公开(公告)号：US4898734A

公开(公告)日：1990-02-06

申请号：US162161

申请日：1988-02-29

Applicant: Edith Mathiowitz ,  Robert S. Langer ,  Abraham Warshawsky ,  Elazar Edelman

Inventor： Edith Mathiowitz ,  Robert S. Langer ,  Abraham Warshawsky ,  Elazar Edelman

IPC: A01N25/34 ,  A61K9/16 ,  A61K9/20 ,  A61K9/70 ,  B01J13/02

CPC classification number: A01N25/34 ,  A61K9/1641 ,  A61K9/1647 ,  A61K9/2077 ,  A61K9/2081 ,  A61K9/7023 ,  B01J13/025

Abstract: The present invention is a method to produce novel composites based on microcapsules or microspheres embedded in contiuous polymeric matrices. Both non-bioerodible and erodible polymers can be used. Material can be incorporated into the microcapsules or microspheres for subsequent release. In one embodiment of the present invention, spheres are homogeneously dispersed in a polymer matrix and then forced to release their contents by exposure to temperature, light or ultrasound. Alternatively, polymers which degrade as a function of time or hydrolysis can be used for controlled releases. The polymer composites have completely different properties from either a continuous polymer matrix or microcapsules or microspheres and are therefore useful for a wide variety of applications. When carbon tetrachloride is the incorporated material, the film is useful as a flame retarding device. When foaming agents are used, especially UV or heat sensitive materials, gas can be evolved inside each capsulThe Government has rights in this invention pursuant to Grant Number 5-R01-GM26698 awarded by the Department of Health and Human Services.

Abstract translation: 本发明是一种基于嵌入在连续聚合物基质中的微胶囊或微球体生产新型复合材料的方法。 可以使用非生物可腐蚀和可侵蚀的聚合物。 可以将材料并入微胶囊或微球体中用于随后的释放。 在本发明的一个实施方案中，球体均匀地分散在聚合物基质中，然后通过暴露于温度，光或超声波被迫释放其内容物。 或者，作为时间或水解的函数降解的聚合物可用于受控释放。 聚合物复合材料与连续聚合物基质或微胶囊或微球具有完全不同的性质，因此可用于各种应用。 当四氯化碳是引入的材料时，该膜可用作阻燃装置。 当使用发泡剂，特别是UV或热敏材料时，可在每个胶囊内放出气体，以在聚合物中形成气泡。 当药物或其他生物活性剂掺入球体并用聚合物包封时，仅通过侵蚀或破裂的球体释放。 与从包封的微胶囊的释放相反，从聚合物复合材料的释放大约是随时间线性的。 聚合物球体的侵蚀也可用于产生多孔聚合物结构。 这种装置可用于透皮药物递送，血管移植物，伤口愈合膜或作为聚合物多孔膜。

公开(公告)号：US4861627A

公开(公告)日：1989-08-29

申请号：US45840

申请日：1987-05-01

Applicant: Edith Mathiowitz ,  Robert S. Langer

Inventor： Edith Mathiowitz ,  Robert S. Langer

IPC: A01N25/28 ,  A61K8/00 ,  A61K8/18 ,  A61K8/87 ,  A61K8/88 ,  A61K9/16 ,  A61K9/50 ,  A61K9/56 ,  A61K9/58 ,  A61Q13/00 ,  B01J13/14 ,  C05G3/00 ,  C09B67/08 ,  C11B9/00

CPC classification number: A61K9/5089 ,  A61K9/1694 ,  Y10S514/963 ,  Y10T428/2987 ,  Y10T428/2989

Abstract: A single step method for preparation of multi-layer polymeric delivery systems. Any two or three different degradable or non-degradable polymers which are not soluble in each other at a particular concentration, as dictated by their phase diagram, can be used. The multi-layer microcapsules produced by the method are distinguished by extremely uniform dimensioned layers of polymer and actual incorporation of the substance to be delivered into the polymer layers.In the preferred embodiment of the method, two polymers are dissolved in a volatile organic solvent, the substance to be encapsulated is dispersed or dissolved in the polymer solution, the mixture is suspended in an aqueous solution and stirred, and the solvent is slowly evaporated, creating microspheres with an inner core formed by one polymer and an outer layer formed by the second polymer. In another embodiment one polymer may be formed within a layer of the other polymer by increasing the rate of evaporation of the volatile solvent.

Abstract translation: 用于制备多层聚合物递送系统的单步法。 可以使用任何两种或三种不同的可降解或不可降解的聚合物，其特定浓度彼此不溶，如其相图所示。 通过该方法制备的多层微胶囊通过聚合物的非常均匀的尺寸层和实际掺入待递送到聚合物层中的物质来区分。 在该方法的优选实施方案中，将两种聚合物溶解在挥发性有机溶剂中，待包封的物质分散或溶解在聚合物溶液中，将混合物悬浮在水溶液中并搅拌，并将溶剂缓慢蒸发， 产生具有由一种聚合物形成的内芯和由第二聚合物形成的外层的微球。 在另一个实施方案中，通过增加挥发性溶剂的蒸发速率，可以在其它聚合物的层内形成一种聚合物。

公开(公告)号：US5128420A

公开(公告)日：1992-07-07

申请号：US283594

申请日：1988-12-13

Applicant: Abraham J. Domb ,  Robert S. Langer ,  Ernest G. Cravalho ,  Gershon Golomb ,  Edith Mathiowitz ,  Cato T. Laurencin

Inventor： Abraham J. Domb ,  Robert S. Langer ,  Ernest G. Cravalho ,  Gershon Golomb ,  Edith Mathiowitz ,  Cato T. Laurencin

IPC: C08F8/32

CPC classification number: C08F8/32 ,  C08F2800/10 ,  C08F2810/20

Abstract: 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.

Abstract translation: 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。

公开(公告)号：US4933431A

公开(公告)日：1990-06-12

申请号：US269448

申请日：1988-11-09

Applicant: Abraham J. Domb ,  Robert S. Langer ,  Eyal Ron ,  Steven Giannos ,  Rohit Kothari ,  Edith Mathiowitz

Inventor： Abraham J. Domb ,  Robert S. Langer ,  Eyal Ron ,  Steven Giannos ,  Rohit Kothari ,  Edith Mathiowitz

IPC: C08G67/04 ,  C08G69/08 ,  C08G69/10

CPC classification number: C08G69/08 ,  C08G67/04 ,  C08G69/10

Abstract: 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.

Abstract translation: 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。

公开(公告)号：US4916204A

公开(公告)日：1990-04-10

申请号：US80332

申请日：1987-07-31

Applicant: Abraham J. Domb ,  Robert S. Langer ,  Eyal Ron ,  Steven Giannos ,  Rohit Kothari ,  Edith Mathiowitz

Inventor： Abraham J. Domb ,  Robert S. Langer ,  Eyal Ron ,  Steven Giannos ,  Rohit Kothari ,  Edith Mathiowitz

IPC: A61K31/335 ,  A61K31/365 ,  A61K31/39 ,  C08G67/04 ,  C08G69/08 ,  C08G69/10

CPC classification number: A61K31/335 ,  A61K31/365 ,  A61K31/39 ,  C08G67/04 ,  C08G69/08 ,  C08G69/10 ,  Y10S514/863

Abstract: 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.

Abstract translation: 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。

公开(公告)号：US06262183B1

公开(公告)日：2001-07-17

申请号：US08219160

申请日：1994-03-28

Applicant: Abraham J. Domb ,  Robert S. Langer ,  Ernest G. Cravalho ,  Gershon Golomb ,  Edith Mathiowitz ,  Cato T. Laurencin

Inventor： Abraham J. Domb ,  Robert S. Langer ,  Ernest G. Cravalho ,  Gershon Golomb ,  Edith Mathiowitz ,  Cato T. Laurencin

IPC: C08F2056

CPC classification number: C08F8/32 ,  C08F2800/10 ,  C08F8/42 ,  C08F220/56

Abstract: 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.

Abstract translation: 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。

公开(公告)号：US06174952B1

公开(公告)日：2001-01-16

申请号：US09156720

申请日：1998-09-18

Applicant: Ihab M. Hekal ,  Robert S. Langer ,  Alexander M. Klibanov ,  Edith Mathiowitz

Inventor： Ihab M. Hekal ,  Robert S. Langer ,  Alexander M. Klibanov ,  Edith Mathiowitz

IPC: C08J900

CPC classification number: C08L23/02 ,  B01J20/28014 ,  B01J20/28033 ,  B01J20/28042 ,  B29C45/16 ,  B65D81/264 ,  B65D81/266 ,  C08J9/26 ,  C08L23/0861 ,  C08L23/10 ,  C08L29/04 ,  C08L69/00 ,  C08L71/02 ,  C08L77/00 ,  C08L101/00 ,  F26B21/083 ,  Y10S521/905 ,  C08L2666/02 ,  C08L2666/14 ,  C08L2666/04 ,  C08L2666/22 ,  C08L29/00 ,  C08L71/00

Abstract: The present invention includes processes and resulting structures for producing a modified polymer having interconnecting channels. The interconnecting channels act as controlled transmission passages through the polymer. A hydrophilic agent is blended into the polymer so that it is distributed within the polymer. In one embodiment, a water-absorbing material is blended into the polymer so that the water-absorbing material is distributed within the product. The product is solidified so that the hydrophilic agent forms passages in the product through which a desired composition is communicable to the water-absorbing material that is entrained within the product. The solidified product may be used to form a desired shaped article such as plug type inserts and liners for closed containers, or it may be formed into a film, sheet, bead or pellet.

Abstract translation: 本发明包括用于生产具有互连通道的改性聚合物的方法和所得结构。 互连通道充当通过聚合物的受控传输通道。 将亲水剂混合到聚合物中，使其分散在聚合物内。 在一个实施方案中，将吸水材料混合到聚合物中，使得吸水材料分布在产品内。 产品被固化，使得亲水剂在产品中形成通道，通过该通道，期望的组合物可通过其吸入产品中的吸水材料连通。 固化产品可以用于形成所需的成型制品，例如用于密封容器的塞子型插入件和衬垫，或者可以形成为膜，片，珠粒或丸粒。

公开(公告)号：US5912017A

公开(公告)日：1999-06-15

申请号：US906403

申请日：1992-07-01

Applicant: Edith Mathiowitz ,  Robert S. Langer

Inventor： Edith Mathiowitz ,  Robert S. Langer

IPC: A61K9/16 ,  A61K9/50 ,  A61K9/52 ,  B01J13/12

CPC classification number: A61K9/1694 ,  A61K9/5089 ,  Y10S514/963 ,  Y10S514/965 ,  Y10T428/2987 ,  Y10T428/2989

Abstract: A method for preparation of multi-layer polymeric microspheres formed from any degradable or non-degradable polymers which are not soluble in each other at a particular concentration, but which have a positive spreading coefficient in solution. The multi-layer microspheres produced by the method are distinguished by extremely uniform dimensioned layers of polymer and actual incorporation of the substance to be delivered into the polymer layers. In the preferred embodiment of the method, two polymers are dissolved in a volatile organic solvent, the substance to be incorporated is dispersed or dissolved in the polymer solution, the mixture is suspended in an aqueous solution and stirred, and the solvent is slowly evaporated, creating microspheres with an inner core formed by one polymer and an outer layer formed by the second polymer. In another embodiment, solvent is removed by spray drying. In still another embodiment, polymers are melted and combined with the substance to be incorporated, then cooled to form layered microspheres.

Abstract translation: 一种由任何可溶解或不可降解的聚合物制备的多层聚合物微球的方法，它们在特定浓度下彼此不溶，但在溶液中具有正扩散系数。 通过该方法制备的多层微球的特征在于聚合物尺寸非常均匀，并且实际掺入待递送到聚合物层中的物质。 在该方法的优选实施方案中，将两种聚合物溶解在挥发性有机溶剂中，将待引入的物质分散或溶解在聚合物溶液中，将混合物悬浮在水溶液中并搅拌，并将溶剂缓慢蒸发， 产生具有由一种聚合物形成的内芯和由第二聚合物形成的外层的微球。 在另一个实施方案中，通过喷雾干燥除去溶剂。 在另一个实施方案中，将聚合物熔化并与待掺入的物质组合，然后冷却形成层状微球。

公开(公告)号：US5718921A

公开(公告)日：1998-02-17

申请号：US691874

申请日：1996-08-02

Applicant: Edith Mathiowitz ,  Claudy J.P. Mullon ,  Abraham J. Domb ,  Robert S. Langer

Inventor： Edith Mathiowitz ,  Claudy J.P. Mullon ,  Abraham J. Domb ,  Robert S. Langer

IPC: A61K9/50 ,  B01J13/02 ,  A61K9/52 ,  B01J13/12

CPC classification number: B01J13/02 ,  A61K9/5031 ,  Y10S514/866 ,  Y10S514/963 ,  Y10S514/965

Abstract: 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.

Abstract translation: 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。

公开(公告)号：US5100668A

公开(公告)日：1992-03-31

申请号：US206520

申请日：1988-06-14

Applicant: Elazer R. Edelman ,  Robert S. Langer ,  Michael Klagsburn ,  Edith Mathiowitz

Inventor： Elazer R. Edelman ,  Robert S. Langer ,  Michael Klagsburn ,  Edith Mathiowitz

IPC: A61K9/16 ,  A61K9/50 ,  A61K38/18 ,  A61K47/48

CPC classification number: A61K47/4823 ,  A61K38/1825 ,  A61K9/167 ,  A61K9/5036 ,  Y10S530/813 ,  Y10S530/815 ,  Y10S530/816

Abstract: A system for stabilizing fibroblast-derived growth factors, maintaining their bioactivity over a prolonged period of time and controllably releasing them for use is disclosed. The system uses growth factors bound to biocompatible substrates via heparin or heparin derived compounds to maintain the bioactivity of the growth factors. A growth factor bound to a heparin coated substrate can be used independently as a controlled release device, or can be incorporated into a reservoir or matrix type controlled release devices to further enhance the controlled release properties. The stabilized growth factors can be implanted into a patient, thereby providing a means for producing an in vivo controlled release of a growth factor to the patient.

Abstract translation: 公开了一种用于稳定成纤维细胞衍生生长因子的系统，其在长时间内保持其生物活性并且可控地释放它们以供使用。 该系统使用通过肝素或肝素衍生的化合物结合生物相容性底物的生长因子，以维持生长因子的生物活性。 与肝素包被的底物结合的生长因子可以独立地用作控释装置，或者可以并入储存器或基质型受控释放装置中以进一步增强控制释放性质。 可以将稳定的生长因子植入患者体内，从而提供生产体内受控制的生长因子释放给患者的手段。