JP6887713B2 - 両親媒性高分子 - Google Patents
両親媒性高分子 Download PDFInfo
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- JP6887713B2 JP6887713B2 JP2018554686A JP2018554686A JP6887713B2 JP 6887713 B2 JP6887713 B2 JP 6887713B2 JP 2018554686 A JP2018554686 A JP 2018554686A JP 2018554686 A JP2018554686 A JP 2018554686A JP 6887713 B2 JP6887713 B2 JP 6887713B2
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Description
第1ブロックを形成するポリエチレングリコールモノメチルエーテル(polyethyleneglycol monomethyl ether;mPEG−OH)高分子(分子量:5000、製造社:Aldrich)をジクロロメタンに30%濃度で溶解させた後、−OH官能基に対して、トリエチルアミン3当量と2−ブロモイソブチリルブロミド2当量を入れ、反応させてATRP用開始剤を製造する。その後、ジエチルエーテル溶媒に沈殿および捕集過程を2回繰り返して乾燥させて、不純物が除去されたプロミン末端のポリエチレングリコール高分子を収得する。前記収得したブロミン末端のポリエチレングリコール高分子100重量部をフラスコ上でアニソール反応溶媒250重量部に溶かし、スチレン(溶解度パラメーター:8.7(cal/cm3)1/2、B1)17重量部、メチルメタクリレート(溶解度パラメーター:9.5(cal/cm3)1/2、B2)を154重量部を投入し、ゴム栓でフラスコをシールした。その後、常温で30分間窒素パージングおよび撹拌を通じて溶存酸素を除去し、60℃にセットされているオイルバス(oil bath)に浸漬し、第2臭化銅錯体と触媒還元剤を投入して反応を進めた。所望の分子量が製造されると、反応を終了して、両親媒性高分子(P1)を製造した。前記両親媒性高分子(P1)の分子量およびブロック比(A:B)と第2ブロック(B)内の重合単位重量比(B1:B2)は、下記表1に示された通りである。
第1ブロックを形成するポリエチレングリコールモノメチルエーテル(polyethyleneglycol monomethyl ether;mPEG−OH)高分子(分子量:5000、製造社:Aldrich)ジクロロメタンに30%濃度で溶解させた後、−OH官能基に対して、4−シアノ−4−[(ドデシルスルファニルチオカルボニル)スルファニル]ペンタン酸1.5当量と、1、3−ジシクロヘキシルカルボジイミド1.5当量および4−(ジメチルアミノ)ピリジン1.5当量を入れ、反応させてRAFT用開始剤を製造する。その後、ジエチルエーテル溶媒に沈殿および捕集過程を2回繰り返して乾燥させて、不純物が除去されたRAFT剤の末端のポリエチレングリコール高分子を収得する。前記収得したRAFT剤の末端のポリエチレングリコールモノメチルエーテル高分子をフラスコ上でアニソール反応溶媒に溶かし、N、N−ジメチルビニルベンジルアミン(B1):メチルメタクリレート(溶解度パラメーター:9.5(cal/cm3)1/2、B2)を10:90の重量比で投入し、ゴム栓でフラスコをシールした。その後、常温で30分間窒素パージングおよび撹拌を通じて溶存酸素を除去し、60℃にセットされているオイルバスに浸漬し、AIBNを投入して反応を進めた。所望の分子量が製造されると、反応を終了して両親媒性高分子(P2)を製造した。前記両親媒性高分子(P2)の分子量およびブロック比(A:B)と第2ブロック(B)内の重合単位重量比(B1:B2)は、下記表1に示された通りである。
TEMPO((2、2、6、6−Tetramethyl−piperidin−1−yl)oxyl)5重量部に対してNaH 2.5重量部を10%濃度でDMF(dimethylformaldehyde)に溶解させて、リフラックス(Reflux)下に1時間撹拌した後、DMF(dimethylformaldehyde)に20%濃度で溶解したブロミン末端のポリエチレングリコールモノメチルエーテル(実施例1で製造)高分子100重量部を滴下する。24時間リフラックス下に撹拌した後、過量のNaHをメタノールを滴下させて除去した後、ジエチルエーテル溶媒に沈殿および捕集過程を2回繰り返して乾燥させて、不純物が除去されたアルコキシアミン末端のポリエチレングリコール高分子を収得する。前記で製造されたアルコキシアミン末端のポリエチレングリコールモノメチルエーテル高分子をフラスコ上でアニソール反応溶媒に溶かし、4−3−ビニルフェニルピリジン(B1):メチルメタクリレート(溶解度パラメーター:9.5(cal/cm3)1/2、B2)を30:70重量比で投入した後、ゴム栓でフラスコをシールした。その後、常温で30分間窒素パージングおよび撹拌を通じて溶存酸素を除去し、120℃にセットされているオイルバスに浸漬して反応を進めた。所望の分子量が製造されると、反応を終了して両親媒性高分子(P1)を製造した。前記両親媒性高分子(P1)の分子量およびブロック比(A:B)と第2ブロック(B)内の重合単位重量比(B1:B2)は、下記表1に示された通りである。
第1ブロックを形成するポリエチレングリコールモノメチルエーテル高分子(分子量:5000、製造社:Aldrich)をジクロロメタンに30%濃度で溶解させた後、−OH官能基に対して、4−シアノ−4−[(ドデシルスルファニルチオカルボニル)スルファニル]ペンタン酸1.5当量と、1、3−ジシクロヘキシルカルボジイミド1.5当量および4−(ジメチルアミノ)ピリジン1.5当量を入れ、反応させてRAFT用開始剤を製造する。その後、ジエチルエーテル溶媒に沈殿および捕集過程を2回繰り返して乾燥させて、不純物が除去されたRAFT剤の末端のポリエチレングリコール高分子を収得する。前記収得したRAFT剤の末端のポリエチレングリコールモノメチルエーテル高分子をフラスコ上でアニソール反応溶媒に溶かし、スチレン(B1):メチルメタクリレート(溶解度パラメーター:9.5(cal/cm3)1/2、B2)を50:50重量比で投入し、ゴム栓でフラスコをシールした。その後、常温で30分間窒素パージングおよび撹拌を通じて溶存酸素を除去し、80℃にセットされているオイルバスに浸漬し、AIBNを投入して反応を進めた。所望の分子量が製造されると、反応を終了して両親媒性高分子を製造した。
第1ブロックを形成するポリエチレングリコールモノメチルエーテル高分子(分子量:5000、製造社:Aldrich)をSn(Oct)2と2口丸底フラスコで110℃、真空下に4時間乾燥させて水分を除去した後、反応器を常温に冷却した。窒素雰囲気の反応器にポリエチレングリコールモノメチルエーテルと同量のε−カプロラクトンを添加した後、60℃で1時間真空乾燥した。反応器を窒素雰囲気で130℃に徐々に昇温して、18時間反応させ、室温に冷却して反応を終結させた。室温に冷却した反応器にメチレンクロリドを添加して反応物を溶かした後、過量の冷たいエチルエーテルに徐々に添加しつつ共重合体を沈殿させた。沈殿したブロック共重合体は、フィルタリングした後、48時間40℃で真空乾燥させて、最終的にポリエチレングリコール(A)−ポリカプロラクトン(B)共重合体(P5)を得た。
共重合体の合成時にポリエチレングリコールモノメチルエーテルに対して2倍量のε−カプロラクトンを添加したことを除いて、比較例1と同じ方式で合成して、ポリエチレングリコール(A)−ポリカプロラクトン(B)共重合体(P6)を製造した。
第1ブロックを形成するポリエチレングリコールモノメチルエーテル高分子(分子量:5000、製造社:Aldrich)をジクロロメタンに30%濃度で溶解させた後、−OH官能基に対して、トリエチルアミン3当量と2−ブロモイソブチリルブロミド2当量を入れ、反応させてATRP用開始剤を製造する。その後、ジエチルエーテル溶媒に沈殿および捕集過程を2回繰り返して乾燥させて、不純物が除去されたブロミンの末端のポリエチレングリコール高分子を収得する。前記収得したブロミン末端のポリエチレングリコール高分子100重量部をフラスコ上でアニソール反応溶媒250重量部に溶かし、メチルメタクリレートを150重量部投入し、ゴム栓でフラスコをシールした。その後、常温で30分間窒素パージングおよび撹拌を通じて溶存酸素を除去し、60℃にセットされているオイルバスに浸漬し、第2臭化銅錯体と触媒還元剤を投入して反応を進めた。所望の分子量が製造されると、反応を終了して両親媒性高分子を製造した。
TEMPO((2、2、6、6−Tetramethyl−piperidin−1−yl)oxyl)5重量部に対してNaH 2.5重量部を10%濃度でDMF(dimethylformaldehyde)に溶解させてリフラックス下に1時間撹拌した後、DMF(dimethylformaldehyde)に20%濃度で溶解したブロミン末端のポリエチレングリコールモノメチルエーテル(実施例1で製造)高分子100重量部を滴下する。24時間リフラックス下に撹拌した後、過量のNaHをメタノールを滴下させて除去した後、ジエチルエーテル溶媒に沈殿および捕集過程を2回繰り返して乾燥させて、不純物が除去されたアルコキシアミン末端のポリエチレングリコール高分子を収得する。前記で製造されたアルコキシアミンの末端のポリエチレングリコールモノメチルエーテル高分子をフラスコ上でアニソール反応溶媒に溶かし、スチレン(B1)を投入した後、ゴム栓でフラスコをシールした。その後、常温で30分間窒素パージングおよび撹拌を通じて溶存酸素を除去し、120℃にセットされているオイルバスに浸漬して反応を進めた。所望の分子量が製造されると、反応を終了して両親媒性高分子を製造した。
製造された両親媒性高分子(P1〜P8)のブロック比および分子量を下記方法によって評価して、表1に示した。
合成された両親媒性高分子(P1〜P8)を利用して難溶性物質であるゲニステインをカプセル化した。まず、両親媒性高分子10gを30mLのエタノールに溶かした溶液をジプロピレングリコール(Dipropylene glycol、DPG))20gにゲニステイン2gを溶かした溶液と混合した。0.5%ポリビニルアルコール水溶液100mLに撹拌しつつ前記溶液を徐々に添加した。エタノール溶媒を蒸発するために所定時間撹拌して放置した後、残余のエタノールをロータリーエバポレーターを利用して除去して、ゲニステインの含量が2%になるように溶液を製造した。製造した溶液を10倍の精製水で希釈した後、7日間常温(25℃)で保管して、経時変化の有無を濁度測定装置(Turbidity measurement)で確認して表2に示した。Formulaction社のタービスキャン(Turbiscan)を利用して測定し、7日間保管した溶液の上澄み液を分取して透過度を測定し、下記数式1によって濁度(Turbidity)を示した。
前記実験例2においてゲニステインの含量が2%になるように製造した溶液を10倍の精製水で希釈した後、シリンジフィルター(気孔サイズ:1μm)で濾過して析出したゲニステインを除去した後、液体クロマトグラフィー(HPLC)から両親媒性高分子ミセル粒子にカプセル化されたゲニステインの含量を測定した。両親媒性高分子の薬物捕集容量(Drug loading capacity)および薬物捕集効率(Drug loading efficiency)は、次のような式により計算され、薬物が捕集された両親媒性高分子を含むミセルの粒子のサイズは、Malvern社のZetasizer 3000を利用して測定した。
200 両親媒性高分子
201 第1ブロック
202 第2ブロック
Claims (26)
- 第1ブロック(A)と;
前記第1ブロック(A)と相分離し、下記化学式1を満たす重合性単量体の重合単位(B1)および単一高分子の溶解度パラメーターが10.0(cal/cm3)1/2未満であるアクリル系単量体またはビニル系単量体の重合単位(B2)を含む第2ブロック(B)と;を含み、
前記重合単位(B1)と重合単位(B2)が異なる重合単位である両親媒性高分子であって、
前記第1ブロックが親水性部位であり、第2ブロックが疎水性部位である、両親媒性高分子:
- 前記第1ブロック(A)は、溶解度パラメーターが10(cal/cm3)1/2以上である高分子を含む、請求項1に記載の両親媒性高分子。
- 前記第1ブロック(A)は、ポリエチレングリコール、ポリエチレングリコール−プロピレングリコール共重合体、ポリビニルピロリドンおよびポリエチレンイミンよりなる群から選択されるいずれか一つである、請求項1に記載の両親媒性高分子。
- 前記化学式2のQは、水素または炭素数1〜4のアルキル基であり、Bは、炭素数1以上のアルキル基または炭素数6〜12の脂環式炭化水素基である、請求項4に記載の両親媒性高分子。
- 前記第2ブロック(B)内の前記化学式1を満たす重合性単量体の重合単位(B1)と単一高分子の溶解度パラメーターが10.0(cal/cm3)1/2未満であるアクリル系単量体またはビニル系単量体の重合単位(B2)の重量比(B1:B2)は、0.5:99.5〜50:50の範囲内にある、請求項1に記載の両親媒性高分子。
- 前記第2ブロック(B)内の前記化学式1を満たす重合性単量体の重合単位(B1)と単一高分子の溶解度パラメーターが10.0(cal/cm3)1/2未満であるアクリル系単量体またはビニル系単量体の重合単位(B2)の重量比(B1:B2)は、1:99〜30:70である、請求項7に記載の両親媒性高分子。
- 前記第1ブロック(A)と第2ブロック(B)のブロック比(A:B)は、互いに異なる、請求項1に記載の両親媒性高分子。
- 前記第1ブロック(A)と第2ブロック(B)のブロック比(A:B)は、1:9〜9:1である、請求項1に記載の両親媒性高分子。
- 前記第1ブロック(A)と第2ブロック(B)のブロック比(A:B)は、3:7〜7:3である、請求項10に記載の両親媒性高分子。
- 請求項1に記載の両親媒性高分子を含むミセル。
- 前記両親媒性高分子によりカプセル化されている薬物をさらに含む、請求項12に記載のミセル。
- 前記両親媒性高分子の第2ブロックが薬物に隣接する、請求項13に記載のミセル。
- 平均粒径が1nm〜10,000nmの範囲内にある、請求項12に記載のミセル。
- 前記薬物は、生理活性物質を含む、請求項13に記載のミセル。
- 前記生理活性物質は、難溶性である、請求項16に記載のミセル。
- 前記難溶性である生理活性物質は、ゲニステイン、ダイゼイン、ククルビタシン、プランゲニジンまたはこれらの誘導体;ポリフェノール;および
これらの混合物;よりなる群から選択されるいずれか一つである、請求項17に記載のミセル。 - 請求項12に記載のミセルを含む粒子製造用組成物。
- 前記ミセルは、両親媒性高分子によりカプセル化されている薬物をさらに含む、請求項19に記載の粒子製造用組成物。
- 請求項12に記載のミセルを含む薬学組成物。
- 前記ミセルは、両親媒性高分子によりカプセル化されている薬物をさらに含む、請求項21に記載の薬学組成物。
- 油中水型または水中油型のエマルジョン形態である、請求項22に記載の薬学組成物。
- 請求項12に記載のミセルを含む化粧料組成物。
- 前記ミセルが両親媒性ポリマーによりカプセル化されている薬剤をさらに含む、請求項24に記載の化粧料組成物。
- 油中水型または水中油型のエマルジョン形態である、請求項25に記載の化粧料組成物。
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