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51. 发明授权

US5912017A Multiwall polymeric microspheres 失效
标题翻译：多壁聚合物微球
公开(公告)号：US5912017A
公开(公告)日：1999-06-15
申请号：US906403
申请日：1992-07-01
申请人： Edith Mathiowitz , Robert S. Langer
发明人： Edith Mathiowitz , Robert S. Langer
IPC分类号： A61K9/16 , A61K9/50 , A61K9/52 , B01J13/12
CPC分类号： A61K9/1694 , A61K9/5089 , Y10S514/963 , Y10S514/965 , Y10T428/2987 , Y10T428/2989
摘要： 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.
摘要翻译：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。

52. 发明授权

US5911223A Introduction of modifying agents into skin by electroporation 失效
标题翻译：通过电穿孔将改性剂引入皮肤
公开(公告)号：US5911223A
公开(公告)日：1999-06-15
申请号：US695367
申请日：1996-08-09
申请人： James C. Weaver , Tani Chen , Christopher Cullander , Richard Guy , Robert S. Langer , Thomas E. Zewert , Uwe Pliquett , Rita Vanbever , Mark R. Prausnitz
发明人： James C. Weaver , Tani Chen , Christopher Cullander , Richard Guy , Robert S. Langer , Thomas E. Zewert , Uwe Pliquett , Rita Vanbever , Mark R. Prausnitz
IPC分类号： A61B17/00 , A61N1/32 , A61B19/00
CPC分类号： A61N1/0424 , A61N1/325 , A61B2017/00765 , A61N1/0428 , Y10S607/901
摘要： A method of modifying epidermis for transport of a material by electroporation includes applying to epidermis an agent that, upon entry into the epidermis, will modify the epidermis to thereby cause and altered rate of transport of a material across the epidermis. Typically, the altered rate will be an increased rate of transport. The epidermis is electroporated, whereby at least a portion of the modifying agent enters the electroporated epidermis, thereby modifying the epidermis to cause an altered rate of transport of a material across the epidermis. In another embodiment, the modifying agent can modify the epidermis to enable measurement and/or monitoring of physiological conditions or change within or beneath the epidermis. The modifying agents can also be employed to facilitate discharge of fluids from within an organism, such as by providing pathways for discharge of fluids from a tumor. Examples of modifying agents include: oxidizing agents; reducing agents; particles, such as optical indicator beads or beads that include drugs to be released into tissue; electrically-charged particles or molecules; etc. Materials that can be transported by the method of the invention include, for example, proteins, nucleic acids, electrically charged molecules or particles, microorganisms suitable for immunization, etc. Also, tissues other than skin can be employed in the method of the invention.
摘要翻译：通过电穿孔来改变用于运输材料的表皮的方法包括向表皮施加一种在进入表皮时将改变表皮从而引起和改变材料穿过表皮的运输速率的试剂。通常，改变率将是增加的运输速度。表皮被电穿孔，由此至少一部分改性剂进入电穿孔表皮，从而改变表皮，导致材料穿过表皮的转运速率。在另一个实施方案中，修饰剂可以修饰表皮以使得能够测量和/或监测生理条件或在表皮内或下表面的变化。还可以使用改性剂来促进从生物体内排出流体，例如通过提供从肿瘤排出流体的途径。改性剂的实例包括：氧化剂; 还原剂; 颗粒，例如包括要释放到组织中的药物的光学指示剂珠粒或珠粒; 带电粒子或分子; 可以通过本发明的方法传输的材料包括例如蛋白质，核酸，带电分子或颗粒，适合免疫的微生物等。另外，皮肤以外的组织可以用于发明。

53. 发明授权

US5874064A Aerodynamically light particles for pulmonary drug delivery 失效
公开(公告)号：US5874064A
公开(公告)日：1999-02-23
申请号：US739308
申请日：1996-10-29
申请人： David A. Edwards , Giovanni Caponetti , Jeffrey S. Hrkach , Noah Lotan , Justin Hanes , Abdell Aziz Ben-Jebria , Robert S. Langer
发明人： David A. Edwards , Giovanni Caponetti , Jeffrey S. Hrkach , Noah Lotan , Justin Hanes , Abdell Aziz Ben-Jebria , Robert S. Langer
IPC分类号： A61K9/12 , A61K9/00 , A61K9/14 , A61K9/16 , A61K9/72 , A61K31/137 , A61K47/32
CPC分类号： A61K9/0075 , A61K31/137 , A61K9/1647
摘要： Improved aerodynamically light particles for drug delivery to the pulmonary system, and methods for their synthesis and administration are provided. In a preferred embodiment, the aerodynamically light particles are made of a biodegradable material and have a tap density less than 0.4 g/cm.sup.3 and a mass mean diameter between 5 .mu.m and 30 .mu.m. The particles may be formed of biodegradable materials such as biodegradable polymers. For example, the particles may be formed of a functionalized polyester graft copolymer consisting of a linear .alpha.-hydroxy-acid polyester backbone having at least one amino acid group incorporated therein and at least one poly(amino acid) side chain extending from an amino acid group in the polyester backbone. In one embodiment, aerodynamically light particles having a large mean diameter, for example greater than 5 .mu.m, can be used for enhanced delivery of a therapeutic agent to the alveolar region of the lung. The aerodynamically light particles incorporating a therapeutic agent may be effectively aerosolized for administration to the respiratory tract to permit systemic or local delivery of wide variety of therapeutic agents.

54. 发明授权

US5814599A Transdermal delivery of encapsulated drugs 失效
标题翻译：经皮递送包封的药物
公开(公告)号：US5814599A
公开(公告)日：1998-09-29
申请号：US511583
申请日：1995-08-04
申请人： Samir S. Mitragotri , Daniel Blankschtein , Robert S. Langer
发明人： Samir S. Mitragotri , Daniel Blankschtein , Robert S. Langer
IPC分类号： A61B5/00 , A61B17/00 , A61B18/20 , A61K9/00 , A61K41/00 , A61K49/22 , A61M37/00 , A61N1/32 , A61K38/28 , A61M31/00 , A61N1/30
CPC分类号： A61B5/14514 , A61B5/1486 , A61B5/681 , A61K41/0047 , A61K49/22 , A61K9/0009 , A61M37/0092 , A61N1/325 , A61B18/203 , A61B2017/00172 , A61B2017/00765 , A61B2018/00452 , A61B2018/0047 , A61B2562/0295 , A61M2037/0007
摘要： Applications of low-frequency (20 KHz) ultrasound enhances transdermal transport of high-molecular weight proteins. This method includes a simultaneous application of ultrasound and protein on the skin surface in order to deliver therapeutic doses of proteins across the skin. Examples demonstrate in vitro and in vivo administration of insulin (molecular weight 6,000 D), and in vitro administration of gamma interferon (molecular weight 17,000 D), and erythropoeitin (molecular weight 48,000 D).
摘要翻译：低频（20KHz）超声波的应用增强了高分子量蛋白质的透皮转运。该方法包括在皮肤表面上同时施加超声波和蛋白质，以便递送治疗剂量的蛋白质穿过皮肤。实施例证明胰岛素的体外和体内施用（分子量为6,000D），以及γ干扰素（分子量17,000D）和红细胞生成素（分子量48,000D）的体外施用。

55. 发明授权

US5804178A Implantation of cell-matrix structure adjacent mesentery, omentum or peritoneum tissue 失效
标题翻译：植入细胞基质结构邻近肠系膜，网膜或腹膜组织
公开(公告)号：US5804178A
公开(公告)日：1998-09-08
申请号：US203509
申请日：1994-02-28
申请人： Joseph P. Vacanti , Robert S. Langer , Lynt Johnson
发明人： Joseph P. Vacanti , Robert S. Langer , Lynt Johnson
IPC分类号： A61L27/36 , A61L27/38 , C12N5/00 , C12N11/08 , A61F2/18 , A61F2/28
CPC分类号： A61L27/3839 , A61L27/3843 , A61L27/3869 , C12N5/0068 , A61L2430/06 , C12N2501/18 , C12N2533/30 , C12N2533/40
摘要： A matrix structure containing attached cells such as endocrine cells, fibroblasts, endothelial cells or genitourinary cells is implanted in a patient adjacent tissue having a high surface area and vasculature such as mesentery, omentum or peritoneum tissue. Large volumes of cells can be attached to the matrix and the matrix implanted with minimum trauma and blood loss into a patient to produce a functional organ equivalent. Multiple matrix structures containing cells can be implanted to functionally resemble naturally occurring organs. Implanting multiple matrices between folds of the mesentery is particularly well suited for growth of endocrine structures, including liver, pancreas, and adrenal gland. The matrix structure is preferably formed from a biodegradable artificial polymer. Collagen and non-biodegradable materials can also be used, and the matrix structure can be overlaid with a material that enhances cell attachment. Materials such as angiogenesis factors can be incorporated into a matrix and implanted prior to implanting the matrix containing cells or the materials can be incorporated into the matrix containing cells. Cells attached to the matrix may be cultured in vitro prior to implanting. Matrix structures containing different types of cells can be implanted juxtapositioned with each other.
摘要翻译：将包含附着细胞如内分泌细胞，成纤维细胞，内皮细胞或泌尿生殖细胞的基质结构植入具有高表面积和脉管系统如肠系膜，网膜或腹膜组织的邻近组织中。大量的细胞可以连接到基质上，并且基质以最小的创伤和失血植入患者体内以产生功能性器官当量。可以将包含细胞的多个基质结构植入功能上类似天然存在的器官。在肠系膜的折叠之间植入多个基质特别适用于内分泌结构的生长，包括肝，胰腺和肾上腺。基质结构优选由生物可降解的人造聚合物形成。还可以使用胶原蛋白和不可生物降解的材料，并且可以用增强细胞附着的材料覆盖基质结构。诸如血管生成因子的材料可以掺入基质中并在植入包含细胞的基质之前植入，或者该材料可以并入含有基质的细胞中。附着于基质的细胞可以在植入前在体外培养。含有不同类型细胞的基质结构可以彼此并置。

56. 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。

57. 发明授权

US5696175A Preparation of bonded fiber structures for cell implantation 失效
标题翻译：用于细胞植入的粘合纤维结构的制备
公开(公告)号：US5696175A
公开(公告)日：1997-12-09
申请号：US473216
申请日：1995-06-07
申请人： Antonios G. Mikos , Robert S. Langer
发明人： Antonios G. Mikos , Robert S. Langer
IPC分类号： A61L27/34 , A61L27/38 , B29B15/12 , C12N5/00 , D04H1/42 , C08K9/00
CPC分类号： A61L27/34 , A61L27/38 , B29B15/10 , C12N5/0068 , D04H1/4266 , D04H1/43 , D04H1/4382 , C12M25/14 , C12N2533/40 , Y10T442/60
摘要： A novel processing technique is reported to bond non-woven fibers and, thus, prepare structural interconnecting fiber networks with different shapes for organ implants. The fibers are physically joined without any surface or bulk modification and have their initial diameter.
摘要翻译：据报道，一种新型的加工技术可以粘合无纺纤维，从而制备用于器官植入物的具有不同形状的结构互连纤维网络。纤维物理连接，没有任何表面或体积改性并具有其初始直径。

58. 发明授权

US5626862A Controlled local delivery of chemotherapeutic agents for treating solid tumors 失效
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：US5626862A
公开(公告)日：1997-05-06
申请号：US284341
申请日：1994-08-02
申请人： Henry Brem , Robert S. Langer , Abraham J. Domb
发明人： Henry Brem , Robert S. Langer , Abraham J. Domb
IPC分类号： A61K9/00 , A61K9/20 , A61K9/22 , A61K31/282 , A61K31/337 , A61K31/47 , A61K31/4745 , A61K38/00 , A61K39/395 , A61K45/00 , A61K47/34 , A61K31/335
CPC分类号： A61K9/0085 , A61K31/337 , A61K31/4745 , A61K31/555 , A61K9/2027 , A61K9/2031 , A61K9/204
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。

59. 发明授权

US5569600A Purification, composition and specificity of heparinase I, II, and III from flavobacterium heparinum 失效
标题翻译：肝素肝素Ⅰ，Ⅱ和Ⅲ的纯化，组成和特异性
公开(公告)号：US5569600A
公开(公告)日：1996-10-29
申请号：US378789
申请日：1995-01-26
申请人： Ramnath Sasisekharan , Daniel L. Lohse , Charles L. Cooney , Robert J. Linhardt , Robert S. Langer
发明人： Ramnath Sasisekharan , Daniel L. Lohse , Charles L. Cooney , Robert J. Linhardt , Robert S. Langer
IPC分类号： G01N33/573 , C07K16/40 , C12N9/88 , C12P19/26 , C12P21/08 , C12R1/20 , C12R1/91 , C12N9/00 , C12N1/20 , C12N9/52
CPC分类号： C12N9/88 , Y10S435/822 , Y10S435/85
摘要： A single, reproducible scheme to simultaneously purify all three of the heparin lyases from F. heparinum to apparent homogeneity is disclosed herein. The kinetic properties of the heparin lyases have been determined as well as the conditions to optimize their activity and stability. Monoclonal antibodies to the three heparinases are also described and are useful for detection, isolation and characterization of the heparinases.
摘要翻译：本文公开了将来自肝素肝素的所有三种肝素裂解酶同时纯化到表观均一性的单一可再现方案。已经确定了肝素裂解酶的动力学性质以及优化其活性和稳定性的条件。还描述了三种肝素酶的单克隆抗体，并且其可用于肝素酶的检测，分离和表征。

60. 发明授权

US5545409A Delivery system for controlled release of bioactive factors 失效
标题翻译：用于控制释放生物活性因子的递送系统
公开(公告)号：US5545409A
公开(公告)日：1996-08-13
申请号：US222880
申请日：1994-04-05
申请人： Cato T. Laurencin , Paul A. Lucas , Glenn T. Syftestad , Abraham Domb , Julianne Glowacki , Robert S. Langer
发明人： Cato T. Laurencin , Paul A. Lucas , Glenn T. Syftestad , Abraham Domb , Julianne Glowacki , Robert S. Langer
IPC分类号： A61K9/00 , A61K9/20 , A61L27/18 , A61L27/22 , A61L27/54 , A61L27/58 , C08G67/04 , A61F2/28 , A61K38/39 , C07K14/485 , C07K14/51
CPC分类号： A61K9/0024 , A61K9/2031 , A61K9/204 , A61L27/18 , A61L27/227 , A61L27/54 , A61L27/58 , C08G67/04 , A61L2300/252 , A61L2300/414 , A61L2300/604 , Y10S530/84
摘要： A composition and method for controlled release of water-soluble proteins comprising a surface-eroding polymer matrix and water-soluble bioactive factors is described. The composition bioerodes in the biological environment of the subject at a controlled rate, thereby releasing the water soluble proteins at a rate which allows them to interact with local cell populations.
摘要翻译：描述了包含表面侵蚀聚合物基质和水溶性生物活性因子的水溶性蛋白质的控制释放组合物和方法。组合物以受控的速率在受试者的生物环境中生物反应，从而以允许其与局部细胞群体相互作用的速率释放水溶性蛋白质。

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