公开(公告)号：EP0706375A1

公开(公告)日：1996-04-17

申请号：EP94920205.0

申请日：1994-06-14

申请人： Emisphere Technologies, Inc.

发明人： MILSTEIN, Sam J. ,  KANTOR, Martin L.

IPC分类号： A61K8 ,  A61K9 ,  A61K47 ,  A61Q13 ,  C07C229 ,  C07C233 ,  C07C235 ,  C07C237 ,  C08G69

CPC分类号： A61K9/167 ,  A61K8/025 ,  A61K8/11 ,  A61K8/64 ,  A61K9/1641 ,  A61K2800/652 ,  A61Q13/00 ,  C07C229/42 ,  C07C233/55 ,  C07C233/63 ,  C07C233/87 ,  C07C235/38 ,  C07C235/64 ,  C07C235/84 ,  C07C237/22 ,  C07C2601/02 ,  C07C2601/14 ,  C07C2601/18

摘要： Improved proteinoid carriers and methods for their preparation and use as oral delivery systems for pharmaceutical agents are described. The proteinoid carriers are soluble within selected pH ranges within the gastrointestinal tract and display enhanced stability towards at least one of photolysis or decomposition over time. The proteinoid carriers are prepared from proteinoids having between 2 and 20 amino acids and having a molecular weight of between about 250 and 2400 daltons.

摘要翻译： 描述了改进的蛋白质类载体及其制备和用作药物的口服递送系统的方法。 蛋白质类载体可溶于胃肠道内选定的pH范围内，并随着时间的推移表现出对光解或分解中的至少一种的增强的稳定性。 蛋白质类载体由具有2至20个氨基酸并具有约250至2400道尔顿的分子量的蛋白质类制备。

公开(公告)号：EP0696208A1

公开(公告)日：1996-02-14

申请号：EP94916578.0

申请日：1994-04-22

申请人： Emisphere Technologies, Inc.

发明人： MILSTEIN, Sam J. ,  BARANTSEVITCH, Evgueni N., Apartment 2B ,  SARUBBI, Donald J. ,  LEONE-BAY, Andrea ,  PATON, Duncan R.

IPC分类号： A61K9 ,  A61K31 ,  A61K38 ,  A61K39 ,  A61K45 ,  A61K47 ,  C07B61 ,  C07C229 ,  C07C233 ,  C07C235 ,  C07C237 ,  C07C311

CPC分类号： A61K31/16 ,  A61K9/1617 ,  A61K31/352 ,  A61K31/727 ,  A61K38/212 ,  A61K38/23 ,  A61K38/25 ,  A61K38/27 ,  C07C229/42 ,  C07C233/55 ,  C07C233/63 ,  C07C233/87 ,  C07C235/38 ,  C07C235/64 ,  C07C235/84 ,  C07C237/22 ,  C07C2601/02 ,  C07C2601/14 ,  C07C2601/18

摘要： The present invention relates to an oral drug delivery system, and in particular to modified amino acids and modified amino acid derivatives for use as a delivery system of sensitive agents such as bioactive peptides. The modified amino acids and derivatives can form non-covalent mixtures with active biological agents and in an alternate embodiment can releasably carry active agents. Modified amino acids can also form drug containing microspheres. These mixtures are suitable for oral administration of biologically active agents to animals. Methods for the preparation of such amino acids are also disclosed.

公开(公告)号：EP0696208B1

公开(公告)日：2001-08-22

申请号：EP94916578.1

申请日：1994-04-22

申请人： Emisphere Technologies, Inc.

发明人： MILSTEIN, Sam J. ,  BARANTSEVITCH, Evgueni N., Apartment 2B ,  SARUBBI, Donald J. ,  LEONE-BAY, Andrea ,  PATON, Duncan R.

IPC分类号： A61K9/16

CPC分类号： A61K31/16 ,  A61K9/1617 ,  A61K31/352 ,  A61K31/727 ,  A61K38/212 ,  A61K38/23 ,  A61K38/25 ,  A61K38/27 ,  C07C229/42 ,  C07C233/55 ,  C07C233/63 ,  C07C233/87 ,  C07C235/38 ,  C07C235/64 ,  C07C235/84 ,  C07C237/22 ,  C07C2601/02 ,  C07C2601/14 ,  C07C2601/18

公开(公告)号：EP0781124A1

公开(公告)日：1997-07-02

申请号：EP95939863.0

申请日：1995-10-24

申请人： Emisphere Technologies, Inc.

发明人： MILSTEIN, Sam J. ,  BARANTSEVITCH, Evgueni ,  LEONE-BAY, Andrea ,  WANG, Nai Fang ,  SARUBBI, Donald J. ,  SANTIAGO, Noemi B.

IPC分类号： A61K9 ,  A61K8 ,  A61K31 ,  A61K38 ,  A61K39 ,  A61K45 ,  A61K47 ,  A61Q13 ,  C07C229 ,  C07C233 ,  C07C235 ,  C07C237 ,  C07C279 ,  C07K1 ,  C07K5

CPC分类号： A61K8/64 ,  A61K9/1617 ,  A61K9/1641 ,  A61K9/167 ,  A61K9/2013 ,  A61K31/16 ,  A61K31/28 ,  A61K31/35 ,  A61K31/352 ,  A61K31/715 ,  A61K31/727 ,  A61K38/212 ,  A61K38/23 ,  A61K38/25 ,  A61K38/27 ,  A61K38/28 ,  A61K47/12 ,  A61K47/18 ,  A61K47/183 ,  A61K47/62 ,  A61Q13/00 ,  C07C229/42 ,  C07C233/55 ,  C07C233/63 ,  C07C233/87 ,  C07C235/38 ,  C07C235/54 ,  C07C235/64 ,  C07C235/84 ,  C07C237/22 ,  C07C279/14 ,  C07C2601/02 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2601/18 ,  C07K1/1077 ,  C07K5/06043

摘要： Methods for transporting a biologically active agent across a cellular membrane or a lipid bilayer. A first method includes the steps of: a) providing a biologically active agent which can exist in a native conformational state, a denatured conformational state, and an intermediate conformational state which is reversible to the native state and which is conformationally between the native and denatured states; b) exposing the biologically active agent to a complexing perturbant to reversibly transform the biologically active agent to the intermediate state and to form a transportable supramolecular complex; and c) exposing the membrane or bilayer to the supramolecular complex, to transport the biologically active agent across the membrane or bilayer. The perturbant has a molecular weight between about 150 and about 600 daltons, and contains at least one hydrophilic moiety and at least one hydrophobic moiety. The supramolecular complex comprises the perturbant non-covalently bound or complexed with the biologically active agent. In the present invention, the biologically active agent does not form a microsphere after interacting with the perturbant. A method for preparing an orally administrable biologically active agent comprising steps (a) and (b) above is also provided as are oral delivery compositions. Additionally, mimetics and methods for preparing mimetics are contemplated.

摘要翻译： 用于在细胞膜或脂质双层上输送生物活性剂的方法。 第一种方法包括以下步骤：（a）提供可以以天然构象状态，变性构象状态和中和构象状态存在的生物活性剂，其可天然状态是可逆的，并且其在天然和/ 变性状态 （b）将生物活性剂暴露于络合的扰动剂以将生物活性剂可逆地转化为中间状态并形成可运输的超分子复合物; 和（c）将膜或双层暴露于超分子复合物，以将生物活性剂转运穿过膜或双层。 扰动剂具有约150至约600道尔顿之间的分子量，并且含有至少一个亲水部分和至少一个疏水部分。 超分子复合物包括与生物活性剂非共价结合或络合的扰动剂。 在本发明中，生物活性剂在与扰动剂相互作用后不形成微球体。 也提供了包含上述步骤（a）和（b）的可口服给药的生物活性剂的方法，口服递送组合物也是如此。 另外，可以考虑用于制备模拟物的模拟物和方法。

公开(公告)号：EP0674507A1

公开(公告)日：1995-10-04

申请号：EP94906480.0

申请日：1993-12-21

申请人： Emisphere Technologies, Inc.

发明人： MILSTEIN, Sam J. ,  BARANTSEVITCH, Evgueni N.

IPC分类号： A61K9 ,  A61K47

CPC分类号： A61K9/1658

摘要： Modified hydrolyzed vegetable protein microspheres and methods for their preparation and use as oral delivery systems for pharmaceutical agents are described.

公开(公告)号：EP0784469B1

公开(公告)日：2004-03-24

申请号：EP95938814.1

申请日：1995-10-16

申请人： Emisphere Technologies, Inc.

发明人： SANTIAGO, Noemi B. ,  HAAS, Susan ,  LEONE-BAY, Andrea ,  MILSTEIN, Sam J. ,  BARANTSEVITCH, Evgueni

IPC分类号： A61K39/00 ,  A61K39/385 ,  A61K31/195 ,  A61K9/48 ,  A61K9/14 ,  A61K47/18 ,  A61K9/16 ,  A61K39/39

CPC分类号： A61K31/16 ,  A61K9/1617 ,  A61K31/352 ,  A61K31/727 ,  A61K38/212 ,  A61K38/23 ,  A61K38/25 ,  A61K38/27 ,  A61K39/12 ,  A61K39/39 ,  A61K47/183 ,  A61K2039/5252 ,  A61K2039/542 ,  A61K2039/55544 ,  A61K2039/55555 ,  C07C229/42 ,  C07C233/55 ,  C07C233/63 ,  C07C233/87 ,  C07C235/38 ,  C07C235/64 ,  C07C235/84 ,  C07C237/22 ,  C07C279/14 ,  C07C2601/02 ,  C07C2601/08 ,  C07C2601/14 ,  C07C2601/18 ,  C07K1/1077 ,  C07K5/06043 ,  C12N2720/10034

公开(公告)号：EP0726771B1

公开(公告)日：2002-01-23

申请号：EP94932077.4

申请日：1994-10-24

申请人： Emisphere Technologies, Inc.

发明人： MILSTEIN, Sam J. ,  BARANTSEVITCH, Evgueni N.

IPC分类号： A01N43/16 ,  A61K9/16 ,  A61K31/16 ,  A61K31/35 ,  A61K38/23 ,  A61K38/28

CPC分类号： A61K8/64 ,  A61K8/11 ,  A61K9/1617 ,  A61K9/1641 ,  A61K9/167 ,  A61K31/16 ,  A61K31/28 ,  A61K31/35 ,  A61K31/352 ,  A61K31/727 ,  A61K38/212 ,  A61K38/23 ,  A61K38/25 ,  A61K38/27 ,  A61K38/28 ,  A61Q13/00 ,  C07C229/42 ,  C07C233/55 ,  C07C233/63 ,  C07C233/87 ,  C07C235/38 ,  C07C235/64 ,  C07C235/84 ,  C07C237/22 ,  C07C2601/02 ,  C07C2601/14 ,  C07C2601/18

摘要： Modified amino acids and methods for their preparation and use as oral delivery systems for pharmaceutical agents are described. The modified amino acids are preparable by reacting single amino acids or mixtures of two or more kinds of amino acids with an amino modifying agent such as benzene sulfonyl chloride, benzoyl chloride, and hippuryl chloride. The modified amino acids may form encapsulating microspheres in the presence of the active agent under sphere-forming conditions. Alternatively, the modified amino acids may be used as a carrier by simply mixing the amino acids with the active agent. The preferred acylated amino acid carrier is salicyloyl-phenylalanine. The modified amino acids are particularly useful in delivering biologically active agents, e.g., desferrioxamine, insulin or cromolyn sodium, or other agents which are sensitive to the denaturing conditions of the gastrointestinal tract.

摘要翻译： 描述了修饰的氨基酸及其制备和用作药物的口服递送系统的方法。 修饰的氨基酸可以通过使单个氨基酸或两种或更多种氨基酸的混合物与氨基改性剂如苯磺酰氯，苯甲酰氯和马尿酰氯反应来制备。 修饰的氨基酸可以在球形成条件下在活性剂存在下形成包封微球。 或者，修饰的氨基酸可以通过简单地将氨基酸与活性剂混合而用作载体。 优选的酰化氨基酸载体是水杨酰基苯丙氨酸。 修饰的氨基酸特别可用于递送生物活性剂，例如去铁胺，胰岛素或色甘酸钠或对胃肠道变性条件敏感的其它试剂。

公开(公告)号：EP0726771A1

公开(公告)日：1996-08-21

申请号：EP94932077.0

申请日：1994-10-24

申请人： Emisphere Technologies, Inc.

发明人： MILSTEIN, Sam J. ,  BARANTSEVITCH, Evgueni N.

IPC分类号： A61K47 ,  A61K8 ,  A61K9 ,  A61K31 ,  A61K38 ,  A61P3 ,  A61P5 ,  A61P7 ,  A61P11 ,  A61P39 ,  A61Q13 ,  C07C229 ,  C07C233 ,  C07C235 ,  C07C237

CPC分类号： A61K8/64 ,  A61K8/11 ,  A61K9/1617 ,  A61K9/1641 ,  A61K9/167 ,  A61K31/16 ,  A61K31/28 ,  A61K31/35 ,  A61K31/352 ,  A61K31/727 ,  A61K38/212 ,  A61K38/23 ,  A61K38/25 ,  A61K38/27 ,  A61K38/28 ,  A61Q13/00 ,  C07C229/42 ,  C07C233/55 ,  C07C233/63 ,  C07C233/87 ,  C07C235/38 ,  C07C235/64 ,  C07C235/84 ,  C07C237/22 ,  C07C2601/02 ,  C07C2601/14 ,  C07C2601/18

摘要： Modified amino acids and methods for their preparation and use as oral delivery systems for pharmaceutical agents are described. The modified amino acids are preparable by reacting single amino acids or mixtures of two or more kinds of amino acids with an amino modifying agent such as benzene sulfonyl chloride, benzoyl chloride, and hippuryl chloride. The modified amino acids may form encapsulating microspheres in the presence of the active agent under sphere-forming conditions. Alternatively, the modified amino acids may be used as a carrier by simply mixing the amino acids with the active agent. The preferred acylated amino acid carrier is salicyloyl-phenylalanine. The modified amino acids are particularly useful in delivering biologically active agents, e.g., desferrioxamine, insulin or cromolyn sodium, or other agents which are sensitive to the denaturing conditions of the gastrointestinal tract.

公开(公告)号：EP0696192A1

公开(公告)日：1996-02-14

申请号：EP94915419.0

申请日：1994-04-22

申请人： Emisphere Technologies, Inc.

发明人： MILSTEIN, Sam J. ,  BARANTSEVITCH, Evgueni Apartment 2B

IPC分类号： A61K9 ,  A61K47

CPC分类号： A61K9/1658

摘要： Modified hydrolyzed vegetable protein microspheres and methods for their preparation and use as oral delivery systems for pharmaceutical agents are described. Figure 1 illustrates levels of glucose detected in rat serum taken from rats orally administered microsphere encapsulated insulin or raw (unencapsulated) insulin as described in example 4. Figure 2 illustrates rat serum calcium levels after oral administration of calcitonin and calcitonin encapsulated in the vegetable protein microsphere of the present invention as described in example 5. Figure 3 illustrates an HPLC trace of the hydrolyzed vegetable protein before modification. Figure 4 illustrates the change in the hydrolyzed vegetable protein after modification with benzene sulfonyl chloride in an HPLC trace.