JP5394244B2 - 生体吸収性ポリマー - Google Patents
生体吸収性ポリマー Download PDFInfo
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- JP5394244B2 JP5394244B2 JP2009532888A JP2009532888A JP5394244B2 JP 5394244 B2 JP5394244 B2 JP 5394244B2 JP 2009532888 A JP2009532888 A JP 2009532888A JP 2009532888 A JP2009532888 A JP 2009532888A JP 5394244 B2 JP5394244 B2 JP 5394244B2
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- caprolactone
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Description
(a)カプロラクトン部位及びポリ(アルキレンオキシド)部位の共重合単位を含むプレポリマー、
(b)カプロラクトン及び炭素数2〜6のジオールの共重合単位を含むポリカプロラクトンジオール、及び
(c)ジイソシアネート
を共に反応して得られるポリマーが提供される。
その他、本発明は上記(a)、(b)、(c)の成分を共に結合したものに由来する部位を含むポリマーを提供する。
(1)(a)カプロラクトン部位及びポリ(アルキレンオキシド)部位の共重合単位を含むプレポリマー、
(b)カプロラクトン及び炭素数2〜6のジオールの共重合単位を含むポリカプロラクトンジオール、
(c)ジイソシアネート
を提供すること、及び
(2)成分(a)、(b)、(c)を共に反応することを含むポリマーの製造方法が提供される。
出願人は、本明細書に記載された目的が本発明のポリマー、特にカプロラクトン−PEGポリウレタン共重合体により達成されることを実証した。
PEGブロック長(400、600、2000、4000、8000g/mol)及びカプロラクトンブロック長(500〜3500g/mol)を変え、目的のプレポリマーの分子量が1000〜11000g/molの間になるよう選択した。プレポリマーのバッチサイズは、約500〜600gとした。プレポリマーは下記の通り組成を変えて製造した(表1参照):
バッチA)PEG400 273.00g(15.7モル%)、カプロラクトン 418.17g(84.3モル%)及びオクタン酸スズ(II)(tin(II)octoate)、 0.528g(0.03モル%)を用い、理論分子量1013g/molを目的として製造したプレポリマーA、
バッチB)PEG400 90.05g(5.0モル%)、カプロラクトン 488.10g(94.97モル%)及びオクタン酸スズ(II) 0.547g(0.03モル%)を用い、理論分子量2568g/molを目的として製造したプレポリマーB、
バッチC)PEG400 29.95g(1.6モル%)、カプロラクトン 525.48g(98.37モル%)及びオクタン酸スズ(II) 0.569g(0.03モル%)を用い、理論分子量7418g/molを目的として製造したプレポリマーC、
バッチD)PEG600 122.25g(5.0モル%)、カプロラクトン 441.76g(94.97モル%)及びオクタン酸スズ(II) 0.495g(0.03モル%)を用い、理論分子量2768g/molを目的として製造したプレポリマーD、
バッチE)PEG600 46.80g、カプロラクトン 547.41g及びオクタン酸スズ(II) 0.592g(0.03モル%)を用い、理論分子量7618g/molを目的として製造したプレポリマーE、
バッチF)PEG2000 330.31g(5.0モル%)、カプロラクトン 358.09g(94.97モル%)及びオクタン酸スズ(II) 0.401g(0.03モル%)を用い、理論分子量4168g/molを目的として製造したプレポリマーF、
バッチG)PEG2000 152.76g(1.6モル%)、カプロラクトン 536.06g(98.37モル%)及びオクタン酸スズ(II) 0.580g(0.03モル%)を用い、理論分子量9018g/molを目的として製造したプレポリマーG、
バッチH)PEG4000 549.63g(10.0モル%)、カプロラクトン 139.38g(89.97 モル%)及びオクタン酸スズ(II) 0.165g(0.03モル%)を用い、理論分子量5077g/molを目的として製造したプレポリマーH、
バッチI)PEG4000 447.28g(5.00モル%)、カプロラクトン 139.38g(94.97モル%)及びオクタン酸スズ(II) 0.268g(0.03モル%)を用い、理論分子量6218g/molを目的として製造したプレポリマーI、
バッチJ)PEG4000 257.29g(1.6モル%)、カプロラクトン 451.42g(98.37モル%)及びオクタン酸スズ(II) 0.489g(0.03モル%)を用い、理論分子量11018g/molを目的として製造したプレポリマーJ、
バッチK)PEG8000 584.57g(10.0モル%)、カプロラクトン 75.04g(89.97 モル%)及びオクタン酸スズ(II) 0.089g(0.03モル%)を用い、理論分子量9027g/molを目的として製造したプレポリマーK、
バッチL)PEG8000 170.77g(5.0モル%)、カプロラクトン 46.28g(94.97モル%)及びオクタン酸スズ(II) 0.052g(0.03モル%)を用い、理論分子量10168g/molを目的として製造したプレポリマーL。
3)及び結晶化度の測定には示差走査熱量測定法(DSC)を使用した(表2参照)。
700mlの撹拌槽型反応器に、319.00g(10モル%)の乾燥PEG4000(分子量4050g/mol)、80.90g(89.97モル%)のε−カプロラクトン及び0.096g(0.03モル%)のオクタン酸スズ(II)をこの順番で供給した。反応器には乾燥窒素を連続的にパージした。反応器は油浴を用いて100rpmの混合速度で160℃に予熱した。PEG4000を反応器に加える前にロータリーエバポレーター中で乾燥し溶融した。その後ε−カプロラクトンを加え、最後にオクタン酸スズ(II)触媒を加えた。PEG−PCLプレポリマーの予備重合(prepolymerization)時間は4時間であった。プレポリマーの理論分子量は5077g/molであった。
プレポリマーH(実施例1の表1)とポリカプロラクトンジオール(分子量530g/mol以下)を、予熱(110℃)した反応器に供給し少なくとも1時間以上前に70℃の真空において混合、乾燥及び溶融した。1,4−ブタンジイソシアネートを反応器に供給する前に反応混合物を窒素下で30分間混合(60rpm)した。プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は0.25:1.0:1.25であった。反応時間は150分であった(ポリマー2及びポリマー3)。
)はそれぞれ−48.7℃及び38.9℃であった。FTIR(フーリエ変換赤外分光分析)を用いて分析したところ、、ウレタン(N−H,3341cm-1)及びエステルボンド(C=O,1731cm-1)の特性ピークが生体吸収性ポリマーに確認された。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーHを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2であった。反応時間は120分であった(ポリマー4)。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーJを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2であった。反応時間は20分であった(ポリマー5)。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーJを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2.5であった。反応時間は120分であった(ポリマー6)。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーBを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2.1であった。反応時間は2分であった(ポリマー7)。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーCを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2.1であった。反応時間は60分であった(ポリマー8)。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーDを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2であった。反応時間は60分であった(ポリマー9)。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーDを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2.2であった。反応時間は90分であった(ポリマー10)。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーEを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2であった。反応時間は60分であった(ポリマー11)。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーFを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2.2であった。反応時間は120分であった(ポリマー12)。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーGを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2であった。反応時間は120分であった(ポリマー13)。
鎖延長重合を実施例3と同様に行った。ただしプレポリマーとして実施例1、表1のプレポリマーKを用い、プレポリマー、ポリ(ε−カプロラクトン)ジオール、BDIのモル比は1:1:2であった。反応時間は120分であった(ポリマー14)。
実施例2及び3のポリマーを重合後、非溶媒へ沈殿させて精製した。最初にポリマーをジクロロメタン(DCM)、クロロホルムまたはテトラヒドロフラン(THF)を溶媒として用いて溶解し、ジエチルエーテルを沈殿溶媒として用いた。沈殿したポリマーを真空乾燥し、さらなる実験に備えてデシケーターに保存した。
実施例3の生体吸収性ポリマーを、加熱圧搾機を用いて加工する前に、真空下で一晩乾燥した。上部板及び下部板の温度を130℃に設定した。型と熱板の間に2枚のテフロン(登録商標)シートを配置した。2分間溶融した後、〜170barの加圧下に30秒間保持した。正確な量のポリマーを型に満たし、室温まで冷却した後、試料(30mm×10mm×1mm)を機械的に型抜きし、さらなる分析のため冷凍庫に保存した。
合成したポリマーの生体吸収性を実証するために、いくつかのポリマーを選択し、生分解試験を行った(実施例18〜20)。
分解実験用のポリマー試料(大きさ30mm×10mm×1mm)は、生物分解可能ポリマーを加熱圧搾したフィルムから型抜きして作成した。
実施例18と同様に生分解実験用ペッサリーを製造した。分解はポリマーの変更により容易に調整可能であろう。ポリマーは分解に適するよう調整して作成した。
実施例18と同様に生分解実験用ペッサリーを製造した。温度を高くすることにより分解速度が上昇した。
Claims (16)
- (i)(a)カプロラクトン部位及びポリアルキレンオキシド部位の共重合単位を含むプレポリマー、
(b)カプロラクトン及び炭素数2〜6のポリ(アルキレンオキシド)ジオールの共重合単位を含み、前記炭素数2〜6のポリ(アルキレンオキシド)ジオールはプレポリマー成分(a)のポリ(アルキレンオキシド)部位よりも低い分子量を有している、ポリカプロラクトンジオール、及び
(c)ジイソシアネート
を共に反応して得られるポリマー、及び
(ii)薬学的活性剤
を含む、固形投与型の薬剤放出制御組成物。 - (a)プレポリマーのポリアルキレンオキシドが、ポリ(C2〜C3アルキレンオキシド)、またはそれらの混合物である請求項1に記載の組成物。
- ポリアルキレンオキシドが、ポリエチレングリコールである請求項2に記載の組成物。
- ポリエチレングリコールが、HO(CH2CH2O)nH(nは1〜800の整数である。)の構造をもつ請求項3に記載の組成物。
- ポリエチレングリコールの平均分子量が、300〜10,000g/molである請求項3または4に記載の組成物。
- ポリエチレングリコールの平均分子量が、400〜10,000g/molである請求項5に記載の組成物。
- (a)プレポリマーが、(CAP)n−PEG(CAP)n(CAPはカプロラクトン、PEGはポリエチレングリコール、各CAPブロックのnは3〜40である。)の構造をもつブロック共重合体である請求項1〜6のいずれかに記載の組成物。
- nが5〜31である請求項7に記載の組成物。
- カプロラクトンとポリエチレングリコール(PEG)のモル比が、2:1〜124:1である請求項3〜8のいずれか1項に記載の組成物。
- オクタン酸スズを重合触媒として用いる請求項1〜9のいずれかに記載の組成物。
- (b)成分の炭素数2〜6のジオールが、ポリエチレンオキシドである請求項1〜10のいずれかに記載の組成物。
- カプロラクトンとエチレングリコールの比が、4:2である請求項11に記載の組成物。
- (c)ジイソシアネートが、1,6−ヘキサメチレンジイソシアネートまたはL−リシンジイソシアネートである請求項1〜12のいずれかに記載の組成物。
- (c)ジイソシアネートが、1,4−ブタンジイソシアネートである請求項1〜12のいずれかに記載の組成物。
- 請求項1〜14のいずれかに記載の組成物を含むデリバリーデバイス。
- 成分(a)、(b)、(c)を共に反応させてポリマーを製造することを含む請求項1の組成物の製造方法。
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2006
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GB0620685D0 (en) | 2006-11-29 |
US8524254B2 (en) | 2013-09-03 |
DE602007005391D1 (de) | 2010-04-29 |
CN101541849B (zh) | 2012-04-18 |
JP2010506991A (ja) | 2010-03-04 |
AU2007311654A1 (en) | 2008-04-24 |
BRPI0717632B1 (pt) | 2019-03-26 |
PL2076556T3 (pl) | 2010-08-31 |
ATE461235T1 (de) | 2010-04-15 |
WO2008047100A1 (en) | 2008-04-24 |
DK2076556T3 (da) | 2010-07-19 |
BRPI0717632B8 (pt) | 2021-07-27 |
CA2664545C (en) | 2015-07-14 |
CN101541849A (zh) | 2009-09-23 |
ES2342503T3 (es) | 2010-07-07 |
AU2007311654B2 (en) | 2012-08-30 |
PT2076556E (pt) | 2010-06-17 |
BRPI0717632A2 (pt) | 2013-10-29 |
EP2076556A1 (en) | 2009-07-08 |
US20100317745A1 (en) | 2010-12-16 |
EP2076556B1 (en) | 2010-03-17 |
CA2664545A1 (en) | 2008-04-24 |
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