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1. 发明申请

US20110256175A1 AMINO LIPIDS AND METHODS FOR THE DELIVERY OF NUCLEIC ACIDS 有权
标题翻译：氨基酸和提供核酸的方法
公开(公告)号：US20110256175A1
公开(公告)日：2011-10-20
申请号：US13123307
申请日：2009-10-09
申请人： Michael J. Hope , Sean C. Semple , Jianxin Chen , Thomas D. Madden , Pieter R. Cullis , Marco A. Ciufolini , Barbara Low Shoud Mui
发明人： Michael J. Hope , Sean C. Semple , Jianxin Chen , Thomas D. Madden , Pieter R. Cullis , Marco A. Ciufolini , Barbara Low Shoud Mui
IPC分类号： A61K39/12 , C07D319/06 , C07D405/06 , C07D413/06 , A61K47/44 , A61K31/7088 , A61K48/00 , A61K31/713 , C12N5/071 , C12N15/63 , A61K39/02 , A61K39/00 , A61P37/04 , A61P35/00 , A61P31/12 , A61P31/04 , A61P33/00 , C07D317/28
CPC分类号： A61K47/22 , A61K9/1271 , A61K31/713 , A61K39/39 , A61K2039/55511 , C07D317/28 , C07D319/06
摘要： The present invention provides superior compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of specific target proteins at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.
摘要翻译：本发明提供优异的用于将治疗剂递送至细胞的组合物和方法。特别地，这些包括提供核酸的有效包封的新型脂质和核酸 - 脂质颗粒，并将包封的核酸有效地递送到细胞体内。本发明的组合物是高度有效的，从而允许在相对低的剂量下有效击倒特异性靶蛋白。此外，与本领域已知的组合物和方法相比，本发明的组合物和方法毒性低，并提供更大的治疗指数。

2. 发明授权

US5837279A Encapsulation of ionizable agents in liposomes 失效
标题翻译：电离剂在脂质体中的封装
公开(公告)号：US5837279A
公开(公告)日：1998-11-17
申请号：US450831
申请日：1995-05-25
申请人： Andrew S. Janoff , Pieter R. Cullis , Marcel B. Bally , Michael W. Fountain , Richard S. Ginsberg , Michael J. Hope , Thomas D. Madden , Hugh P. Schieren , Regina L. Jablonski
发明人： Andrew S. Janoff , Pieter R. Cullis , Marcel B. Bally , Michael W. Fountain , Richard S. Ginsberg , Michael J. Hope , Thomas D. Madden , Hugh P. Schieren , Regina L. Jablonski
IPC分类号： C07D475/08 , A61K9/00 , A61K9/10 , A61K9/127 , A61K31/435 , A61K31/505 , A61K31/519 , A61K31/70 , A61K31/7028 , A61K31/7034 , A61K31/704 , A61K31/7042 , A61K31/7052 , A61K31/7064 , A61K31/7068 , A61K31/715 , A61K45/00 , A61K45/08 , A61K47/26 , A61K47/36 , A61K47/48 , A61P35/00 , B01J13/02 , B01J13/04 , C07D519/00 , C07H15/252 , C07H19/09
CPC分类号： A61K9/1277 , A61K9/1271 , A61K9/1278
摘要： Dehydrated liposomes are prepared by drying liposome preparations under reduced pressure in the presence of one or more protective sugars, e.g., the disaccharides trehalose and sucrose. Preferably, the protective sugars are present at both the inside and outside surfaces of the liposome membranes. Freezing of the liposome preparation prior to dehydration is optional. Alternatively, the protective sugar can be omitted if: (1) the liposomes are of the type which have multiple lipid layers; (2) the dehydration is done without prior freezing; and (3) the dehydration is performed to an end point which results in sufficient water being left in the preparation (e.g., at least 12 moles water/mole lipid) so that the integrity of a substantial portion of the multiple lipid layers is retained upon rehydration. Concentration gradients capable of generating transmembrane potentials can be created across the liposome membranes either before or after dehydration, and the transmembrane potentials resulting from these gradients can be used to load charged materials, e.g., drugs, into the liposomes.
摘要翻译：通过在一种或多种保护性糖例如二糖类海藻糖和蔗糖的存在下，减压干燥脂质体制剂来制备脱水脂质体。优选地，保护性糖存在于脂质体膜的内表面和外表面。在脱水之前冻干脂质体制剂是任选的。或者，如果：（1）脂质体是具有多个脂质层的类型，则可以省略保护性糖; （2）脱水是在没有预先冻结的情况下进行的; 和（3）脱水进行到终点，导致制剂中留有足够的水（例如，至少12摩尔水/摩尔脂质），使得大部分多脂质层的完整性保持在补液。可以在脱水之前或之后在脂质体膜上产生能够产生跨膜电位的浓度梯度，并且由这些梯度产生的跨膜电位可用于将带电材料（例如药物）加载到脂质体中。

3. 发明授权

US5736155A Encapsulation of antineoplastic agents in liposomes 失效
标题翻译：抗肿瘤剂在脂质体中的封装
公开(公告)号：US5736155A
公开(公告)日：1998-04-07
申请号：US461212
申请日：1995-06-05
申请人： Marcel B. Bally , Pieter R. Cullis , Michael J. Hope , Thomas D. Madden , Lawrence D. Mayer
发明人： Marcel B. Bally , Pieter R. Cullis , Michael J. Hope , Thomas D. Madden , Lawrence D. Mayer
IPC分类号： A61K9/127 , A61K47/48
CPC分类号： A61K9/1278 , A61K9/1271 , A61K9/1277
摘要： Methods for encapsulating ionizable antineoplastic agents in liposomes using transmembrane potentials are provided. Trapping efficiencies approaching 100% and rapid loading are readily achieved. Dehydration protocols which allow liposomes to be conveniently used in the administration of antineoplastic agents in a clinical setting are also provided. In accordance with other aspects of the invention, transmembrane potentials are used to reduce the rate of release of ionizable drugs from liposomes.
摘要翻译：提供了使用跨膜电位将可电离抗肿瘤剂包封在脂质体中的方法。捕获效率接近100％，快速加载容易实现。还提供允许脂质体在临床环境中方便地用于施用抗肿瘤剂的脱水方案。根据本发明的其他方面，使用跨膜电位来降低可离子化药物从脂质体释放的速率。

4. 发明申请

US20100041152A1 METHODS FOR ENCAPSULATING PLASMIDS IN LIPID BILAYERS 审中-公开
标题翻译：用于在脂质双层中包封PLASMIDS的方法
公开(公告)号：US20100041152A1
公开(公告)日：2010-02-18
申请号：US12404837
申请日：2009-03-16
申请人： Jeffery J. Wheeler , Michael J. Hope , Pieter R. Cullis , Marcel B. Bally
发明人： Jeffery J. Wheeler , Michael J. Hope , Pieter R. Cullis , Marcel B. Bally
IPC分类号： C12N15/88 , C12N15/63
CPC分类号： C12N15/88 , A61K9/1272 , Y10S436/829 , Y10S514/851 , Y10S977/80 , Y10S977/907
摘要： Plasmid-lipid particles which are useful for transfection of cells in vitro or in vivo are described. The particles can be formed using either detergent dialysis methods or methods which utilize organic solvents. The particles are typically 65-85 nm, fully encapsulate the plasmid and are serum-stable.
摘要翻译：描述了可用于体外或体内转染细胞的质粒 - 脂质颗粒。可以使用洗涤剂透析方法或利用有机溶剂的方法形成颗粒。颗粒通常为65-85nm，完全包封质粒并且是血清稳定的。

5. 发明授权

US5922350A Methods of dehydrating, storing and rehydrating liposomes 失效
标题翻译：脱脂，储存和再水化脂质体的方法
公开(公告)号：US5922350A
公开(公告)日：1999-07-13
申请号：US876938
申请日：1997-06-16
申请人： Andrew S. Janoff , Pieter R. Cullis , Marcel B. Bally , Michael W. Fountain , Richard S. Ginsberg , Michael J. Hope , Thomas D. Madden , Hugh P. Schieren , Regina L. Jablonski
发明人： Andrew S. Janoff , Pieter R. Cullis , Marcel B. Bally , Michael W. Fountain , Richard S. Ginsberg , Michael J. Hope , Thomas D. Madden , Hugh P. Schieren , Regina L. Jablonski
IPC分类号： C07D475/08 , A61K9/00 , A61K9/10 , A61K9/127 , A61K31/435 , A61K31/505 , A61K31/519 , A61K31/70 , A61K31/7028 , A61K31/7034 , A61K31/704 , A61K31/7042 , A61K31/7052 , A61K31/7064 , A61K31/7068 , A61K31/715 , A61K45/00 , A61K45/08 , A61K47/26 , A61K47/36 , A61K47/48 , A61P35/00 , B01J13/02 , B01J13/04 , C07D519/00 , C07H15/252 , C07H19/09
CPC分类号： A61K9/1277 , A61K9/1271 , A61K9/1278
摘要： Dehydrated liposomes are prepared by drying liposome preparations under reduced pressure in the presence of one or more protective sugars, e.g., the disaccharides trehalose and sucrose. Preferably, the protective sugars are present at both the inside and outside surfaces of the liposome membranes. Freezing of the liposome preparation prior to dehydration is optional. Alternatively, the protective sugar can be omitted if: (1) the liposomes are of the type which have multiple lipid layers; (2) the dehydration is done without prior freezing; and (3) the dehydration is performed to an end point which results in sufficient water being left in the preparation (e.g., at least 12 moles water/mole lipid) so that the integrity of a substantial portion of the multiple lipid layers is retained upon rehydration. Concentration gradients capable of generating transmembrane potentials can be created across the liposome membranes either before or after dehydration, and the transmembrane potentials resulting from these gradients can be used to load charged materials, e.g., drugs, into the liposomes.
摘要翻译：通过在一种或多种保护性糖例如二糖类海藻糖和蔗糖的存在下，减压干燥脂质体制剂来制备脱水脂质体。优选地，保护性糖存在于脂质体膜的内表面和外表面。在脱水之前冻干脂质体制剂是任选的。或者，如果：（1）脂质体是具有多个脂质层的类型，则可以省略保护性糖; （2）脱水是在没有预先冻结的情况下进行的; 和（3）脱水进行到终点，导致制剂中留有足够的水（例如，至少12摩尔水/摩尔脂质），使得大部分多脂质层的完整性保持在补液。可以在脱水之前或之后在脂质体膜上产生能够产生跨膜电位的浓度梯度，并且由这些梯度产生的跨膜电位可用于将带电材料（例如药物）加载到脂质体中。

6. 发明授权

US5204112A Induction of asymmetry in vesicles 失效
公开(公告)号：US5204112A
公开(公告)日：1993-04-20
申请号：US61837
申请日：1987-06-12
申请人： Michael J. Hope , Pieter R. Cullis
发明人： Michael J. Hope , Pieter R. Cullis
IPC分类号： A61K9/127 , A61K9/133
CPC分类号： A61K9/1277 , A61K9/1278 , Y10S436/829 , Y10T428/2984
摘要： Methods are described for controlling the transbilayer distribution of ionizable lipids and proteins in vesicles. Control of the ion gradient of the exterior bathing medium in relation to that of the interior entrapped aqueous compartment of the vesicles induces migration of ionizable lipids or proteins to one or the other of the monolayers comprising the bilayer. This can result in an asymmetric distribution of the ionizable lipid or ionizable protein. The basic ionizable lipids, such as stearylamine and sphingosine, are sequestered into the inner monolayer when the liposome interior is acidic relative to the liposome exterior. Conversely, acidic ionizable lipids such as oleic acid and stearic acid are sequestered into the inner monolayer when the liposome interior is basic relative to the liposome exterior bathing solution. Likewise, phospholipids such as phosphatidylglycerol, phosphatidylinositol, and cardiolipin may also be sequestered into the inner monolayer in response to a relatively acidic exterior medium. Such vesicles may contain bioactive agents and may be administered to mammals including humans.

7. 发明授权

US08021686B2 Lipid-encapsulated polyanionic nucleic acid 有权
标题翻译：脂质包封的聚阴离子核酸
公开(公告)号：US08021686B2
公开(公告)日：2011-09-20
申请号：US12028696
申请日：2008-02-08
申请人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter R. Cullis , Peter Scherrer , Dan Debeyer
发明人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter R. Cullis , Peter Scherrer , Dan Debeyer
IPC分类号： A61K9/127 , A61K31/70 , C12N11/02 , C12N15/88 , C07H21/00
CPC分类号： A61K9/1277 , A61K9/1272 , Y10T428/2984
摘要： Methods for the preparation of a lipid-nucleic acid composition are provided. According to the methods, a mixture of lipids containing a protonatable or deprotonatable lipid, for example an amino lipid and a lipid such as a PEG- or Polyamide oligomer-modified lipid is combined with a buffered aqueous solution of a charged therapeutic agent, for example polyanionic nucleic acids, to produce particles in which the therapeutic agent is encapsulated in a lipid vesicle. Surface charges on the lipid particles are at least partially neutralized to provide surface-neutralized lipid-encapsulated compositions of the therapeutic agents. The method permits the preparation of compositions with high ratios of therapeutic agent to lipid and with encapsulation efficiencies in excess of 50%.
摘要翻译：提供了制备脂质 - 核酸组合物的方法。根据该方法，将包含可质子化或不可质令排泄的脂质，例如氨基脂质和脂质如PEG-或聚酰胺低聚物修饰的脂质的脂质混合物与带电疗法的缓冲水溶液组合，例如聚阴离子核酸，以产生其中治疗剂包封在脂质囊泡中的颗粒。脂质颗粒上的表面电荷至少部分被中和，以提供治疗剂的表面中和的脂质包封的组合物。该方法允许制备具有高比例的治疗剂与脂质并且包封效率超过50％的组合物。

8. 发明申请

US20110117125A1 COMPOSITIONS AND METHODS FOR THE DELIVERY OF NUCLEIC ACIDS 审中-公开
标题翻译：用于提供核酸的组合物和方法
公开(公告)号：US20110117125A1
公开(公告)日：2011-05-19
申请号：US12811195
申请日：2008-12-31
申请人： Michael J. Hope , Sean C. Semple , Jianxin Chen , Thomas D. Madden , Barbara Mui , Pieter R. Cullis , Marco A. Ciufolini , Kim F. Wong , Muthiah Manoharan , Rajeev G. Kallanthottathil
发明人： Michael J. Hope , Sean C. Semple , Jianxin Chen , Thomas D. Madden , Barbara Mui , Pieter R. Cullis , Marco A. Ciufolini , Kim F. Wong , Muthiah Manoharan , Rajeev G. Kallanthottathil
IPC分类号： A61K39/12 , A61K39/00 , A61K39/02 , C12N5/02 , A61K31/7088 , A61P37/00 , C07D295/12 , C07D241/04 , C07D317/00 , C11C3/00 , C07C229/00 , C07C229/30 , C07C321/00
CPC分类号： A61K31/7088 , A61K9/127 , A61K9/1275 , C07C215/10 , C07C217/08 , C07C217/28 , C07C219/08 , C07C229/12 , C07C271/12 , C07C323/25 , C07D317/28
摘要： The present invention provides compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of specific target protein at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.
摘要翻译：本发明提供了将治疗剂递送至细胞的组合物和方法。特别地，这些包括提供核酸的有效包封的新型脂质和核酸 - 脂质颗粒，并将包封的核酸有效地递送到细胞体内。本发明的组合物是高度有效的，从而允许以相对低的剂量有效击倒特异性靶蛋白。此外，与本领域已知的组合物和方法相比，本发明的组合物和方法毒性低，并提供更大的治疗指数。

9. 发明授权

US5376452A Induction of asymmetry in vesicles 失效
标题翻译：诱导囊泡不对称
公开(公告)号：US5376452A
公开(公告)日：1994-12-27
申请号：US132711
申请日：1993-10-06
申请人： Michael J. Hope , Pieter R. Cullis
发明人： Michael J. Hope , Pieter R. Cullis
IPC分类号： A61K9/127 , B01J13/06
CPC分类号： A61K9/1277 , A61K9/1278 , Y10S436/829 , Y10T428/2984
摘要： Methods are described for controlling the transbilayer distribution of ionizable lipids and proteins in vesicles. Control of the ion gradient of the exterior bathing medium in relation to that of the interior entrapped aqueous compartment of the vesicles induces migration of ionizable lipids or proteins to one or the other of the monolayers comprising the bilayer. This can result in an asymmetric distribution of the ionizable lipid or ionizable protein. The basic ionizable lipids, such as stearylamine and sphingosine, are sequestered into the inner monolayer when the liposome interior is acidic relative to the liposome exterior. Conversely, acidic ionizable lipids such as oleic acid and stearic acid are sequestered into the inner monolayer when the liposome interior is basic relative to the liposome exterior bathing solution. Likewise, phospholipids such as phosphatidylglycerol, phosphatidylinositol, and cardiolipin may also be sequestered into the inner monolayer in response to a relatively acidic exterior medium. Such vesicles may contain bioactive agents and may be administered to mammals including humans.
摘要翻译：描述了用于控制囊泡中可离子化脂质和蛋白质的跨膜分布的方法。外部洗浴介质的离子梯度的控制相对于囊泡的内部包封的水分区域的离子梯度的诱导将可电离的脂质或蛋白质迁移到包含双层的单层或另一个单层中。这可导致可电离脂质或可电离蛋白质的不对称分布。当脂质体内部相对于脂质体外部呈酸性时，碱性可离子化的脂质如硬脂胺和鞘氨醇被隔离在内层中。相反，当脂质体内部相对于脂质体外部洗浴溶液是碱性时，酸性可离子化的脂质如油酸和硬脂酸被螯合到内部单层中。同样地，磷酸酯如磷脂酰甘油，磷脂酰肌醇和心磷脂也可以响应于相对酸性的外部培养基而被隔离到内单层中。这样的囊泡可以含有生物活性剂并且可以施用于包括人的哺乳动物。

10. 发明授权

US09139554B2 Amino lipids and methods for the delivery of nucleic acids 有权
标题翻译：氨基脂质和递送核酸的方法
公开(公告)号：US09139554B2
公开(公告)日：2015-09-22
申请号：US13123307
申请日：2009-10-09
申请人： Michael J. Hope , Sean C. Semple , Jianxin Chen , Thomas D. Madden , Pieter R. Cullis , Marco A. Ciufolini , Barbara Low Shoud Mui
发明人： Michael J. Hope , Sean C. Semple , Jianxin Chen , Thomas D. Madden , Pieter R. Cullis , Marco A. Ciufolini , Barbara Low Shoud Mui
IPC分类号： C07D317/28 , A61K9/127 , C07D319/06
CPC分类号： A61K47/22 , A61K9/1271 , A61K31/713 , A61K39/39 , A61K2039/55511 , C07D317/28 , C07D319/06
摘要： The present invention provides superior compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of specific target proteins at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.
摘要翻译：本发明提供优异的用于将治疗剂递送至细胞的组合物和方法。特别地，这些包括提供核酸的有效包封的新型脂质和核酸 - 脂质颗粒，并将包封的核酸有效地递送到细胞体内。本发明的组合物是高度有效的，从而允许在相对低的剂量下有效击倒特异性靶蛋白。此外，与本领域已知的组合物和方法相比，本发明的组合物和方法毒性低，并提供更大的治疗指数。

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