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公开(公告)号：US5837221A
公开(公告)日：1998-11-17
申请号：US681710
申请日：1996-07-29
CPC分类号： A61K49/0002 , A61K49/0004 , A61K49/223
摘要： It has been discovered that the incorporation of gases, especially fluorinated gases such as perfluorocarbons, into microparticles formed from the combination of a natural or synthetic polymer and lipid have significantly enhanced echogenicity as compared with microparticles not including the lipid. Compounds other than lipids which are hydrophobic and limit the penetration and/or uptake of water into the microparticles can also be incorporated into the microparticles to enhance echogenicity. In the preferred embodiment, the polymers are synthetic biodegradable polymers. The microparticles are manufactured with a diameter suitable for the targeted tissue to be imaged, for example, with a diameter of between 0.5 and 8 microns for intravascular administration, and a diameter of between 0.5 and 5 mm for oral administration for imaging of the gastrointestinal tract or other lumens. Preferred polymers are polyhydroxy acids such as polylactic acid-co-glycolic acid, most preferably conjugated to polyethylene glycol or other materials inhibiting uptake by the reticuloendothelial system (RES). The most preferred lipids are phospholipids, preferably dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine, dilignoceroylphatidylcholine (DLPC), incorporated at a ratio of between 0.01-30 (w lipid/w polymer), most preferably between 0.1-10 (w lipid/w polymer). Microparticles for imaging using other detectable agents can be similarly manufactured.
摘要翻译： 已经发现，与不包括脂质的微粒相比，将天然或合成聚合物和脂质的组合形成的气体，特别是氟化气体（例如全氟化碳）并入微型颗粒中显着增强了回声反应性。 疏水性的脂质以外的化合物也限制在微粒中的渗透和/或吸收也可以并入微粒中以增强回声性。 在优选的实施方案中，聚合物是合成的可生物降解的聚合物。 制造具有适于待成像的目标组织的直径的微粒，例如直径为0.5至8微米，用于血管内施用，并且用于口服给药的直径在0.5至5mm之间以用于胃肠道成像 或其他流明。 优选的聚合物是聚羟基酸，例如聚乳酸 - 共 - 乙醇酸，最优选与聚乙二醇缀合或抑制网状内皮系统（RES）摄取的其它物质。 最优选的脂质是磷脂，优选二棕榈酰磷脂酰胆碱（DPPC），二硬脂酰磷脂酰胆碱（DSPC），二酰氨基磷脂酰胆碱（DAPC），二苯甲酰磷脂酰胆碱（DBPC），二硫代酰基磷脂酰胆碱，二烯酰基脂肪酰胆碱（DLPC），其比例为0.01-30（w脂质/ ），最优选0.1-10（w脂/ w聚合物）。 可以类似地制造用于使用其它可检测试剂成像的微粒。
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公开(公告)号：US5716644A
公开(公告)日：1998-02-10
申请号：US478502
申请日：1995-06-07
IPC分类号： A61K9/00 , A61K9/16 , A61K9/50 , A61K9/51 , A61K9/52 , A61K38/17 , A61K38/18 , A61K38/22 , A61K47/02 , A61K47/12 , A61K47/18 , A61K47/26 , A61K47/30 , A61K47/32 , A61K47/34 , A61K47/42 , A61P7/00
CPC分类号： B82Y5/00 , A61K38/1816 , A61K9/0019 , A61K9/1611 , A61K9/1647 , A61K9/1658 , A61K9/5031 , A61K9/5052 , A61K9/5153 , A61K9/5169 , A61K47/02 , A61K47/26 , A61K9/1694 , Y10S514/963 , Y10S514/965
摘要： A composition, and methods of forming and using said composition, for the sustained release of non-aggregated, biologically active, erythropoietin (EPO). The sustained release composition of this invention comprises a polymeric matrix of a biocompatible polymer and particles of biologically active, aggregation-stabilized EPO, wherein said particles are dispersed within the biocompatible polymer. The method of the invention for producing a composition for the sustained release of biologically active EPO, includes dissolving a biocompatible polymer in a polymer solvent to form a polymer solution, dispersing particles of biologically active, aggregation-stabilized EPO in the polymer solution, and then solidifying the polymer to form a polymeric matrix containing a dispersion of said EPO particles. The method for using a composition of the invention is a method for providing a therapeutically effective blood level of biologically active, non-aggregated erythropoietin in a subject for a sustained period. In this method, a subject is administered an effective dose of the sustained release composition of the present invention.
摘要翻译： 用于持续释放非聚集的，生物活性的促红细胞生成素（EPO）的组合物和形成和使用所述组合物的方法。 本发明的持续释放组合物包含生物相容性聚合物的聚合物基质和生物活性聚集稳定的EPO颗粒，其中所述颗粒分散在生物相容性聚合物内。 用于制备用于持续释放生物活性EPO的组合物的本发明的方法包括将生物相容性聚合物溶解在聚合物溶剂中以形成聚合物溶液，将生物活性聚集稳定的EPO的颗粒分散在聚合物溶液中，然后 固化聚合物以形成含有所述EPO颗粒的分散体的聚合物基质。 使用本发明组合物的方法是在持续时间内在受试者中提供治疗有效的血液中生物活性，非聚集的促红细胞生成素的方法。 在该方法中，给予受试者有效剂量的本发明的持续释放组合物。
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63.发明申请PROCESSES FOR MAKING PARTICLE-BASED PHARMACEUTICAL FORMULATIONS FOR ORAL ADMINISTRATION 审中-公开制造基于粒子的药物制剂进行口腔管理的方法公开(公告)号：US20070148211A1
公开(公告)日：2007-06-28
申请号：US11610802
申请日：2006-12-14
申请人： David Altreuter , Howard Bernstein , Luis Brito , Shaina Brito , Donald Chickering , Eric Huang , Rajeev Jain , Sridhar Narasimhan , Julie Straub
发明人： David Altreuter , Howard Bernstein , Luis Brito , Shaina Brito , Donald Chickering , Eric Huang , Rajeev Jain , Sridhar Narasimhan , Julie Straub
CPC分类号： A61K9/145 , A61K9/0056 , A61K9/0095 , A61K9/2072 , A61K9/2077 , A61K9/2095
摘要： A method is provided for making an oral dosage form of a pharmaceutical agent which includes the steps of (a) providing particles which include a pharmaceutical agent; (b) blending the particles with particles of a pre-processed excipient to form a primary blend, wherein the pre-processed excipient is prepared by (i) dissolving a bulking agent (e.g., a sugar) and at least one non-friable excipient (e.g., a waxy or liquid surfactant) in a solvent to form an excipient solution, and (ii) removing the solvent from the excipient solution to form the pre-processed excipient in dry powder form; (c) milling the primary blend to form a milled pharmaceutical formulation blend that includes microparticles or nanoparticles of the pharmaceutical agent; and (d) processing the milled pharmaceutical formulation blend into a solid oral dosage form or liquid suspension for oral administration. The process yields formulations having improved wettability or dispersibility.
摘要翻译： 提供了制备药剂口服剂型的方法，其包括以下步骤：（a）提供包含药剂的颗粒; （b）将颗粒与预处理的赋形剂的颗粒混合以形成初级共混物，其中预处理的赋形剂通过以下步骤制备：（i）将填充剂（例如糖）和至少一种不易碎的赋形剂 （例如，蜡状或液体表面活性剂）在溶剂中形成赋形剂溶液，和（ii）从赋形剂溶液中除去溶剂以形成干粉末形式的预处理赋形剂; （c）研磨初级共混物以形成包含药剂的微粒或纳米颗粒的研磨的药物配制物混合物; 和（d）将经研磨的药物制剂混合物加工成固体口服剂型或用于口服给药的液体悬浮液。 该方法产生具有改善的润湿性或分散性的制剂。
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公开(公告)号：US20050271591A1
公开(公告)日：2005-12-08
申请号：US11143170
申请日：2005-06-02
CPC分类号： A61K49/223
摘要： Clinical studies have been conducted and specific dosage formulations developed using polymeric microparticles having incorporated therein perfluorocarbon gases that provide significantly enhanced images of long duration. The dosage formulation includes microparticles formed of a biocompatible polymer, preferably including a lipid incorporated therein, and containing a perfluorocarbon that is a gas at body temperature. The microparticles are provided to a patient in an amount effective to enhance ultrasound imaging in the ventricular chambers for more than 5 minutes or in the mycocardium for more than a minute, in a dose ranging from 0.025 to 8.0 mg microparticles/kg body weight. Preferably the dose ranges from 0.05 to 4.0 mg microparticles/kg body weight. The dosage formulation typically is provided in a vial. A typical formulation is in the form of a dry powder that is reconstituted with sterile water prior to use by adding the water to the vial or syringe of the dry powder and shaking to yield an isosmotic or isotonic suspension of microparticles.
摘要翻译： 已经进行了临床研究，并且使用其中结合有全氟化碳气体的聚合物微粒开发特定的剂型，其提供了长时间显着增强的图像。 剂量制剂包括由生物相容性聚合物形成的微粒，其优选包括掺入其中的脂质，并且含有在体温下作为气体的全氟化碳。 将微粒以有效量的方式提供给患者，剂量范围为0.025至8.0mg微粒/ kg体重的剂量，以有效增强心室中的超声成像超过5分钟或在心肌中超过一分钟。 剂量优选为0.05至4.0mg微粒/ kg体重。 剂型通常提供在小瓶中。 典型的制剂是干粉的形式，其在使用前通过将水添加到干粉末的小瓶或注射器中并且摇动以产生微粒的等渗或等渗悬浮液而在使用前用无菌水重构。
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65.发明授权
公开(公告)号：US6045777A
公开(公告)日：2000-04-04
申请号：US885933
申请日：1997-06-30
CPC分类号： A61B8/481 , A61K49/223
摘要： It has been discovered microparticles formed from natural or synthetic polymer with thicker walls have significantly enhanced echogenicity as compared with microparticles having thinner walls. The effect of wall thickness has been determined experimentally as well as inserted into a formula for use in predicting the optimum conditions. In the preferred embodiment, the polymers are synthetic biodegradable polymers and the wall thickness is between about 100 and 660 nm, although wall thicknesses from about 20 nm to in excess of 500 nm can be used. The microparticles are manufactured with a diameter suitable for the targeted tissue to be imaged, for example, with a diameter of between 0.5 and 8 microns for intravascular administration, and a diameter of between 0.5 and 5 mm for oral administration for imaging of the gastrointestinal tract or other lumens. Preferred polymers are polyhydroxy acids such as polylactic acid-co-glycolic acid, polylactide or polyglycolide, most preferably conjugated to polyethylene glycol or other materials inhibiting uptake by the reticuloendothelial system (RES). The microspheres may be used in a variety of ultrasound imaging applications including cardiology applications, blood perfusion applications as well as for organ and peripheral vein imaging.
摘要翻译： 与具有较薄壁的微粒相比，发现由具有较厚壁的天然或合成聚合物形成的微粒具有显着增强的回声性。 实验确定了壁厚的影响，并将其插入到用于预测最佳条件的公式中。 在优选的实施方案中，聚合物是合成的可生物降解聚合物，并且壁厚度在约100至660nm之间，尽管可以使用约20nm至超过500nm的壁厚。 制造具有适于待成像的目标组织的直径的微粒，例如，用于血管内施用的直径为0.5至8微米，并且用于口服给药以用于胃肠道成像的直径为0.5至5毫米 或其他流明。 优选的聚合物是聚羟酸，例如聚乳酸 - 共 - 乙醇酸，聚丙交酯或聚乙交酯，最优选与聚乙二醇缀合或抑制网状内皮系统（RES）吸收的其它物质。 微球可以用于各种超声成像应用，包括心脏应用，血液灌注应用以及器官和外周静脉成像。
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公开(公告)号：US5912015A
公开(公告)日：1999-06-15
申请号：US56566
申请日：1998-04-07
申请人： Howard Bernstein , Yan Zhang , M. Amin Khan , Mark A. Tracy
发明人： Howard Bernstein , Yan Zhang , M. Amin Khan , Mark A. Tracy
CPC分类号： A61K9/7007 , A61K38/212 , A61K38/27 , A61K38/35 , A61K38/465 , A61K9/1611 , A61K9/1647 , A61K9/1694 , C12Y301/27005 , Y10S514/805 , Y10S514/965
摘要： The present invention relates to a composition for the modulated release of a biologically active agent. The composition comprises a biocompatible polymeric matrix, a biologically active agent which is dispersed within the polymeric matrix, and a metal cation component which is separately dispersed within the polymeric matrix, whereby the metal cation component modulates the release of the biologically active agent from the polymeric matrix. The present invention also relates to a method for modulating the release of a biologically active agent from a biocompatible polymeric matrix, comprising the steps of dissolving a biocompatible polymer in a solvent to form a polymer solution and also separately dispersing a metal cation component and a biologically active agent within the polymer solution. The polymer solution is then solidified to form a polymeric matrix, wherein at least a significant portion of the metal cation component is dispersed in the polymeric matrix separately from the biologically active protein, and whereby the metal cation component modulates the release of the biologically active agent from the polymeric matrix.
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公开(公告)号：US5679377A
公开(公告)日：1997-10-21
申请号：US261690
申请日：1994-06-17
CPC分类号： B01J13/12 , A01N25/28 , A61K9/1658 , B01J13/125 , Y10S514/866 , Y10S514/963 , Y10S514/965 , Y10T428/2984 , Y10T428/2985 , Y10T428/2989
摘要： Biodegradable, protein microspheres for in vivo release of a biologically active agent, as well as agricultural and environmental applications. The microspheres can be administered orally, intravenously, or subcutaneously for subsequent release. By selecting particular size ranges and the specific protein used to form the microsphere, it is possible to target the microspheres to a cell types such as macrophages, or to effect localized absorption of the microspheres to regions such as the mucosal membranes of the mouth, gastrointestinal tract, or urogenital areas. Larger forms of the microspheres can also be made using standard techniques of the desirable degradation properties.
摘要翻译： 可生物降解的蛋白质微球，用于体内释放生物活性剂，以及农业和环境应用。 微球可以口服，静脉内或皮下给药以便随后释放。 通过选择特定尺寸范围和用于形成微球的特定蛋白质，可以将微球靶向诸如巨噬细胞的细胞类型，或者将微球局部吸收到诸如口腔粘膜的区域，胃肠道 道或泌尿生殖系。 也可以使用所需降解性能的标准技术制备较大形式的微球。
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公开(公告)号：US5656297A
公开(公告)日：1997-08-12
申请号：US237057
申请日：1994-05-03
申请人： Howard Bernstein , Yan Zhang , M. Amin Khan , Mark A. Tracy
发明人： Howard Bernstein , Yan Zhang , M. Amin Khan , Mark A. Tracy
IPC分类号： A61K9/00 , A61K9/16 , A61K9/52 , A61K9/70 , A61K38/21 , A61K38/22 , A61K38/35 , A61K38/46 , A61K47/30 , A61K47/34 , A61K9/14
CPC分类号： A61K9/1694 , A61K33/10 , A61K33/30 , A61K38/212 , A61K38/27 , A61K38/35 , A61K38/465 , A61K9/1611 , A61K9/1647 , A61K9/7007 , C12Y301/27005 , Y10S514/805 , Y10S514/935
摘要： The present invention relates to a composition for the modulated release of a biologically active agent. The composition comprises a biocompatible polymeric matrix, a biologically active agent which is dispersed within the polymeric matrix, and a metal cation component which is separately dispersed within the polymeric matrix, whereby the metal cation component modulates the release of the biologically active agent from the polymeric matrix. The present invention also relates to a method for modulating the release of a biologically active agent from a biocompatible polymeric matrix, comprising the steps of dissolving a biocompatible polymer in a solvent to form a polymer solution and also separately dispersing a metal cation component and a biologically active agent within the polymer solution. The polymer solution is then solidified to form a polymeric matrix, wherein at least a significant portion of the metal cation component is dispersed in the polymeric matrix separately from the biologically active protein, and whereby the metal cation component modulates the release of the biologically active agent from the polymeric matrix.
摘要翻译： 本发明涉及用于调节释放生物活性剂的组合物。 组合物包含生物相容性聚合物基质，分散在聚合物基质内的生物活性剂和分散分散在聚合物基质内的金属阳离子组分，由此金属阳离子组分调节生物活性剂从聚合物中的释放 矩阵。 本发明还涉及一种用于调节生物相容性聚合物基质释放生物活性剂的方法，包括以下步骤：将生物相容性聚合物溶解在溶剂中以形成聚合物溶液，并且还分别分散金属阳离子组分和生物相容性聚合物 聚合物溶液中的活性剂。 然后将聚合物溶液固化以形成聚合物基质，其中至少大部分金属阳离子组分与生物活性蛋白质分开分散在聚合物基质中，由此金属阳离子组分调节生物活性剂的释放 从聚合物基质。
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公开(公告)号：US5654010A
公开(公告)日：1997-08-05
申请号：US473544
申请日：1995-06-07
IPC分类号： A01N25/28 , A61F2/02 , A61K9/16 , A61K9/26 , A61K9/50 , A61K9/52 , A61K31/415 , A61K31/74 , A61K38/27 , A61K47/32 , A61K47/34 , A61K9/14 , A61K38/24
CPC分类号： B82Y5/00 , A61K38/27 , A61K9/1611 , A61K9/1647 , A61K9/1694 , Y10S514/839 , Y10S530/839 , Y10T428/2985
摘要： A composition, and methods of forming and using said composition, for the sustained release of biologically active, stabilized human growth hormone (hGH). The sustained release composition of this invention comprises a polymeric matrix of a biocompatible polymer and particles of biologically active, stabilized hGH, wherein said particles are dispersed within the biocompatible polymer. The method of the invention for producing a composition for the sustained release of biologically active hGH, includes dissolving a biocompatible polymer in a polymer solvent to form a polymer solution, dispersing particles of biologically active, stabilized hGH in the polymer solution, and then solidifying the polymer to form a polymeric matrix containing a dispersion of said hGH particles. The method for using a composition of the invention is a method for providing a therapeutically effective blood level of biologically active, non-aggregated hGH in a subject for a sustained period. In this method, a subject is administered an effective dose of the sustained release composition of the present invention. The method of using the sustained release composition of the present invention comprises providing a therapeutically effective blood level of biologically active, non-aggregated human growth hormone in a subject for a sustained period by administering to the subject a dose of said sustained release composition.
摘要翻译： 一种组合物，以及形成和使用所述组合物用于持续释放生物活性稳定的人生长激素（hGH）的方法。 本发明的持续释放组合物包含生物相容性聚合物的聚合物基质和生物活性稳定的hGH颗粒，其中所述颗粒分散在生物相容性聚合物内。 用于生产用于持续释放生物活性的hGH的组合物的本发明的方法包括将生物相容性聚合物溶解在聚合物溶剂中以形成聚合物溶液，将生物活性稳定的hGH的颗粒分散在聚合物溶液中，然后固化 聚合物以形成含有所述hGH颗粒的分散体的聚合物基质。 使用本发明组合物的方法是在持续时间内在受试者中提供治疗有效的血液水平的生物活性，非聚集的hGH的方法。 在该方法中，给予受试者有效剂量的本发明的持续释放组合物。 使用本发明的持续释放组合物的方法包括通过向受试者施用一定剂量的所述持续释放组合物，在持续的时间内提供治疗有效的血液中的生物活性的，非聚集的人生长激素。
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公开(公告)号：US5271961A
公开(公告)日：1993-12-21
申请号：US902505
申请日：1992-06-23
CPC分类号： A61K9/1658 , A61K9/1647 , A61K9/5052
摘要： Protein microspheres are formed by phase separation in a non-solvent followed by solvent removal. The preferred proteins are prolamines, such as zein, that are hydrophobic, biodegradable, and can be modified proteolytically or chemically to endow them with desirable properties, such as a selected degradation rate. Composite microspheres can be prepared from a mixture of proteins or a mixture of proteins with one or more bioerodible polymeric materials, such as polylactides. Protein coatings can also be made. Compounds are readily incorporated into the microspheres for subsequent release. The process does not involve agents which degrade most labile proteins. The microspheres have a range of sizes and multiple applications, including drug delivery and delayed release of pesticides, fertilizers, and agents for environmental cleanup. Selection of microsphere size in the range of less than five microns and mode of administration can be used to target the microparticles to the cells of the reticuloendothelial system, or to the mucosal membranes of the mouth or gastrointestinal tract. Larger implants formed from the microspheres can also be utilized, especially for agricultural applications.
摘要翻译： 通过在非溶剂中相分离形成蛋白质微球，随后除去溶剂。 优选的蛋白质是疏水性的，可生物降解的，可以被蛋白水解或化学修饰以赋予它们所需性质（例如选择的降解速率）的醇溶蛋白，例如玉米醇溶蛋白。 复合微球可以由蛋白质或蛋白质与一种或多种生物可腐蚀的聚合物材料如聚交酯的混合物的混合物制备。 蛋白质涂层也可以制成。 化合物容易地并入微球体中用于随后的释放。 该过程不涉及降解大多数不稳定蛋白质的试剂。 微球具有一定范围的尺寸和多种应用，包括药物输送和农药，肥料和环境清洁剂的延迟释放。 可以使用在小于5微米范围内的微球大小的选择和给药方式将微粒靶向网状内皮系统的细胞，或将其靶向口腔或胃肠道的粘膜。 也可以利用由微球形成的更大的植入物，特别是在农业应用中。
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