JP2007534729A - ペグ化ナノ粒子 - Google Patents
ペグ化ナノ粒子 Download PDFInfo
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- JP2007534729A JP2007534729A JP2007510054A JP2007510054A JP2007534729A JP 2007534729 A JP2007534729 A JP 2007534729A JP 2007510054 A JP2007510054 A JP 2007510054A JP 2007510054 A JP2007510054 A JP 2007510054A JP 2007534729 A JP2007534729 A JP 2007534729A
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- Prior art keywords
- nanoparticles
- polyethylene glycol
- peg
- pegylated
- nanoparticle
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Abstract
Description
本発明は生物分解性ポリマーとポリエチレングリコールを基材とするペグ化(pegylated)ナノ粒子、それらを含む処方物でペグ化(pegylated)ナノ粒子を製造する方法、および薬物投与系としてのそれらの使用に関する。
近年、生物分解性のポリマー性ナノ粒子が新規な薬物投与系として提案されてきている。それらが提供する最も重要な性質の一つは、組込まれた薬物の制御放出である。これにより、大きな治療効果が得られ、患者にとって投与がより苦痛の無いものとなり、かつ過剰摂取を防止することができる。さらに、様々な物理化学的特性を有する薬物を包含することができ、体液中でのそれらの安定性を向上させることができる。この事実は、一般に、抗原、タンパク質、および高分子の場合に極めて重要である。さらに、ナノ粒子の大きさが小さいため、ナノ粒子は経口、非経口、および点眼のような様々な経路を通る薬物の投与に適している(Kreuter, Adv. Drug Del. Rey., 7 (1991) 71-86、Gref et al., Science, 263 (1994) 1600-1603、Zimmer and Kreuter, Adv. Drug Del. Rev., 16 (1995) 61-73)。
HO - (CH2-CH2-O)n - H
(式中、(n)はEOモノマーまたは単位の数である)を有する直鎖のポリマーである。これらの単位はあるいはプロピレン基を含む。
ポリオキシエチレンエステル: PEGモノメチルエーテルモノスクシンイミジルコハク酸エステル、PEGモノメチルエーテルモノカルボキシメチルエーテル、PEGアジピン酸、PEGジステアリン酸塩、PEGモノステアリン酸塩、PEGヒドロキシステアリン酸塩、PEGジラウリン酸塩、PEGジオレイン酸塩、PEGモノオレイン酸塩、PEGモノリシンオレイン酸塩、PEGヤシ油エステル。
ポリオキシエチレンアルキルエーテル: PEGモノメチルエーテルまたはメトキシPEG (mPEG)、PEGジメチルエーテル。
その他: ポリ(エチレングリコールテレフタレート)、ポリオキシエチレン誘導体、およびソルビタンエステルおよび脂肪酸、エチレンオキシドとプロピレンオキシドのコポリマー、エチレンオキシドとアクリルアミドとのコポリマー。
PEG誘導体: O,O'-ビス-(2-アミノエチル)ポリエチレングリコール(DAE-PEG 2000)、O,O'-ビス-(2-アミノプロピル)ポリプロピレングリコール-ポリエチレングリコール-ポリプロピレングリコール。
a) H(OCH2CH2)nOH
b) H3C(OCH2CH2)nOH
c) H2N(CH2CH2O)nCH2CH2NH2
d) H2NCHCH3CH2(OCHCH3CH2)(OCH2CH2)n(OCH2CHCH3)NH2
a) ポリエチレングリコール400、1000、または2000(PEG 400、PEG 1000、またはPEG 2000)、
b) ポリエチレングリコールメチルエーテル2000(mPEG 2000)、
c) O,O'-ビス-(2-アミノエチル)ポリエチレングリコール2000(DAE-PEG 2000)、
d) O,O'-ビス-(2-アミノプロピル)ポリプロピレングリコール-ポリエチレングリコール-ポリプロピレングリコール(DAP-PEG 2000)
a) 疎水性薬物: 有機相(アセトン)へ添加、および攪拌(機械、磁気、または超音波攪拌)を行いながら可変時間(一時間まで)、PVMMAおよびPEGと合同培養/溶媒和。
b) 親水性薬物: 有機相(アセトン)へ添加、および希薄アセトン懸濁液を得るまで攪拌(機械、磁気、または超音波攪拌)を行いながら可変時間(一時間まで)、PVMMAおよびPEGと合同培養。この方法はタンパク質モデル(卵白アルブミン、44kDaのタンパク質)を封入するのに良好に用いられてきた。配合は効率的であり、タンパク質モデルを高率で封入することができた。
c) 親水性薬物: 水相へ添加して、予備成形したナノ粒子と培養(これは実施例で用いる二種類の蛍光マーカー(FITCおよびRBITC)を封入するのに用いられる場合である)。
ポリエチレングリコール2000 (PEG-NP)を用いるペグ化(pegylated)ナノ粒子の調製
二つの方法を試験した:
有機相での二種類のポリマーの混合。
予備成形したナノ粒子のPEGによるコーティング。
この方法は有機相でのPVM/MAおよびPEG 2000の同時培養によって行われる。
PVM/MA 100mgを有機溶媒(アセトン)5mlに溶解させる。次に、エタノール10mlおよび蒸留水10mlをこの溶液に攪拌しながら加える。生成する混合物を5分間均質化させる。次に、ナノ粒子懸濁液をいずれの溶媒も除去されるまで減圧留去する。水性ナノ懸濁液の容積を水で5mlに調節し、PEG 2000 10-25mgを含む水溶液5mlを加える。ポリエチレングリコール中でのナノ粒子の培養はマグネティックスターラーを用いて一時間行う。懸濁液を遠心分離(17000rpmで20分間、二回)(Sigma 3K30、ドイツ)によって精製する。上清を除いて、残渣をスクロース水溶液(5%(w/v))に再懸濁する。ナノ粒子懸濁液を最後にGenesis 12EL装置(Virtis、米国)で凍結させ、凍結乾燥させる。
工程を実施例1.1に記載のPVM/MAと所望なポリエチレングリコール(PEG 400、PEG 1000、またはPEG 2000)の同時培養によって行う。
ポリエチレングリコールメチルエーテル2000(mPEG-NP)を用いるペグ化(pegylated)ナノ粒子の調製
この方法は有機相でのPVM/MAとmPEGの同時培養によって行われる。
O,O'-ビス-(2-アミノエチル)ポリエチレングリコール2000を用いるペグ化(pegylated)ナノ粒子の調製(DAE-PEG-NP)
この方法は有機相でのPVM/MAおよびDAE-PEG 2000の同時培養により行われる。
O,O'-ビス-(2-アミノプロピル)-プロピレングリコール-ポリエチレングリコール-ポリプロピレングリコール2000 (DAP-PEG-NP)を用いるペグ化(pegylated)ナノ粒子の調製
この方法は有機相でのPVM/MAおよびDAP-PEG 2000の同時培養によって行われる。
ペグ化(pegylated)ナノ粒子の工程収率および構造の検討
図3はナノ粒子に変換されるPVM/MAの割合および工程の総収率におけるポリエチレングリコールの種類の影響を示している。一般にナノ粒子に変換されるコポリマーの割合は約73%である。ナノ粒子をPEGまたはmPEGで修飾すると、粒子に変換されるPVM/MAの割合はあまり変更されないことが観察される。しかしながら、DAE-PEGまたはDAP-PEGを用いるナノ粒子のペグ化(pegylation)は工程収率を減少させる。
ラットの消化管におけるペグ化(pegylated)ナノ粒子の生体接着特性の検討
この研究は動物実験に関する欧州法(86/609/EU)に従いナバラ大学の倫理委員会の規則に従って行った。
消化管粘膜におけるペグ化(pegylated)ナノ粒子の観察
消化管粘膜におけるペグ化(pegylated)ナノ粒子を蛍光顕微鏡法および光学顕微鏡法によって観察する。その目的のため、ペグ化(pegylated)ナノ粒子をローダミンBイソチオシアネート(RBITC)およびフルオレセインイソチオシアネート(FITC)のような蛍光分子で標識した。ラットで経口投与の後、腸の様々な部分を集めて、前記のように食塩リン酸緩衝液(pH=7.4、0.15M)で洗浄する。
Claims (27)
- 生物分解性ポリマーと、ポリエチレングリコールまたはその誘導体とを含んでなる、生物活性分子を運搬するためのペグ化(pegylated)ナノ粒子。
- 前記生物分解性ポリマーが、ビニルメチルエーテル・無水マレイン酸(PVM/MA)コポリマーである、請求項1に記載のナノ粒子。
- 前記コポリマーの分子量が100-2400KDa、さらに好ましくは200-2000KDa、特に好ましくは180-250KDaである、請求項2に記載のナノ粒子。
- 前記ポリエチレングリコールまたはその誘導体の分子量が400-35,000Daである、先行する請求項のいずれか一項に記載のナノ粒子。
- 前記ポリエチレングリコールが、ポリエチレングリコール、ポリプロピレングリコール、これら二種類の単位を含むブロックまたはランダムコポリマー、それらの混合物、またはそれらの誘導体からなる群から選択される、先行する請求項のいずれか一項に記載のナノ粒子。
- 前記ポリエチレングリコールが、好ましくはアルコキシ、アクリレート、メタクリレート、アルキル、アミノ、リン酸塩、イソチオシアネート、スルフヒドリル、メルカプト、または硫酸基で修飾された少なくとも一個の末端水酸基を有する、先行する請求項のいずれか一項に記載のナノ粒子。
- 前記ポリアルキレングリコールが、ポリエチレングリコール2000、ポリエチレングリコールメチルエーテル2000、O,O'-ビス-(2-アミノエチル)ポリエチレングリコール2000、O,O'-ビス(2-アミノプロピル)プロピレングリコール-ポリエチレングリコール-ポリプロピレングリコール2000、またはそれらの混合物からなる群から選択される、先行する請求項のいずれか一項に記載のナノ粒子。
- ポリエチレングリコールと前記生物分解性ポリマーの重量比が1:2-6、好ましくは1:2-4、さらに好ましくは約1:4である、先行する請求項のいずれか一項に記載のナノ粒子。
- 活性分子としてタンパク質またはペプチドを含んでなる、先行する請求項のいずれか一項に記載のナノ粒子。
- DNA、RNA、ヌクレオシド、ヌクレオチド、オリゴヌクレオチド、またはポリヌクレオチドからなる群から選択される化合物を活性分子として含んでなる、先行する請求項のいずれか一項に記載のナノ粒子。
- 抗腫瘍薬または腫瘍に対する抗原を活性分子として含んでなる、先行する請求項のいずれか一項に記載のナノ粒子。
- 中枢神経系の保護薬、または糖質コルチコイドを活性分子として含んでなる、先行する請求項のいずれか一項に記載のナノ粒子。
- ワクチン接種に対する抗原、または免疫療法に対するアレルゲンを活性分子として含んでなる、先行する請求項のいずれか一項に記載のナノ粒子。
- 請求項1−13のいずれか一項に記載のペグ化(pegylated)ナノ粒子を、賦形剤、担体、またはアジュバントと共に含んでなる、医薬組成物。
- 生物体の粘膜へ接近できる経路によって投与される、好ましくは経口投与、直腸投与、経鼻投与、経膣投与、または点眼投与するための、請求項14に記載の医薬組成物。
- 経口投与用の、請求項15に記載の医薬組成物。
- 点眼投与用の、請求項15に記載の医薬組成物。
- 薬剤の製造のための、請求項1−13のいずれか一項に記載のナノ粒子の使用。
- 請求項1−13のいずれか一項に記載のペグ化(pegylated)ナノ粒子を含んでなる、凍結乾燥生成物。
- 前記ポリマーと前記ポリエチレングリコールとを有機溶媒中で同時にインキュベートした後、前記ポリマーを水性アルコール溶液で脱溶媒和する工程を含んでなる、請求項1−13のいずれか一項に記載のペグ化(pegylated)ナノ粒子の製造方法。
- 前記生物分解性ポリマーの濃度が0.001-10%(w/v)であり、前記ポリアルキレングリコールの濃度が0.001-5%(w/v)である、請求項20に記載の方法。
- 前記有機相/水性アルコール溶液比が1/1-1/10の範囲である、請求項20または21に記載の方法。
- 前記有機溶媒の除去および/または精製の工程をさらに含んでなる、請求項20−22のいずれか一項に記載の方法。
- 前記活性分子を、前記ポリマーと前記ポリエチレングリコールとを有機溶媒中で同時にインキュベートする工程において加える、請求項20−23のいずれか一項に記載の方法。
- 前記活性分子を既に形成したナノ粒子の水性懸濁液に加える、請求項20−23のいずれか一項に記載の方法。
- 場合によって凍結防止剤の存在下での、好ましくはスクロースまたはマンニトールの存在下での、凍結乾燥工程をさらに含んでなる、請求項20−25のいずれか一項に記載の方法。
- 前記生物分解性ポリマーが、前記ビニルメチルエーテル・無水マレイン酸(PVM/MA)コポリマーであり、好ましくは分子量が100-2400kDaである、請求項20−26のいずれか一項に記載の方法。
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WO2005104648A3 (es) | 2005-12-08 |
MXPA06012583A (es) | 2007-03-21 |
ATE442841T1 (de) | 2009-10-15 |
CN1976688A (zh) | 2007-06-06 |
EP1752142A2 (en) | 2007-02-14 |
AU2005237270B2 (en) | 2011-02-17 |
RU2400215C2 (ru) | 2010-09-27 |
AU2005237270A1 (en) | 2005-11-10 |
CA2564982C (en) | 2015-04-21 |
ES2246694A1 (es) | 2006-02-16 |
EP1752142B1 (en) | 2009-09-16 |
DE602005016674D1 (de) | 2009-10-29 |
BRPI0509827B8 (pt) | 2021-05-25 |
US8628801B2 (en) | 2014-01-14 |
RU2006142100A (ru) | 2008-06-20 |
ES2246694B1 (es) | 2007-05-01 |
BRPI0509827A (pt) | 2007-10-23 |
WO2005104648A2 (es) | 2005-11-10 |
ES2333659T3 (es) | 2010-02-25 |
CA2564982A1 (en) | 2005-11-10 |
US20080248125A1 (en) | 2008-10-09 |
BRPI0509827B1 (pt) | 2020-11-03 |
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