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

IPC分类号： A61K9/28 ,  A61K9/48 ,  A61K9/20 ,  A61K9/14

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。

公开(公告)号：US20070178166A1

公开(公告)日：2007-08-02

申请号：US11610814

申请日：2006-12-14

申请人： Howard Bernstein ,  Shaina Brito ,  Donald Chickering ,  Eric Huang ,  Rajeev Jain ,  Julie Straub

发明人： Howard Bernstein ,  Shaina Brito ,  Donald Chickering ,  Eric Huang ,  Rajeev Jain ,  Julie Straub

IPC分类号： A61K9/14

CPC分类号： A61K9/0075 ,  A61K9/0043 ,  A61K9/0073 ,  A61K9/143 ,  A61K9/145

摘要： Dry powder pharmaceutical formulations for pulmonary or nasal administration are made to provide an improved respired dose. These formulations may be blends of milled blends and may include a phospholipid, alone or in combination with other excipient materials. In one case, the process includes the steps of (a) providing particles which comprise a pharmaceutical agent, (b) blending the particles with particles of at least one first excipient to form a first powder blend; (c) milling the first powder blend to form a milled blend which comprises microparticles or nanoparticles of the pharmaceutical agent; and (d) blending the milled blend with particles of a second excipient to form a blended dry powder blend pharmaceutical formulation suitable for pulmonary or nasal administration.

摘要翻译： 制备用于肺或鼻给药的干粉药物制剂以提供改善的呼吸剂量。 这些制剂可以是研磨的共混物的混合物，并且可以包括单独或与其它赋形剂材料组合的磷脂。 在一种情况下，该方法包括以下步骤：（a）提供包含药剂的颗粒，（b）将颗粒与至少一种第一赋形剂的颗粒混合以形成第一粉末混合物; （c）研磨第一粉末混合物以形成包含药剂的微粒或纳米颗粒的研磨混合物; 和（d）将研磨的共混物与第二赋形剂的颗粒混合以形成适于肺或鼻施用的混合的干粉混合药物制剂。

公开(公告)号：US20070178165A1

公开(公告)日：2007-08-02

申请号：US11610791

申请日：2006-12-14

申请人： David Altreuter ,  Howard Bernstein ,  Luis Brito ,  Shaina Brito ,  Olinda Carneiro ,  Donald Chickering ,  Eric Huang ,  Rajeev Jain ,  Sridhar Narasimhan ,  Namrata Pandit ,  Julie Straub

发明人： David Altreuter ,  Howard Bernstein ,  Luis Brito ,  Shaina Brito ,  Olinda Carneiro ,  Donald Chickering ,  Eric Huang ,  Rajeev Jain ,  Sridhar Narasimhan ,  Namrata Pandit ,  Julie Straub

IPC分类号： A61K9/14

CPC分类号： A61K9/0019 ,  A61K9/145 ,  A61K9/146 ,  A61K9/19

摘要： A method is provided for making a parenteral dosage form of a pharmaceutical agent which includes (a) providing particles of a pharmaceutical agent; (b) blending the particles with particles of at least one bulking agent to form a first powder blend, which does not include a surfactant; (c) milling the first powder blend to form a milled blend which comprises microparticles or nanoparticles of the pharmaceutical agent; and (d) reconstituting the milled blend with a liquid vehicle, which includes at least one surfactant, for parenteral administration. A method also is provided which includes (a) providing particles of a pharmaceutical agent; (b) blending these particles with particles of an excipient to form a first blend; and (c) milling the first blend to form a milled blend that includes microparticles or nanoparticles, which exhibits a greater dispersibility, wettability, and suspendability as compared to the particles of step (a) or the first blend.

摘要翻译： 提供了制备药物的胃肠外剂型的方法，其包括（a）提供药剂的颗粒; （b）将颗粒与至少一种填充剂的颗粒混合以形成不包括表面活性剂的第一粉末混合物; （c）研磨第一粉末混合物以形成包含药剂的微粒或纳米颗粒的研磨混合物; 和（d）将研磨的共混物与包含至少一种表面活性剂的液体载体重组，用于肠胃外给药。 还提供了一种方法，其包括（a）提供药剂的颗粒; （b）将这些颗粒与赋形剂的颗粒混合以形成第一共混物; 和（c）研磨第一共混物以形成包含微粒或纳米颗粒的研磨的共混物，其与步骤（a）或第一共混物的颗粒相比表现出更大的分散性，润湿性和悬浮性。

公开(公告)号：US20050079138A1

公开(公告)日：2005-04-14

申请号：US10955261

申请日：2004-09-30

申请人： Donald Chickering ,  Shaina Reese ,  Sridhar Narasimhan ,  Julie Straub ,  Howard Bernstein ,  David Altreuter ,  Eric Huang ,  Luis Brito ,  Rajeev Jain

发明人： Donald Chickering ,  Shaina Reese ,  Sridhar Narasimhan ,  Julie Straub ,  Howard Bernstein ,  David Altreuter ,  Eric Huang ,  Luis Brito ,  Rajeev Jain

IPC分类号： A61K9/00 ,  A61K9/14 ,  A61K9/16 ,  B01D1/18 ,  B01J2/04 ,  A61L9/04

CPC分类号： B01D1/18 ,  A61K9/0075 ,  A61K9/145 ,  A61K9/1647 ,  A61K9/1694 ,  B01J2/04

摘要： Methods are provided for making a dry powder blend pharmaceutical formulation, comprising the steps of: (a) providing microparticles which comprise a pharmaceutical agent; (b) blending the microparticles with at least one excipient in the form of particles to form a powder blend; and (c) jet milling the powder blend to form a dry powder blend pharmaceutical formulation having improved dispersibility, suspendability, or wettability as compared to the microparticles of step (a) or the powder blend of step (b). The method can further include dispersing the dry powder blend pharmaceutical formulation in a liquid pharmaceutically acceptable vehicle to make an formulation suitable for injection. Alternatively, the method can further include processing the dry powder blend pharmaceutical formulation into a solid oral dosage form. In one embodiment, the microparticles of step (a) are formed by a solvent precipitation or crystallization process.

摘要翻译： 提供用于制备干粉混合药物制剂的方法，包括以下步骤：（a）提供包含药剂的微粒; （b）将微粒与颗粒形式的至少一种赋形剂混合以形成粉末混合物; 和（c）与步骤（a）的微粒或步骤（b）的粉末混合物相比，喷粉研磨粉末混合物以形成具有改善的分散性，悬浮性或润湿性的干粉混合物药物制剂。 该方法还可以包括将干粉混合物药物制剂分散在液体药学上可接受的载体中以制备适于注射的制剂。 或者，该方法还可以包括将干粉混合药物制剂加工成固体口服剂型。 在一个实施方案中，步骤（a）的微粒通过溶剂沉淀或结晶过程形成。

公开(公告)号：US20060093678A1

公开(公告)日：2006-05-04

申请号：US11305620

申请日：2005-12-16

申请人： Donald Chickering ,  Shaina Reese ,  Sridhar Narasimhan ,  Julie Straub ,  Howard Bernstein ,  David Altreuter ,  Eric Huang

发明人： Donald Chickering ,  Shaina Reese ,  Sridhar Narasimhan ,  Julie Straub ,  Howard Bernstein ,  David Altreuter ,  Eric Huang

IPC分类号： A61K9/14

CPC分类号： B01D1/18 ,  A61K9/0075 ,  A61K9/145 ,  A61K9/1647 ,  A61K9/1694 ,  B01J2/04

摘要： Methods are provided for making a dry powder blend pharmaceutical formulation comprising (i) forming microparticles which comprise a pharmaceutical agent; (ii) providing at least one excipient in the form of particles having a volume average diameter that is greater than the volume average diameter of the microparticles; (iii) blending the microparticles with the excipient to form a powder blend; and (iv) jet milling the powder blend to deagglomerate at least a portion of any of the microparticles which have agglomerated, while substantially maintaining the size and morphology of the individual microparticles. Jet milling advantageously can eliminate the need for more complicated wet deagglomeration processes, can lower residual moisture and solvent levels in the microparticles (which leads to better stability and handling properties for dry powder formulations), and can improve wettability, suspendability, and content uniformity of dry powder blend formulations.

摘要翻译： 提供用于制备干粉混合物药物制剂的方法，其包含（i）形成包含药剂的微粒; （ii）提供至少一种具有体积平均直径大于微粒的体积平均直径的颗粒形式的赋形剂; （iii）将微粒与赋形剂混合以形成粉末混合物; 和（iv）喷射研磨粉末共混物以使至少一部分具有附聚的任何微粒分解，同时基本保持各个微粒的尺寸和形态。 喷射铣削有利地可以消除对更复杂的湿解聚过程的需要，可以降低微粒中的残留水分和溶剂水平（这导致干粉配方的更好的稳定性和处理性能），并且可以改善润湿性，悬浮性和含量均匀性 干粉混合配方。

公开(公告)号：US20070264343A1

公开(公告)日：2007-11-15

申请号：US11829629

申请日：2007-07-27

申请人： Howard Bernstein ,  Donald Chickering ,  Eric Huang ,  Sridhar Narasimhan ,  Shaina Reese ,  Julie Straub

发明人： Howard Bernstein ,  Donald Chickering ,  Eric Huang ,  Sridhar Narasimhan ,  Shaina Reese ,  Julie Straub

IPC分类号： A61K9/14 ,  A61K31/56 ,  A61K31/7088 ,  A61K38/00 ,  A61K9/10

CPC分类号： A61K9/1647 ,  A61K9/1617

摘要： Pharmaceutical formulations and methods are provided for the sustained delivery of a pharmaceutical agent to a patient by injection. The injectable formulation includes porous microparticles which comprise a pharmaceutical agent and a matrix material, wherein upon injection of the formulation a therapeutically or prophylactically effective amount of the pharmaceutical agent is released from the microparticles for at least 24 hours. A method for making the injectable, sustained release pharmaceutical formulation may include dissolving a hydrophobic matrix material in a volatile solvent to form a first solution; adding a pharmaceutical agent to the first solution to form an emulsion, suspension, or second solution; and removing the volatile solvent from the emulsion, suspension, or second solution to yield porous microparticles which comprise the pharmaceutical agent dispersed, entrapped or encapsulated within the structure of the hydrophobic matrix material.

摘要翻译： 提供药物制剂和方法用于通过注射将药剂持续递送至患者。 可注射制剂包括包含药剂和基质材料的多孔微粒，其中在注射制剂时，治疗或预防有效量的药剂从微粒释放至少24小时。 制备可注射的缓释药物制剂的方法可包括将疏水基质材料溶解在挥发性溶剂中以形成第一溶液; 向第一溶液中加入药剂以形成乳液，悬浮液或第二溶液; 并从乳液，悬浮液或第二溶液中除去挥发性溶剂以产生包含在疏水基质材料的结构内分散，包埋或包封的药剂的多孔微粒。

公开(公告)号：US20050069591A1

公开(公告)日：2005-03-31

申请号：US10950856

申请日：2004-09-27

申请人： Howard Bernstein ,  Donald Chickering ,  Eric Huang ,  Sridhar Narasimhan ,  Shaina Reese ,  Julie Straub

发明人： Howard Bernstein ,  Donald Chickering ,  Eric Huang ,  Sridhar Narasimhan ,  Shaina Reese ,  Julie Straub

IPC分类号： A61K9/16 ,  A61K48/00 ,  A61K9/14 ,  A61K31/56 ,  A61K38/17

CPC分类号： A61K9/1647 ,  A61K9/1617

摘要： Pharmaceutical formulations and methods are provided for the sustained delivery of a pharmaceutical agent to a patient by injection, by oral administration or by topical administration. The injectable formulation includes porous microparticles which comprise a pharmaceutical agent and a matrix material, wherein upon injection of the formulation a therapeutically or prophylactically effective amount of the pharmaceutical agent is released from the microparticles for at least 24 hours. The oral formulation includes porous microparticles which comprise a pharmaceutical agent and a matrix material, wherein a therapeutically or prophylactically effective amount of the pharmaceutical agent is released from the microparticles for at least 2 hours following oral administration. The topical formulation includes porous microparticles which comprise a pharmaceutical agent and a matrix material, wherein a therapeutically or prophylactically effective amount of the pharmaceutical agent is released from the microparticles for at least 2 hours following topical administration.

摘要翻译： 提供药物制剂和方法用于通过注射，口服给药或通过局部给药将药剂持续递送至患者。 可注射制剂包括包含药剂和基质材料的多孔微粒，其中在注射制剂时，治疗或预防有效量的药剂从微粒释放至少24小时。 口服制剂包括包含药剂和基质材料的多孔微粒，其中在口服给药后至少2小时将治疗或预防有效量的药剂从微粒释放至少2小时。 局部制剂包括包含药剂和基质材料的多孔微粒，其中治疗或预防有效量的药剂在局部给药后从微粒释放至少2小时。

公开(公告)号：US20060093677A1

公开(公告)日：2006-05-04

申请号：US11305461

申请日：2005-12-16

申请人： Donald Chickering ,  Shaina Reese ,  Sridhar Narasimhan ,  Julie Straub ,  Howard Bernstein ,  David Altreuter ,  Eric Huang

发明人： Donald Chickering ,  Shaina Reese ,  Sridhar Narasimhan ,  Julie Straub ,  Howard Bernstein ,  David Altreuter ,  Eric Huang

IPC分类号： A61K9/14

CPC分类号： B01D1/18 ,  A61K9/0075 ,  A61K9/145 ,  A61K9/1647 ,  A61K9/1694 ,  B01J2/04

摘要： Methods are provided for making a dry powder blend pharmaceutical formulation comprising (i) forming microparticles which comprise a pharmaceutical agent; (ii) providing at least one excipient in the form of particles having a volume average diameter that is greater than the volume average diameter of the microparticles; (iii) blending the microparticles with the excipient to form a powder blend; and (iv) jet milling the powder blend to deagglomerate at least a portion of any of the microparticles which have agglomerated, while substantially maintaining the size and morphology of the individual microparticles. Jet milling advantageously can eliminate the need for more complicated wet deagglomeration processes, can lower residual moisture and solvent levels in the microparticles (which leads to better stability and handling properties for dry powder formulations), and can improve wettability, suspendability, and content uniformity of dry powder blend formulations.

公开(公告)号：US20070269381A1

公开(公告)日：2007-11-22

申请号：US11834111

申请日：2007-08-06

申请人： Richard Walovitch ,  Howard Bernstein ,  Donald Chickering ,  Julie Straub

发明人： Richard Walovitch ,  Howard Bernstein ,  Donald Chickering ,  Julie Straub

IPC分类号： A61K49/22

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，以在室室内超过5分钟或在心肌中增强超声成像超过一分钟。 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。

公开(公告)号：US20070104656A1

公开(公告)日：2007-05-10

申请号：US11617935

申请日：2006-12-29

申请人： Howard Bernstein ,  Donald Chickering ,  Sarwat Khattak ,  Julie Straub

发明人： Howard Bernstein ,  Donald Chickering ,  Sarwat Khattak ,  Julie Straub

IPC分类号： A61K9/14

CPC分类号： A61K9/1617 ,  A61K9/1647 ,  Y10S514/951 ,  Y10S514/952

摘要： A lipid or other hydrophobic or amphiphilic compound (collectively referred to herein as “hydrophobic compounds”) is integrated into a polymeric matrix for drug delivery to alter drug release kinetics. In embodiments where the drug is water soluble, the drug is released over longer periods of time as compared to release from the polymeric matrix not incorporating the hydrophobic compound into the polymeric material. In contrast to methods in which a surfactant or lipid is added as an excipient, the hydrophobic compound is actually integrated into the polymeric matrix, thereby modifying the diffusion of water into the microparticle and diffusion of solubilized drug out of the matrix. The integrated hydrophobic compound also prolongs degradation of hydrolytically unstable polymers forming the matrix, further delaying release of encapsulated drug.

摘要翻译： 将脂质或其它疏水性或两亲性化合物（本文统称为“疏水化合物”）整合到用于药物递送的聚合物基质中以改变药物释放动力学。 在药物是水溶性的实施方案中，与不将疏水化合物掺入聚合物材料的聚合物基质的释放相比，药物在更长的时间内释放。 与其中加入表面活性剂或脂质作为赋形剂的方法相反，疏水化合物实际上整合到聚合物基质中，从而改变水进入微粒的扩散并将溶解的药物扩散出基质。 整合的疏水化合物还延长了形成基质的水解不稳定聚合物的降解，进一步延缓了包封药物的释放。