公开(公告)号：US06482810B1

公开(公告)日：2002-11-19

申请号：US08227100

申请日：1994-04-13

申请人： Henry Brem ,  Rafael J. Tamargo ,  Robert A. Bok

发明人： Henry Brem ,  Rafael J. Tamargo ,  Robert A. Bok

IPC分类号： A61K3165

CPC分类号： A61K31/70 ,  A61K31/65 ,  A61K31/675 ,  A61K31/715 ,  A61K38/04 ,  A61K31/17 ,  A61K31/505 ,  A61K31/475 ,  A61K31/335 ,  A61K31/195 ,  A61K31/255 ,  A61K31/52 ,  A61K31/09 ,  A61K2300/00

摘要： Pharmaceutical compositions for delivering an effective dose of an angiogenesis inhibitor consisting of a tetracycline or tetracycline such as minocycline. The effective dosage for inhibition of angiogenesis based on in vitro testing is between one and 500 micromolar. The compositions are delivered topically, locally or systemically using implants or injection. The composition is extremely selective for growth of endothelial cells, inhibiting growth, but is not cytotoxic at the effective dosages.

摘要翻译： 用于递送有效剂量的由四环素或四环素如米诺环素组成的血管生成抑制剂的药物组合物。 基于体外测试的抑制血管发生的有效剂量在1微米到500微摩尔之间。 使用植入物或注射剂局部或全身地递送组合物。 该组合物对内皮细胞生长具有极大的选择性，抑制生长，但在有效剂量下不具有细胞毒性。

公开(公告)号：US5846565A

公开(公告)日：1998-12-08

申请号：US750736

申请日：1996-12-18

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 ,  A61K9/14

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 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.

摘要翻译： PCT No.PCT / US95 / 09805 Sec。 371日期：1996年12月18日 102（e）日期1996年12月18日PCT提交1995年8月2日PCT公布。 公开号WO96 / 03984 日期1996年2月15日描述了一种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，其特征在于生物利用度差和/或体内半衰期短。 这些装置由长期释放药物的储存器组成，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。

公开(公告)号：US5651986A

公开(公告)日：1997-07-29

申请号：US663711

申请日：1996-06-14

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 ,  A61K9/14

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.

公开(公告)号：US20110313010A1

公开(公告)日：2011-12-22

申请号：US13163223

申请日：2011-06-17

申请人： Violette Renard Recinos ,  Betty Tyler ,  Sarah Brem Sunshine ,  Henry Brem

发明人： Violette Renard Recinos ,  Betty Tyler ,  Sarah Brem Sunshine ,  Henry Brem

IPC分类号： A61K31/4188 ,  A61P35/00 ,  A61K31/175

CPC分类号： A61K31/175 ,  A61K31/4188 ,  A61K31/495 ,  A61K2300/00

摘要： The additive effect of combined intracranial carmustine (“BCNU”) with intracranial temozolomide (“TMZ”), and particularly in combination with radiation (“XRT”), in the treatment of two rat intracranial glioma models, the 9L gliosarcoma and the F98 glioma, demonstrates that local delivery of both drugs, especially in combination with radiation, is far more effective than delivery of either drug alone or one systemically and one locally, either with or without radiation. The triple therapy showed a significant improvement in survival when compared to controls (p=0.0004), local BCNU (p=0.0043), oral TMZ (p=0.0026), local TMZ (p=0.0105), and the combinations of either BCNU and XRT (p=0.0378) or oral TMZ and local BCNU (p=0.0154).

摘要翻译： 联合颅内卡莫司汀（“BCNU”）与颅内替莫唑胺（“TMZ”），特别是与辐射（“XRT”）联合治疗两只大鼠颅内神经胶质瘤模型，9L胶质神经胶质瘤和F98胶质瘤 表明，两种药物的地方交付，特别是与辐射相结合的药物，比单独或单独使用一种药物，或者在有或没有辐射的情况下，都是有效的。 与对照组（p = 0.0004），局部BCNU（p = 0.0043），口服TMZ（p = 0.0026），局部TMZ（p = 0.0105）相比，三联治疗显示出显着改善，以及BCNU和 XRT（p = 0.0378）或口服TMZ和局部BCNU（p = 0.0154）。

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。

公开(公告)号：US08895597B2

公开(公告)日：2014-11-25

申请号：US13163223

申请日：2011-06-17

申请人： Violette Renard Recinos ,  Betty Tyler ,  Sarah Brem Sunshine ,  Henry Brem

发明人： Violette Renard Recinos ,  Betty Tyler ,  Sarah Brem Sunshine ,  Henry Brem

IPC分类号： A61K31/415 ,  A61K31/175 ,  A61K31/4188

CPC分类号： A61K31/175 ,  A61K31/4188 ,  A61K31/495 ,  A61K2300/00

摘要： The additive effect of combined intracranial carmustine (“BCNU”) with intracranial temozolomide (“TMZ”), and particularly in combination with radiation (“XRT”), in the treatment of two rat intracranial glioma models, the 9L gliosarcoma and the F98 glioma, demonstrates that local delivery of both drugs, especially in combination with radiation, is far more effective than delivery of either drug alone or one systemically and one locally, either with or without radiation. The triple therapy showed a significant improvement in survival when compared to controls (p=0.0004), local BCNU (p=0.0043), oral TMZ (p=0.0026), local TMZ (p=0.0105), and the combinations of either BCNU and XRT (p=0.0378) or oral TMZ and local BCNU (p=0.0154).

摘要翻译： 联合颅内卡莫司汀（“BCNU”）与颅内替莫唑胺（“TMZ”），特别是与辐射（“XRT”）联合治疗两只大鼠颅内神经胶质瘤模型，9L胶质神经胶质瘤和F98胶质瘤 表明，两种药物的地方交付，特别是与辐射相结合的药物，比单独或单独使用一种药物，或者在有或没有辐射的情况下，都是有效的。 与对照组（p = 0.0004），局部BCNU（p = 0.0043），口服TMZ（p = 0.0026），局部TMZ（p = 0.0105）相比，三联治疗显示出显着改善，以及BCNU和 XRT（p = 0.0378）或口服TMZ和局部BCNU（p = 0.0154）。

公开(公告)号：US20080260834A1

公开(公告)日：2008-10-23

申请号：US12165036

申请日：2008-06-30

申请人： Martin Burke ,  Maria-Christina White ,  Mark C. Watts ,  Jae Kyoo Lee ,  Betty M. Tyler ,  Gary H. Posner ,  Henry Brem

发明人： Martin Burke ,  Maria-Christina White ,  Mark C. Watts ,  Jae Kyoo Lee ,  Betty M. Tyler ,  Gary H. Posner ,  Henry Brem

IPC分类号： A61K31/59 ,  A61K9/10 ,  A61P35/00 ,  A61P25/28

CPC分类号： A61K9/0024 ,  A61K9/0085 ,  A61K9/1641

摘要： Localized delivery of 1,25 D3 directly to a target area using biodegradable polymeric matrices maximizes the efficacy of this drug while minimizing systemic exposure and toxicity. Anticalcemic analogs of 1,25 D3 have also been incorporated into controlled release polymer formulations to achieve efficacious intracranial concentrations of 1,25 D3 analogs for the treatment of intracranial tumors as well as neurodegenerative disorders such as Alzheimer's disease as well as to maximize the efficacy of these analogs in the treatment of systemic malignancies. The therapeutic efficacy of these formulations was demonstrated through a variety of studies in vitro and in vivo. Hybrid analogs of 1,25 D3 were incorporated into biodegradable polymer wafers composed of a polyanhydride copolymer of 1,3-bis(p-carboxyphenoxy)propane (CPP) and sebacic acid (SA) in a 20:80 molar ratio. In addition to providing improved treatments for malignancies and neurodegenerative disorders, the spatial localization and high reproducibility of this controlled delivery methodology presents a unique opportunity to study in vivo the poorly understood mechanisms of 1,25 D3's antiangiogenic, antiproliferative, and transcriptional regulating activities.

摘要翻译： 使用可生物降解的聚合物基质直接向目标区域局部递送1,25 D 3 N使该药物的功效最大化，同时使全身暴露和毒性最小化。 1,25 D 3 N的类似物也被并入控释聚合物制剂中，以实现颅内肿瘤治疗的有效颅内浓度1,25D 3 N 3类似物 以及神经变性疾病如阿尔茨海默病，以及使这些类似物在治疗全身性恶性肿瘤中的功效最大化。 通过体外和体内的各种研究证实了这些制剂的治疗功效。 将1,25 D 3 N的混合类似物掺入到由20重量份的1,3-双（对羧基苯氧基）丙烷（CPP）和癸二酸（SA）的聚酐共聚物组成的可生物降解的聚合物晶片中 ：80摩尔比。 除了为恶性肿瘤和神经变性疾病提供改进的治疗之外，这种受控递送方法的空间定位和高重现性提供了一个独特的机会，可以在体内研究一个不太了解的1,25 D 3 抗血管生成，抗增殖和转录调节活性。