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    Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers
    53.
    发明授权
    Nanoparticles and microparticles of non-linear hydrophilic-hydrophobic multiblock copolymers 失效
    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：US6007845A

    公开(公告)日：1999-12-28

    申请号：US582993

    申请日：1996-03-25

    申请人： Abraham J. Domb ,  Ruxandra Gref ,  Yoshiharu Minamitake ,  Maria Teresa Peracchia ,  Robert S. Langer

    发明人： Abraham J. Domb ,  Ruxandra Gref ,  Yoshiharu Minamitake ,  Maria Teresa Peracchia ,  Robert S. Langer

    IPC分类号： A61K9/51 ,  A61K9/50 ,  A61K9/14 ,  A61K9/16 ,  A61K9/48

    CPC分类号： A61K9/5153 ,  Y10S514/963 ,  Y10T428/2985 ,  Y10T428/2989

    摘要： Particles are provided that are not rapidly cleared from the blood stream by the macrophages of the reticuloendothelial system, and that can be modified to achieve variable release rates or to target specific cells or organs. The particles have a core of a multiblock copolymer formed by covalently linking a multifunctional compound with one or more hydrophobic polymers and one or more hydrophilic polymers, and contain a biologically active material. The terminal hydroxyl group of the poly(alkylene glycol) can be used to covalently attach onto the surface of the particles biologically active molecules, including antibodies targeted to specific cells or organs, or molecules affecting the charge, lipophilicity or hydrophilicity of the particle. The surface of the particle can also be modified by attaching biodegradable polymers of the same structure as those forming the core of the particles. The typical size of the particles is between 180 nm and 10,000 nm, preferably between 180 nm and 240 nm, although microparticles can also be formed as described herein. The 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. The 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： PCT No.PCT / US94 / 08287 Sec。 371日期1996年1月22日 102（e）日期1996年1月22日PCT提交1994年7月22日PCT公布。 公开号WO95 / 03356 日期1995年2月2日提供了不被网状内皮系统的巨噬细胞迅速从血液中清除的颗粒，并且可以修饰以实现可变释放速率或靶向特定细胞或器官。 颗粒具有通过共价连接多官能化合物与一种或多种疏水性聚合物和一种或多种亲水性聚合物形成的多嵌段共聚物的核心，并含有生物活性材料。 聚（亚烷基二醇）的末端羟基可用于共价附着到颗粒表面上的生物活性分子，包括靶向特定细胞或器官的抗体或影响颗粒的电荷，亲油性或亲水性的分子。 颗粒的表面也可以通过连接与形成颗粒核心的那些相同结构的可生物降解的聚合物来进行改性。 颗粒的典型尺寸在180nm和10,000nm之间，优选在180nm和240nm之间，尽管也可以如本文所述形成微粒。 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，要递送到位点的生物活性分子或用于靶向颗粒的化合物。 与不含表面上的聚（亚烷基二醇）部分的颗粒相比，颗粒在血液中具有延长的半衰期。

    Materials and methods for enhancing cellular internalization
    54.
    发明授权
    Materials and methods for enhancing cellular internalization 失效
    用于增强细胞内化的材料和方法

    公开(公告)号：US5985320A

    公开(公告)日：1999-11-16

    申请号：US810275

    申请日：1997-03-03

    申请人： David A. Edwards ,  Daniel R. Deaver ,  Robert S. Langer

    发明人： David A. Edwards ,  Daniel R. Deaver ,  Robert S. Langer

    IPC分类号： A61K9/06 ,  A61K9/00 ,  A61K9/127 ,  A61K31/70 ,  A61K31/7088 ,  A61K38/00 ,  A61K38/22 ,  A61K38/43 ,  A61K38/55 ,  A61K39/395 ,  A61K47/10 ,  A61K47/26 ,  A61K47/32 ,  A61K47/36 ,  A61K47/38 ,  A61K48/00 ,  A61K49/00

    CPC分类号： A61K9/0043 ,  A61K47/38 ,  A61K9/0034 ,  A61K47/10 ,  A61K47/26 ,  A61K47/36 ,  Y10S436/829

    摘要： Compositions and methods for delivering agents across cell membranes are disclosed. The compositions include an agent to be delivered, a viscous material, such as a hydrogel, lipogel or viscous sol, and, optionally, a carrier that includes a ligand that binds to or interacts with cell surface receptors. The agent to be delivered binds to or otherwise interacts with cell surface receptors, is attached, either covalently or ionically to a molecule that binds to or interacts with a cell surface receptor, or is associated with the carrier. Agents to be delivered include bioactive compounds and diagnostic agents. The compositions have an apparent viscosity roughly equal to the viscosity of the cytosol in the cell to which the agent is to be delivered. The rate of cellular internalization is higher when the viscosity of the viscous material and that of the cytosol in the cell are approximately the same, relative to when they are not the same. The compositions enhance cellular entry of bioactive agents and diagnostic materials when administered vaginally, nasally, rectally ocularly, orally, or to the respiratory or pulmonary system.

    摘要翻译： 公开了用于递送细胞膜的药剂的组合物和方法。 组合物包括待递送的试剂，粘性物质，例如水凝胶，脂凝胶或粘稠溶胶，以及任选的包含与细胞表面受体结合或与细胞表面受体相互作用的配体的载体。 待递送的药剂与细胞表面受体结合或以其他方式相互作用，与结合细胞表面受体或与细胞表面受体相关的分子共价或离子地连接。 待递送的试剂包括生物活性化合物和诊断剂。 组合物的表观粘度大致等于试剂要递送的细胞中细胞溶胶的粘度。 当粘性物质和细胞质中的细胞溶胶的粘度相差不大时，细胞内化速率较高。 当阴道，鼻，直肠眼，口服或呼吸或肺部系统施用时，组合物增强生物活性剂和诊断材料的细胞进入。

    Multiwall polymeric microspheres
    55.
    发明授权
    Multiwall polymeric microspheres 失效
    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。

    Introduction of modifying agents into skin by electroporation
    56.
    发明授权
    Introduction of modifying agents into skin by electroporation 失效
    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。

    Implantation of cell-matrix structure adjacent mesentery, omentum or peritoneum tissue
    59.
    发明授权
    Implantation of cell-matrix structure adjacent mesentery, omentum or peritoneum tissue 失效
    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。

    Microspheres comprising polymer and drug dispersed there within
    60.
    发明授权
    Microspheres comprising polymer and drug dispersed there within 失效
    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。