is taken to refer to non-covalent, non-ionic and non-semipolar bonds and / or interactions.
[0040]
Following selection of this active compound, its properties necessary to create a geometric model are determined. A polymer is then selected that is suitable for complexing with a given compound. The main properties of this polymer include its HLB (hydrophilic-lipophilic balance), the length and mobility of the polymer chain, and the polar state of the hydrophilic group. The HLB of the polymer is selected in such a way that the combined HLB of the complex solubilizes the complex after it is combined with the active compound. At this stage, a geometric model of the complex is created and the length of polymer chain fragments required for the complex is determined. The HLB is calculated following construction of a virtual complex on the computer screen. For this purpose, existing computer programs for animation of molecular structures are used. The HLB can be calculated as the ratio of hydrophilic groups to lipophilic groups on the surface of this virtual complex. The molecular weight of this complex is easily calculated and its shape is determined. More precisely, the total HLB of the complex according to the invention can be calculated after virtually constructing the complex on the computer screen of a computer system in which the algorithm is loaded as software. The algorithm for determining the approximate HLB therefore plays an important role in the selection of the components from which the complex is formed. Parameters and library information related to the active compound and polymer molecules and polymer molecules are stored in a computer program that calculates the approximate HLB of the complex formed.
[0041]
This “amphiphilic polymer and active molecular weight” weight correlation is then determined. This determination is essential for the creation of this geometric model. This correlation is based on the total length of the polymer chain, the length of the fragment required to make the complex, the molecular weight of the active compound and the molecular weight of the fragment:
formula:
[0042]
[Expression 1]

here:
N _c -"Amphiphilic polymer to lipophilic compound" weight ratio.
[0043]
M _f The molecular weight of the polymer fragment.
[0044]
M _l The molecular weight of the lipophilic compound.
[0045]
M _p -Molecular weight of the polymer
N _f The amount of polymer fragments that can participate in complex formation.
[0046]
Next, the physical parameters of the aqueous solvent of the polymer are evaluated. At this stage, the determination of the pH needed to make this complex, the necessary ionic force and the necessary carrier for the lipophilic compound is made. Use of the above components provides optimum conditions for controlling the mobility of the polymer chain.
[0047]
A carrier non-aqueous solvent is then selected. The purpose of this solvent is to move the active compound to a very weak (low concentration) solution so that the molecules of the dissolved compound do not actually react with each other. This solution is then a chemical reactor to create a nanodispersion (eg, nanoemulsion (which has a liquid core material) or nanosuspension (which has a solid core material)). (This is described in detail below) and is delivered to the reaction zone.
[0048]
As used herein, the term “suspension” generally refers to a dispersion of particulates in a liquid.
[0049]
As used herein, the term “emulsion” means a mixture of two normally non-mixable liquids, one colloidally suspended in the other (which defines the dispersed phase). . The particle size of the dispersed phase in the emulsion is generally between a few hundred nanometers and a few tens of micrometers.
[0050]
Unlike known nano-sized particle preparation methods that use polymers to stabilize the dispersions formed, these dispersion stabilizations involve the amphiphilic polymer (which was calculated earlier). Only a part of (with a sex-lipophilic balance HLB) is used. Furthermore, due to the dynamic three-dimensional configuration of the amphiphilic polymer in this dispersion, specific conditions are selected, which do not act as a viscosity-imparting agent (ie, one that increases viscosity) It serves as the creator of the complex and the anchor of the core active compound. The previously calculated HLB provides the necessary solubilization for this active compound.
[0051]
The specific conditions for creating an amphiphilic polymer in this “nanodispersion” formation result in two elements: (1) free rotation of the motion segment of the polymer chain around its chemical bond ( Therefore, these segments are attached) and (2) non-valent interactions between the lipophilic functional group of the amphiphilic polymer and the hydrophilic group of the compound intended to solubilize That rule. These specific conditions include: the pH parameter of the dispersive medium, the ionic force of the dispersive medium, the component composition of the dispersive medium, the temperature of the composite formulation, the duration of the process and the mechanical elements of the process. Each of these specific conditions is described in further detail below.
[0052]
(PH parameter of dispersible medium)
If the composition of this amphiphilic polymer contains ionic functional groups, the polymer is higher than the isoelectric point (polyacid) or lower than the isoelectric point depending on the polarity of these groups (Polybase) Can be soluble at pH. In both of these cases, this isoelectric point can be determined with high accuracy for the "polymer solution viscosity-polymer solution pH" curve. These two polymers can precipitate only in the pH range where the solution is a viscous liquid in making the complex. For polymers with nonionic functional groups, there is no well-defined isoelectric point, and for this reason, these polymers can participate in making this complex over a wide pH range.
[0053]
(Ion power of dispersive media)
Under the influence of ions of the water-soluble salt in the polymer solution, the shape of the amphiphilic polymer changes. This factor is used to create stereospecific conditions for noncovalent interactions between the lipophilic group of the polymer and the lipophilic compound itself. Nevertheless, many polymers react very vigorously at the appearance of these salts (the “salting out” process of the polymer), so this factor is always used for complexation reactions. Is not possible.
[0054]
There is competition between these ions and the polymer for water molecules, and these ions acquire water from the hydrate shell of the polymer. As a result of the reduction of the hydrate shell, the polymer is wound around the globules. The higher the ionic activity, the more the polymer is wound around the small sphere.
[0055]
(Component composition of dispersible medium)
With the help of the solvent composition, it is possible to flexibly control the shape of these polymers. However, for the purpose of making pharmaceuticals, food additives and cosmetic compounds soluble (solubilized), biologically safe solvents such as glycerol, ethylene glycol, and less often ethyl alcohol, Only isobutanol and dimethyl sulfoxide) can be used. Adding a solvent reduces the water dissolution performance. This is similar to the addition of salt (ie, non-coiled polymer chains that convert to loose or dense globules). The options for this method are therefore limited.
[0056]
(Composite formation temperature)
As the temperature of the polymer solution changes, the hydration state of the polymer molecule, and hence its configuration in the solution, changes significantly. When the temperature is raised, the hydration shell surrounding the polymer molecule begins to desorb, and the linear polymer begins to take a small spherical shape. At the same time, the mobility of this polymer is increased. As a result, another positive condition for complex creation is created.
[0057]
(Process duration)
Due to the non-valent interactions in creating the inclusion, the limiting step in this process consists of the diffusion of these lipophilic compounds and macromolecules to each other, which for each reaction system Is present in a minimum time. If shorter times are allowed, the system remains two-phase. This two-phase nanodispersion is thermodynamically unstable. In the next step of evaporating the carrier, the dispersed phase particles are sized in the range of 1-1000 nm. The polymer molecules in the solution then cover and incorporate these active compounds, creating particles. The carrier is evaporated to form stable nanoparticles.
[0058]
(Mechanical elements of the process)
By means of mixers, dispersers, homogenizers and other equipment, the active compound is dispersed maximally in the water-polymer solution and the emulsion or suspension of nano-sized particles in the dispersed phase. Formation is accelerated. A novel chemical reactor advantageous for forming the nanoemulsion or nanosuspension of the present invention and nanosoluble particles is described in detail below.
[0059]
The combined effect of the above conditions is optimal during the complex formation for the specifically selected dimensions and proportions of this complex, the maximum dispersion of active compounds and the non-valent interactions between those compounds and the polymer. Help achieve the condition.
[0060]
As listed above, preparing this complex in accordance with the present invention requires performing a number of calculations and procedures prior to initiating the method of preparing the complex. Some calculations and procedures (which are determined using algorithms on a computer system) include the following steps:
(A) calculating the composition and properties of the components that prepare the complex, which contains the active compound, amphiphilic polymer and carrier solvent;
(B) calculating the weight ratio of the amphiphilic polymer to the active compound;
(C) evaluating the physical parameters of the aqueous solvent for the amphiphilic polymer;
(D) determining the correct non-aqueous solvent;
(E) creating a geometric model of the composite;
[0061]
This algorithm is not limited to these calculations, and can be programmed to add calculations and decisions as needed, depending on the nature and properties of the complex to be produced.
[0062]
As listed, the production of a molecular complex comprising the active compound of the present invention and an amphiphilic polymer requires that the active compound be dispersed to the nanoparticle size. These nano-sized particles guarantee an almost immediate interaction between the dispersed nano-sized particles of the active compound and the polymer molecules. In accordance with the method of the present invention and preventing back-aggregation (coacervation) of these nano-sized particles, ensuring an immediate interaction between the dispersed nano-sized particles of this active compound and the polymer molecule There is a need. This ensures the formation of an antenna complex (inclusion or otherwise). The size of this active compound is determined by creating its geometric model (considering the length of the bond and the angle between the bonds) and then converting the compound into a spherical or other geometric shape. Determined by The diameter of the sphere is the measurement size that determines the active compound. It is necessary to consider that a lipophilic substance having a long chain structure exhibits a shape having a small sphere structure in principle.
[0063]
In accordance with the present invention, during the process of forming this soluble nanosized particle or “soluble nanoparticle”, the polymer is added to an aqueous solvent (preferably water) in the first vessel of the chemical reactor. To form a polymer solution. In addition, components that adjust the pH and ionic force levels of the solution can be added as needed based on the parameters determined by the algorithms required to select the active compound and polymer. The second vessel of this chemical reactor contains the active compound, which is advantageously an insoluble lipophilic substance. The active compound (or core) can be of any size, dimension or weight and can contain any of a variety of functional groups. This non-aqueous solvent (or solvent mixture) solution of an insoluble lipophilic or hydrophilic compound is called a “carrier”. The rate at which the carrier is poured or added to the polymer solution is one or more adjustment taps (which ensure that the lipophilic solution added to the polymer solution has a concentration of less than 0.1%) It is adjusted by.
[0064]
This lipophilic solution is formed when the polymer solution is heated, and the vapor from the heated polymer solution condenses and dissolves the lipophilic material present in the second container. The lipophilic solution (in the carrier) is then mixed with the polymer solution to form a dispersed phase in the emulsion or suspension. Within the chemical reactor, the emulsion is fed into a turbulent region caused by a disperser (more precisely, a nanodisperser), which is contained within the emulsion or suspension. Cause the formation of nano-sized lipophilic molecules. This turbulent region is called the “action zone” or “interaction zone”. The emulsion or suspension delivered to this turbulent region has a Reynolds number of Re> 10,000. This emulsion is therefore a “nanoemulsion” or “nanosuspension” having particles in the range of about 1 to about 1000 nm. This particle production can also be extended to include small micron sized particles. Within the nanoemulsion or nanosuspension is a dispersion medium (which consists of the polymer solution) and a dispersed phase (which contains the lipophilic carrier solution). ing. However, this two-phase nanoemulsion or nanosuspension is unstable. Evaporating the carrier leaves dispersed phase particles in the size range of about 1 to about 1000 nanometers. The polymer molecules in the polymer solution then surround or enclose the active compound remaining in the dispersed phase particles after evaporation of the carrier, and more suitably encapsulate, so that in the inclusion complex. To form a uniform nano-sized dispersion of a water-insoluble lipophilic compound encased by a hydrophilic polymer. The remaining carrier is then degassed by vapor deposition or other suitable drying technique (eg lyophilization, vacuum distillation). As a result of the algorithm used to select the optimal active compound and polymer for formation of this emulsion or suspension and the resulting complex, generally, after evaporation of the carrier, the free polymer is Does not remain. Following evaporation of the carrier, the stable inclusion complex is composed of amorphous and / or partially crystallized or crystallized active elements. It is known to those skilled in the art that this amorphous state is preferred for drug delivery as it can actually increase bioavailability.
[0065]
In an advantageous and preferred embodiment of the invention, the polymer molecules in the polymer solution are non-valent interactions between the polymer and the active compound (eg electrostatic forces, van der Waals forces, hydrogen bonds). Thereby "wrapping" this active compound so that its non-valent interaction fixes the active compound in the polymer, thereby reducing the molecular mobility of the active compound and polymer.
[0066]
The present invention further includes a novel chemical reactor designed to produce nano-soluble particles according to the present invention. As illustrated in FIG. 1, the chemical reactor 10 includes a first container 12 and a second container 14. In accordance with the present invention, a polymer solution 16 having a concentration, pH and ionic character according to previously determined parameters, which is composed of a selected polymer in water, is prepared. Distilled water container 52 contains distilled water labeled “W” and is located on cover 18. Distilled water in distilled water container 52 is transferred to polymer container 54, to which an estimated amount of selected polymer is added. The polymer solution formed in the polymer container 54 is transferred to the first container 12 by the action of the peristaltic pump 42 as indicated by the directional arrow “X”. The polymer solution 16 is added to the first container 12 via the opening in the cover 18 with the help of a peristaltic pump 42. A non-aqueous solvent (“carrier”) is added to the polymer solution 16 in the first container 12.
[0067]
This active compound is added to the second container 14, which is connected via the reverse tube 20 to the first container to allow fluid communication between the second container 14 and the first container 12. 12 is connected. Carbon dioxide (CO with a pressure reducing valve 58 ₂ ) The balloon 56 is placed in the second container 14 with CO. ₂ Gas can be supplied. Carbon dioxide acid gas CO in organic solution ₂ The following operating characteristics are improved:
(A) reduction of the boiling point of the solvent;
(B) decrease in solvent density;
(C) a reduction in the heat capacity of the solvent; and
(D) Initiation (cavitation) of micro-drip “explosion” effect of organic solution impinging on polymer solution.
[0068]
Factors (a)-(d) facilitate rapid and complete removal of the organic solvent from the water-polymer solution. Factor (d) facilitates a more complete resolution of the microdrip of the organic solution.
[0069]
In order to create high shear and turbulence in this solution and also to disperse the solution entering the first container 12 from the second container 14 via the reverse tube 20 (in this carrier) 22 is positioned in the first container 12. The nano-dispersing device 22 creates nano-sized lipophilic particles in the polymer solution 16 in the first container 12. The nanodisperser 22 is also commonly referred to as a disperser or homogenizer. A first cooler 24 connected to the vacuum pump 26 extends to the first container 12. A second cooler 28 is connected to the second container 14. In order to control the first and second coolers 24, 28 and regulate the flow of solution and vapor between the first vessel 12 and the second vessel 14, various ones on the chemical reactor are provided. Are provided with taps 30A, 30B and 30C.
[0070]
Below the first container 12, an electric heater 32 is positioned to heat the solution 16 therein. The first container 12 is heated to a temperature higher than the boiling point of the carrier but lower than the boiling point of the polymer solution 16. In order to control and monitor the temperature of the solution 16 in the first container 12, an electric thermometer 34 extends in the first container 12. Under the second container 14 is positioned a magnetic mixer and heater 36 for heating the lipophilic compound and mixing it with the carrier solvent in the second container 14.
[0071]
As a result of this heating, the vapor of the non-aqueous solvent (carrier) in the second vessel 12 rises through the vapor pipe 38 and enters the second vessel 14 where it condenses. In the second container 14, the active compound is slowly dissolved in the non-aqueous solvent and the resulting lipophilic solution is refluxed to the first container 12 via the reverse tube 20. The opening 40 of the reverse tube 20 enters the first container 12 in the region where this lipophilic solution is close to the nanodisperser 22 (referred to as the “working zone” or “reaction zone”). Arranged in such a manner as to have a Reynolds number turbulence> 10,000. This Reynolds number is a measure of fluid flow smoothness. A high Reynolds number means that the flow is turbulent, while a low Reynolds number means that the flow is laminar. This emulsion or suspension is formed here. In this zone of action, the nanodisperser operates at a rotational speed range of about 10,000 or more per minute.
[0072]
The screen 44 prevents this turbulent flow from entering the void 46 of the first container 12 above the liquid phase. This process is continued until the entire active compound is transferred to the polymer solution 16. This non-aqueous solvent is removed from both the containers 12 and 14 via the cooler 48 to the condensate container 50. This removal of the non-aqueous solvent is illustrated by an arrow labeled with the letter “C”. The remaining non-aqueous solvent in the first container 12 is removed with the help of the vacuum pump 26. As a result, a uniform nano-size dispersion of the water-insoluble lipophilic compound encapsulated in the inclusion polymer within the hydrophilic polymer is obtained.
[0073]
Depending on the protocol previously determined for a given reaction regimen, the temperature is then reduced to room temperature while reducing its rotational speed to zero.
[0074]
In an exemplary embodiment of the present invention, nanosized soluble particles of macrolide drugs erythromycin and clarithromycin were prepared according to the present invention as inclusion complexes and are described herein in the Examples. Are described in more detail. However, the present invention is not limited to the formation of nano-sized soluble particles of erythromycin and clarithromycin. Other types of pharmaceuticals and drugs are contemplated by the present invention, for example: analgesics, anti-inflammatory drugs, anthelmintics, anti-anginal drugs, antiarrhythmic drugs, antibiotics (including penicillin antibiotics) ), Anticoagulants, antidepressants, antidiabetics, antiepileptics, antigonadotropins, antihistamines, antihypertensives, antimuscarinic agents, anti actinomycetes, anticancer drugs, immunosuppressants, antithyroid Drugs, antiviral drugs, antineoplastic and chemotherapeutic drugs, anti-anxiety sedatives (hypnotics and neuroleptics), astringents, beta-adrenergic receptor blockers, blood products and substitutes, cardiacinotropic agents ), Contrast agents, corticosteroids, cough medicines (decoratives and mucolytic agents), diagnostic agents, diagnostic imaging agents, diuretics, dopamine agonists (antiparkinsonian agents), hemostatic agents, immunosuppression Cyclic oligopeptides, immune drugs, lipid modulators, muscle relaxants, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostaglandins, radiopharmaceuticals, sex hormones (including steroids), antiallergic drugs, stimulants and Appetite suppressants, sympathomimetics, thyroid drugs, vasodilators and xanthines. Preferred drug substances include those for oral administration, intravenous administration, mucosal administration and pulmonary administration. A description of these types of drugs and a list of species that enter each type can be found in Martindale, The Extra Pharmacopoeia, Twenty-Ninth Edition, The Pharmaceutical Press, London, 1989.
[0075]
Although the present invention has been described in connection with use in the human body, the present invention is not limited in this respect, and inclusion complexes can be used in accordance with the present invention for veterinary medicines and other products. But can be used to use.
【Example】
[0076]
(Example 1, Experimental procedure for generating inclusion complex)
A. Preparation of polymer solution
500 ml of distilled water is transferred from the distilled water container 52 to the polymer container 54. An estimated amount of polymer was added to the polymer container 54, which was selected to create an inclusion complex with the lipophilic compound. At a temperature of 20-25 ° C., the contents of the polymer container 54 are removed for 30-60 minutes. ^-1 Mix at a speed of (rotations / minute) until the polymer is completely dissolved to form a clear or opaque solution.
[0077]
B. Compound loading in the reactor
The polymer solution prepared in the polymer container 54 is transferred to the first container 12 by the pump 42. In the same container, charge the carrier solvent. The second container 14 contains a lipophilic compound.
[0078]
C. Start reactor
Nano disperser 22 for 500-800 minutes ^-1 Start at the speed of. Cooling water is placed in the first and second coolers 24 and 28. The heater (thermostat) 32 is activated so that the temperature is 5 to 10 ° C. higher than the boiling point of the carrier solvent. 5-10 minutes ^-1 The magnetic mixer 36 is activated at a speed of
[0079]
D. Complex synthesis
After reaching the specified temperature, the carrier solvent begins to evaporate from the first container 12. The steam reaches the second container 14 through the steam pipe 38. At this moment, the nano-dispersing machine 22 is operated for 8,000 to 10,000 minutes. ^-1 Accelerate to speed. The active compound carrier solvent solution is then moved from the second container 14 through the reverse tube 20 to the first container 12. This solution exits through the opening 40 and reaches the zone where the activity of the nanodisperser 22 is most active. The temperature of the heater 32 is further increased by 5-10 ° C. and the concentration of the active compound in this carrier solvent is kept within the range of 0.02-0.1%. This process continues until all lipophilic compounds pass from the second container 14 to the first container 12.
[0080]
E. Removal of carrier solvent
The speed of this nano disperser is 200-300 minutes ^-1 Lowered. The tap 30A in the conduit connecting the first container 12 with the cooler 48 and the condensation container 50 is opened. The carrier solvent is distilled off to condense the container 50. After the solvent is transferred, the tap 30A is closed with the tap 30B on the cooler 28. Tap 30C (which is located in the conduit connecting first container 12 with vacuum pump 26) is then opened. Next, the temperature of the heater 32 is lowered to 30 to 35 ° C., the vacuum pump 26 is started, and the residue of this solvent is degassed in 1 to 2 hours. The vacuum pump 26 is then turned off, all taps 30A, 30B and 30C are opened and the speed of the nanodisperser is set to 30-60 minutes. ^-1 Lower.
[0081]
F. Experiment complete
The inclusion complex solution was removed from the first container 12 and analyzed. The results are shown in Table 1.
[0082]
Table 1—Aqueous phase, polymer, active compound, processing temperature (which is used to prepare selected nanoemulsions and nanosuspensions), and their stability (pre-formulation level—this Is determined by the time length (days))
[0083]
[Table 1]

(Example 2, modification of polysaccharide)
Distilled water with polysaccharides in various amounts was placed in a container. Thereafter, citric acid was added until the pH 2 specified during mixing was reached. X1 means the amount of polysaccharide in water, and X2 means the pH value of the aqueous polysaccharide solution.
[0084]
The resulting suspension is heated to 70-95 ° C. for about 10-20 minutes with continuous mixing at room temperature until a uniform opaque mass is obtained. The resulting mass is placed in an autoclave at time X3 and exposed to a temperature of 160-180 ° C. in the autoclave. Under these conditions, the polysaccharide network structure is partially or completely converted into a linear, weakly branched polymer that dissolves in water. When the autoclave time ends, cooling below 100 ° C. occurs, and a polymer solution is obtained. A solution of polyethylene glycol-400 (PEG-400) is added in the amount X4 (% relationship with polysaccharide). The resulting mixture is placed in an autoclave and heated to a temperature of 160-180 ° C. during time X5. When this autoclave time is over, cooling below 100 ° C. is performed to obtain a modified polymer. The turbidity and viscosity of the solution were measured. The observed data is shown in Table 2.
[0085]
Table 2-Modified starches based on potato starch
[0086]
[Table 2]

(Example 3, Preparation of soluble nanoparticles encapsulated in modified polysaccharide (parts by weight))
The polysaccharide was dissolved in distilled water, first heated at 160-180 ° C. with molecular weight (5-10) × 10 (4) and modified with polyethylene glycol PEG-400. Modification conditions: ratio 2: 1-4: 1 “polysaccharide-polyethylene glycol PEG-400” ratio, pH 2-5 acidic environment created with citric acid, 160-180 ° C. temperature, 60-180 minutes modification time . The modified polysaccharide solution is placed in a reaction vessel and heated to 60 ° C. while mixing with a homogenizer at a speed of 10,000 or more rotations / minute.
[0087]
At the same time, an organic solvent solution of macrolide is prepared. When the polysaccharide solution is allowed to reach a predetermined temperature of 60 ° C., then the macrolide solution begins to be added at a rate of about 1 ml / sec. Increase homogenizer speed to 10,000 rpm / min. The macrolide interacts with the polymer to form nanoparticles and evaporate the organic solvent. This organic solvent is condensed in a direct cooler. After all macrolides interact with the polymer and solubilized as an inclusion complex "macrolide-polymer", the organic solvent is evaporated under reduced pressure with continuous mixing to form a solution of the complex Was cooled to 30-35 ° C.
[0088]
The turbidity (Table 3) and viscosity of the cooled solution are measured. The presence of the crystalline phase and the particle size of the complex were measured.
[0089]
Table 3-Complexes with clarithromycin
[0090]
[Table 3]

Stable turbidity = stable nanodispersion.
[0091]
(Example 4, in vitro microbial results using clarithromycin in a nanoparticle complex)
The microbial activity of the conjugated clarithromycin prepared in Example 5 at various concentrations was tested and directly compared to the same concentration of unconjugated clarithromycin. The test method used was the generally accepted method for agar-filled petri dish tests. The test microorganism used is Micrococcus luteus, which is sensitive to macrolide antibiotics. A disk cut from a small filter paper was impregnated with a test antibiotic at a specific solution concentration. The diameter of the bacteriostatic zone was measured against time. Concentrations for both control and complexed test substances varied significantly and were observed until 216 hours after application. These results are illustrated in FIG.
[0092]
This test further demonstrated that complexed clarithromycin has the same microbial activity as commercially available clarithromycin, using 1/10 of its amount (concentration). Furthermore, for the same drug concentration, the microbial activity of this clarithromycin disappeared in about 48 hours, whereas the microbial activity of complexed clarithromycin persisted significantly until about 216 hours of the current measurement. The inventor has continued the measurement. It was also observed that the difference in microbial activity of complexed clarithromycin with different orders of magnitude difference was much greater than the corresponding difference seen with clarithromycin alone.
[0093]
Example 5 In vivo study using clarithromycin inclusion complex
Rats were given clarithromycin with a nanoparticle complex according to the invention at 150 mg / kg by gavage. Blood samples were collected at time intervals via the jugular vein catheter.
[0094]
The 0 hour value was the control baseline for each animal. Following oral administration of clarithromycin in the nanoparticle complex, it was confirmed that the drug reached its maximum plasma value 4 hours after administration. The initial absorption phase was rapid up to 1 hour and lasted up to 4 hours. The clearance was significantly slower compared to published data using commercial clarithromycin. Its circulating half-life was in the range of 2 hours. The Area Under the Curve (AUC) of the clarithromycin complex according to the present invention _{0-24 hours} ) Published data using the same dose of commercial clarithromycin in rats (same oral dose of 150 mg / kg, AUC _{0-24 hours} = 32.54 microg ^* h / ml) is significantly higher than 54.2 microg ^* h / ml. It is therefore conceivable that: The conjugated clarithromycin according to the invention exhibits high bioavailability or delayed intestinal release following oral administration.
[0095]
This clarithromycin conjugate showed the same range of circulating half-life, i.e. 2 hours, following IV bolus administration compared to the marketed drug. It has a significantly higher AUC after oral administration, supporting the assumption of improved bioavailability or sustained release characteristics.
[0096]
A comparison of the pharmacokinetic constants of the test clarithromycin in the nanoparticle complex with the commercially available clarithromycin published data is illustrated in FIG. The PK constant of clarithromycin in the nanoparticle complex is compared to a commercial study of commercial clarithromycin and is shown in FIG.
[0097]
Example 6 Physical Measurements and Properties of Clarithromycin and Erythromycin in Nanoparticle Complex
1. Particle size and distribution
For the complex of erythromycin or clarithromycin + polymer in aqueous solution, the technique of the present invention allows a controllable nanoparticle size (in the range of 1 nanometer to 1000 nm) with a very uniform particle size distribution. It has become clear that it is possible to prepare a drug-polymer dispersion having
[0098]
The clarithromycin complex prepared according to the method of the present invention showed the same dispersion spectrum after 5 weeks. FIG. 5 illustrates complexed clarithromycin particles having a size of about 190 nm. Sizing of erythromycin and clarithromycin complexes was performed using an “ALV-Particle Sizer” (which has a resolution of 3 to 3000 nm). FIG. 6 is a SEM micrograph, which illustrates consistent spherical complexed clarithromycin particles prepared according to the method of the present invention.
[0099]
2. Solubility
Erythromycin (an antibiotic that is virtually insoluble in water) was re-formulated into a thermodynamically stable nanodispersion with a controllable particle size distribution of the particles in the dispersed phase. The resulting new formulation had 8% (w / v) active drug, which was 40 times higher than the water solubility (0.2%) of the original drug. Furthermore, drug particles were obtained with very uniform size composites (95% or more). The erythromycin was released from the inclusion complex at a sufficient concentration under physiological conditions. Existing solubilization techniques (eg, surfactants, liposomes, encapsulation, etc.) were not used. A comparison of erythromycin alone and clarithromycin alone with erythromycin and clarithromycin as part of the inclusion complex of the present invention is illustrated in FIG.
[0100]
3. Stability
The transparent aqueous solution of the inclusion complex was observed with respect to the absence of phase separation and the maintenance of particle size and particle size distribution. The following findings and results were obtained:
(A) Over 75 days, re-formulated 8% erythromycin test revealed no phase separation and maintenance of particle size and particle size distribution.
[0101]
(B) The stability of the complexed clarithromycin according to the invention was observed for 12 weeks at room temperature and 4 weeks at 35 ° C. and found to be stable.
[0102]
(C) Even when the conjugated clarithromycin was lyophilized and subsequently rehydrated, the particle size of the drug-polymer complex was retained. Over 30 days there was no aggregation and the nanodispersion was stable.
[0103]
4). X-ray diffraction results and characteristics
X-ray diffraction measurements showed that the crystalline drug erythromycin converted to an amorphous form material upon re-formulation into a nanodispersion.
[0104]
Figures 8 and 9 illustrate X-ray diffraction comparisons of intact erythromycin and intact clarithromycin compared to the inclusion complex of erythromycin and clarithromycin according to the present invention, respectively.
[0105]
A comparison of the known spectra of erythromycin (FIG. 8) and clarithromycin (FIG. 9) with the inclusion complex of the present invention was performed. The known spectrum of erythromycin (FIG. 8) as a dry powder showed a clear crystal pattern.
[0106]
In contrast, this erythromycin inclusion complex (FIG. 8) showed that most of the peaks derived from crystalline erythromycin were absent and the few remaining peaks were significantly reduced in height. Yes. This spectrum is undoubtedly related to that of known erythromycin, however, it implies that another “shape” exists after conjugation.
[0107]
Observing the mean scattering angle in both the complexed erythromycin and clarithromycin spectra, it can clearly be seen that certain peaks have become “flattened”, which effectively broadens the baseline peak. It shows that. This phenomenon implies an amorphous state.
[0108]
These results indicate that the complexing of erythromycin and clarithromycin using the technique of the present invention causes the drug to be immobilized in the inclusion polymer based on van der Waals forces and hydrogen bonds. It is clear that the crystallinity of the uncomplexed drug is lowered because it cannot form a crystal lattice. This amorphous state is known to be favorable for drug delivery because it can actually enhance bioavailability.
[0109]
The X-ray spectrum of FIG. 10 depicts a 6 month clarithromycin complexed sample (bottom trace) compared to commercial clarithromycin (top trace). This particular complexed sample is the same as that seen in FIG. 9 and that seen in the microbial test described in Example 6. This confirms the technical performance of preparing a unique complexed drug conjugate according to the present invention, which exhibits a highly stabilized amorphous state.
[0110]
The present inventors have increased the opportunity for higher bioavailability, as demonstrated in the literature, by stabilizing the amorphous or partially amorphous drug state in this inclusion complex. I think it can be done. Taken together with other parameters achieved using the method and apparatus of the present invention (eg, very accurate size control), the method itself is easily adapted to significantly enhanced bioavailability. .
[0111]
(Example 7, sustained release from erythromycin inclusion complex)
Re-formulation of these drugs represents a new means of achieving a sustained release system that delivers drugs at a specific rate and pattern. To examine the experimental sustained release pattern of erythromycin from this inclusion complex, a dialysis method was performed. In this method, the drug-polymer nanodispersions were placed in a dialysis membrane bag. Such membranes allow only molecules and ions with a size of less than 3000 Da to diffuse while maintaining their nanodispersions. Dialysis was performed at room temperature for 24 hours with constant stirring. Samples were periodically removed from the external buffer to analyze drug release. The concentration of erythromycin released from this inclusion complex was determined by its O.D. D. It was detected by measuring (optical density). After 24 hours incubation, the concentration of erythromycin in the external fluid was 25% of the initial erythromycin concentration in the inclusion complex (initial concentration is 4 mg / ml (8% w / v)). The released concentration also reflects the maximum solubility of erythromycin in the serum modeled solution. Therefore, this result indicates that this nanodispersion has the ability to sustain the release of erythromycin.
[0112]
(Example 8, in vitro human cell compatibility study)
Red blood cells were separated from fresh donor WBC and suspended in isotonic buffer. Red blood cells to be treated were suspended in the designated buffer in water and lysis buffer. The hemolysis reaction was performed at 37 ° C. with shaking (40 rpm) in a total volume of 1 ml. At 4 hours, a 250 μl aliquot was removed and at 18 hours the remainder was collected. Aliquots were centrifuged at 250 g for 5 minutes and the supernatant was read at 540 nm. The results of this study showed that complexed clarithromycin is compatible with human blood.
[0113]
(Example 9, suspension polymerization with nano-soluble particles)
Caprolactam was dissolved in ethyl ether using the chemical reactor of the present invention illustrated in FIG. Amylose was modified with urea to a degree of amidation of 10%, after which a modified amylose solution was prepared. The polymer solution was transferred to the first container 12 and the caprolactam solution was transferred to the second container 14. The nano disperser 22 and the heater 32 were activated. The heater (thermostat) 32 was started at 50 to 55 ° C. The caprolactam solution was then transferred from the second container 14 through the reverse tube 20 to the first container 12. After feeding all the reverse caprolactam solution through the reverse tube 20, the temperature of the reaction mixture was lowered to 25-35 ° C and evaporated from the reactor.
[0114]
Upon polymerization of polycaprolactam (nylon-6,6), the resulting “solution” was sprayed at a temperature of 260-280 ° C. in a vacuum column. From the bottom of the yarn, the polymer was taken out as a fine uniform powder (with uniform particle size). The molecular weight of the polymer was determined by the viscosity method. The results are shown in Table 4.
[0115]
Table 4
[0116]
[Table 4]

(Equivalence)
Thus, while the basic novel features of the invention have been shown, described and pointed to as applied to preferred embodiments thereof, there are various omissions and features in the form or detail of the disclosed invention. It will be appreciated that substitutions and modifications can be made by those skilled in the art without departing from the spirit of the invention. Accordingly, it is intended that the invention be limited only by the scope of the claims appended hereto.
[0117]
It should be understood that the drawings are not necessarily drawn to scale, but are merely conceptual.
[Brief description of the drawings]
[0118]
FIG. 1 is a schematic diagram of a chemical reactor for producing nano-sized soluble particles according to the present invention.
FIG. 2 illustrates control and complexed clarithromycin test substance concentrations observed up to 216 hours after application.
FIG. 3 is a chart comparing the pharmacokinetic constants of test clarithromycin in a nanoparticle complex with published data of commercial clarithromycin.
FIG. 4 is a chart comparing the PK constant of clarithromycin in a nanoparticle composite with published studies using commercial clarithromycin.
FIG. 5 illustrates complexed clarithromycin particles having a size of about 190 nm.
FIG. 6 is a SEM micrograph, which illustrates a consistent spherical complexed clarithromycin particle prepared according to the method of the present invention.
FIG. 7 illustrates a solubility comparison between erythromycin and clarithromycin alone and erythromycin and clarithromycin as part of an inclusion complex of the present invention.
FIG. 8 illustrates an X-ray diffraction comparison of intact erythromycin compared to each of the inclusion complex of erythromycin according to the present invention.
FIG. 9 illustrates an X-ray diffraction comparison of intact clarithromycin compared to clathromycin inclusion complexes according to the present invention, respectively.
FIG. 10 is an X-ray spectrum of a 6 month old clarithromycin complexed sample (lower trace) compared to commercially available clarithromycin (upper trace).

Claims (93)

A hydrophilic colloidal dispersion comprising:
A water-insoluble or water-soluble active compound; and an amphiphilic polymer, encapsulating the active compound in an amorphous manner to form a nano-sized molecular element in which no valence bond is formed,
Wherein the amphiphilic polymer makes the molecular element hydrophilic in water and bioavailable in the human body. The active compound is encapsulated in the polymer through a non-valent interaction between the amphiphilic polymer and the active compound, and the interaction fixes the active compound in the polymer. The hydrophilic colloid dispersion according to claim 1, wherein molecular mobility is lowered. The hydrophilic colloid dispersion according to claim 2, wherein the non-valence interaction includes electrostatic force, van der Waals force and hydrogen bond. The hydrophilic colloidal dispersion according to claim 2, wherein the active compound encapsulated in the amphiphilic polymer does not form either a rigid matrix or a crosslinked polymer. The hydrophilic colloid dispersion according to claim 1, wherein the active compound encapsulated in the amphiphilic polymer is fixed in the polymer. The hydrophilic colloidal dispersion according to claim 1, wherein the nano-sized molecular element is substantially spherical. The hydrophilic colloidal dispersion according to claim 1, wherein the molecular element having an active compound wrapped in the polymer exhibits reduced mobility and reduced crystallinity of the active compound. The amphiphilic polymer is a natural polysaccharide, polyacrylic acid and derivatives thereof, polyethyleneimine and derivatives thereof, polymethacrylic acid and derivatives thereof, polyethylene oxide and derivatives thereof, polyvinyl alcohol and derivatives thereof, polyacetylene derivatives, polyisoprene derivatives. The hydrophilic colloid dispersion according to claim 1, which is selected from the group consisting of and a polybutadiene derivative. 2. The hydrophilic colloid according to claim 1, wherein the active compound may contain organic substances selected from the group consisting of pharmaceutical compounds, food additives, cosmetics, agricultural products and pet food and other compounds and / or intermediates. Dispersion. The active compound is selected from the group consisting of peptides and polypeptides, nucleotides and coenzymes, vitamins, steroids, porphyrins, metal complexes, purines, pyrimidines, antibiotics and hormones and other compounds. Hydrophilic nano-size soluble particles. The hydrophilic nanosize soluble particle according to claim 1, wherein the active compound is a pharmaceutical compound. 12. The hydrophilic colloid dispersion of claim 11, wherein the pharmaceutical compound can include chemotherapeutic drugs, antibiotics and neoplastic drugs. 13. A hydrophilic colloid dispersion according to claim 12, wherein the antibiotic and neoplastic drug comprises erythromycin and clarithromycin. The hydrophilic colloidal dispersion according to claim 1, wherein the amphiphilic polymer and the active compound form a polymer complex having a hydrophilic-lipophilic balance that renders the polymer complex water-soluble. The hydrophilic colloid dispersion of claim 1, wherein the nano-sized molecular elements are sized in the range of about 10 to about 1000 nanometers. 16. The hydrophilic colloid dispersion of claim 15, wherein the active compound in the molecular element is sized in the range of about 1 to about 5 microns. The hydrophilic colloid dispersion according to claim 1, wherein the molecular element is an inclusion complex. The hydrophilic colloidal dispersion according to claim 1, wherein the active compound of the molecular element is present in an amorphous form. The hydrophilic colloidal dispersion according to claim 1, wherein the active compound is lipophilic. A method of forming an inclusion complex containing hydrophilic nano-size soluble particles, the method comprising the following steps:
(A) preparing a polymer solvent containing amphiphilic polymer molecules in an aqueous solvent;
(B) preparing a carrier solvent containing a lipophilic compound in a non-aqueous solution;
(C) adding the carrier solution to the polymer solution to form an emulsion;
(D) adding the emulsion to the turbulent zone in the polymer solution to disperse the lipophilic compound in the emulsion, wherein the lipophilic compound is a nanomilk Forming a nano-sized lipophilic compound in the suspension;
(E) removing the carrier solvent from the nanoemulsion, wherein the polymer molecule surrounds the nanosize lipophilic compound to form the hydrophilic inclusion complex. Process,
Including the method. 21. The polymer solution of claim 20, wherein the polymer solution in preparation step (a) is contained in a first vessel of a chemical reactor and the lipophilic solution is contained in a second vessel of a chemical reactor. Method. The method of claim 21, wherein the dispersing step (d) occurs in turbulent flow in the polymer solution in the chemical reactor. 24. The method of claim 22, wherein the turbulent flow is generated by a high shear device. The lipophilic solution is selected from the group consisting of peptides and polypeptides, nucleotides and coenzymes, vitamins, steroids, porphyrins, metal complexes, purines, pyrimidines, antibiotics and hormones and other compounds and / or intermediates 21. A method according to claim 20, comprising a lipophilic compound. 21. The method of claim 20, wherein the lipophilic compound is water insoluble. 21. The method of claim 20, wherein the polymer is an amphiphilic polymer. The amphiphilic polymer is a natural polysaccharide, polyacrylic acid and derivatives thereof, polyethyleneimine and derivatives thereof, polymethacrylic acid and derivatives thereof, polyethylene oxide and derivatives thereof, polyvinyl alcohol and derivatives thereof, polyacetylene derivatives, polyisoprene derivatives. 21. The method of claim 20, wherein the method is selected from the group consisting of: and polybutadiene derivatives. 21. The method of claim 20, wherein the removing step further comprises evaporating the carrier solvent by a drying technique. 30. The method of claim 28, wherein the drying technique is vacuum distillation. 30. The method of claim 28, wherein the drying technique is lyophilization. 21. The method of claim 20, wherein the emulsion of the adding step (c) has a Reynolds number of 10,000 or greater. The method further includes the step of heating the mixture of the polymer solution and the carrier to generate steam, the steam condensing to dissolve the lipophilic compound to form the lipophilic solution. Item 21. The method according to Item 20. 31. The method of claim 30, wherein the polymer solution is heated to a temperature above the boiling point of the carrier solution but below the boiling point of the polymer solution. A chemical reactor that forms an emulsion used in the preparation of an inclusion complex, the chemical reactor comprising:
A first container for containing the polymer solution;
A second container for containing a lipophilic compound and a non-aqueous solvent of the lipophilic compound;
A carbon dioxide balloon for supplying carbon dioxide to the solvent in the second container; and a dispersion device, the dispersion device dispersing the solution of the lipophilic compound on a carrier in the polymer solution. The dispersing device is located in the first container and creates a high shear turbulence in the polymer solution, the first and second containers being connected together, A dispersing device that allows continuous circulation, wherein the lipophilic compound moves from the second vessel to the first vessel;
A reactor. 35. The chemical reactor of claim 34, wherein the dispersing device disperses the lipophilic compound in the lipophilic solution into nano-sized particles. 36. A chemical reactor according to claim 35, wherein the dispersing device is a nano-dispersing machine. 35. The chemical reactor of claim 34, wherein the dispersing device operates at a rotational speed of about 5,000 to 30,000 per minute in the first vessel. The chemical reactor according to claim 34, further comprising a first heating device, wherein the first heating device heats the polymer solution in the first container. 35. The chemical reactor of claim 34, further comprising a mixing device, the mixing device positioned below the second container for mixing the lipophilic solution in the second container. 35. The chemical reactor of claim 34, further comprising a first cooler, wherein the first cooler is connected to a vacuum pump, and the vacuum pump extends into the first container. The chemical reactor of claim 34, further comprising a second cooler, wherein the second cooler is coupled to the second vessel. The polymer solution in the first container is in fluid communication with the lipophilic solution in the second container via a tube connected between the first container and the second container. 35. A chemical reactor according to claim 34. The lipophilic solution is added to the polymer solution in the first container via the tube connected between the first container and the second container, and the tube has an outlet end. The outlet end extends into the polymer solution in the first container, wherein the lipophilic solution flowing through the outlet end of the tube is in the intense turbulent region; 43. The chemical reactor of claim 42, wherein the chemical reactor enters the first vessel. 44. The chemical reactor of claim 43, wherein the first container includes a void above the polymer solution. The first container further includes a screen, the screen is located on the polymer solution in the first container, and the turbulent flow is in the gap above the polymer solution. 45. The chemical reactor of claim 44, wherein the chemical reactor is prevented from entering. 35. The chemical reactor of claim 34, further comprising a pump, wherein the pump circulates the lipophilic solution and the polymer solution between the first container and the second container. A method for forming nano-sized soluble particles, wherein the particles comprise an active lipophilic or hydrophilic core, wherein the core is encapsulated in an amphiphilic polymer in a non-crystallized fashion, wherein No valence bond is formed and the method comprises the following steps:
(A) preparing an emulsion or suspension, the emulsion or suspension comprising an aqueous solvent solution of amphiphilic polymer molecules and a non-aqueous solvent carrier of the active compound; Process;
(B) Dispersing the active compound in the emulsion or suspension, wherein the active compound forms nano-sized particles, the nano-sized particles being colloidal nano-dispersions And (c) removing the carrier solvent from the nanodispersion, wherein the polymer molecules surround the lipophilic particles to form the nanosized soluble particles. The process,
Including the method. 48. Prior to the dispersing step (b), the method further comprises heating the emulsion to a temperature below the boiling point of the emulsion but above the boiling point of the carrier solvent. The method described in 1. 48. The method of claim 47, wherein the preparing, dispersing and removing steps occur in a chemical reactor. 50. The method of claim 49, wherein the dispersing step (b) occurs in high shear turbulence in the polymer solution in the chemical reactor. 48. The lipophilic compound of claim 47, selected from the group consisting of organic substances selected from the group consisting of drugs, food additives, cosmetics, agricultural products and pet food and other compounds and / or intermediates. Method. The polymer in the polymer solution is a natural polysaccharide, polyacrylic acid and derivatives thereof, polyethyleneimine and derivatives thereof, polymethacrylic acid and derivatives thereof, polyethylene oxide and derivatives thereof, polyvinyl alcohol and derivatives thereof, polyacetylene derivatives, poly 48. The method of claim 47, selected from the group consisting of isoprene derivatives and polybutadiene derivatives. Prior to the preparation step (a), the method comprises determining and calculating the properties and properties of the polymer molecule and the lipophilic compound used in forming the nanosized soluble particles. 48. The method of claim 47. 53. The method of claim 52, wherein the polymer is selected based on the molecular weight, size, polarity, and solubility in a non-aqueous solvent of the lipophilic compound used in forming the nanosized soluble particles. . The polymer has the following properties of the polymer: molecular weight, basic polymer chain length, length of motion unit, solubility in water, solubility, degree of mobility of the polymer chain, integrated hydrophilicity- 48. The method of claim 47, selected by an algorithm that takes into account one or more of lipophilic balance and hydrophilic group polarity. 51. The method of claim 50, wherein the emulsion that enters the high shear turbulence in the dispersing step (b) has a Reynolds number greater than 10,000. 48. The method of claim 47, wherein the nano-sized soluble particles are present in an amorphous amorphous form. A method of forming a hydrophilic inclusion complex in a chemical reactor, the method comprising the following steps:
(A) preparing a dispersion in the first vessel of the chemical reactor, the dispersion containing a carrier solvent and an amphiphilic polymer solution;
(B) adding an active compound to the second vessel of the chemical reactor;
(C) heating the dispersion, wherein the vapor generated from the dispersion condenses in the second container to dissolve the active compound to form an active compound solution. ;
(D) adding the active compound solution to the dispersion in the first container, wherein the active compound solution is in the vicinity of the dispersing device located in the first container Added to the process;
(E) Dispersing the active compound solution, wherein the active compound forms nano-sized particles in a nanoemulsion or suspension;
(F) removing the carrier solvent from the nanoemulsion or nanosuspension, wherein the amphiphilic polymer surrounds the nanosized particles to form an amorphous amorphous shape. Providing the lipophilic inclusion complex having:
Including the method. 59. The method of claim 58, wherein the dispersing step (e) occurs in turbulent flow in the polymer solution in the first vessel. The lipophilic solution is selected from the group consisting of peptides and polypeptides, nucleotides and coenzymes, vitamins, steroids, porphyrins, metal complexes, purines, pyrimidines, antibiotics and hormones and other compounds and / or intermediates 59. The method of claim 58, comprising a lipophilic compound. The amphiphilic polymer is a natural polysaccharide, polyacrylic acid and derivatives thereof, polyethyleneimine and derivatives thereof, polymethacrylic acid and derivatives thereof, polyethylene oxide and derivatives thereof, polyvinyl alcohol and derivatives thereof, polyacetylene derivatives, polyisoprene derivatives. 59. The method of claim 58, selected from the group consisting of and a polybutadiene derivative. 59. The method of claim 58, wherein the removing step (f) further comprises evaporating the carrier solvent by a drying technique. 64. The method of claim 62, wherein the drying technique is vacuum distillation. 64. The method of claim 62, wherein the drying technique is lyophilization. 59. The method of claim 58, wherein the emulsion added to the polymer solution in the adding step has a Reynolds number greater than 10,000. 59. The method of claim 58, wherein the polymer solution is heated to a temperature above the boiling point of the carrier solvent but below the boiling point of the polymer solution. Nano-sized soluble particles, wherein the particles comprise an active lipophilic or hydrophilic core, which is encapsulated in an amphiphilic polymer in an amorphous manner, in which the atomic polymer Particles in which no valence bond is formed. The core is encapsulated in the polymer through a non-valent interaction between the amphiphilic polymer and the core, and the interaction fixes the core in the polymer to move the molecule. 68. The nano-sized particle of claim 67, wherein the nano-sized particle is made to reduce properties. 69. The nano-sized particle of claim 68, wherein the non-valent interaction comprises electrostatic force, van der Waals force and hydrogen bonding. 68. The nano-sized particle of claim 67, wherein the active core encapsulated within the amphiphilic polymer forms neither a rigid matrix nor a crosslinked polymer. 68. The nano-sized particle according to claim 67, wherein the active core wrapped in the amphiphilic polymer is fixed in the polymer. 68. The nanosized particle of claim 67, wherein the particle is substantially spherical. 68. Nanosized particle according to claim 67, wherein the active core is an amorphous amorphous element. 68. The nano-sized particle of claim 67, wherein the particle having a core wrapped in the polymer exhibits reduced mobility and reduced crystallinity of the core. The active core and the polymer are dissolved in two different immiscible liquids and the particles are produced by gradually adding the core solution to the polymer solution under vigorous stirring. 68. Nanosized particles according to claim 67. The amphiphilic polymer is a natural polysaccharide, polyacrylic acid and derivatives thereof, polyethyleneimine and derivatives thereof, polymethacrylic acid and derivatives thereof, polyethylene oxide and derivatives thereof, polyvinyl alcohol and derivatives thereof, polyacetylene derivatives, polyisoprene derivatives. 68. Nanosized particles according to claim 67, selected from the group consisting of and polybutadiene derivatives. 68. Nanosized particle according to claim 67, wherein the active core is a pharmaceutical compound. 78. Nanosized particles according to claim 77, wherein the pharmaceutical compound can include chemotherapeutic drugs, antibiotics and neoplastic drugs. 79. Nanosized particles according to claim 78, wherein the active core is erythromycin and clarithromycin. 68. The nanosized particle of claim 67, wherein the particle is sized in the range of about 10 to about 1000 nanometers. A chemical reactor for forming an emulsion used in the preparation of hydrophilic nano-sized soluble particles, the chemical reactor comprising:
A first container for containing the polymer solution;
A second container for containing a lipophilic compound and a non-aqueous solvent of the lipophilic compound;
A carbon dioxide balloon for supplying carbon dioxide to the solvent in the second container; and a dispersion device, the dispersion device dispersing the solution of the lipophilic compound on a carrier in the polymer solution. The dispersing device is located in the first container and creates intense high shear turbulence in the polymer solution, the first and second containers being connected to each other and the carrier A dispersing device, wherein the lipophilic compound is transferred from the second vessel to the first vessel,
A reactor. 82. The chemical reactor of claim 81, wherein the dispersing device disperses the lipophilic compound in the lipophilic solution into nano-sized particles. 83. A chemical reactor according to claim 82, wherein the dispersing device is a nanodisperser. 82. The chemical reactor of claim 81, wherein the dispersing device operates at a rotational speed of about 5,000 to 30,000 per minute in the first vessel. The chemical reactor according to claim 81, further comprising a first heating device, wherein the first heating device heats the polymer solution in the first container. 82. The chemical reactor of claim 81, further comprising a mixing device, wherein the mixing device is located below the second container and mixes the lipophilic solution in the second container. 82. The chemical reactor of claim 81, further comprising a first cooler, wherein the first cooler is connected to a vacuum pump, and the vacuum pump extends into the first container. The chemical reactor of claim 81, further comprising a second cooler, wherein the second cooler is connected to the second vessel. The polymer solution in the first container is in fluid communication with the lipophilic solution in the second container via a tube connected between the first container and the second container. 82. A chemical reactor according to claim 81. The lipophilic solution is added to the polymer solution in the first container via the tube connected between the first container and the second container, and the tube has an outlet end. The outlet end extends into the polymer solution in the first container, wherein the lipophilic solution flowing through the outlet end of the tube is in the intense turbulent region; 90. The chemical reactor of claim 89, entering the first vessel. 92. The chemical reactor of claim 90, wherein the first container includes a void above the polymer solution. The first container further includes a screen, the screen is located on the polymer solution in the first container, and the turbulent flow is in the gap above the polymer solution. 92. The chemical reactor of claim 91 which prevents entry. 82. The chemical reactor of claim 81, further comprising a pump, wherein the pump circulates the lipophilic solution and the polymer solution between the first container and the second container.

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