JP2010540664A - 合成物の持続的な放出のためのデンドリマー - Google Patents
合成物の持続的な放出のためのデンドリマー Download PDFInfo
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Abstract
【選択図】図2
Description
多くの効果的な医薬品や薬は、標的組織に及ばない、または、臨床的な有効性を達成するのに十分な間、標的領域に滞留できない。重症のブドウ膜炎に対する合成コルチコステロイドであるフルオシノロンアセトニドはこの一例である。ブドウ膜炎とは、眼の血液供給を担う構造が炎症を起こす、あるいは、腫れる。それらの構造は、ブドウ膜束として知られ、虹彩、毛様体、コロイドを含む。ブドウ膜は、それが影響を及ぼす構造潜在的な原因、および、それが慢性(6週間より長い)か急性か否かを決定づける構造によって分類される。
マイクログリアは、網膜と中枢神経系の樹状細胞の免疫系のメンバーであって、損傷を受けた脂質膜内にある細菌細胞壁リポ多糖類とガングリオシドを含む多くの刺激物によって活性化される(Jou, I. et al., The American Journal of Pathology 2006; 168:1619-1630; Min, K.J. et al., Glia 2004; 48:197-206; Pyo, H. et al., The Journal of Biological Chemistry 1999; 274:34584-34589.)。
本明細書で用いられる”ナノ物質”及び/または”ナノシステム”は、相互に交換可能に、デンドリマーと少なくとも1つの他の治療薬を含むマイクロ粒子またはナノ粒子として用いられる。
本開示によれば、調合薬は、薬が関連するか、または薬と複合体となった重合体物質を含むナノ物質として眼に投与される。実施形態において、重合体物質は、高度に均一化された分子、狭い分子量分布、特異的な大きさと形態的特徴、および、高機能性の末端表面を有するように製造されたデンドリマーの形で含まれる。例えば、エチレンジアミン−コア・ポリ(アミドアミン)(以下、PAMAM)デンドリマーは、”デンス・スター”重合体といわれる巨大分子構造のクラスの代表である。一部の実施形態では、デンドリマーが、部分的に世代4または世代5(それぞれG4またはG5)がアセチル化されたポリアミドアミン(PAMAM)、またはポリプロピルアミン(POPAM)デンドリマーである。
治療に適した疾患は、加齢性黄斑変性症(ARMD)、網膜色素変性症(RP)が含まれ、これらは、臨床試験に先立って、動物で検討できる共通の根本的な病状を共有している。どちらの疾患も、網膜色素上皮の機能が低下する結果、直接的及び/または間接的に光受容体が損傷を受けるという生化学的な異常を示す。光受容体の損傷は、最終的に、細胞またはミトコンドリア膜のレベルで起きる。ミトコンドリア外膜が脂質過酸化反応を介して損傷を受けると(通常、状態異常の網膜内での酸化ストレスの結果として)、ミトコンドリアマトリクスへの過度のカルシウムと超酸化物陰イオンの流入が起こる(Marchetti, P., et al. J Exp Med 184(3):1155-60 (1996); Green, D.R., et al. Science 305(5684):626-9 (2004); Spierings, D., et al. Science 310(5745):66-7 (2005))。この超酸化物及び/またはカルシウムの過負荷(カルパイン誘導アポトーシス)への応答において、ミトコンドリアはチトクロムcを細胞質ゾルへ放出し、ここで、チトクロムcは、APAF−1とカスパーゼ−9にアポトソームを形成するために相互作用する。このアポトーシスへの過程によって、DNA修復、複製、及び形質導入が停止し、細胞死につながる。結果として、ミトコンドリア外膜を安定化する抗酸化物質や薬は、アポトーシスによる細胞死に拮抗する作用で神経保護的である。
薬または医薬組成物の選択は、第一に、治療対象の疾患、あるいは抑制対象の状態に依存する。例えば、合成コルチコステロイドであるフルオシノロンアセトニド(FA)は、重症のブドウ膜炎患者に対して長期の硝子体内投与が可能な、持続的放出製剤としてFDAの承認を受けた(Jaffe, G.J. et al., Ophthalmology 2000;107:2024-2033; Jaffe, G.J. et al., Ophthalmology 2006;113:1020-1027; Jaffe, G.J. et al., Investigative Ophthalmology & Visual Science 2000;41:3569-3575)。ミノサイクリンは、その抗炎症効果が知られており、神経炎症状態の治療に用いられる。
実施例1
in vitroとin vivoでのマイクログリア細胞によるデンドリマーの取り込み
細胞内輸送とデンドリマーからの薬の放出におけるデンドリマーの表面電荷の役割が報告された(Kannan, S. et al., J. Biomaterials Science: Polymers Edition. 2004; 15:311; Khandare, J. et al., Bioconjugate Chem. 2005; 60:330-337)が、治療の試みの対象であるマイクログリア細胞との関係はこれまでに報告されていない。
PAMAM−G4−OH−フルオシノロンアセトニド(D−FA)複合体(ナノ物質)と持続的に放出する移植物質との比較
D−FA複合体(ナノ物質)の調製と評価は以下のように実施された。ナノ物質の調製には、PAMAM−G4−OHデンドリマーが選ばれた(Jayanth Khandare, P.K. et al. (2005); P. Kolhe, J.K. et al., Biomaterials 27:660-669 (2006))。デンドリマーは、アルドリッチから入手し、混在するであろう小さな、低い世代の不純物を除去するために透析された。PAMAM−G4−OH(分子量=14,217Da、64−OH末端基、大きさ約5nm)は、2段階ジシクロヘキシル・カルボジイミド(DCC)カップリング反応(図6)を用いて複合体とされた。反応混合液は3日間撹拌し、DCUを取り除くためにフィルターにかけられた。
したところ、複合体由来のごく微量の薬が放出されたことが示唆された。このことは、複合体はとても安定で、そして、遊離の(複合体でない)FAはごくわずかであった。
RCSラットで神経保護的であったフルオシノロンアセトニド
本実施例によると、ステロイドであるフルオシノロンアセトニド(FA)は、持続的に放出する硝子体内への薬輸送移植物質(IDDIs)によって輸送されると、RCSラットのゆっくりした網膜変性に対して、高い神経保護作用を示した。図9Bは、4週間の試験期間で、FAを0.2μg/日、FAを0.5μg/日、活性のない薬を輸送する移植物質(右眼に)、非外科的な対照をそれぞれ受けた4つの、9週齢のRCSラットの群における外顆粒層細胞(光受容体細胞本体)の密度を示す。定量組織解析によって、FAを0.2μg/日で処理された眼の外顆粒層の細胞密度が、非外科的な対照群の2.38±0.12倍大きく(p<0.001)、活性のない薬を輸送する移植物質群の4.85±0.24倍大きい(p<0.001)ことが示された。FAを0.5μg/日で処理された眼の外顆粒層の数が、非外科的な対照群の1.78±0.21倍大きく(p値はクラスカル-ウォリス検定で0.02)、活性のない薬を輸送する移植物質群の3.56±0.17倍大きい(p<0.001)ことが示された。群間で内顆粒層の数における違いはなかった。
PAMAM−G4−OHデンドリマーは、通常のSDラットではみられないが、RCSラットでは、変性した外顆粒層への取り込みの強化を示した。
図5は、スピローグ−ディウリー(SD)ラットとRCSラットにおける網膜の低温切開片から得た落射蛍光像を示す。これらは、遊離の、複合体でないFITC、デンドリマー複合体であるFITC(D−FITC)、及びPLGAマイクロスフィアに封入されたD−FITC(PLGA−(D−FITC))を硝子体内に注射して、その24時間後に作製された。図5BのRCSラットの網膜において、D−FITCは、網膜の外側への取り込みが強化されることを示し、外顆粒層、活性化されたマイクログリア、及び外側の壊死組織領域の間に、正確に局在したことが明らかである。この取り込み様式は、他のどの正常なSDラットでもみられなかった(図5A、C、D)。画像の赤色は、TRITCフィルターの自己蛍光による。
PLGAマイクロ粒子はデンドリマー−FITC複合体を封入して調製される。
PLGAマイクロ粒子は、次のようにして、デンドリマー−FITC複合体を封入して調製される。FAのような水に溶けない薬に適しているo/w法ではなく、ウォーター・イン・オイル・イン・ウォーター法(w/o/w)が、デンドリマー−薬複合体のような水溶性のナノ物質の封入には適している(Jayanth Panyam, M. M. D. et al., Journal of Controlled Release 92:173-187 (2003); Jayanth Panyam, S. K. S. et al., International Journal of Pharmaceutics 262:1-11 (2003))。妥当なPLGAの量(分子量が90,000から125,000Da、75% PLA/25% PGA)がクロロホルムに溶ける。別々に、2.5%のPVA溶液が、クロロホルムが飽和した冷たい蒸留水で調製された。
ミノサイクリンの投与は、生体内のマイクログリア細胞の活性化の抑制につながる。
本実施例によると、マイクログリア特異的リガンドである[11C]PK11195を用いたマイクロPETによって、生後のミノサイクリンの投与によるマイクログリアの活性化の経時変化が減少した。ミノサイクリン投与によるミクログリアの阻害を示すために、ミノサイクリン投与をしたときと投与しないときの生後5日の子犬における[11C]PK11195の取り込みをPET画像で評価した。
黄斑変性症のラットモデル
光受容体神経保護と網膜の神経炎症の抑制におけるミノサイクリンの投与量が検討された。本実施例の目的は、デンドリマー−ミノサイクリンナノ物質(D−Mino)の効果を評価することである。デンドリマー複合体となったフルオシノロンアセトニドの効果に基づいて、この実施例は、RCSラット神経変性モデルに関連する網膜の神経炎症の抑制におけるD−Mino複合体の効果を評価するために行われた。ミノサイクリンはRCSラット網膜で高い神経保護とマイクログリア抑制を示すので、ミノサイクリンが使用された(Chang, C. J. et al., Ophthalmic Res. 2005;37:202-13; Hughes, E. H. et al., Exp Eye Res. 2004; 78(6): 1077-84; Shimazawa, M. et al., Brain Res. 2005;1053:185-94; Zhang, C. et al,. Invest Ophthalmol Vis Sci. 2004;45:2753-9)。
遊離のFITCとD−FITCの生体内分布と滞留時間
本実施例の目的は、遊離のFITCとD−FITCの硝子体内注射を用いて、網膜の神経保護を維持するために必要なデンドリマー−フルオシノロン(D−FA)の投与量を同定することである。この実験は、5週齢、体重150−180グラムのrdy遺伝子ホモ接合型劣性アルビノRCSラットの雌雄双方を用いて行われた。2群が確立された。遊離のFITC群は、それぞれが1μgの遊離のFITCの両面性の硝子体内の注射を受ける6匹の動物から成る。もうひとつの群は、D−FITCの硝子体内への注射を受ける10匹の動物である。
生体内で持続的な硝子体内D−FAの効果の評価
本実施例は、RCSラットで、持続的な網膜の光受容体の神経保護と、網膜電位b−波の振幅を維持するために、適切な投与と適切な投与間隔で、硝子体内への注射を繰り返すことによる持続的なD−FAの輸送を調べるために行われる。RCSラットは、0.2μgまたは1μgのD−FA投与(薬基準で)によって、15匹の2つの群に分けられる。1つの群の動物は、D−FAの硝子体内への注射を受け、もう1つの群は、PBS溶液(遊離のFAと遊離のデンドリマーを含む2%DMSO)を受ける。網膜電位の記録は、1ヶ月に1回行われる。D−FAと対照の再注射は、D−FA群の網膜電位B−波の振幅が、前2回の網膜電位記録の平均と比較して、10%まで下がったときに実行される。
注射可能な、持続的に放出される、混成[PLGA−(D−FA)ナノ物質]マイクロスフィアに基づく硝子体内への薬輸送基盤
本実施例は、PLGA−(D−FITC)マイクロスフィアの生体内分布と滞留時間を決定するために実行される。10匹の動物からなる1つの群が、実施例8の生体内分布の研究に加えられ、これらの動物は、PLGA−(D−FITC)マイクロ粒子の、両面性の硝子体内注射を受ける。これらの動物は、10日、1ヶ月、2ヶ月、4ヶ月、及び6ヶ月の時点で安楽死される。
RCSラットの網膜電位と光受容体の維持における混成[PLGA−(D−FA)ナノ物質]マイクロスフィアの薬力学的効果
実施例10に記載された実験における6ヶ月間のデータ収集とデータ解析の後で、本実施例は、成体RCSラットの網膜電位b−波の振幅の維持と、光受容体の細胞数の維持におけるPLGA−(D−FA)の単回注射の薬力学的効果を調べるために実行される。この研究では、実施例10に従って、実験的に効果が確認された放出速度でD−FAを放出するように、PLGA−(D−FA)マイクロスフィア構築された。
RCSラットにおけるデンドリマー複合体の、及び非複合体のフルオシノロンアセトニドの硝子体内注射に関連する網膜電位の知見
本実施例では、D−FAナノ物質の効果が、遊離の薬と同程度の薬の濃度と比較された。効果は網膜電位(ERG)と組織像を用いて解析された。この結果によって、もっとも低い投与濃度でのデンドリマーナノ物質の単回の硝子体内への注射によって、網膜電位の減少を防ぐだけでなく、網膜電位が十分に強化されることが示唆される。
1.3.0μgのデンドリマー複合体化されたフルオシノロンアセトニド(FA)の、1.0μLのリン酸緩衝液(PBS)溶液の硝子体内注射;
2.1.0μgのデンドリマー複合体化されたFAの、1.0μLのPBS溶液の硝子体内注射;
3.3.0μgのFAの、1.0μLのPBS溶液の硝子体内注射;
4.1.0μgのFAの、1.0μLのPBS溶液の硝子体内注射;
5.1.0μLのPBS溶液の硝子体内注射(対照群);
6.光に曝された未処理群
デンドリマーの生体内分布と効果及びナノ粒子の生体内分布と効果
本実施例によると、PAMAM−G4−OHデンドリマーは、RCSラットの変性した外顆粒への取り込みの強化を示すが、通常のSDラットでは示さない。このことは、神経炎症を標的にできるということを示唆する。遊離のFITCとデンドリマー複合体FITC(D−FITC)の網膜での生体内分布は、正常なスピローグ−ディウリー(SD)ラットと、強い神経炎症を伴う英国外科医師会網膜変性モデル(RCS)ラットで研究された。
Claims (36)
- ナノ規模の薬ナノ粒子製剤を含む組成物であって、
前記薬ナノ粒子製剤は、少なくとも1つの生物学的に活性な合成物を含むことを特徴とする組成物。 - 前記ナノ粒子の大きさが約500nm以下、約200nm以下、約150nm以下、約100nm以下、約90nm以下、約80nm以下、約70nm以下、約60nm以下、約50nm以下、約40nm以下、約30nm以下、約20nm以下、約19nm以下、約18nm以下、約17nm以下、約16nm以下、約15nm以下、約14nm以下、約13nm以下、約12nm以下、約11nm以下、約10nm以下、約5nm以下、約4nm以下、約3nm以下、約2nm以下、約1nm以下のいずれか、これらの間、若しくは、それ以下である、
ことを特徴とする請求項1に記載の組成物。 - 前記組成物は、マイクログリア、星状細胞、ミューラー細胞、マクロファージ、網膜色素上皮細胞、及び血管を含む神経炎症の過程に関連する複数の細胞種を対象として優先的に分布する性質を備える、
ことを特徴とする請求項1に記載の組成物。 - 前記生物学的に活性な合成物は、コルチコステロイド、抗炎症剤、ビタミン類、ペプチド、成長因子、中枢神経系刺激物、オリゴヌクレオチド、siRNA、マイクロRNA、レゾルビン、神経刺激物、及び神経保護物を含むグループから選択される、
ことを特徴とする請求項1に記載の組成物。 - 前記合成物は、フルオシノロンアセトニド、ラニビズマブ、ミノサイクリン、ラパマイシン、メチルプレドニゾン、デキサメタゾン、インシュリン、エストラジオール、毛様体神経栄養因子、ビタミンA、ビタミンC、ビタミンE、及びオリゴヌクレオチド、または、薬学的に許容されるこれらの塩を含むグループから選択される、
ことを特徴とする請求項4に記載の組成物。 - 前記ナノ粒子は、軟質のナノ粒子である、
ことを特徴とする請求項1に記載の組成物。 - 前記ナノ粒子は、デンドリマー様に枝分かれした、または星状に枝分かれした重合体である、
ことを特徴とする請求項6に記載の組成物。 - 前記デンドリマー様に枝分かれした重合体は、ポリアミドアミン(PAMAM)、プリオスター、ポリエステル、ポリエーテル、ポリリシン、またはポリエチレングリコール(PEG)デンドリマーから成って、
前記星状に枝分かれした重合体は、星状ポリエチレングリコールである、
ことを特徴とする請求項7に記載の組成物。 - 前記デンドリマーは、1.5ナノメートルから14.5ナノメートルの直径である、
ことを特徴とする請求項7に記載の組成物。 - 前記デンドリマーは、2ナノメートルから10ナノメートルの直径である、
ことを特徴とする請求項7に記載の組成物。 - 前記薬は、封入、錯体形成、または共有結合によって超分岐製剤に組み込まれる、
ことを特徴とする請求項1に記載の組成物。 - 前記結合は、前記薬と前記重合体をつなぐための、ペプチド、グルタル酸、またはポリエチレングリコールから成るスペーサを含む、
ことを特徴とする請求項11に記載の組成物。 - 前記薬ナノ粒子は、薬−超分岐重合体を取り込んでいるさらに大きい規模の物質に取り込まれていて、
前記さらに大きい規模の物質は、重合体マトリックス、マイクロ粒子、ナノ粒子、リポソーム、マイクロカプセル、ナノカプセル、注入可能なヒドロゲル、または放出制御される移植物質から成る、
ことを特徴とする請求項9に記載の組成物。 - ナノ規模の薬−超分岐重合体製剤であって、
移植可能な物質の被覆として用いられる、
ことを特徴とする請求項1に記載の組成物。 - 活性な合成物の持続的な放出が一定期間起こる、
ことを特徴とする請求項1に記載の組成物。 - 前記放出は、数分、数時間、数日、数月、または数年の間起こる、
ことを特徴とする請求項15に記載の組成物。 - 患者の対象部位への前記合成物の持続的な輸送をもたらす、
ことを特徴とする請求項1に記載の組成物。 - 前記対象部位は、眼の硝子体液である、
ことを特徴とする請求項17に記載の組成物。 - 前記持続的な輸送は、数時間にわたってである、
ことを特徴とする請求項17に記載の組成物。 - 前記持続的な輸送は、数日にわたってである、
ことを特徴とする請求項19に記載の組成物。 - 前記持続的な輸送は、数週間にわたってである、
ことを特徴とする請求項19に記載の組成物。 - 前記持続的な輸送は、数ヶ月にわたってである、
ことを特徴とする請求項19に記載の組成物。 - 少なくとも1つの、デンドリマーへ複合体化された抗炎症合成物を含む組成物であって、
前記組成物は、PLAナノ粒子及びPGLAマイクロ粒子から成るグループから選択される生物分解性の粒子に封入される、
ことを特徴とする組成物。 - 前記デンドリマーは、ヒドロキシ基またはカルボキシル基で終端となって、PAMAMまたはプリオスター群に属し、
前記抗炎症合成物は、フルオシノロンアセトニド、ミノサイクリン、メチルプレドニゾン、及びデキサメタゾンから成るグループから選択される、
ことを特徴とする請求項23に記載の組成物。 - 請求項1に記載の組成物を投与することを含む、神経炎症関連疾患の治療方法であって、
前記神経炎症関連疾患は、網膜、中枢神経系、脊髄、及び/または末梢神経系の疾患である神経炎症関連疾患の治療方法。 - 網膜の疾患の治療方法であって、
組成物は、硝子体内に、適切な用量と間隔において注入され、加齢性黄斑変性症(ARMD)を治療する、
ことを特徴とする請求項25に記載の治療方法。 - 中枢神経系の疾患の治療方法であって、
組成物は、髄腔内に、適切な用量と間隔において注入され、脳性麻痺を治療する、
ことを特徴とする請求項25に記載の治療方法。 - 前記疾患は、網膜色素変性症、加齢性黄斑変性症、視神経炎、眼への、感染、サルコイド、鎌状赤血球病、網膜剥離、側頭動脈炎、網膜虚血、動脈硬化性網膜症、高血圧性網膜症、網膜動脈の閉塞、網脈静脈の閉塞、低血圧症、糖尿病性網膜症、及び黄斑浮腫を含む眼疾患のグループから選択される疾患である、
ことを特徴とする請求項25に記載の治療方法。 - 前記疾患は、脳卒中、脳性麻痺、脳への鈍傷及び貫通性外傷、アルツハイマー病、パーキンソン病、脳または脊髄の損傷、サルコイド、鎌状赤血球病、エイズ認知症、加齢性認知能力の減少、記憶障害、筋萎縮性側索硬化症、発作性疾患、アルコール依存症、加齢、及び神経細胞の脱落を含む、中枢または末梢神経系の疾患のグループから選択される疾患である、
ことを特徴とする請求項25に記載の治療方法。 - ヒトの進行性の失明の治療方法であって、
請求項1に記載の組成物を前記ヒトの眼に投与することを含む方法。 - 前記進行性の失明は、ブドウ膜炎、加齢性黄斑変性症、糖尿病性網膜症、及び網膜色素変性症から成るグループから選択される、少なくとも1つの病態と関連する、
ことを特徴とする請求項30に記載の方法。 - ヒトの眼球の神経炎症の治療方法であって、
請求項23に記載の組成物を少なくとも1つを前記ヒトの眼に投与することを含む方法。 - 前記投与が1回である、
ことを特徴とする請求項32に記載の方法。 - 前記投与が、数日間、数週間または数ヶ月にわたって、2回または2回以上である、
ことを特徴とする請求項32に記載の方法。 - 請求項1に記載の組成物及び前記組成物を投与する方法を含む医療機器。
- 請求項23に記載の組成物及び前記組成物を投与する方法を含む医療機器。
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JP2020514410A (ja) * | 2017-01-25 | 2020-05-21 | 2シー テック コーポレイション | 眼薬持続送達用のナノ粒子および使用法 |
JP2020520393A (ja) * | 2017-04-27 | 2020-07-09 | ザ・ジョンズ・ホプキンス・ユニバーシティー | 血管造影において使用するためのデンドリマー組成物 |
JP7178108B2 (ja) | 2017-04-27 | 2022-11-25 | ザ・ジョンズ・ホプキンス・ユニバーシティー | 血管造影において使用するためのデンドリマー組成物 |
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US11684569B2 (en) | 2023-06-27 |
JP5484339B2 (ja) | 2014-05-07 |
EP2214646A2 (en) | 2010-08-11 |
HUE055815T2 (hu) | 2021-12-28 |
US20110034422A1 (en) | 2011-02-10 |
PL2214646T3 (pl) | 2021-12-20 |
EP2214646A4 (en) | 2014-08-27 |
EP2214646B1 (en) | 2021-06-23 |
US20200390694A1 (en) | 2020-12-17 |
WO2009046446A2 (en) | 2009-04-09 |
CA2701291A1 (en) | 2009-04-09 |
US20160279054A1 (en) | 2016-09-29 |
US20170216200A1 (en) | 2017-08-03 |
WO2009046446A3 (en) | 2009-06-04 |
US10463609B2 (en) | 2019-11-05 |
PT2214646T (pt) | 2021-09-29 |
DK2214646T3 (da) | 2021-10-04 |
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