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：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：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：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：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：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：US20050209099A1

公开(公告)日：2005-09-22

申请号：US11142917

申请日：2005-06-02

申请人： Donald Chickering ,  Sridhar Narasimhan ,  David Altreuter ,  Paul Kopesky ,  Mark Keegan ,  Julie Straub ,  Howard Bernstein

发明人： Donald Chickering ,  Sridhar Narasimhan ,  David Altreuter ,  Paul Kopesky ,  Mark Keegan ,  Julie Straub ,  Howard Bernstein

IPC分类号： A61K9/16 ,  B01D1/18 ,  B01J2/04 ,  F26B3/12 ,  F26B17/10 ,  B01J23/00

CPC分类号： F26B17/102 ,  A61K9/1647 ,  A61K9/1688 ,  B01D1/18 ,  B01J2/04 ,  F26B3/12

摘要： Methods and apparatus are provided for making particles comprising: (a) spraying an emulsion, solution, or suspension, which comprises a solvent and a bulk material (e.g., a pharmaceutical agent), through an atomizer and into a primary drying chamber, having a drying gas flowing therethrough, to form droplets comprising the solvent and bulk material dispersed in the drying gas; (b) evaporating, in the primary drying chamber, at least a portion of the solvent into the drying gas to solidify the droplets and form particles dispersed in drying gas; and (c) flowing the particles and at least a portion of the drying gas through a jet mill to deagglomerate or grind the particles. By coupling spray drying with “in-line” jet milling, a single step process is created from two separate unit operations, and an additional collection step is advantageously eliminated. The one-step, in-line process has further advantages in time and cost of processing.

摘要翻译： 提供了用于制备颗粒的方法和装置，包括：（a）通过雾化器喷雾包含溶剂和散装材料（例如药剂）的乳液，溶液或悬浮液，并进入初级干燥室，其具有 干燥气体流过其中以形成包含分散在干燥气体中的溶剂和散装材料的液滴; （b）在初级干燥室中将至少一部分溶剂蒸发到干燥气体中以固化液滴并形成分散在干燥气体中的颗粒; 和（c）使颗粒和至少一部分干燥气体流过喷射磨机以使颗粒解聚或研磨。 通过将喷雾干燥与“直列式”喷射研磨相结合，由两个单独的单元操作产生单步骤，有利地消除了另外的收集步骤。 一步一步的在线过程在处理时间和成本方面具有进一步的优势。

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：US20050058710A1

公开(公告)日：2005-03-17

申请号：US10928886

申请日：2004-08-27

申请人： Julie Straub ,  David Altreuter ,  Howard Bernstein ,  Donald Chickering ,  Sarwat Khattak ,  Greg Randall

发明人： Julie Straub ,  David Altreuter ,  Howard Bernstein ,  Donald Chickering ,  Sarwat Khattak ,  Greg Randall

IPC分类号： A61K9/16 ,  A61K9/26 ,  A61K9/14

CPC分类号： A61K9/1635 ,  A61K9/1611 ,  A61K9/1623 ,  A61K9/1688 ,  A61K9/1694

摘要： Drugs, especially low aqueous solubility drugs, are provided in a porous matrix form, preferably microparticles, which enhances dissolution of the drug in aqueous media. The drug matrices preferably are made using a process that includes (i) dissolving a drug, preferably a drug having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution and hydrophilic or hydrophobic excipients that stabilize the drug and inhibit crystallization, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug. Hydrophobic or hydrophilic excipients may be selected to stabilize the drug in crystalline form by inhibiting crystal growth or to stabilize the drug in amorphous form by preventing crystallization. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug. In a preferred embodiment, microparticles of the porous drug matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.

摘要翻译： 药物，特别是低含水溶性药物以多孔基质形式提供，优选微粒，其增强药物在水性介质中的溶解。 药物基质优选使用以下方法制备，所述方法包括（i）将挥发性溶剂中的药物（优选为低溶解度的药物）溶解以形成药物溶液，（ii）将至少一种成孔剂与药物溶液 以形成稳定药物并抑制结晶的乳液，悬浮液或第二溶液和亲水或疏水赋形剂，和（iii）从乳液，悬浮液或第二溶液中除去挥发性溶剂和成孔剂以产生多孔基质 药物。 可以选择疏水性或亲水性赋形剂，以通过抑制晶体生长来稳定药物的结晶形式，或者通过防止结晶来稳定药物的无定形形式。 成孔剂可以是与药物溶剂或挥发性固体化合物，优选挥发性盐不混溶的挥发性液体。 在优选的实施方案中，使用喷雾干燥来除去溶剂和成孔剂。 与药物的无孔基质形式相比，得到的多孔基质在给予患者后具有更快的溶解速率。 在优选的实施方案中，多孔药物基质的微粒用水性介质重新配制，并肠胃外给药，或使用标准技术加工成用于口服给药的片剂或胶囊。