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1. 发明授权

US06262183B1 Hydroxamic acid polymers formed from primary amide polymers 失效
标题翻译：由主要酰胺聚合物形成的羟肟酸聚合物
公开(公告)号：US06262183B1
公开(公告)日：2001-07-17
申请号：US08219160
申请日：1994-03-28
申请人： Abraham J. Domb , Robert S. Langer , Ernest G. Cravalho , Gershon Golomb , Edith Mathiowitz , Cato T. Laurencin
发明人： Abraham J. Domb , Robert S. Langer , Ernest G. Cravalho , Gershon Golomb , Edith Mathiowitz , Cato T. Laurencin
IPC分类号： C08F2056
CPC分类号： C08F8/32 , C08F2800/10 , C08F8/42 , C08F220/56
摘要： Hydroxamic acid polymers which are comprised of hydroxamic groups and carboxylic acid groups wherein the carboxylic acid groups constitute less than about 3% of the functional groups. The polymers hereof are also especially useful in biomedical applications because, for example, the low concentration of carboxylic acid groups decreases the incidence of bioincompatibility. Additionally, the polymers exhibit anticoagulant activity, urease inhibition activity, metal chelating activity and ion exchange activity.
摘要翻译：由异羟肟基和羧酸基组成的羟肟酸聚合物，其中羧酸基构成少于官能团的约3％。这里的聚合物在生物医学应用中也特别有用，因为例如低浓度的羧酸组降低生物相容性的发生率。另外，聚合物显示抗凝血活性，脲酶抑制活性，金属螯合活性和离子交换活性。

2. 发明授权

US5128420A Method of making hydroxamic acid polymers from primary amide polymers 失效
标题翻译：由一级酰胺聚合物制备异羟肟酸聚合物的方法
公开(公告)号：US5128420A
公开(公告)日：1992-07-07
申请号：US283594
申请日：1988-12-13
申请人： Abraham J. Domb , Robert S. Langer , Ernest G. Cravalho , Gershon Golomb , Edith Mathiowitz , Cato T. Laurencin
发明人： Abraham J. Domb , Robert S. Langer , Ernest G. Cravalho , Gershon Golomb , Edith Mathiowitz , Cato T. Laurencin
IPC分类号： C08F8/32
CPC分类号： C08F8/32 , C08F2800/10 , C08F2810/20
摘要： A method for preparing hydroxamic acid polymers from primary amide polymers wherein polyvinyl monomers such as polyacrylamide are reacted with hydroxyl amine in aqueous solution at room temperature. The low reaction temperature is crucial to producing a high yield (70%) of polymer with hydroxamic acid groups and having a low carboxylic acid content (less than 15%, preferably less than 3%). The polymers display high metal affinity over a broad pH range.The polymers are particularly useful for biomedical applications due to the low carboxylic acid content and for the removal and purification of metals due to the high binding constants and rapid reaction rates.
摘要翻译：由聚酰胺聚合物制备异羟肟酸聚合物的方法，其中聚乙烯基单体例如聚丙烯酰胺在室温下与羟胺在水溶液中反应。低反应温度对于用异羟肟酸基团产生高产率（70％）的聚合物和低羧酸含量（小于15％，优选小于3％）是至关重要的。聚合物在宽pH范围内显示出高的金属亲和力。由于高的结合常数和快速的反应速率，由于羧酸含量低以及金属的去除和纯化，聚合物特别适用于生物医学应用。

3. 发明授权

US5286763A Bioerodible polymers for drug delivery in bone 失效
标题翻译：用于骨中药物递送的生物可分解聚合物
公开(公告)号：US5286763A
公开(公告)日：1994-02-15
申请号：US908438
申请日：1992-06-30
申请人： Tobin N. Gerhart , Cato T. Laurencin , Abraham J. Domb , Robert S. Langer , Wilson C. Hayes
发明人： Tobin N. Gerhart , Cato T. Laurencin , Abraham J. Domb , Robert S. Langer , Wilson C. Hayes
IPC分类号： A61K9/00 , A61K9/20 , A61L17/10 , A61L24/00 , A61L27/18 , A61L27/22 , A61L27/54 , A61L27/58 , C08G67/04 , A61M31/00 , C08G63/02
CPC分类号： A61K9/0024 , A61K9/2027 , A61K9/2031 , A61K9/204 , A61L17/10 , A61L24/0015 , A61L27/18 , A61L27/227 , A61L27/54 , A61L27/58 , C08G67/04 , A61L2300/406 , A61L2300/414 , A61L2300/416 , A61L2300/604 , A61L2430/02
摘要： Bioerodible polymers which degrade completely into nontoxic residues over a clinically useful period of time, including polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, and copolymers thereof, are used for the delivery of bioactive agents, including antibiotics, chemotherapeutic agents, inhibitors of angiogenesis, and simulators of bone growth, directly into bone.
摘要翻译：用于在临床有用的时间段内完全降解成无毒残留物的生物可降解聚合物，包括聚酐，聚原酸酯，聚乙醇酸，聚乳酸及其共聚物，用于递送生物活性剂，包括抗生素，化学治疗剂，血管发生抑制剂，和骨骼生长的模拟器，直接进入骨骼。

4. 发明授权

US4888176A Controlled drug delivery high molecular weight polyanhydrides 失效
标题翻译：受控药物递送高分子量聚酐
公开(公告)号：US4888176A
公开(公告)日：1989-12-19
申请号：US61294
申请日：1987-06-12
申请人： Robert S. Langer , Abraham J. Domb , Cato T. Laurencin
发明人： Robert S. Langer , Abraham J. Domb , Cato T. Laurencin
IPC分类号： A61L17/10 , A61L27/18 , A61L27/58 , C08G67/04
CPC分类号： C08G67/04 , A61L17/10 , A61L27/18 , A61L27/58
摘要： A bioerodible controlled drug release device is produced as a homogeneous polymeric matrix from a high molecular weight polyanhydride and a suitable biologically active substance. The high molecular weight polyanhydride is defined by a molecular weight greater than 20,000 and an intrinsic viscosity greater than 0.3 dl/g. The controlled drug release device is preferrably formed by solvent casting with the biologically active substance and exhibits zero order release, improved correlation between the rate of release and polymer degradation, and an induction period between introduction to the eroding environment and the initial release of the biologically active substance. The controlled drug release devices are stable for extended periods of time, flexible and durable and not subject to fracture and disintegration.
摘要翻译：生物腐蚀控制药物释放装置由高分子量聚酐和合适的生物活性物质制成均匀的聚合物基质。高分子量聚酐的分子量大于20,000，特性粘度大于0.3dl / g。受控药物释放装置优选地通过与生物活性物质的溶剂流延形成并显示零级释放，改善释放速率和聚合物降解之间的相关性，以及引入到侵蚀环境和生物学上的初始释放之间的诱导期活性物质。受控药物释放装置长时间稳定，柔韧耐用，不会破裂和分解。

5. 发明授权

US4916204A Pure polyanhydride from dicarboxylic acid and coupling agent 失效
标题翻译：来自二羧酸和偶联剂的纯聚酐
公开(公告)号：US4916204A
公开(公告)日：1990-04-10
申请号：US80332
申请日：1987-07-31
申请人： Abraham J. Domb , Robert S. Langer , Eyal Ron , Steven Giannos , Rohit Kothari , Edith Mathiowitz
发明人： Abraham J. Domb , Robert S. Langer , Eyal Ron , Steven Giannos , Rohit Kothari , Edith Mathiowitz
IPC分类号： A61K31/335 , A61K31/365 , A61K31/39 , C08G67/04 , C08G69/08 , C08G69/10
CPC分类号： A61K31/335 , A61K31/365 , A61K31/39 , C08G67/04 , C08G69/08 , C08G69/10 , Y10S514/863
摘要： A method for synthesizing polyanhydrides in solution using coupling agents and a removable acid acceptor to effect a one-step polymerization of dicarboxylic acids. As used in the method, these coupling agents include phosgene, diphosgene, and acid chlorides. Insoluble acid acceptors include insoluble polyamines and crosslinked polyamines such as polyethyleneimine and polyvinylpyridine and inorganic bases such as K.sub.2 CO.sub.3, Na.sub.2 CO.sub.3, NaHCO.sub.3, and CaCO.sub.3. The only byproduct formed is a removable hydrochloric acid-acid acceptor.Examples are provided of the polymerization of highly pure polyanhydrides using phosgene, diphosgene or an acid chloride as the coupling agent, in combination with either an insoluble acid acceptor or a soluble acid acceptor in a solvent wherein the polymerization byproduct or polymer is insoluble.A particularly important application of these polyanhydrides is in the formation of drug delivery devices containing bioactive compounds. The method is also useful in the polymerization of dicarboxylic acids including heat liable dipeptides of glutamic or aspartic acid.
摘要翻译：使用偶联剂和可除去的酸受体在溶液中合成聚酐以进行二羧酸的一步聚合的方法。如该方法所用，这些偶联剂包括光气，双光气和酰氯。不溶性酸受体包括不溶性多胺和交联聚胺如聚乙烯亚胺和聚乙烯吡啶以及无机碱如K 2 CO 3，Na 2 CO 3，NaHCO 3和CaCO 3。形成的唯一副产物是可除去的盐酸酸受体。提供了使用光气，双极光或酰氯作为偶联剂的高纯度聚酐与在溶剂中的不溶性酸受体或可溶性酸受体组合的聚合反应，其中聚合副产物或聚合物是不溶的。这些多酸酐的特别重要的应用是形成含有生物活性化合物的药物递送装置。该方法也可用于二羧酸的聚合，包括谷氨酸或天冬氨酸的热应答二肽。

6. 发明授权

US4933431A One step preparation of poly(amide-anhydride) 失效
标题翻译：聚（酰胺 - 酐）一步法制备
公开(公告)号：US4933431A
公开(公告)日：1990-06-12
申请号：US269448
申请日：1988-11-09
申请人： Abraham J. Domb , Robert S. Langer , Eyal Ron , Steven Giannos , Rohit Kothari , Edith Mathiowitz
发明人： Abraham J. Domb , Robert S. Langer , Eyal Ron , Steven Giannos , Rohit Kothari , Edith Mathiowitz
IPC分类号： C08G67/04 , C08G69/08 , C08G69/10
CPC分类号： C08G69/08 , C08G67/04 , C08G69/10
摘要： A method for synthetizing polyanhydrides in solution using coupling agents and a removable acid acceptor to effect a one-step polymerization of dicarboxylic acids. As used in the method, these coupling agents include phosgene, diphosgene, and acid chlorides. Insoluble acid acceptors include insoluble polyamines and crosslinked polyamines such as polyethyleneimine and polyvinylpyridine and inorganic bases such as K.sub.2 CO.sub.3, Na.sub.2 CO.sub.3, NaHCO.sub.3, and CaCO.sub.3. The only byproduct formed is a removable hydrochloric acid-acid acceptor.Examples are provided of the polymerization of highly pure polyanhydrides using phosgene, diphosgene or an acid chloride as the coupling agent, in combination with either an insoluble acid acceptor or a soluble acid acceptor in a solvent wherein the polymerizaiton byproduct or polymer is insoluble.A particularly important application of these polyanhydrides is in the formation of drug delivery devices containing bioactive compounds. The method is also useful in the polymerization of dicarboxylic acids including heat liable dipeptides of glutamic or aspartic acid.
摘要翻译：使用偶联剂和可除去的酸受体在溶液中合成聚酐以实现二羧酸的一步聚合的方法。如该方法所用，这些偶联剂包括光气，双光气和酰氯。不溶性酸受体包括不溶性多胺和交联聚胺如聚乙烯亚胺和聚乙烯吡啶以及无机碱如K 2 CO 3，Na 2 CO 3，NaHCO 3和CaCO 3。形成的唯一副产物是可除去的盐酸酸受体。提供了使用光气，双光气或酰氯作为偶联剂的高纯度聚酐与在溶剂中的不溶性酸受体或可溶性酸受体组合的聚合反应，其中聚合物副产物或聚合物是不溶的。这些多酸酐的特别重要的应用是形成含有生物活性化合物的药物递送装置。该方法也可用于二羧酸的聚合，包括谷氨酸或天冬氨酸的热应答二肽。

7. 发明授权

US5718921A Microspheres comprising polymer and drug dispersed there within 失效
标题翻译：包含分散在其中的聚合物和药物的微球
公开(公告)号：US5718921A
公开(公告)日：1998-02-17
申请号：US691874
申请日：1996-08-02
申请人： Edith Mathiowitz , Claudy J.P. Mullon , Abraham J. Domb , Robert S. Langer
发明人： Edith Mathiowitz , Claudy J.P. Mullon , Abraham J. Domb , Robert S. Langer
IPC分类号： A61K9/50 , B01J13/02 , A61K9/52 , B01J13/12
CPC分类号： B01J13/02 , A61K9/5031 , Y10S514/866 , Y10S514/963 , Y10S514/965
摘要： A method for preparation of biodegradable polymeric drug delivery devices using relatively low temperatures and non-aqueous solutions which is particularly useful with polyanhydrides, thermolabile drugs, and in forming multi-layered devices. In a first embodiment, the polymer is dissolved in a volatile organic solvent, the drug is dispersed or dissolved in the polymer solution, the mixture is suspended in an organic oil, and the organic solvent is extracted into the oil, creating microspheres. The preferred polymers are polyanhydrides since they are biodegradable and have been proven to be useful in vivo. In a second embodiment, the polymer is dissolved in organic solvent with or without the drug, and the mixture is suspended in glycerol. The suspension is frozen and the organic solvent slowly evaporated. Using these embodiments, alone or in combination with other methods including the "hot melt" technique, multi-walled microspheres having each wall degrading at a different rate or containing different drugs can be manufactured.
摘要翻译：一种使用相对较低温度制备可生物降解的聚合物药物递送装置的方法以及非常适用于聚酐，不耐热药物和形成多层装置的非水溶液。在第一实施方案中，将聚合物溶解在挥发性有机溶剂中，将药物分散或溶解在聚合物溶液中，将混合物悬浮在有机油中，并将有机溶剂萃取到油中，形成微球体。优选的聚合物是聚酐，因为它们是可生物降解的并且已被证明在体内是有用的。在第二个实施方案中，将聚合物溶解在有或者没有药物的有机溶剂中，并将混合物悬浮在甘油中。将悬浮液冷冻并缓慢蒸发有机溶剂。使用这些实施方案，可单独使用或与包括“热熔融”技术在一起的其它方法结合使用，可以制造具有以不同速率降解或含有不同药物的各壁的多壁微球体。

8. 发明授权

US5019379A Unsaturated polyanhydrides 失效
标题翻译：不饱和聚酐
公开(公告)号：US5019379A
公开(公告)日：1991-05-28
申请号：US80090
申请日：1987-07-31
申请人： Abraham J. Domb , Robert S. Langer
发明人： Abraham J. Domb , Robert S. Langer
IPC分类号： A61K9/20 , A61L24/00 , A61L24/04 , C08G67/04
CPC分类号： C08G67/04 , A61K9/2031 , A61L24/0042 , A61L24/046 , A61L2430/02
摘要： A class of unsaturated polyanhydrides having double bonds available for secondary polymerization is disclosed. A crosslinked material having improved or different physical and mechanical properties can be prepared from these polyanhydrides, via secondary polymerization. The synthesis and characteristics of one unsaturated polyanhydride based on fumaric acid and its copolymers with aliphatic and aromatic diacids, prepared by either the melt-polycondensation method or by solution polymerization, is described in detail.These polymers are well suited for use in controlled release drug delivery devices. The polymers can also be used as a bioerodible bone cement where the polymer is first cast as a solution onto a bone fracture and then crosslinked by radiation or radical polymerization to yield a strong, adhesive material.
摘要翻译：公开了一类具有可用于二次聚合的双键的不饱和聚酐。可以通过二次聚合从这些聚酐制备具有改善或不同物理和机械性能的交联材料。详细描述了通过熔融缩聚法或通过溶液聚合制备的一种不饱和聚酐与富马酸及其与脂族和芳族二酸的共聚物的合成和特性。这些聚合物非常适合用于控释药物递送装置。聚合物也可以用作生物可蚀解的骨水泥，其中首先将聚合物作为溶液浇铸到骨折上，然后通过辐射或自由基聚合进行交联以产生强的粘合剂材料。

9. 再颁专利

USRE37410E1 Controlled local delivery of chemotherapeutic agents for treating solid tumors 有权
标题翻译：用于治疗实体瘤的化疗药物的局部控制
公开(公告)号：USRE37410E1
公开(公告)日：2001-10-16
申请号：US09363519
申请日：1999-07-29
申请人： Henny Brem , Robert S. Langer , Abraham J. Domb
发明人： Henny Brem , Robert S. Langer , Abraham J. Domb
IPC分类号： A61K914
CPC分类号： A61K9/0085 , A61K9/2027 , A61K9/2031 , A61K9/204 , A61K31/337 , A61K31/4745 , A61K31/555
摘要： A method and devices for localized delivery of a chemotherapeutic agent to solid tumors, wherein the agent does not cross the blood-brain barrier and is characterized by poor bioavailability and/or short half-lives in vivo, are described. The devices consist of reservoirs which release drug over an extended time period while at the same time preserving the bioactivity and bioavailability of the agent. In the most preferred embodiment, the device consists of biodegradable polymeric matrixes, although reservoirs can also be formulated from non-biodegradable polymers or reservoirs connected to implanted infusion pumps. The devices are implanted within or immediately adjacent the tumors to be treated or the site where they have been surgically removed. The examples demonstrate the efficacy of paclitaxel and camptothecin delivered in polymeric implants prepared by compression molding of biodegradable and non-biodegradable polymers, respectively. The results are highly statistically significant.
摘要翻译：描述了用于将化学治疗剂局部递送至实体瘤的方法和装置，其中所述药物不穿过血脑屏障并且其特征在于体内生物利用度差和/或半衰期短。这些装置包括在延长的时间段内释放药物的储存器，同时保持药剂的生物活性和生物利用度。在最优选的实施方案中，该装置由可生物降解的聚合物基质组成，尽管储存器也可以由与植入的输注泵连接的不可生物降解的聚合物或储存器配制。这些装置被植入到待治疗的肿瘤内或紧邻其中，或被手术切除的部位。这些实施例证明分别通过压缩成型可生物降解和不可生物降解的聚合物制备的聚合物植入物中递送的紫杉醇和喜树碱的功效。结果具有很高的统计学意义。

10. 发明授权

US5578325A Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers 失效
标题翻译：非线性亲水疏水多嵌段共聚物的纳米颗粒和微粒
公开(公告)号：US5578325A
公开(公告)日：1996-11-26
申请号：US265440
申请日：1994-06-24
申请人： Abraham J. Domb , Ruxandra Gref , Yoshiharu Minamitake , Maria T. Peracchia , Robert S. Langer
发明人： Abraham J. Domb , Ruxandra Gref , Yoshiharu Minamitake , Maria T. Peracchia , Robert S. Langer
IPC分类号： A61K9/50 , A61K9/51 , A61K47/30 , A61K47/48 , A61K49/00 , A61K49/22 , A61K51/12 , C08G63/66 , C08G63/664 , C08G65/00 , C08G67/00 , C08G77/46 , C08G81/00 , C08J3/14 , A61K9/48 , A61K31/74
CPC分类号： A61K9/5153 , A61K47/48907 , A61K49/223 , A61K51/1241 , A61K51/1251 , A61K9/0019 , A61K9/1635 , A61K9/1647 , A61K9/5138 , B82Y5/00 , C08G63/664 , C08G81/00 , C08J3/14 , A61K2123/00 , C08J2300/16 , C08J2367/04 , C08J2371/02 , Y10S514/963 , Y10T428/2985 , Y10T428/2989 , Y10T428/2991
摘要： Injectable particles are provided that are not rapidly cleared from the blood stream by the macrophages of the reticuloendothelial system, and that can be modified as necessary to achieve variable release rates or to target specific cells or organs as desired. The injectable particles can include magnetic particles or radiopaque materials for diagnostic imaging, biologically active molecules to be delivered to a site, or compounds for targeting the particles. Biodistribution experiments indicate that the injectable particles have a prolonged half-life in the blood compared to particles not containing poly(alkylene glycol) moieties on the surface.
摘要翻译：提供的注射性颗粒不被网状内皮系统的巨噬细胞迅速地从血液中清除，并且可以根据需要进行修饰以达到可变释放速率或者根据需要靶向特定的细胞或器官。可注射颗粒可以包括用于诊断成像的磁性颗粒或不透射线的材料，待递送至位点的生物活性分子或用于靶向颗粒的化合物。生物分布实验表明，与不含表面上的聚（亚烷基二醇）部分的颗粒相比，可注射颗粒在血液中具有延长的半衰期。

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