公开(公告)号：US20080311191A1

公开(公告)日：2008-12-18

申请号：US11661541

申请日：2005-08-29

Applicant: Avinash Nangia ,  Jules Jacob ,  Edith Mathiowitz ,  Thomas Ricketts ,  Mark R. Kreitz

Inventor： Avinash Nangia ,  Jules Jacob ,  Edith Mathiowitz ,  Thomas Ricketts ,  Mark R. Kreitz

IPC: A61K9/52 ,  A61K9/32 ,  A61K9/48 ,  A61K9/24

CPC classification number: A61K9/0065 ,  A61K9/209 ,  A61K9/2886 ,  A61K31/19 ,  A61K31/198 ,  A61K31/496 ,  A61K31/522

Abstract: Bioadhesives coatings increase the gastrointestinal retention time of orally-ingested medicaments. Certain bioadhesive coatings producing a fracture strength of at least 100 N/m2, as measured on rat intestine, when applied to at least one surface of a pharmaceutical dosage form for oral delivery of a drug, result in a gastrointestinal retention time of at least 4 hours in a fed beagle dog model, during which the drug is released from the dosage form.Multi-layer tablets, particularly those including hydrophobic excipients, are useful in administering hygroscopic and/or deliquescent drugs. In addition, varying the amount of drug in multi-layer tablets allows the release rate of the drug to be controlled.

Abstract translation: 生物粘合剂涂层增加了口服药物的胃肠停留时间。 当在大鼠肠道上测量时产生至少100N / m 2的断裂强度的某些生物粘合剂涂层当应用于用于口服递送药物的药物剂型的至少一个表面时，导致胃肠停留时间至少为4 在喂养的比格犬模型中，药物从剂型中释放出来。 多层片剂，特别是包括疏水性赋形剂的片剂，可用于施用吸湿和/或潮解性药物。 此外，改变多层片剂中的药物的量允许控制药物的释放速率。

公开(公告)号：US06531154B1

公开(公告)日：2003-03-11

申请号：US09093868

申请日：1998-06-09

Applicant: Edith Mathiowitz ,  Wendy L. Webber ,  Christopher G. Thanos

Inventor： Edith Mathiowitz ,  Wendy L. Webber ,  Christopher G. Thanos

IPC: A61K910

CPC classification number: A61K9/1611 ,  A61K9/1647 ,  A61K9/2009 ,  A61K9/204 ,  A61K9/7007

Abstract: Sustained delivery compositions which modulate the release of incorporated prophylactic, therapeutic, and/or diagnostic agents, and methods of preparation and use thereof, are disclosed. The compositions include a biocompatible polymeric matrix; a prophylactic, therapeutic, and/or diagnostic agent dispersed within the polymeric matrix; and a monovalent cation component which is separately dispersed within the polymeric matrix. The monovalent cation component modulates the release of the incorporated agent from the polymeric matrix. The compositions can be prepared by dissolving a biocompatible polymer in a solvent to form a polymer solution, and separately dispersing a monovalent cation and a prophylactic, therapeutic, and/or diagnostic agent within the polymer solution. The polymer solution is then solidified to form a polymeric matrix, wherein a significant amount of the monovalent cations is dispersed in the polymeric matrix separately from the incorporated agent. The cation modulates the release of the incorporated agent from the polymeric matrix.

Abstract translation: 公开了调节掺入的预防，治疗和/或诊断剂的释放的持续递送组合物及其制备和使用方法。 组合物包括生物相容性聚合物基质; 分散在聚合物基质内的预防，治疗和/或诊断剂; 和分别分散在聚合物基质内的一价阳离子组分。 一价阳离子组分调节掺合剂从聚合物基质中的释放。 组合物可以通过将生物相容性聚合物溶解在溶剂中以形成聚合物溶液，并将单价阳离子和预防剂，治疗剂和/或诊断剂分散在聚合物溶液内来制备。 然后将聚合物溶液固化以形成聚合物基质，其中大量的一价阳离子与掺入的试剂分开分散在聚合物基质中。 阳离子调节掺入的试剂从聚合物基质中的释放。

公开(公告)号：US06475779B2

公开(公告)日：2002-11-05

申请号：US09173205

申请日：1998-10-15

Applicant: Edith Mathiowitz ,  Yong Shik Jong ,  Kim Boekelheide

Inventor： Edith Mathiowitz ,  Yong Shik Jong ,  Kim Boekelheide

IPC: C12N1563

CPC classification number: A61K9/1647 ,  A61K9/1272 ,  A61K9/2027 ,  A61K48/00

Abstract: A means for obtaining efficient introduction of exogenous genes into a patient, with long term expression of the gene, is disclosed. The gene, under control of an appropriate promoter for expression in a particular cell type, is encapsulated or dispersed with a biocompatible, preferably biodegradable polymeric matrix, where the gene is able to diffuse out of the matrix over an extended period of time, for example, a period of three to twelve months or longer. The matrix is preferably in the form of a microparticle such as a microsphere (where the gene is dispersed throughout a solid polymeric matrix) or microcapsule (gene is stored in the core of a polymeric shell), a film, an implant, or a coating on a device such as a stent. The size and composition of the polymeric device is selected to result in favorable release kinetics in tissue. The size is also selected according to the method of delivery which is to be used, typically injection or administration of a suspension by aerosol into the nasal and/or pulmonary areas. The matrix composition can be selected to not only have favorable degradation rates, but to be formed of a material which is bioadhesive, to further increase the effectiveness of transfer when administered to a mucosal surface.

Abstract translation: 公开了一种用于获得有效引入外源基因到患者中的方法，其具有该基因的长期表达。 在特定细胞类型中用于表达的适当启动子的控制下的基因用生物相容的，优选可生物降解的聚合物基质包封或分散，其中基因能够在延长的时间段内扩散出基质，例如 ，期限为三至十二个月或更长。 基质优选为微粒，例如微球（其中基因分散在整个固体聚合物基质中）或微胶囊（基因存储在聚合物壳的核心中），膜，植入物或涂层 在诸如支架的装置上。 选择聚合物装置的尺寸和组成以在组织中产生有利的释放动力学。 还根据要使用的递送方法选择大小，通常通过气雾剂将悬浮液注射或施用于鼻和/或肺部区域。 可以选择基质组合物不仅具有良好的降解速率，而且由生物粘附的材料形成，以进一步提高施用于粘膜表面时转移的有效性。

公开(公告)号：US06365187B2

公开(公告)日：2002-04-02

申请号：US09773229

申请日：2001-01-31

Applicant: Edith Mathiowitz ,  Donald E. Chickering, III ,  Jules Serge Jacob

Inventor： Edith Mathiowitz ,  Donald E. Chickering, III ,  Jules Serge Jacob

IPC: A61K914

CPC classification number: A61K9/1641 ,  A61K9/167 ,  Y10S514/962 ,  Y10S977/906 ,  Y10S977/915 ,  Y10S977/928

Abstract: Bioadhesive polymers in the form of, or as a coating on, microcapsules containing drugs or bioactive substances which may serve for therapeutic, or diagnostic purposes in diseases of the gastrointestinal tract, are described. The polymeric microspheres all have a bioadhesive force of at least 11 mN/cm2 (110 N/m2) Techniques for the fabrication of bioadhesive microspheres, as well as a method for measuring bioadhesive forces between microspheres and selected segments of the gastrointestinal tract in vitro are also described. This quantitative method provides a means to establish a correlation between the chemical nature, the surface morphology and the dimensions of drug-loaded microspheres on one hand and bioadhesive forces on the other, allowing the screening of the most promising materials from a relatively large group of natural and synthetic polymers which, from theoretical consideration, should be used for making bioadhesive microspheres.

Abstract translation: 描述了可以用作胃肠道疾病中的治疗或诊断目的的药物或生物活性物质的形式或作为包衣形式的生物粘附聚合物。 聚合物微球全部具有至少11mN / cm 2（110N / m 2）的生物附着力。用于制造生物粘附性微球的技术以及用于测量微球和体外胃肠道选定区段之间的生物粘附力的方法是 也描述。 这种定量方法提供了一种手段来建立化学性质，表面形态和药物负载微球的尺寸与生物粘附力之间的相关性，另一方面可以从相对较大的组中筛选出最有希望的材料 天然和合成的聚合物，从理论上考虑，应用于制造生物粘附微球。

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：US5985354A

公开(公告)日：1999-11-16

申请号：US478103

申请日：1995-06-07

Applicant: Edith Mathiowitz ,  Jules S. Jacob ,  Donald E. Chickering, III ,  Kathleen Jo Pekarek

Inventor： Edith Mathiowitz ,  Jules S. Jacob ,  Donald E. Chickering, III ,  Kathleen Jo Pekarek

IPC: A61K9/16 ,  A61K9/50 ,  A61K9/52 ,  B01J13/04 ,  B01J13/06 ,  B01J13/20

CPC classification number: B01J13/04 ,  A61K9/1641 ,  A61K9/1652 ,  A61K9/1694 ,  A61K9/5036 ,  A61K9/5052 ,  A61K9/5089 ,  B29K2003/00 ,  Y10S514/963 ,  Y10S514/965 ,  Y10T428/2984 ,  Y10T428/2985 ,  Y10T428/2989 ,  Y10T428/2991

Abstract: Two or more hydrophilic polymers that are not soluble in each other at a particular concentration and temperature, but which have a positive spreading coefficient in solution, are used to form multi-layered polymeric microspheres. The multi-layer microspheres produced by the method are distinguished by extremely uniform dimensioned polymer layers and actual incorporation of a substance to be delivered into the polymer layers. In the preferred embodiment of the method, two polymers are dissolved in an aqueous solvent, the substance to be incorporated is dispersed or dissolved in the polymer solution, the mixture is suspended in an organic solvent or polymer/water mixture 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.

公开(公告)号：US5955096A

公开(公告)日：1999-09-21

申请号：US670326

申请日：1996-06-25

Applicant: Camila A. Santos ,  Jules S. Jacob ,  Benjamin A. Hertzog ,  Gerardo P. Carino ,  Edith Mathiowitz

Inventor： Camila A. Santos ,  Jules S. Jacob ,  Benjamin A. Hertzog ,  Gerardo P. Carino ,  Edith Mathiowitz

IPC: B82B1/00 ,  A61K9/16 ,  A61K9/51 ,  C08G67/04 ,  A61F2/00 ,  A61K9/00

CPC classification number: A61K9/5138 ,  A61K9/1641 ,  A61K9/1647 ,  A61K9/5153

Abstract: Methods and compositions are provided for enhancing the bioadhesive properties of polymers used in drug delivery systems. The bioadhesive properties of a polymer are enhanced by incorporating an anhydride oligomer into the polymer to enhance the ability of the polymer to adhere to a tissue surface such as a mucosal membrane. Anhydride oligomers which enhance the bioadhesive properties of a polymer include oligomers synthesized from dicarboxylic acid monomers, preferably those found in Krebs glycolysis cycle, especially fumaric acid. The oligomers can be incorporated within a wide range of polymers including proteins, polysaccharides and synthetic biocompatible polymers. In one embodiment, anhydride oligomers can be incorporated within polymers used to form or coat drug delivery systems, such as microspheres, which contain a drug or diagnostic agent. The oligomers can either be solubilized and blended with the polymer before manufacture or else used as a coating with polymers over existing systems. The polymers, for example in the form of microspheres, have improved ability to adhere to mucosal membranes, and thus can be used to deliver a drug or diagnostic agent via any of a range of mucosal membrane surfaces including those of the gastrointestinal, respiratory, excretory and reproductive tracts.

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。