CN107106509A - 用于递送酸敏感药物的药物递送系统 - Google Patents
用于递送酸敏感药物的药物递送系统 Download PDFInfo
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Abstract
本发明涉及包含核和壳的药物递送系统,其中核包含可水解降解的聚合物X,所述聚合物X的聚合物主链包含悬挂的酯官能团和悬挂的酸官能团,并且其中所述壳包含可水解降解的聚合物Y。可水解降解的聚合物X和Y是不同的聚合物。聚合物X在聚合物主链中还包含氨基酸,并通过零级降解动力学降解至少3个月的时间。聚合物Y通过自动加速降解动力学降解。
Description
本发明涉及包含核和壳的药物递送系统。本发明还涉及包含核和壳的纤维。本发明还涉及用于制造药物递送系统的方法。
本发明特别涉及药物持续递送到眼的领域,更特别地涉及治疗和/或预防升高的眼内压,例如与青光眼相关的升高的眼内压。
青光眼在世界的发达国家是失明的主要原因之一。青光眼的主要病理生理特征是升高的眼内压。用于降低眼内压的手术和/或药物是青光眼最常见的治疗。目前使用的主要药物治疗是通过滴眼剂局部施用药物溶液。药物例如是缩瞳剂(例如匹鲁卡品、卡巴胆碱和二乙氧膦酰硫胆碱),其张开小梁网以增加液体流出眼的速率。
滴眼剂的自我施用常常会导致大部分的滴剂由于溢出而损失。递送到眼睛表面的大部分药物溶液然后立即被眼泪冲走。而且,渗透角膜的那部分药物会导致初始的组织浓度峰值,随后逐渐减少,因此在下次施用滴眼剂之前,组织浓度可能低于为产生预期的药理学效果所需要的浓度。滴眼剂的变化的和间歇的局部施用,结合病人对于处方方案的依从性的变幻莫测,导致在眼中局部抗青光眼剂的高浓度和低浓度的循环,以及眼内压的可能的循环。因此,视神经可能随时间而受到不可逆地损伤,理想的治疗将在眼中始终保持治疗有效量的药物。
包含核和壳的药物递送系统是本领域已知的。在EP2233112中,公开了药物递送装置,其形状和尺寸被用于注射,并且其包括包含一种或更多种药物的核;以及至少部分地围绕所述核的聚合物外皮,其中外皮包含聚合物,例如聚(乙酸乙烯酯)、聚(己内酯)、聚乙二醇、聚(dl-丙交酯-共-乙交酯)、乙烯乙酸乙烯酯聚合物、聚(乳酸)(PLA)、聚(乙醇酸)(PGA)、聚氰基丙烯酸烷基酯(polyalkyl cyanoacralate)、聚氨酯或尼龙。
旨在提供药物的持续释放的药物递送系统应提供受控的释放,即应随时间以相对线性的方式释放药物,以便不仅保持延长的释放,而且保持相对恒定的和治疗有效的药物浓度。释放的持续时间应该足够长,使得装置的插入并非不方便地频繁的。根据待治疗的病症,所述装置可能会在数周、数月甚至数年的时间内提供受控的释放。这对于诸如青光眼的慢性病人的病症尤其重要(有益处)。
在药物被分散在聚合物基质中的情况下,当药物溶解并扩散出基质时药物被释放。在基于聚合物基质的装置中,分散在基质中的药物可以以溶解的或分散的形式存在。由药物溶解的装置的释放遵循菲基(Fickian)动力学。当药物被分散在聚合物基质中时,根据t1/2动力学释放,直到基质中的浓度降至饱和值以下,此时释放速率减慢,并且观察到菲基释放。由于这些原因,长时间维持治疗窗口内的药物浓度可能难以用聚合物基质体系实现。
在一些药物递送系统中,通过聚合物基质的扩散是非常缓慢的,并且只有随着聚合物基质被降解,才准备释放药物。已经证明很难将这种方法用于线性释放。
本发明的一个目的是提供一种药物递送系统,其满足随时间线性释放的,满足延长的释放,以及满足相对恒定的和治疗有效的药物浓度。
特别地,本发明的一个目的是提供用于治疗和/或预防青光眼和与升高的眼内压相关的其他适应症的改进的方法,所述方法是通过以避免与局部施用相关的变化的药物浓度问题的方式向眼施用药物而不引起系统性副作用。
本发明的目的得以实现,因为提供了一种药物递送系统,其包含核和壳,其中核包含可水解降解的聚合物X,聚合物X的聚合物主链包含悬挂的(pendant)酯官能团和悬挂的酸官能团,并且其中壳包含可水解降解的聚合物Y。
优选地,可水解降解聚合物X和Y是不同的聚合物。
令人惊奇地发现,根据本发明的药物递送系统不仅提供了延长的释放,而且提供了治疗有效浓度的药物的相对恒定释放。此外,令人惊讶地发现,尽管聚合物X的水解导致羧基的产生,但在聚合物降解期间,在聚合物基质中可水解降解的聚合物X不构建酸性微气候。
酸性微气候的缺乏有利于保持酸敏感药物的结构,这意味着保持其稳定性。例如,在拉坦前列素的早期开发中观察到眼部充血和其它副作用,并引发了当今临床使用中的前药(拉坦前列素酯)结构的开发。拉坦前列素是前列腺素F2a类似物。具体地,拉坦前列素是前列腺素类选择性FP受体激动剂,其据信通过增加房水的流出来降低眼内压(IOP)。升高的IOP是青光眼视野缺损的主要危险因素。IOP水平越高,视神经损伤和视觉视野缺损的可能性就越大。拉坦前列素是异丙酯,且该酯被发现改善了眼部渗透性,从而改善了眼部降压的效力。重要的是,酯形式足够稳定,不会被快速脱酯化,而是被组织酯酶水解来具有充足的眼内降压作用。因此,药物结构保持对于高生物利用率(低剂量下的经过组织的药物转运和效能)以及减少副作用(例如结膜充血和眼部刺激)来说是关键的。
除了酸敏感药物的剩余稳定性之外,还发现根据本发明的药物递送系统在接下来的3个月内从第10天开始提供恒定剂量的药物的释放。这对于治疗青光眼和与升高的眼内压有关的其他适应症是至关重要的,并且避免了药物浓度变化的问题。目前的药物递送系统的目标是将药物水平维持在治疗范围内,并且理想地是恒定的和可预测的水平。为了达到相对恒定的水平,药物应该以随时间变化很小的速率从递送系统被释放。
已经发现水解的聚合物X通过假零级降解动力学降解至少3个月的时间。零级反应的速率与反应物和反应产物的浓度无关。增加反应产物的浓度将不会加速反应的速率,即被反应的物质的量与时间成比例。通常生物可降解的聚合物通过自动加速动力学降解,因为降解产生进一步催化降解的羧酸基团。尽管本发明中聚合物X的降解产生羧基,但降解不遵循自动加速动力学。
聚合物主链包含悬挂的酯和悬挂的酸官能团。优选地,其包含基于总的悬挂的官能团的至少15%的酸基团。聚合物X优选地在聚合物主链中还包含氨基酸。最优选地,聚合物X是聚酯酰胺共聚物。在主链中聚酯酰胺共聚物优选地包含构筑基元(building blocks)A和B,其中基元A为L-赖氨酸-H(=赖氨酸游离羧基)并且基元B为L-赖氨酸-苄基(=赖氨酸苄酯)。
在WO-A-2012175746中公开了其中存在L-赖氨酸-H以及L-赖氨酸-苄基的聚酯酰胺(以下称为PEA-X)。这些PEA-X聚合物提供生物活性剂的持续释放,并通过本体侵蚀机制(bulk erosion mechanism)在生理条件下水解降解。
在降解期间产生的赖氨酸游离羧基和酸性物质看起来处于适当的平衡来催化沿聚酯酰胺链的键断裂,但在生理条件下不损害材料的表现性能。此外,悬挂的羧基防止聚合物降解过程的自动加速,这有助于更受控的和延长的材料的生物降解。
在优选的实施方式中,聚酯酰胺共聚物(PEA-X)是无规共聚物。最优选地,聚酯酰胺共聚物(PEA-X)包含结构式I
其中,
-m+p从0.9至0.1变化,并且q从0.1至0.9变化
-m+p+q=1,其中m或p可以为0
-n从5至300变化;
-R1独立地选自(C2-C20)亚烷基、(C2-C20)亚烯基及其组合组成的组;
-在单个主链单元m或p中,R3和R4分别独立地选自氢、(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基、(C6-C10)芳基、(C1-C6)烷基、-(CH2)SH、-(CH2)2S(CH3)、-CH2OH、-CH(OH)CH3、-(CH2)4NH3+、-(CH2)3NHC(=NH2+)NH2、-CH2COOH、-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-组成的组;
-R5选自(C2-C20)亚烷基、(C2-C20)亚烯基、烷氧基或低聚乙二醇组成的组
-R6选自结构式(II)的1,4:3,6-二脱水己糖醇(dianhydrohexitol)的双环片段;环烷基片段如1,4-环己烷二醇衍生物,芳族片段或杂环片段如己糖衍生的片段。
-R7选自(C6-C10)芳基(C1-C6)烷基组成的组。
-R8是-(CH2)4-;其中a为至少0.05,b为至少0.05并且a+b=1。
在以下的实施方式中,在式(I)的聚酯酰胺共聚物中,n优选地从50-200变化,a可以为至少0.15,更优选地为至少0.5,最优选地为0.75,甚至更优选地至少0.8。
在一个实施方式中,根据式(I)的聚酯酰胺共聚物包含p=0和m+q=1,其中m=0.75、a=0.5并且a+b=1,R1是(CH2)8,R3是-(CH3)2-CH-CH2-,R5是己基,R7是苄基并且R8是-(CH2)4-。该聚酯酰胺被称为PEA-I-H/Bz 50%H。
在另一个优选的实施方式中,根据式(I)的聚酯酰胺共聚物包含m+p+q=1,q=0.25,p=0.45并且m=0.3,其中a为0.5并且a+b=1,其中R1为-(CH2)8;R3和R4分别为-(CH3)2-CH-CH2-,R5选自(C2-C20)亚烷基组成的组,R6选自结构式(II)的1,4∶3,6-二脱水己糖醇的双环片段;R7为苄基并且R8为-(CH2)4。该聚酯酰胺被称为PEA-III-H/Bz 50%H。
在一个进一步优选的实施方式中,根据式(I)的聚酯酰胺共聚物包含m+p+q=1,q=0.25,p=0.45并且m=0.3,其中a为0.25并且a+b=1,并且其中R1为-(CH2)8;R3和R4分别为-(CH3)2-CH-CH2-,R5选自(C2-C20)亚烷基组成的组,R6选自结构式(II)的1,4∶3,6-二脱水己糖醇的双环片段;R7为苄基并且R8为-(CH2)4。该聚酯酰胺被称为PEA-III-H/Bz 75%H。
在一个仍然进一步优选的实施方式中,根据式(I)的聚酯酰胺共聚物包含m+p+q=1,q=0.25,p=0.45并且m=0.3,其中a为0.75并且a+b=1,其中R1为-(CH2)8;R4为(CH3)2-CH-CH2-,R7为苄基,R8为-(CH2)4-,R5选自(C2-C20)亚烷基组成的组并且R6选自结构式(II)的1,4∶3,6-二脱水己糖醇的双环片段。该聚酯酰胺被称为PEA-III-H/Bz 25%H。
在一个还进一步优选的实施方式中,根据式(I)的聚酯酰胺共聚物包含m+p+q=1,q=0.1,p=0.30并且m=0.6,其中a=0.5并且a+b=1。R1为-(CH2)4;R3和R4分别为(CH3)2-CH-CH2-,R5选自(C2-C20)亚烷基组成的组,R7为苄基,R8为-(CH2)4-,并且R6选自结构式(II)的1,4∶3,6-二脱水己糖醇的双环片段。该聚酯酰胺被称为PEA-II-H/Bz 50%H。
本文所用的术语“烷基”是指一价直链或支链烃基,包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正己基以及类似基团。
如本文所用,术语“亚烷基”是指二价支链或非支链烃链,例如-CH2-、-(CH2)2-、-(CH2)3-、-(CH2)4-、-(CH2)5-以及类似基团。
如本文所用,术语“烯基”是指在主链或侧链中含有至少一个不饱和键的单价直链或支链烃基。
如本文所用,“亚烯基”是指本文的结构式,其表示在主链或侧链中含有至少一个不饱和键的二价支链或非支链烃链。
如本文所用,“炔基”是指具有至少一个碳-碳三键的直链或支链烃基。
在本文中与结构式有关的术语“芳基”用于表示苯基基团或具有约9至10个环原子且其中至少一个环是芳族的邻位稠合的双环碳环基团,。芳基的实例包括但不限于苯基、萘基和硝基苯基。
术语“生物可降解的”是指当暴露于体内的环境中或在有代表性的体外时材料能够被完全或基本上被降解或腐蚀。当聚合物例如,通过受试者体内的水解、酶解、氧化、代谢过程、本体或表面侵蚀和类似行为可以被逐渐分解、再吸收、吸收和/或清除时,其能够被降解或者腐蚀。术语“生物可吸收的”和“生物可降解的”在本申请中可互换使用。
本文所用的术语“无规共聚物”是指式(I)的聚酯酰胺的m、p和q单元的分布是随机分布。
根据式(I)的聚酯酰胺共聚物中使用的至少一种α-氨基酸是天然α-氨基酸。例如,当R3或R4是苄基时,合成中使用的天然α-氨基酸是L-苯丙氨酸。或者,在其中R3或R4是-CH2-CH(CH3)2时,共聚物含有天然氨基酸,亮氨酸。在如本文所述的两种共聚单体的变体范围内通过独立地改变R3和R4,也可以使用其它天然α-氨基酸,例如甘氨酸(当R3或R4是H时)、丙氨酸(当R3或R4是CH3时)、缬氨酸(当R3或R4是-CH(CH3)2时)、异亮氨酸(当R3或R4是-CH(CH3)2-CH2-CH3时)、苯丙氨酸(当R3或R4是CH2-C6H5时)、赖氨酸(当R3或R4(CH2)4-NH2)时)或甲硫氨酸(当R3或R4是-(CH2)2S(CH3)时)及其混合物。
式(I)的聚酯酰胺共聚物优选地具有范围是15000至200000道尔顿的数均分子量(Mn)。本文所述的聚酯酰胺共聚物可以以各种分子量和在主链中m、p和q单元的各种相对比例构造。本领域技术人员容易确定用于特定用途的适当的分子量。合适的Mn将为约15000至约100000道尔顿,例如约30000至约80000或约35000至约75000的级别。以聚苯乙烯作为标准通过在THF中的GPC测量Mn。
聚酯酰胺的基本聚合方法是以G.Tsitlanadze等人的J.Biomater.Sci.Polym.Edn.(2004)15∶1-24中描述的方法为基础,但是使用了不同的构筑基元和活化基团。
式(I)的聚酯酰胺例如如方案1所示被合成;通过对甲苯磺酸二胺盐(X1,X2,X3)与活化二酸(Y1)的溶液缩聚。通常使用二甲基亚砜或二甲基甲酰胺作为溶剂。通常三乙胺作为碱被添加,反应在恒定搅拌下在惰性气氛下在60℃下进行24-72小时。随后将所得反应混合物通过水沉淀随后进行有机沉淀和过滤来纯化。在减压下干燥产生聚酯酰胺。
根据本发明的药物递送系统包含壳,所述壳包含可水解降解的聚合物Y。优选地,聚合物Y通过自动加速动力学降解。通常,可水解降解聚合物包含主要负责水解降解性能的沿聚合物链的多重(multiple)酯键。水解降解过程开始于酯键的断裂,其导致游离羧基的产生。这些羧基进一步催化水解,加速降解过程和产生新的羧基。总的来说,羧基表现为(appear)一种化学反应产物,并且它们的浓度随时间增加。另一方面,羧基表现为水解过程的催化剂,其加速降解。可以设计由这样的聚合物制备的壳,以便在开始时相对缓慢地降解,抑制药物从药物递送系统核爆发释放。之后,当壳的阻隔性能不再被需要时,加速降解速率将导致壳的快速腐蚀吸引药物从核聚合物中释放。
可水解降解聚合物Y优选地是聚酯,其是以主链中的酯键为特征的一类聚合物,例如聚(乳酸)(PLA)、聚(乙醇酸)(PGA)、聚(丙交酯-共-乙交酯))(PLGA)等。PLGA是在开发药物递送系统中最常用的可降解聚合物之一。PLGA通过两种不同单体(乳酸和乙醇酸的环状二聚体(1,4-二恶烷-2,5-二酮))的开环共聚合成。PLGA在水存在下通过其酯键的水解而降解。
根据本发明的药物递送系统包含核和壳,优选地,药物递送系统是微米颗粒、纳米颗粒、棒、纤维或植入物。更优选地,药物递送系统是纤维。
通常,纤维的平均直径在50μm和1000μm之间。优选的平均直径取决于预期用途和优选的给药。例如,在纤维将被用作可注射药物递送系统的情况下,特别是作为眼部药物递送系统,可期望的是50-500μm的平均直径、更优选地100-300μm的平均直径。优选地,纤维的形状和尺寸适用于尺寸范围从30号(gauge)到12号的针的注射。
核-壳系统由聚合物圆柱形核和厚度在0.5μm和5μm之间的聚合物壳组成。核的两端可以被完全打开或在一端或两端被密封来控制药物释放动力学。优选地,核的两端被完全打开。当期望小程度的药物爆发时,例如类似于滴眼剂的在IOP上的立即的效果,药物也可以存在于壳中。
本发明的药物递送系统可以用作药物或生物活性剂的递送系统。所述系统为递送酸敏感药物提供了额外的优势。
根据本发明的药物递送系统可以包含一种或更多种生物活性剂。
如本文所用,术语“生物活性剂”是指,例如当施用于包括哺乳动物(例如人类)在内的动物时,在体内具有治疗特性、预防特性或诊断特性的试剂。合适的治疗性活性剂和/或预防性活性剂的实例包括蛋白质,例如激素、抗原和生长因子;核酸,如反义分子;和较小的分子,例如抗生素、类固醇、减充血剂、神经活性剂、麻醉剂、镇静剂和抗体,例如与生长激素受体结合的抗体,包括人源化的抗体、佐剂及其组合。合适的诊断性活性剂和/或治疗性活性剂的实例包括放射性同位素和不透射线性试剂。活性剂可以包括有机分子,例如药物,肽,蛋白质,碳水化合物(包括单糖、寡糖和多糖),核蛋白,粘蛋白,脂蛋白,合成多肽或蛋白质,或与蛋白质连接的小分子,糖蛋白,类固醇,核酸(任何形式的DNA,包括cDNA,或RNA,或其片段),核苷酸,核苷,寡核苷酸(包括反义寡核苷酸),基因,脂质,激素,维生素,包括维生素C和维生素E,或其组合。代表性的治疗性活性剂包括免疫抑制剂,抗氧化剂,麻醉剂,化学治疗剂,类固醇(包括类视色素),激素,抗生素,抗病毒药,抗真菌剂,抗增生剂,抗组胺剂,抗凝剂,抗光老化剂,促黑色素激素(melanotropic)肽,非甾族和甾族抗炎化合物,抗精神病药,和辐射吸收物,包括UN-吸收物。活性剂的其它非限制性实例包括抗感染剂如呋喃西林(nitrofurazone),丙酸钠,抗生素,包括青霉素、四环素、氧四环素、氯四环素、杆菌肽、制霉菌素(nystatin)、链霉素、新霉素、多粘菌素、短杆菌肽、氯霉素、红霉素和阿奇霉素;磺酰胺,包括磺胺乙酰胺、磺胺二甲唑、磺胺二甲嘧啶、磺胺嘧啶、磺胺甲基嘧啶和磺胺异恶唑;以及抗病毒剂,包括碘苷(idoxuridine);抗过敏原;例如安他唑啉、美沙吡林(methapyritene)、氯苯那敏、吡拉明(pyrilamine)、非尼拉敏(prophenpyridamine)、氢化可的松、可的松、醋酸氢化可的松、地塞米松、地塞米松21-磷酸盐、氟轻松(fluocinolone)、曲安缩松(triamcinolone)、甲羟松(medrysone)、泼尼松龙、泼尼松龙21-琥珀酸钠和醋酸泼尼松龙;脱敏剂,例如豚草花粉抗原、枯草热花粉抗原、灰尘抗原和奶抗原;解充血剂,例如苯肾上腺素、萘甲唑林和四氢唑琳(tetrahydrazoline);缩瞳剂和抗胆碱酯酶,例如毛果芸香碱、水杨酸毒扁豆碱(esperine salicylate)、卡巴胆碱、氟磷酸二异丙酯、碘化二乙氧磷酸硫胆碱和地美溴铵;副交感神经抑制剂,例如硫酸阿托品、环喷托酯、后马托品、东莨菪碱、托品酰胺、尤卡托品和羟苯丙胺(hydroxyamphetamine);拟交感神经药,例如肾上腺素;镇静剂和催眠剂,例如戊巴比妥钠、苯巴比妥、司可巴比妥钠、可待因、(a-溴异戍酰基)脲、卡溴脲;心力加强剂,例如醋酸3-(2-氨基丙基)吲哚和醋酸3-(2-氨基丁基)吲哚;镇定剂,例如利血平、氯丙嗪(chlorpromayline)、醋酸奋乃静(thiopropazate);雄激素类固醇,例如甲睾酮(methyl-testosterone)和氟甲睾酮(fIuorymesterone);雌激素,例如雌酮、17-β-雌二醇、乙炔雌二醇和二乙基己烯雌酚(diethyl stilbestrol);促孕剂,例如孕酮、甲地孕酮、美仑孕酮、氯地孕酮(chlormadinone)、炔孕酮、异炔诺酮(norethynodrel)、19-去甲孕酮(19-norprogesterone)、炔诺酮、甲羟孕酮和17-β-羟基-孕酮;体液剂,例如前列腺素,例如PGE15、PGE2和PGF2;退热剂,例如阿司匹林、水杨酸钠和水杨酰胺;镇痉剂,例如阿托品、甲胺太林、罂粟碱和甲溴东莨菪喊;抗疟药,例如4-氨基喹啉、8-氨基喹啉、氯喹和乙胺嘧啶;抗组胺剂,例如苯海拉明、茶苯海明、曲吡那明(tripelennamine)、奋乃静(pefhenazine)和氯苯嗪(chlorphenazine);心脏活性剂,例如二苯并氢氟噻嗪(dibenzhydroflume thiazide)、氟甲噻嗪(flumethiazide)、氯噻嗪和三硝酸三乙醇胺酯;天然的和合成的生物活性肽和蛋白质,包括生长因子、细胞粘附因子、细胞因子和生物应答调节剂。
待被掺入药物递送系统中的生物活性剂的量将根据如下因素而变化:具体的生物活性剂、在计划的释放水平时生物活性剂的期望的效果以及生物活性剂应当被释放的时间跨度。
生物活性剂也可以与本领域己知的一种或更多种赋形剂如稳定剂混合。
酸敏感药物的实例尤其是包括生理活性蛋白或肽类的生物药物或者水解敏感分子。包括生理活性蛋白或肽类的生物药物的实例是依那西普、兰尼单抗(ranibizumab)以及贝伐单抗(bevacizumab)。水解敏感分子的实例是拉坦前列素、比马前列素和曲伏前列素。
根据本发明,如果存在生物活性剂,则其优选地存在于核中。核中一种或更多种生物活性剂的浓度可以通过被治疗的医学适应症的治疗窗口以及通过给药方法来确定。药物递送系统的核中的一种或更多种生物活性剂的浓度可以为,基于药物递送系统的总重量的,至少是1wt%,特别地是至少5wt%,更特别地是至少10wt%。根据需要,浓度可以是至多90wt%,至多70wt%,至多50wt%或至多30wt%。
聚合物X或Y和生物活性剂或酸敏感药物优选地是溶剂混合的,所用溶剂的选择一般取决于所选择的聚合物和生物活性剂,以及要使用的具体的溶剂去除方式。溶剂的实例是丙酮、甲基乙基酮、四氢呋喃、乳酸乙酯、乙酸乙酯或二氯甲烷。
除了聚合物X和Y之外,本发明的药物递送系统还可以在核或在壳中包含一种或更多种选自其它生物相容性聚合物的其它聚合物。
生物相容性聚合物的实例是聚(酸酐)、聚(磷酸酯)、聚(三亚甲基碳酸酯)、聚(氧杂酯)、聚(氧杂-酰胺)、聚(碳酸亚乙酯)、聚(碳酸亚丙酯)、聚(磷酸酯)、聚(磷腈)、聚(酪氨酸衍生的碳酸酯)、聚(酪氨酸衍生的芳基化物)、聚(酪氨酸衍生的亚氨基碳酸酯),这些聚合物与聚(乙二醇)(PEG)的共聚物,或其组合。
本发明还涉及通过包括熔融加工步骤和涂布步骤的两步法来制备本发明的药物递送系统的方法。或者也可以通过一步法,特别是通过共挤出,来制造药物递送系统。
尤其是对于纤维的制造,有三种常用的方法可用,例如湿纺、干纺和熔纺。湿纺包括将聚合物溶液穿过孔口挤出到非溶剂中使聚合物凝结。在干纺过程中,将聚合物溶液强制穿过孔口并送入蒸发溶剂的加热柱来形成长丝。在熔纺中,将热塑性聚合物加热至高于其熔点,穿过孔口挤出,并冷却形成长丝。在同轴纺丝的同时,药物被挤出作为纤维的核同时作为速率控制的聚合物壳。典型的同轴喷丝头(spinneret)由两个同心环组成。纯的形式的药物或分散在聚合物基质中的药物被泵送穿过内环,其在内环处形成核。速率控制的聚合物被泵送穿过外环以形成壳。当两种材料的流从喷丝头出现时,它们固化形成同轴的纤维或储层系统。将两种聚合物泵送到同轴喷丝头的速率决定了壳的厚度和纤维的尺寸。
聚合物或药物通过在溶剂中熔融或溶解而被液化来挤出。优选的方法是熔融挤出,其中使用两个挤出机来处理核和壳。核制剂被送入同轴模具的中心管,并且壳聚合物被送入到同一模具的同心外环,使得当聚合物离开模具时,壳聚合物在核上形成均匀的涂层。核和壳的相对直径由模具的规格、挤出条件、两个挤出机的相对挤出速率以及相对的牵引(take-off)速度来控制。以这种方式,可以独立地控制核直径和壳厚度。
本发明的纤维的另一种制备方法是,首先通过简单的挤出方法制备核制剂,然后通过核的表面处理形成壳。表面处理可以通过暴露于升高的温度下或暴露于用于聚合物赋形剂的溶剂而表面退火来实现,使得聚合物在表面形成薄的外皮,其然后用作速率控制的壳。壳也可以通过溶液涂布方法通过涂覆壳制剂的涂层来添加。可以使用溶液涂布方法来涂覆不同组成的附加层,从而构造多层同轴纤维。
制备本发明的纤维的另一种方法是首先将壳制备成空管,然后通过将核制剂注入管的中心来添加核制剂。作为示例,核制剂可以由掺入液体聚合物基质中的药物组成。虽然一般以横截面为圆形的几何形状形成,但纤维也可以用任何其他横截面几何形状制备,例如椭圆形、凸角、正方形或三角形。
药物可以以各种方式被添加到制剂中。如果核制剂含有聚合物,则药物和聚合物可以通过溶剂共混、干混或熔融共混来混合。可以通过挤出药物-基质两次获得更均匀的混合。在优选的实施方式中,通过如下来配制核:干混合药物和聚合物,熔融挤出共混物并研磨挤出物以形成用于第二次挤出的原料。
最终的药物递送系统通过如下来形成:将核/壳制剂切割成期望剂量的适当长度,以及将核的暴露端密封。在优选的实施方式中,初始加载剂量可以是期望的,对于某些药物来说其可以通过仅密封一个暴露端或不密封暴露端使得存在短暂时间(briefperiod)的较高释放(higher release)来实现。可以使用多种方法来密封药物递送系统的端部。如果药物递送系统含有固体核,其可以通过如下来被密封:用壳聚合物的溶液涂布或通过涂布熔融的壳聚合物或者简单地通过用热刀或线切割药物递送系统,使得其在切割进行时被热密封。如果药物递送系统包含液体核,则可以将端部热密封,或者通过将聚合物塞放入壳制剂的内腔中来将端部密封。当使用聚合物塞时,其可以任选地被热密封到壳上。根据药物的总剂量和预想的施用方法,药物递送系统可以以各种尺寸制备。在一个优选实施方式中,总体直径在0.05mm至5.0mm之间。对于人体皮下施用,可以使用1.0mm至4.0mm,优选地在0.2mm至2mm之间的总直径。药物递送系统的长度通常在0.5mm和20mm之间。优选地,长度在约1mm和10mm之间,更优选地长度在2mm和8mm之间,甚至更优选在2mm和6mm之间。
本发明还涉及通过采用根据本发明的药物递送系统向眼施用生物活性剂来治疗青光眼、高眼压症和与升高的眼内压相关的其它适应症的方法。与升高的眼内压相关的其它适应症例如是糖尿病性视网膜病变或黄斑变性。
本发明还涉及用作药剂的药物递送系统。
本发明还涉及根据本发明的用于治疗青光眼、高眼压症、糖尿病性视网膜病变或黄斑变性的药物递送系统。
优选地,药物递送系统是纤维,其优选地通过挤出方法制造,例如熔融挤出,其中生物可降解的聚合物和最终的附加化合物使用Retsch低温容器均化。然后将所得粉末填充到预热微挤出机中,其中预热微挤出机具有5cc桶内径和连接到微纤维纺丝装置的双螺杆。生物可降解的聚合物优选地在120℃-140℃下的停留时间为5-10分钟,然后将其拉伸至直径范围为100-250μm的纤维中。挤出通常在惰性气氛下进行,以便在该过程中最小化聚合物的氧化降解。在张力(tension)下,随后在室温下冷却。优选地从纤维辊切割长度为1-6cm的纤维,并通过浸涂或喷涂涂覆聚合物涂层。在浸涂过程中,纤维被夹紧并以受控的速度(例如,1.5cm/s)浸入聚合物溶液浴中。然后在受控的环境(20℃,40%RH)中干燥。在喷涂过程中,将纤维固定在水平旋转的支持体(support)上,并在受控环境(20℃,40%RH)中从顶部用聚合物溶液喷射。聚合物溶液通过超声波喷嘴以特定流速(例如0.1mL/min)泵送来产生待被施加在旋转纤维上的柔速(soft velocity)喷雾。所得到的纤维然后优选地从例如5mm切割成块,从而产生具有开放端的纤维。纤维可以在冷却条件下通过γ射线灭菌。
或者,本发明的纤维也可以通过注射成型制备。在该过程中,纤维在注射成型机中在100-200℃的温度下形成,得到直径约为200μm的纤维。然后将模具冷却至室温,然后打开,取出纤维。该处理方法的关键是如此获得的纤维在暴露于水环境中时不会重新成型,很好地保持其长度和直径。优选地,切割长度为1-6cm的纤维,并通过浸涂或喷涂涂覆聚合物涂层。然后将得到的纤维优选地从例如5mm切成块,产生具有开放端的纤维。纤维可以通过伽马射线在冷却的条件下灭菌。
根据本发明,可以提供具有具备令人满意的包封效率(即纤维中生物活性剂的量除以使用的活性剂的量)具有一种或更多种生物活性剂的纤维。根据负载条件,至少20%的效率,至少50%的效率,至少75%或至少90%或更多的效率是可行的。
纤维可以被掺入到例如(快速成型的)支架、涂层、贴片、复合材料、凝胶、石膏或水凝胶中。或者,可以将其它结构(诸如颗粒)掺入到纤维中以形成复合体系。
根据本发明的纤维可以被注射或植入。在一个特别的实施方式中,纤维在眼的结膜下空间中是可注射的。
在另一个实施方式中,纤维可以通过诸如MRI、CT、X射线的特定技术为可成像的。成像剂可以被掺入到在纤维的核或壳内,或者可以被耦合到壳的表面上。合适的成像剂例如是钆。
包含根据本发明的聚酯酰胺共聚物的纤维可以用于医疗领域,尤其是在眼科管理领域的药物递送中。
根据本发明的纤维可以用作尤其用于治疗青光眼的药物洗脱载体。
现在将参考以下仅作为说明的非限制性实施例和附图来详细描述本发明。
通过参考以下非限制性实施例将进一步理解本发明。
附图:
图1:显示了拉坦前列素的累积的释放百分比,表示PEA-III-X25核-壳纤维的恒定的药物释放,而PEA-III-X25核,没有壳,表现出爆发的释放。拉坦前列素的日剂量用不含壳的纤维呈现,在释放的前20天内展示明显的爆发。
图2:显示了不包含壳的纤维的拉坦前列素的日剂量的释放,展示了在释放的前20天内明显的爆发。
图3:显示了在140天期间以0.05μg/天的拉坦前列素的恒定日剂量的拉坦前列素的释放。
图4:显示PEA-III-AcBz核和PEAIIIX25核的累积的释放曲线和日剂量。结果显示,在释放时间范围期间,由于PEA-III-AcBz聚合物核不可降解,日剂量随时间减少。
图5:显示PEA-III-AcBz核和PEA-III-X25核的累积的释放曲线和日剂量。结果显示,在释放时间范围期间,由于PEA-III-AcBz聚合物核的不可降解,日剂量随时间的减少。
图6:显示来自PLGA的拉坦前列素的累积的释放曲线和日剂量,并且显示了较差的控制,其中当聚合物基质被降解时,具有高的拉坦前列素爆发的日剂量。
图7:显示来自PLGA的拉坦前列素的累积的释放曲线和日剂量,并且显示了较差的控制,其中当聚合物基质被降解时,具有高的拉坦前列素爆发的日剂量。
图8:显示由PEA-III-X25和PEA-III-AcBz制成的核壳纤维不会减少爆发效应,表现出与不含壳的纤维相似的药物释放特征。
图9:显示由PEA-III-X25和PEA-III-AcBz制成的核壳纤维不会减少爆发效应,表现出与不含壳的纤维相似的药物释放特征。
图10:显示了1周后纤维的形态。
图11:显示了1个月后纤维的形态。
图12:显示3个月后纤维的形态。
图13:显示8个月后纤维的形态。
图14:显示了比马前列素的累积的释放百分比,表示PEA-III-X25核-壳纤维的受控的药物释放,而PEA-III-X25核,没有壳,表现出爆发的释放。
图15:显示了不含壳的纤维的比马前列素的日剂量,展示了在释放的前10天中明显的爆发。
实施例
实施例1:从包含PEA-III-X25/PLGA的核壳纤维和不包含壳的PEA-III-X25的纤维
中释放拉坦前列素
通过挤出并涂布PLGA制备拉坦前列素负载百分比为10%的由PEA-III-X25制成的纤维。将直径为240μm和5mm长的四根单独纤维置于37℃的1.2ml PBS缓冲溶液中。在不同的时间点,补充(refresh)0.9mL PBS溶液以确保漏槽状态,随后测量药物浓度。通常,在第一周每天测量样品,并在稍后的时间点每周测量样品。为了定量分析拉坦前列素样品的释放,使用了带有光电二极管阵列检测器的Waters e2695Alliance HPLC。使用Agilent ZorbaxEclipse XBD-C18 4.6x250mm,5μm柱采用等度HPLC方法。流动相为乙腈/水(60/40,包含0.05%TFA),流速为1.0ml/min。柱温度设定为25℃,样品温度设定为15℃。在210nm的波长下测量样品。拉坦前列素的系统在1μg-200μg的范围内呈线性,该范围也是用于标准校准曲线的范围。图1显示了拉坦前列素的累积的释放百分比,表示PEA-III-X25核-壳纤维的恒定的药物释放,而PEA-III-X25核,没有壳,表现出爆发的释放。在图2中,呈现了不包含壳的纤维的拉坦前列素的日剂量的释放,展示了在释放的前20天内明显的爆发。
实施例2:从PEA-III-X25/PLLA核-壳纤维中释放拉坦前列素
通过熔融注射制备拉坦前列素负载百分比为15%的由PEA-III-X25制成的纤维,并用PLLA涂布。将直径为200μm和5mm长的四根单独的纤维置于37℃的1.2ml PBS缓冲溶液中。在不同的时间点,补充0.9mL PBS溶液以确保漏槽状态,随后测量药物浓度。
图3显示在140天期间,拉坦前列素的恒定的0.05μg/天的日剂量。
实施例3:从包含PEA-III-X25/PEA-III-X25、PEA-III-X25/PEA-III-AcBz核-壳的
核壳纤维和不含壳的PEA-III-X25纤维中释放拉坦前列素
通过熔融注射拉坦前列素负载百分比为10%的由PEA-III-X25制成的纤维,并用PEA-III-X25和PEA-III-AcBz涂布。将直径为200μm和5mm长的三根单独的纤维置于37℃的1.2ml PBS缓冲溶液中。在不同的时间点,补充0.9mL PBS溶液以确保漏槽状态,随后测量药物浓度。
图8和图9显示,由PEA-III-X25和PEA-III-AcBz制成的核壳纤维不会降低爆发效应,表现出与不含壳的纤维相似的药物释放图况。
实施例4:药物释放期间的PEA-III-X25/PLGA核-壳纤维
通过注射成型制备拉坦前列素负载百分比为15%的由PEA-III-X25制成的纤维,并用PLGA涂布。将四个单独的纤维置于37℃的1.4ml PBS缓冲溶液中。在选定的时间点,使用奥林巴斯CX-41光学显微镜在4倍放大率下将纤维浸没在PBS中成像。图10-13显示在1周,1个月,3个月和8个月的纤维形态。随着PEA-III-X25核从涂层中降解和浸出,纤维末端的表面积增加,药物扩散的可用的表面增加。观察到的效果补偿了药物浓度梯度的降低,产生更恒定的药物释放曲线。
实施例5:从PEA-III-X25/PLLA核-壳纤维释放比马前列素
通过熔融注射制备比马前列素负载百分比为30%的由PEA-III-X25制成的纤维,并用PLLA涂布。将直径为200μm和1.2mm长的5根单独的纤维置于37℃的0.25ml PBS缓冲溶液中。在不同的时间点,补充0.15mL PBS溶液以确保漏槽状态,随后测量药物浓度。图14显示了比马前列素的累积的释放百分比,表示PEA-III-X25核-壳纤维的受控的药物释放,而PEA-III-X25核,没有壳,表现出爆发的释放。在图15中,不含壳的纤维的比马前列素的日剂量,展示了在释放的前10天中明显的爆发。
比较实验A:从PEA-III-AcBz/PLGA、PEA-III-X25/PLGA核-壳和PEA-III-AcBz无壳
系统释放拉坦前列素
通过挤出和用PLGA涂布,来制备由PEA-III-AcBz[(聚-8-[(L-Leu-DAS)0.45(L-Leu-6)0.3-[L-Lys(Bz)]0.25](结构在式III中给出)制造的拉坦前列素的负载百分比为10%的纤维。通过挤出和用PLGA涂布,制备拉坦前列素负载百分比为10%的PEA-III-X25纤维。直径为250μm和5mm长的四个单独的纤维置于37℃的1.2ml PBS缓冲溶液中。在不同的时间点,补充0.9mL PBS溶液以确保漏槽状态,随后测量药物浓度。
图4和图5展示PEA-III-AcBz核和PEAIIIX25核的累积的释放曲线和日剂量。结果显示,在释放时间范围期间,由于PEA-III-AcBz聚合物核不降解,日剂量随时间减少。相比之下,PEA-III-X25制造的纤维由于聚合物降解而显示日剂量增加。
式III
比较实验B:从PLGA盘释放拉坦前列素
通过溶剂流延膜以及从膜上冲出样品,制备拉坦前列素负载百分比为10%的PLGA载药盘。将直径为7mm的三个单独的盘放在37℃的5.0mL PBS缓冲溶液中。在不同的时间点,补充完整的PBS溶液以确保漏槽状态,随后测量药物浓度。
图6和图7展示从PLGA释放拉坦前列素的累积的释放曲线和日剂量,并且显示了较差的控制,其中当聚合物基质被降解时,具有高的拉坦前列素爆发的日剂量。
Claims (16)
1.包含核和壳的药物递送系统,其中核包含可水解降解的聚合物X,所述聚合物X的聚合物主链包含悬挂的酯官能团和悬挂的酸官能团,并且其中所述壳包含可水解降解的聚合物Y。
2.根据权利要求1的药物递送系统,其中所述可水解降解的聚合物X和Y是不同的聚合物。
3.根据权利要求1-2中任一项的药物递送系统,其中聚合物X在聚合物主链中还包含氨基酸。
4.根据权利要求1-3中任一项的药物递送系统,其中聚合物X是聚酯酰胺。
5.根据权利要求4的药物递送系统,其中所述聚酯酰胺包含基于总的悬挂的官能团的至少15%的酸基团。
6.根据权利要求5的药物递送系统,其中所述聚酯酰胺包含构筑基元A和B,其中基元A是包含游离羧基的赖氨酸或L-赖氨酸-H,并且基元B是L-赖氨酸-苄基或赖氨酸苄酯。
7.根据权利要求1-2中任一项的药物递送系统,其中聚合物Y是聚酯。
8.根据权利要求7的药物递送系统,其中所述聚酯是PLLA、PLGA或聚己内酯。
9.根据权利要求1-8中任一项的药物递送系统,其还包含生物活性剂。
10.根据权利要求9的药物递送系统,其在所述核中包含生物活性剂。
11.根据权利要求9-10中任一项的药物递送系统,其中所述生物活性剂是酸敏感的生物活性剂。
12.根据权利要求1-11中任一项的药物递送系统,其包含至少一个开放端。
13.根据权利要求12的药物递送系统,其包含两个开放端。
14.根据权利要求1-13中任一项的药物递送系统,其中所述系统是微米颗粒、纳米颗粒、棒、纤维或植入物。
15.根据权利要求14的药物递送系统,其中所述系统是包含两个开放端的纤维,所述系统在结膜下空间中是可注射的。
16.通过使用根据权利要求9-15中任一项的药物递送系统向眼施用生物活性剂来治疗青光眼、高眼压症、糖尿病性视网膜病变或黄斑变性的方法。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110051650A (zh) * | 2019-04-29 | 2019-07-26 | 南京锐利施生物技术有限公司 | 用于玻璃体注射的贝伐单抗和地塞米松共载的纳米粒药物 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102637575B1 (ko) * | 2016-10-05 | 2024-02-20 | 타이탄 파머슈티컬즈 인코퍼레이티드 | 버스트 방출이 감소된 약물 전달용 이식 가능한 장치 |
DE102017106216A1 (de) * | 2017-03-22 | 2018-09-27 | Amw Gmbh | Extrudierte Depotform zur anhaltenden Wirkstofffreisetzung |
MX2021010599A (es) * | 2019-03-05 | 2021-12-10 | Aerie Pharmaceuticals Inc | Composiciones farmaceuticas para el tratamiento de enfermedades o trastornos oculares. |
WO2022235906A1 (en) | 2021-05-05 | 2022-11-10 | Aerie Pharmaceuticals, Inc. | Pharmaceutical preparation |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050260276A1 (en) * | 2004-05-19 | 2005-11-24 | Agency For Science, Technology And Research | Methods and articles for the delivery of therapeutic agents |
US20070292476A1 (en) * | 2006-05-02 | 2007-12-20 | Medivas, Llc | Delivery of ophthalmologic agents to the exterior or interior of the eye |
CN102397258A (zh) * | 2011-11-18 | 2012-04-04 | 中国科学院长春应用化学研究所 | 胰岛素载药微球及其制备方法 |
US20130323306A1 (en) * | 2012-05-30 | 2013-12-05 | Boston Scientific Scimed, Inc. | Injectable biodegradable particles for controlled therapeutic agent release |
CN103748139A (zh) * | 2011-06-23 | 2014-04-23 | 帝斯曼知识产权资产管理有限公司 | 用于递送生物活性剂的包含生物可降解的聚酯酰胺共聚物的微米颗粒或纳米颗粒 |
WO2014064196A1 (en) * | 2012-10-24 | 2014-05-01 | Dsm Ip Assets B.V. | Fibers comprising polyesteramide copolymers for drug delivery |
Family Cites Families (217)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE505703C2 (sv) | 1995-12-15 | 1997-09-29 | Polyrand Ab | Linjär blockpolymer innefattande urea- och uretangrupper, förfarande för framställning av linjära blockpolymerer samt användning av blockpolymererna som implantat |
US4129594A (en) | 1977-10-27 | 1978-12-12 | Allied Chemical Corporation | Process for the manufacture of aromatic dicarboxylic acid chlorides |
US4221787A (en) | 1978-03-28 | 1980-09-09 | Interx Research Corporation | Esteramide prodrugs of anti-inflammatory corticosteroids |
US4550730A (en) | 1981-12-07 | 1985-11-05 | Ethicon, Inc. | Flexible monofilament surgical sutures comprising poly(polymethylene terephthalate, isophthalate or cyclohexane-1,4-dicarboxylate-co-dimerate) |
US4443563A (en) | 1983-06-08 | 1984-04-17 | The Dow Chemical Company | Polyurethanes based on 1;4-3:6 dianhydrohexitols |
EP0147780A3 (en) | 1984-01-03 | 1987-03-11 | Merck & Co. Inc. | Drug delivery device |
US5057313A (en) | 1986-02-25 | 1991-10-15 | The Center For Molecular Medicine And Immunology | Diagnostic and therapeutic antibody conjugates |
US5721131A (en) | 1987-03-06 | 1998-02-24 | United States Of America As Represented By The Secretary Of The Navy | Surface modification of polymers with self-assembled monolayers that promote adhesion, outgrowth and differentiation of biological cells |
US5482700A (en) | 1987-03-31 | 1996-01-09 | Schering Aktiengesellschaft | Substituted polyamino, polycarboxy complexing agent dimers for MRI and X-ray contrast |
US4994551A (en) | 1987-12-23 | 1991-02-19 | Pfizer Inc. | Bioabsorbable co-polydepsipeptide |
US5091560A (en) | 1988-03-14 | 1992-02-25 | The Clorox Company | Method for synthesizing acyloxycarboxylic acids |
IL90193A (en) | 1989-05-04 | 1993-02-21 | Biomedical Polymers Int | Polurethane-based polymeric materials and biomedical articles and pharmaceutical compositions utilizing the same |
EP0447719B1 (en) | 1990-03-05 | 1993-11-03 | Minnesota Mining And Manufacturing Company | Device for extended delivery of pharmacologically active agents to the ear |
CA2038605C (en) | 1990-06-15 | 2000-06-27 | Leonard Pinchuk | Crack-resistant polycarbonate urethane polymer prostheses and the like |
US5736371A (en) | 1991-06-04 | 1998-04-07 | A Et S Biovecteurs | Biodegradable particulate vector for transporting molecules having biological activity |
HU222501B1 (hu) | 1991-06-28 | 2003-07-28 | Endorecherche Inc. | MPA-t vagy MGA-t tartalmazó nyújtott hatóanyag-felszabadulású gyógyászati készítmény és eljárás előállítására |
US5206341A (en) | 1991-11-21 | 1993-04-27 | Southern Research Institute | Polymers from hydroxy acids and polycarboxylic acids |
US5286837A (en) | 1992-01-15 | 1994-02-15 | Minnesota Mining And Manufacturing Company | Process for increasing stability of poly(esteramides) |
US5599352A (en) | 1992-03-19 | 1997-02-04 | Medtronic, Inc. | Method of making a drug eluting stent |
US5178635A (en) | 1992-05-04 | 1993-01-12 | Allergan, Inc. | Method for determining amount of medication in an implantable device |
DE4224401A1 (de) | 1992-07-21 | 1994-01-27 | Pharmatech Gmbh | Neue biologisch abbaubare Polymere für die Arzneistoffgalenik |
US5514379A (en) | 1992-08-07 | 1996-05-07 | The General Hospital Corporation | Hydrogel compositions and methods of use |
KR940003548U (ko) | 1992-08-14 | 1994-02-21 | 김형술 | 세탁물 건조기 |
WO1994004642A2 (en) | 1992-08-21 | 1994-03-03 | Colgate-Palmolive Company | Fabric conditioning composition |
KR950703582A (ko) | 1992-10-14 | 1995-09-20 | 조이스 이. 마임스 | 킬레이트화 중합체(chelating polymers) |
ES2070076B1 (es) | 1993-04-20 | 1996-04-16 | Cusi Lab | Metodo para aumentar la estabilidad de las nanocapsulas durante su almacenamiento. |
US5762939A (en) | 1993-09-13 | 1998-06-09 | Mg-Pmc, Llc | Method for producing influenza hemagglutinin multivalent vaccines using baculovirus |
ES2370937T3 (es) | 1993-09-13 | 2011-12-23 | Protein Sciences Corporation | Un método para producir vacunas antigripales polivalentes a base de hemaglutinina. |
WO1995008289A2 (en) | 1993-09-16 | 1995-03-30 | Scimed Life Systems, Inc. | Percutaneous repair of cardiovascular anomalies and repair compositions |
US5554692A (en) | 1994-01-06 | 1996-09-10 | Ferro Corporation | Blocked isocyanate crosslinkers based on pentaerythritol for use in thermosetting coatings |
US6551618B2 (en) | 1994-03-15 | 2003-04-22 | University Of Birmingham | Compositions and methods for delivery of agents for neuronal regeneration and survival |
EP0712635B1 (en) | 1994-05-13 | 2003-05-02 | Kuraray Co., Ltd. | Medical polymer gel |
US5516881A (en) | 1994-08-10 | 1996-05-14 | Cornell Research Foundation, Inc. | Aminoxyl-containing radical spin labeling in polymers and copolymers |
DE4432378A1 (de) | 1994-09-12 | 1996-03-14 | Bayer Ag | Injizierbare liposomale Arzneizubereitungen |
US5485496A (en) | 1994-09-22 | 1996-01-16 | Cornell Research Foundation, Inc. | Gamma irradiation sterilizing of biomaterial medical devices or products, with improved degradation and mechanical properties |
DE19500756A1 (de) | 1995-01-13 | 1996-07-18 | Basf Ag | Biologisch abbaubare Polymere, Verfahren zu deren Herstellung sowie deren Verwendung zur Herstellung bioabbaubarer Formkörper |
ATE178414T1 (de) | 1995-02-03 | 1999-04-15 | Novartis Ag | Vernetzte polymere enthaltend ester- oder amidgruppen |
US5852155A (en) | 1995-03-01 | 1998-12-22 | General Electric Company | Compositions of polyesteramides |
US5906934A (en) | 1995-03-14 | 1999-05-25 | Morphogen Pharmaceuticals, Inc. | Mesenchymal stem cells for cartilage repair |
KR100201352B1 (ko) | 1995-03-16 | 1999-06-15 | 성재갑 | 단일주사 백신 제형 |
FR2732218B1 (fr) | 1995-03-28 | 1997-08-01 | Flamel Tech Sa | Particules a base de polyaminoacide(s) et susceptibles d'etre utilisees comme vecteurs de principe(s) actif(s) et leurs procedes de preparation |
AUPN443995A0 (en) | 1995-07-27 | 1995-08-17 | Csl Limited | Papillomavirus polyprotein |
JP3599749B2 (ja) | 1996-02-20 | 2004-12-08 | マサチューセッツ インスティテュート オブ テクノロジー | 整形外科および歯科用途での使用のための生分解性ポリマーネットワーク |
JP3737518B2 (ja) | 1996-03-12 | 2006-01-18 | ピージー−ティーエックスエル カンパニー, エル.ピー. | 水溶性パクリタキセルプロドラッグ |
CA2225792A1 (en) | 1996-04-30 | 1997-11-06 | Toshihide Inoue | Polyester amide copolymer and method of producing the same, polyester amide monomer and method of producing the same, and polyester amide resin composition |
US6228391B1 (en) | 1996-05-02 | 2001-05-08 | Terumo Kabushiki Kaisha | Amidine derivatives and drug carriers comprising the same |
US5610241A (en) | 1996-05-07 | 1997-03-11 | Cornell Research Foundation, Inc. | Reactive graft polymer with biodegradable polymer backbone and method for preparing reactive biodegradable polymers |
US5874064A (en) | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US5916585A (en) | 1996-06-03 | 1999-06-29 | Gore Enterprise Holdings, Inc. | Materials and method for the immobilization of bioactive species onto biodegradable polymers |
US7041785B1 (en) | 1996-08-19 | 2006-05-09 | UNIVERSITé DE SHERBROOKE | B1-bradykinin receptor antagonists and use thereof |
US6056973A (en) | 1996-10-11 | 2000-05-02 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method of preparation |
EP0932390A1 (en) | 1996-10-11 | 1999-08-04 | Sequus Pharmaceuticals, Inc. | Therapeutic liposome composition and method |
CA2591581C (en) | 1996-12-20 | 2013-01-29 | Alza Corporation | Gel composition and methods |
CA2278613A1 (en) | 1997-01-28 | 1998-07-30 | United States Surgical Corporation | Polyesteramide, its preparation and surgical devices fabricated therefrom |
US7062219B2 (en) | 1997-01-31 | 2006-06-13 | Odyssey Thera Inc. | Protein fragment complementation assays for high-throughput and high-content screening |
US5827533A (en) | 1997-02-06 | 1998-10-27 | Duke University | Liposomes containing active agents aggregated with lipid surfactants |
AUPO517897A0 (en) | 1997-02-19 | 1997-04-11 | Csl Limited | Chelating immunostimulating complexes |
US6982249B1 (en) | 1997-04-23 | 2006-01-03 | The Regents Of The University Of Michigan | Bradykinin analogs as selective inhibitors of cell activation |
US6221997B1 (en) | 1997-04-28 | 2001-04-24 | Kimberly Ann Woodhouse | Biodegradable polyurethanes |
US5972027A (en) | 1997-09-30 | 1999-10-26 | Scimed Life Systems, Inc | Porous stent drug delivery system |
US6004573A (en) | 1997-10-03 | 1999-12-21 | Macromed, Inc. | Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties |
US20020164374A1 (en) | 1997-10-29 | 2002-11-07 | John Jackson | Polymeric systems for drug delivery and uses thereof |
SE513149C2 (sv) | 1997-12-05 | 2000-07-17 | Katarina Edwards | Läkemedelsdistributionssystem med tvåstegsmålsökning, till specifika celler eller vävnad och till dess cellkärna |
CN1281355A (zh) | 1997-12-12 | 2001-01-24 | 三阳株式会社 | 用于基因递送的生物可降解性混合聚合胶束 |
EP0926184A1 (en) | 1997-12-25 | 1999-06-30 | Mitsui Chemicals, Inc. | Process for production of polyamino acid derivative |
US6541606B2 (en) | 1997-12-31 | 2003-04-01 | Altus Biologics Inc. | Stabilized protein crystals formulations containing them and methods of making them |
US6841617B2 (en) | 2000-09-28 | 2005-01-11 | Battelle Memorial Institute | Thermogelling biodegradable aqueous polymer solution |
US7658727B1 (en) | 1998-04-20 | 2010-02-09 | Medtronic, Inc | Implantable medical device with enhanced biocompatibility and biostability |
US6171610B1 (en) | 1998-04-24 | 2001-01-09 | University Of Massachusetts | Guided development and support of hydrogel-cell compositions |
EP0963758A3 (en) | 1998-05-07 | 2000-03-22 | Universiteit Gent | Synthetic polyaminoacid complexes for delivery of nucleic acids to target cells |
WO1999061916A1 (en) | 1998-05-29 | 1999-12-02 | Epimmune, Inc. | Identification of broadly reactive dr restricted epitopes |
US6153252A (en) | 1998-06-30 | 2000-11-28 | Ethicon, Inc. | Process for coating stents |
DE69940735D1 (de) | 1998-07-17 | 2009-05-28 | Pacira Pharmaceuticals Inc | Biologisch abbaubare anordnungen zur kontrollierten freigabe eingeschlossener substanzen |
WO2000012619A1 (en) | 1998-08-31 | 2000-03-09 | Cornell Research Foundation, Inc. | Dextran-maleic acid monoesters and hydrogels based thereon |
US6103526A (en) | 1998-10-08 | 2000-08-15 | Protein Sciences Corporation | Spodoptera frugiperda single cell suspension cell line in serum-free media, methods of producing and using |
US7026156B1 (en) | 1999-02-04 | 2006-04-11 | The University Of Georgia Research Foundation, Inc. | Diagnostic and protective antigen gene sequences of ichthyophthirius |
JP2002537415A (ja) | 1999-02-19 | 2002-11-05 | バイオサルフ アーゲー | マイクロカプセルの製造のための生物分解性複合材料 |
US6342300B1 (en) | 1999-02-20 | 2002-01-29 | Celanese Ventures Gmbh | Biodegradable polymers based on natural and renewable raw materials especially isosorbite |
GB9904627D0 (en) | 1999-03-02 | 1999-04-21 | Danbiosyst Uk | Polymer compositions for polynucleotide delivery |
US6716445B2 (en) | 1999-04-12 | 2004-04-06 | Cornell Research Foundation, Inc. | Hydrogel entrapping therapeutic agent and stent with coating comprising this |
US7238368B2 (en) | 1999-04-23 | 2007-07-03 | Alza Corporation | Releasable linkage and compositions containing same |
US6521431B1 (en) | 1999-06-22 | 2003-02-18 | Access Pharmaceuticals, Inc. | Biodegradable cross-linkers having a polyacid connected to reactive groups for cross-linking polymer filaments |
US6352667B1 (en) | 1999-08-24 | 2002-03-05 | Absorbable Polymer Technologies, Inc. | Method of making biodegradable polymeric implants |
US9289487B2 (en) | 1999-09-14 | 2016-03-22 | Antigen Express, Inc. | II-key/antigenic epitope hybrid peptide vaccines |
US20030130185A1 (en) | 2000-09-29 | 2003-07-10 | David Bar-Or | Metal-binding compounds and uses therefor |
US7582311B1 (en) | 1999-10-15 | 2009-09-01 | Genentech, Inc. | Injection vehicle for polymer-based formulations |
US20020007122A1 (en) | 1999-12-15 | 2002-01-17 | Howard Kaufman | Methods of diagnosing disease |
US6703040B2 (en) | 2000-01-11 | 2004-03-09 | Intralytix, Inc. | Polymer blends as biodegradable matrices for preparing biocomposites |
EP1250143A2 (en) | 2000-01-11 | 2002-10-23 | Intralytix Inc. | Reduction in bacterial colonization by administering bacteriophage compositions |
US20070191932A1 (en) | 2000-03-15 | 2007-08-16 | Orbusneich Medical, Inc. | Medical device with coating for capturing genetically-altered cells and methods for using same |
US20070141107A1 (en) | 2000-03-15 | 2007-06-21 | Orbusneich Medical, Inc. | Progenitor Endothelial Cell Capturing with a Drug Eluting Implantable Medical Device |
US9522217B2 (en) | 2000-03-15 | 2016-12-20 | Orbusneich Medical, Inc. | Medical device with coating for capturing genetically-altered cells and methods for using same |
US20070055367A1 (en) | 2000-03-15 | 2007-03-08 | Orbus Medical Technologies, Inc. | Medical device with coating that promotes endothelial cell adherence and differentiation |
US20030229393A1 (en) | 2001-03-15 | 2003-12-11 | Kutryk Michael J. B. | Medical device with coating that promotes cell adherence and differentiation |
US20050271701A1 (en) | 2000-03-15 | 2005-12-08 | Orbus Medical Technologies, Inc. | Progenitor endothelial cell capturing with a drug eluting implantable medical device |
ATE362382T1 (de) | 2000-03-15 | 2007-06-15 | Orbusneich Medical Inc | Beschichtung welche ein anhaften von endothelzellen stimuliert |
AU4574501A (en) | 2000-03-17 | 2001-10-03 | Millennium Pharm Inc | Method of inhibiting stenosis and restenosis |
ATE361738T1 (de) | 2000-05-26 | 2007-06-15 | Color Access Inc | Mehrphasen emulsionen mit niedrigen emulgiermittel |
EP1284756B1 (en) | 2000-05-31 | 2004-09-15 | Mnemoscience GmbH | Shape memory thermoplastics and polymer networks for tissue engineering |
US20040258702A1 (en) | 2000-06-22 | 2004-12-23 | Blonder Joan P. | Vaccine delivery |
MXPA02012749A (es) | 2000-06-30 | 2003-10-06 | Amgen Inc | Moleculas semejantes a b7 y sus usos. |
US7304122B2 (en) | 2001-08-30 | 2007-12-04 | Cornell Research Foundation, Inc. | Elastomeric functional biodegradable copolyester amides and copolyester urethanes |
AU2006204654B2 (en) | 2000-08-30 | 2008-06-05 | Cornell Research Foundation, Inc. | Elastomeric functional biodegradable copolyester amides and copolyester urethanes |
US20060286064A1 (en) | 2000-08-30 | 2006-12-21 | Medivas, Llc | Therapeutic polymers and methods |
US20060177416A1 (en) | 2003-10-14 | 2006-08-10 | Medivas, Llc | Polymer particle delivery compositions and methods of use |
US6503538B1 (en) | 2000-08-30 | 2003-01-07 | Cornell Research Foundation, Inc. | Elastomeric functional biodegradable copolyester amides and copolyester urethanes |
CN1119172C (zh) | 2000-12-12 | 2003-08-27 | 天津大学 | 脂肪族聚酯表面的壳聚糖/明胶网络修饰方法 |
FR2820145B1 (fr) | 2001-01-31 | 2004-01-23 | Aventis Pharma Sa | Souche de levure produisant des steroides de facon autonome |
ES2220247T3 (es) | 2001-05-07 | 2007-11-16 | Cornell Research Foundation, Inc. | Copolimeros biodegradables enlazados a un segmento con una pluralidad de grupos funcionales. |
CA2385140C (en) | 2001-05-07 | 2011-07-26 | Queen's University At Kingston | Biodegradable elastomer and methods of preparing same |
WO2003020906A2 (en) | 2001-08-31 | 2003-03-13 | Abmaxis, Inc. | Multivalent protein conjugate with multiple ligand-binding domains of receptors |
US7030082B2 (en) | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
GB0122318D0 (en) | 2001-09-14 | 2001-11-07 | Novartis Ag | Organic compounds |
FR2831165B1 (fr) | 2001-10-23 | 2005-06-17 | Mane Fils V | Nouveaux derives du norbornane et du norbornene, leur utilisation et produits parfumes les contenant |
GB0126157D0 (en) | 2001-10-31 | 2002-01-02 | Univ Aberdeen | Therapeutic compounds |
WO2003062298A1 (en) | 2002-01-17 | 2003-07-31 | Polyrava Llc | Co-poly(ester amide) and co-poly(ester urethane) compositions which exhibit biodegradability, methods for making same and uses for same |
EP1585817B1 (en) | 2002-02-20 | 2009-09-02 | The General Hospital Corporation | Conjugates comprising a biodegradable polymer and uses therefor |
US20050260259A1 (en) | 2004-04-23 | 2005-11-24 | Bolotin Elijah M | Compositions for treatment with glucagon-like peptide, and methods of making and using the same |
WO2003073993A2 (en) | 2002-03-01 | 2003-09-12 | Colb Mark A | Binding of red blood cell to exposed subendothelial surfaces to impede platelet deposition thereon and/or for use in targeted drug delivery thereto |
AU2003249623A1 (en) | 2002-05-09 | 2003-12-12 | Kurve Technology, Inc. | Particle dispersion chamber for nasal nebulizer |
EP1504046B1 (en) | 2002-05-15 | 2006-07-12 | Rutgers, The State University | Tri-block polymers for nanosphere-based drug or gene delivery |
US20040057958A1 (en) | 2002-05-17 | 2004-03-25 | Waggoner David W. | Immunogenicity-enhancing carriers and compositions thereof and methods of using the same |
US6994867B1 (en) | 2002-06-21 | 2006-02-07 | Advanced Cardiovascular Systems, Inc. | Biocompatible carrier containing L-arginine |
IL166418A0 (en) | 2002-07-31 | 2006-01-15 | Alza Corp | Injectable depot compositions and uses thereof |
US20050019404A1 (en) | 2003-06-30 | 2005-01-27 | Hsing-Wen Sung | Drug-eluting biodegradable stent |
AU2003257604A1 (en) | 2002-08-23 | 2004-03-29 | Bridgestone Corporation | Stent and process for producing the same |
US7794494B2 (en) | 2002-10-11 | 2010-09-14 | Boston Scientific Scimed, Inc. | Implantable medical devices |
AU2003264791A1 (en) | 2002-11-01 | 2004-05-25 | Koninklijke Philips Electronics N.V. | Method of manufacturing of a cholesteric layer |
AU2003297573A1 (en) | 2002-11-27 | 2004-06-23 | Cedric Francois | Compositions and methods for treating transplants |
US20050019366A1 (en) | 2002-12-31 | 2005-01-27 | Zeldis Jerome B. | Drug-coated stents and methods of use therefor |
JP2006523609A (ja) | 2002-12-31 | 2006-10-19 | アルタス ファーマシューティカルズ インコーポレイテッド | タンパク質結晶およびイオン性ポリマーの複合体 |
US20040170685A1 (en) | 2003-02-26 | 2004-09-02 | Medivas, Llc | Bioactive stents and methods for use thereof |
US20040253293A1 (en) | 2003-06-16 | 2004-12-16 | Afshin Shafiee | Rate controlled release of a pharmaceutical agent in a biodegradable device |
WO2005013896A2 (en) | 2003-07-09 | 2005-02-17 | Vaxdesign Corporation | Programmed immune responses using a vaccination node |
US20050013812A1 (en) | 2003-07-14 | 2005-01-20 | Dow Steven W. | Vaccines using pattern recognition receptor-ligand:lipid complexes |
US7744861B2 (en) | 2003-09-17 | 2010-06-29 | Nektar Therapeutics | Multi-arm polymer prodrugs |
EP1682132A1 (en) | 2003-09-18 | 2006-07-26 | Macusight, Inc. | Transscleral delivery |
WO2006083874A2 (en) | 2005-02-01 | 2006-08-10 | Medivas, Llc. | Vaccine delivery compositions and methods of use |
US20060188486A1 (en) | 2003-10-14 | 2006-08-24 | Medivas, Llc | Wound care polymer compositions and methods for use thereof |
US7794706B2 (en) | 2003-10-14 | 2010-09-14 | Medivas, Llc | Bioactive wound dressings and implantable devices and methods of use |
WO2006050091A2 (en) | 2004-10-28 | 2006-05-11 | Medivas, Llc | Bioactive wound dressings and implantable devices and methods of use |
US20080160089A1 (en) | 2003-10-14 | 2008-07-03 | Medivas, Llc | Vaccine delivery compositions and methods of use |
US20060188469A1 (en) | 2003-10-14 | 2006-08-24 | Medivas, Llc | Vaccine delivery compositions and methods of use |
JP2005139139A (ja) | 2003-11-07 | 2005-06-02 | Idemitsu Technofine Co Ltd | 化粧料組成物 |
CA2545136A1 (en) | 2003-11-07 | 2005-05-26 | Gp Medical, Inc. | Drug-eluting biodegradable stent |
PT1696822E (pt) | 2003-11-13 | 2010-04-28 | Psivida Inc | Implante de libertação controlada injectável com um núcleo de matriz biocorrosível e crosta biocorrosível |
JP2008504216A (ja) | 2003-12-02 | 2008-02-14 | サイトイミューン サイエンシズ インコーポレイテッド | モノクローナル抗体の生成のための方法および組成物 |
US7220816B2 (en) | 2003-12-16 | 2007-05-22 | Advanced Cardiovascular Systems, Inc. | Biologically absorbable coatings for implantable devices based on poly(ester amides) and methods for fabricating the same |
US8685431B2 (en) | 2004-03-16 | 2014-04-01 | Advanced Cardiovascular Systems, Inc. | Biologically absorbable coatings for implantable devices based on copolymers having ester bonds and methods for fabricating the same |
AU2005231458A1 (en) | 2004-04-05 | 2005-10-20 | Medivas, Llc | Bioactive stents for type II diabetics and methods for use thereof |
US20080288057A1 (en) | 2004-04-05 | 2008-11-20 | Carpenter Kenneth W | Bioactive Stents For Type II Diabetics and Methods for Use Thereof |
US20060013855A1 (en) | 2004-04-05 | 2006-01-19 | Medivas, Llc | Bioactive stents for type II diabetics and methods for use thereof |
US8163269B2 (en) | 2004-04-05 | 2012-04-24 | Carpenter Kenneth W | Bioactive stents for type II diabetics and methods for use thereof |
CN101080246A (zh) | 2004-04-28 | 2007-11-28 | 安希奥设备国际有限责任公司 | 用于形成交联生物材料的组合物和系统及关联的制备方法与用途 |
US7771742B2 (en) | 2004-04-30 | 2010-08-10 | Allergan, Inc. | Sustained release intraocular implants containing tyrosine kinase inhibitors and related methods |
US7820732B2 (en) | 2004-04-30 | 2010-10-26 | Advanced Cardiovascular Systems, Inc. | Methods for modulating thermal and mechanical properties of coatings on implantable devices |
WO2005107817A2 (en) | 2004-04-30 | 2005-11-17 | Orbus Medical Technologies, Inc. | Medical device with coating for capturing genetically-altered cells and methods of using same |
US20050265960A1 (en) | 2004-05-26 | 2005-12-01 | Pacetti Stephen D | Polymers containing poly(ester amides) and agents for use with medical articles and methods of fabricating the same |
US20050288481A1 (en) | 2004-04-30 | 2005-12-29 | Desnoyer Jessica R | Design of poly(ester amides) for the control of agent-release from polymeric compositions |
US7799336B2 (en) * | 2004-04-30 | 2010-09-21 | Allergan, Inc. | Hypotensive lipid-containing biodegradable intraocular implants and related methods |
CN101426530B (zh) | 2004-05-12 | 2012-03-07 | 梅迪沃什有限公司 | 创伤愈合聚合物组合物及其使用方法 |
US20050271700A1 (en) | 2004-06-03 | 2005-12-08 | Desnoyer Jessica R | Poly(ester amide) coating composition for implantable devices |
US7863406B2 (en) | 2004-06-03 | 2011-01-04 | Cornell Research Foundation, Inc. | Unsaturated poly(ester-amide) biomaterials |
US20050287184A1 (en) | 2004-06-29 | 2005-12-29 | Hossainy Syed F A | Drug-delivery stent formulations for restenosis and vulnerable plaque |
WO2006017347A2 (en) | 2004-07-12 | 2006-02-16 | Allergan, Inc. | Opthalmic compositions and methods for treating ophthalmic conditions |
US8980300B2 (en) | 2004-08-05 | 2015-03-17 | Advanced Cardiovascular Systems, Inc. | Plasticizers for coating compositions |
US7166680B2 (en) | 2004-10-06 | 2007-01-23 | Advanced Cardiovascular Systems, Inc. | Blends of poly(ester amide) polymers |
AU2005299672A1 (en) | 2004-10-22 | 2006-05-04 | Benitec, Inc. | Therapeutic RNAi agents for treating psoriasis |
US7390497B2 (en) | 2004-10-29 | 2008-06-24 | Advanced Cardiovascular Systems, Inc. | Poly(ester amide) filler blends for modulation of coating properties |
US20060159918A1 (en) | 2004-12-22 | 2006-07-20 | Fiber Innovation Technology, Inc. | Biodegradable fibers exhibiting storage-stable tenacity |
JP2008530206A (ja) | 2005-02-17 | 2008-08-07 | メディバス エルエルシー | ポリマー粒子送達組成物および使用法 |
CN100551950C (zh) | 2005-03-21 | 2009-10-21 | 中国科学院成都有机化学有限公司 | 一种可降解聚酯酰胺共聚物的制备方法 |
KR100696125B1 (ko) | 2005-03-30 | 2007-03-22 | 엘지전자 주식회사 | 스크롤 압축기의 고정스크롤 |
CN101180086A (zh) * | 2005-04-08 | 2008-05-14 | 苏尔莫迪克斯公司 | 用于经视网膜下递送的持续释放植入物 |
AU2006255262A1 (en) | 2005-06-03 | 2006-12-14 | Medivas, Llc. | Therapeutic polymers and methods of use |
AU2006295305B2 (en) | 2005-09-16 | 2013-01-31 | Allergan, Inc. | Compositions and methods for the intraocular transport of therapeutic agents |
US8652504B2 (en) | 2005-09-22 | 2014-02-18 | Medivas, Llc | Solid polymer delivery compositions and methods for use thereof |
CA2623198C (en) | 2005-09-22 | 2014-08-05 | Medivas, Llc | Bis-(a-amino)-diol-diester-containing poly(ester amide) and poly(ester urethane) compositions and methods of use |
US20070071790A1 (en) | 2005-09-28 | 2007-03-29 | Northwestern University | Biodegradable nanocomposites with enhance mechanical properties for soft tissue |
JP2009516757A (ja) | 2005-10-21 | 2009-04-23 | メディバス エルエルシー | ポリ(エステルウレア)ポリマーおよび使用法 |
US20070106035A1 (en) | 2005-10-26 | 2007-05-10 | Medivas, Llc | Aromatic di-acid-containing poly (ester amide) polymers and methods of use |
US20070134332A1 (en) | 2005-11-21 | 2007-06-14 | Medivas, Llc | Polymer particles for delivery of macromolecules and methods of use |
WO2007067744A2 (en) | 2005-12-07 | 2007-06-14 | Medivas, Llc | Method for assembling a polymer-biologic delivery composition |
US8974815B2 (en) | 2005-12-16 | 2015-03-10 | Cornell University | Fibrous membrane for biomedical application based on poly(ester-amide)s |
JP2009525341A (ja) | 2006-01-31 | 2009-07-09 | メディバス エルエルシー | ワクチン送達組成物および使用法 |
TWI376239B (en) | 2006-02-01 | 2012-11-11 | Andrew Xian Chen | Vitamin e succinate stabilized pharmaceutical compositions, methods for the preparation and the use thereof |
US8445627B2 (en) | 2006-03-24 | 2013-05-21 | Medivas, Llc | Alkylene-dicarboxylate-containing biodegradable poly(ester-amides) and methods of use |
EP2021141A4 (en) | 2006-05-09 | 2013-07-03 | Medivas Llc | BIODEGRADABLE WATER SOLUBLE POLYMERS |
US7779625B2 (en) | 2006-05-11 | 2010-08-24 | Kalypto Medical, Inc. | Device and method for wound therapy |
US20070299155A1 (en) | 2006-06-09 | 2007-12-27 | Medivas, Llc | Biodegradable polymer adhesion barriers |
JP2008027269A (ja) | 2006-07-24 | 2008-02-07 | Matsushita Electric Ind Co Ltd | 通信機器およびプログラム更新方法 |
WO2008021548A2 (en) | 2006-08-18 | 2008-02-21 | Medivas, Llc | Epoxy-containing poly(ester amides) and methods of use |
US8936780B2 (en) | 2006-08-30 | 2015-01-20 | Advanced Cardiovascular Systems, Inc. | Stimuli responsive polyester amide particles |
EP2068937A2 (en) | 2006-09-05 | 2009-06-17 | Medivas, LLC | Polymer-stabilized liposomal compositions and methods of use |
CN101168595A (zh) | 2006-10-27 | 2008-04-30 | 湖南大学 | 可降解的不饱和聚酯酰胺树脂及其合成方法 |
US7649022B2 (en) | 2007-03-30 | 2010-01-19 | Medivas, Llc | Bioabsorbable elastomeric polymer networks, cross-linkers and methods of use |
US9737638B2 (en) | 2007-06-20 | 2017-08-22 | Abbott Cardiovascular Systems, Inc. | Polyester amide copolymers having free carboxylic acid pendant groups |
CA2693969A1 (en) | 2007-07-17 | 2009-01-22 | Medivas, Llc | Bioabsorbable elastomeric arterial support device and methods of use |
WO2009012449A1 (en) | 2007-07-18 | 2009-01-22 | The Board Of Trustees Of The University Of Illinois | Temporal release of growth factors from 3d micro rod scaffolds for tissue regeneration |
CA2709412A1 (en) | 2007-07-24 | 2009-01-29 | Medivas, Llc | Biodegradable cationic polymer gene transfer compositions and methods of use |
EP2185626A4 (en) | 2007-08-23 | 2010-09-08 | Medivas Llc | BIODEGRADABLE POLYMERIC GENE TRANSFER COMPOSITIONS CONTAINING CATIONIC ALPHA-AMINO ACIDS |
US20110027379A1 (en) | 2007-12-06 | 2011-02-03 | Cornell University | Oligo-Ethylene Glycol-Based Polymer Compositions and Methods of Use |
WO2009137711A1 (en) | 2008-05-07 | 2009-11-12 | Medivas, Llc | Biodegradable metal-chelating polymers and vaccines |
WO2010019716A1 (en) | 2008-08-13 | 2010-02-18 | Medivas, Llc | Aabb-poly(depsipeptide) biodegradable polymers and methods of use |
JP2012505957A (ja) | 2008-10-15 | 2012-03-08 | メディバス エルエルシー | プロリンベースの生分解性ポリマー |
US20100291182A1 (en) * | 2009-01-21 | 2010-11-18 | Arsenal Medical, Inc. | Drug-Loaded Fibers |
US20100247606A1 (en) | 2009-03-25 | 2010-09-30 | Allergan, Inc. | Intraocular sustained release drug delivery systems and methods for treating ocular conditions |
WO2011045443A1 (en) | 2009-10-16 | 2011-04-21 | Dsm Ip Assets B.V. | Coatings comprising bis-(alpha-amino-diol-diester) containing polyesteramide |
WO2011053803A2 (en) * | 2009-10-30 | 2011-05-05 | The Ohio State University | Multi-functional biodegradable particles for selectable targeting, imaging, and therapeutic delivery and use thereof for treating ocular disorders |
JP2013526572A (ja) | 2010-05-17 | 2013-06-24 | アエリエ・ファーマシューティカルズ・インコーポレーテッド | 眼治療薬の送達のための薬物送達装置 |
EP2705182B1 (en) | 2011-05-02 | 2018-10-31 | DSM IP Assets B.V. | Fiber comprising a biodegradable polymer |
US20140105957A1 (en) | 2011-05-02 | 2014-04-17 | Dsm Ip Assets B.V. | Bis-(alpha-amino-diol-diester) containing polyesteramide for ophtamology |
US20150038415A1 (en) | 2011-12-16 | 2015-02-05 | Dsm Ip Assets B.V. | Process for the manufacturing of a drug delivery system based on a polymer comprising a dispersed bioactive agent |
EP2903592B1 (en) | 2012-10-02 | 2019-01-23 | DSM IP Assets B.V. | Drug delivery composition comprising proteins and biodegradable polyesteramides |
US20150246001A1 (en) | 2012-10-23 | 2015-09-03 | Dsm Ip Assets B.V. | Process for the manufacturing of a multilayer drug delivery construct |
US10538864B2 (en) | 2012-10-24 | 2020-01-21 | Dsm Ip Assets, B.V. | Fibers comprising polyesteramide copolymers for drug delivery |
CA2892523A1 (en) | 2012-12-20 | 2014-06-26 | George Mihov | Coating comprising polyesteramide copolymers for drug delivery |
-
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- 2015-12-18 EP EP15816455.8A patent/EP3233067B1/en active Active
- 2015-12-18 JP JP2017527282A patent/JP6720447B2/ja active Active
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050260276A1 (en) * | 2004-05-19 | 2005-11-24 | Agency For Science, Technology And Research | Methods and articles for the delivery of therapeutic agents |
US20070292476A1 (en) * | 2006-05-02 | 2007-12-20 | Medivas, Llc | Delivery of ophthalmologic agents to the exterior or interior of the eye |
CN103748139A (zh) * | 2011-06-23 | 2014-04-23 | 帝斯曼知识产权资产管理有限公司 | 用于递送生物活性剂的包含生物可降解的聚酯酰胺共聚物的微米颗粒或纳米颗粒 |
CN102397258A (zh) * | 2011-11-18 | 2012-04-04 | 中国科学院长春应用化学研究所 | 胰岛素载药微球及其制备方法 |
US20130323306A1 (en) * | 2012-05-30 | 2013-12-05 | Boston Scientific Scimed, Inc. | Injectable biodegradable particles for controlled therapeutic agent release |
WO2014064196A1 (en) * | 2012-10-24 | 2014-05-01 | Dsm Ip Assets B.V. | Fibers comprising polyesteramide copolymers for drug delivery |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110051650A (zh) * | 2019-04-29 | 2019-07-26 | 南京锐利施生物技术有限公司 | 用于玻璃体注射的贝伐单抗和地塞米松共载的纳米粒药物 |
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