JP6135870B2 - 生分解性ポリマーを含む繊維 - Google Patents
生分解性ポリマーを含む繊維 Download PDFInfo
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- JP6135870B2 JP6135870B2 JP2014508785A JP2014508785A JP6135870B2 JP 6135870 B2 JP6135870 B2 JP 6135870B2 JP 2014508785 A JP2014508785 A JP 2014508785A JP 2014508785 A JP2014508785 A JP 2014508785A JP 6135870 B2 JP6135870 B2 JP 6135870B2
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- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 150000004579 taxol derivatives Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- YYSFXUWWPNHNAZ-PKJQJFMNSA-N umirolimus Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[C@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 YYSFXUWWPNHNAZ-PKJQJFMNSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
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Description
に従うポリエステルアミドを含み、式中、
mは約0.01〜約0.99であり、pは約0.99〜約0.01であり、qは約0.99〜0.01であり、かつnは約5〜約350であり、
R1は独立して、(C2〜C20)アルキレン、(C2〜C20)アルケニレン、−(R9−CO−O−R10−O−CO−R9)−、−CHR11−O−CO−R12−COOCR11−、およびこれらの組み合わせからなる群から選択され、
単一のコモノマーmまたはpのそれぞれの中のR3およびR4は独立して、水素、(C1〜C6)アルキル、(C2〜C6)アルケニル、(C2〜C6)アルキニル、(C6〜C10)アリール、(C1〜C6)アルキル、−(CH2)SH、−(CH2)2S(CH3)、−CH2OH、−CH(OH)CH3、−(CH2)4NH3+、−−(CH2)3NHC(=NH2+)NH2、−CH2COOH、−(CH2)COOH、−CH2−CO−NH2、−CH2CH2−CO−NH2、−− −CH2CH2COOH、CH3−CH2−CH(CH3)−、(CH3)2−CH−CH2−、H2N−(CH2)4−、Ph−CH2−、CH=C−CH2−、HO−p−Ph−CH2−、(CH3)2−CH−、Ph−NH−、NH−(CH2)3−C−、NH−CH=N−CH=C−CH2−からなる群から選択され、
R5は、(C2〜C20)アルキレン、(C2〜C20)アルケニレン、アルキルオキシまたはオリゴエチレングリコールからなる群から選択され、
R6は、1,4:3,6−ジアンヒドロヘキシトールの二環式断片であり、
R7は、水素、(C6〜C10)アリール、(C1〜C6)アルキルまたは保護基であり、
R8は独立して、(C1〜C20)アルキルまたは(C2〜C20)アルケニルであり、
R9またはR10は独立して、C2〜C12アルキレンまたはC2〜C12アルケニレンから選択され、
R11またはR12は独立して、H、メチル、C2〜C12アルキレンまたはC2〜C12アルケニレンから選択される。
R1は、(CH2)8であり、
R3およびR4は、(CH3)2−CH−CH2−から選択され、
R5は、(CH2)6から選択され、
R6は、1,4:3,6−ジアンヒドロソルビトール(DAS)であり、
R7は、ベンジル保護基であり、
R8は、(CH2)4である。
a.生分解性ポリマーを、少なくとも25ゲージの注射針に適合する繊維に押出成形するステップと、
b.上記繊維が、張力を受けている間にその乾燥ガラス転移温度よりも低温まで冷却されるステップと
を含む。
以下の実施例では、PEA−III−Ac Bzポリマーが使用される。PEA−III−Ac Bzのより拡張した記載は、ポリ−8−[(L−Leu−DAS)0.45(L−Leu−6)0.3−[L−Lys(Bz)]0.25である。構造は式IIIで与えられる。分率は、合成におけるモノマーの全体の分率を示す。
室温でオーバーヘッドスターラーを備え、窒素を流した500mLの丸底フラスコ内で、ジ−OSu−セバシナート(39.940g、0.1008モル、1.0当量)、L−ロイシン(6)−2TosOH(20.823g、0.0302モル、0.30当量)、L−ロイシン−(DAS)−2TosOH(32.503g、0.0453モル、0.45当量)およびL−リジン(Bz)−2TosOH(14.628g、0.0252モル、0.25当量)の混合物に、トリエチルアミン(30.9mL、0.222モル、2.2当量)およびN,N−ジメチルホルムアミド(53.07mL、0.689モル)を添加した。続いて混合物を60℃に加熱して反応を進行させ、THF中のGPC分析によりモニターした。36時間後に安定した分子量が得られ、続いて、L−ロイシン(6)−2TosOHの一部(4.338g、0.0063モル)をトリエチルアミン(1.76mL、0.0126モル)およびN,N−ジメチルホルムアミド(4.54mL、0.0590モル)と共に添加し、重合反応を終了させた。混合物をさらに24時間加熱し、その後、粘性溶液をN,N−ジメチルホルムアミド(407.85g、5.301モル)でさらに希釈し、室温まで冷却させた。室温において、無水酢酸(1.89mL、0.0199モル)を添加して、ポリマーのアミノ官能性末端基をアシル化した。混合物を室温で24時間攪拌した。スキーム1には、一般的な反応が示される。
0.52gのAPI(医薬品有効成分)および4.31gのPEA III Ac Bzを共にエタノール中に溶解させ、フィルムキャストし、乾燥させた。続いて、フィルムを凍結粉砕した。均一にした凍結粉砕製剤を図3に示されるPharmaミニ押出機で繊維に加工した。ツインスクリュー押出機を用いて、凍結粉砕した粉末を125℃の温度で溶融押出した。押出機ダイは、0.75mmであった。押出されたポリマーを5m/分〜15m/分の速度で紡糸し、その後、窒素下、室温で冷却した。
0.03gのAPIおよび0.25gのポリマーを共に2.5mlのメタノール中に溶解させ、フィルムキャストし、乾燥させた。得られたフィルムを長さ5〜6mmおよび厚さ250μmの繊維に切断した。APIの放出は、個々に秤量した繊維において、37℃のPBS中で放出させて行った。各時点でPBSを新しくし、HPLCによりAPIの量をトリプリケートで測定した。
再構築がなければAPIの約50%が15日以内に繊維から放出されるが、再構築を伴う繊維からは同じ時点でAPIの20%だけが放出される。
2.13gのAPIおよび5.00gのPEA III Ac Bzを共にエタノール中に溶解させ、フィルムキャストし、乾燥させた。続いて、フィルムを凍結粉砕した。ツインスクリュー押出機を用いて、凍結粉砕粉末を115℃の温度で溶融押出した。押出機ダイは、0.75mmであった。押出されたポリマーを5m/分〜15m/分の速度で紡糸し、その後、窒素下、室温で冷却した。
Claims (8)
- ヒトまたは動物の体内に注入されたときに寸法変化を受ける生分解性ポリマーを含む繊維であって、前記寸法変化が、体積に対する表面積の比率の1.05〜10倍の低下であり、
前記生分解性ポリマーが、式Iのポリエステルアミドである、繊維。
(式中、
mは0.01〜0.99であり、pは0.99〜0.01であり、qは0.99〜0.01であり、かつnは5〜350であり、
R 1 は独立して、(C 2 〜C 20 )アルキレン、(C 2 〜C 20 )アルケニレン、−(R 9 −CO−O−R 10 −O−CO−R 9 )−、−CHR 11 −O−CO−R 12 −COOCR 11 −、およびこれらの組み合わせからなる群から選択され、
単一のコモノマーmまたはpのそれぞれの中のR 3 およびR 4 は独立して、水素、(C 1 〜C 6 )アルキル、(C 2 〜C 6 )アルケニル、(C 2 〜C 6 )アルキニル、(C 6 〜C 10 )アリール、(C 1 〜C 6 )アルキル、−(CH 2 )SH、−(CH 2 ) 2 S(CH 3 )、−CH 2 OH、−CH(OH)CH 3 、−(CH 2 ) 4 NH 3 + 、−(CH 2 ) 3 NHC(=NH 2 + )NH 2 、−CH 2 COOH、−(CH 2 )COOH、−CH 2 −CO−NH 2 、−CH 2 CH 2 −CO−NH 2 、−CH 2 CH 2 COOH、CH 3 −CH 2 −CH(CH 3 )−、(CH 3 ) 2 −CH−CH 2 −、H 2 N−(CH 2 ) 4 −、Ph−CH 2 −、CH=C−CH 2 −、HO−p−Ph−CH 2 −、(CH 3 ) 2 −CH−、Ph−NH−、
からなる群から選択され、
R 5 は、(C 2 〜C 20 )アルキレン、(C 2 〜C 20 )アルケニレン、アルキルオキシおよびオリゴエチレングリコールからなる群から選択され、
R 6 は、1,4:3,6−ジアンヒドロヘキシトールの二環式断片であり、
R 7 は、水素、(C 6 〜C 10 )アリール、(C 1 〜C 6 )アルキルまたは保護基であり、
R 8 は独立して、(C 1 〜C 20 )アルキルまたは(C 2 〜C 20 )アルケニルであり、
R 9 またはR 10 は独立して、C 2 〜C 12 アルキレンまたはC 2 〜C 12 アルケニレンから選択され、
R 11 またはR 12 は独立して、H、メチル、C 2 〜C 12 アルキレンまたはC 2 〜C 12 アルケニレンから選択される。) - mが0.3であり、pが0.45であり、qが0.25であり、かつnが5〜100であり、
R1が、(CH2)8または(CH2)4であり、
R3およびR4が、(CH3)2−CH−CH2−から選択され、
R5が、(CH2)6から選択され、
R6が、1,4:3,6−ジアンヒドロソルビトール(DAS)であり、
R7が、ベンジル保護基であり、
R8が、(CH2)4である、請求項1に記載の繊維。 - 前記寸法変化が、体積に対する表面積の比率の1.25〜5倍の低下である、請求項1又は2に記載の繊維。
- 前記繊維が、少なくとも25ゲージの口径を有する薬剤注射針による注入のためのサイズである、請求項1〜3のいずれか一項に記載の繊維。
- 前記ポリエステルアミドが、37℃よりも低い湿潤Tgを有する、請求項1〜4のいずれか一項に記載の繊維。
- 少なくとも生物活性剤を含む、請求項1〜5のいずれか一項に記載の繊維。
- 薬物溶出媒体として使用される、請求項1〜6のいずれか一項に記載の繊維。
- 請求項1〜7のいずれか一項に記載の繊維を製造するための方法であって、以下のプロセスステップ:
a.生分解性ポリマーを、少なくとも25ゲージの注射針に適合する繊維に押出成形するステップと、
b.前記繊維が、張力を受けている間にその乾燥ガラス転移温度よりも低温まで冷却されるステップと
を含む方法。
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PCT/EP2012/058036 WO2012150265A1 (en) | 2011-05-02 | 2012-05-02 | Fiber comprising a biodegradable polymer |
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US8658210B2 (en) | 2006-04-17 | 2014-02-25 | Advanced Cardiovascular Systems, Inc. | Polyesteramide platform for site specific drug delivery |
US9873764B2 (en) | 2011-06-23 | 2018-01-23 | Dsm Ip Assets, B.V. | Particles comprising polyesteramide copolymers for drug delivery |
US9873765B2 (en) | 2011-06-23 | 2018-01-23 | Dsm Ip Assets, B.V. | Biodegradable polyesteramide copolymers for drug delivery |
CN104717962B (zh) | 2012-10-02 | 2017-07-21 | 帝斯曼知识产权资产管理有限公司 | 包含蛋白质和可生物降解聚酯酰胺的药物递送组合物 |
CA2969171C (en) * | 2014-12-18 | 2023-12-12 | Dsm Ip Assets B.V. | Drug delivery system for delivery of acid sensitive drugs |
KR101646561B1 (ko) * | 2014-12-26 | 2016-08-12 | 도레이케미칼 주식회사 | 내열성이 우수한 섬유용 수용성 폴리에스테르, 그 제조방법 및 이를 포함하는 복합섬유 |
AU2016361579B2 (en) | 2015-11-25 | 2022-08-04 | Incept, Llc | Shape changing drug delivery devices and methods |
AU2020232314C1 (en) * | 2019-03-05 | 2024-03-28 | Alcon Inc. | Pharmaceutical compositions for treating ocular diseases or disorders |
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US20060159918A1 (en) * | 2004-12-22 | 2006-07-20 | Fiber Innovation Technology, Inc. | Biodegradable fibers exhibiting storage-stable tenacity |
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US8969415B2 (en) * | 2006-12-01 | 2015-03-03 | Allergan, Inc. | Intraocular drug delivery systems |
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