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1. 发明授权

US5616334A Low toxicity drug-lipid systems 失效
标题翻译：低毒性药物 - 脂质体系
公开(公告)号：US5616334A
公开(公告)日：1997-04-01
申请号：US430699
申请日：1995-04-28
申请人： Andrew S. Janoff , Lawrence Boni , Thomas D. Madden , Pieter R. Cullis , Robert P. Lenk , John J. Kearns , Anthony G. Durning , Robert Klimchak , Joel Portnoff
发明人： Andrew S. Janoff , Lawrence Boni , Thomas D. Madden , Pieter R. Cullis , Robert P. Lenk , John J. Kearns , Anthony G. Durning , Robert Klimchak , Joel Portnoff
IPC分类号： A61K9/127 , A61K9/16 , A01N25/32 , A01N57/26 , A61K31/685
CPC分类号： A61K9/127 , A61K31/7048 , A61K47/48053 , A61K9/1277 , A61K9/1617 , G03B2227/325 , Y10T428/2984
摘要： Methods and compositions are described for nonliposomal lipid complexes in association with toxic hydrophobic drugs such as the polyene antibiotic amphotericin B. Lipid compositions are preferably a combination of the phospholipids dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) in about a 7:3 mole ratio. The lipid complexes contain a bioactive agent, and may be made by a number of procedures, at high drug:lipid ratios. These compositions of high drug:lipid complexes (HDLCs) may be administered to mammals such as humans for the treatment of infections, with substantially equivalent or greater efficacy and reduced drug toxicities as compared to the drugs in their free form. Also disclosed is a novel liposome-loading procedure, which may also be used in the formation of the HDLCs.
摘要翻译：描述了与毒性疏水性药物如多烯抗生素两性霉素B相关的非脂质体脂质复合物的方法和组合物。脂质组合物优选以约7:3摩尔比组合磷脂二肉豆蔻酰磷脂酰胆碱（DMPC）和二肉豆蔻酰磷脂酰甘油（DMPG）。脂质复合物含有生物活性剂，并且可以以高药物：脂质比例通过多种方法制备。与其游离形式的药物相比，高药物：脂质复合物（HDLC）的这些组合物可以施用于哺乳动物例如人以治疗感染，具有基本相同或更大的功效和降低的药物毒性。还公开了一种新的脂质体加载程序，其也可用于HDLC的形成。

2. 发明授权

US06406713B1 Methods of preparing low-toxicity drug-lipid complexes 失效
标题翻译：制备低毒药物 - 脂质复合物的方法
公开(公告)号：US06406713B1
公开(公告)日：2002-06-18
申请号：US08430661
申请日：1995-04-28
申请人： Andrew S. Janoff , Thomas D. Madden , Pieter R. Cullis , John J. Kearns , Anthony G. Durning
发明人： Andrew S. Janoff , Thomas D. Madden , Pieter R. Cullis , John J. Kearns , Anthony G. Durning
IPC分类号： A61K9127
CPC分类号： A61K9/127 , A61K9/1277 , A61K9/1617 , A61K31/7048 , A61K47/544 , G03B2227/325 , Y10T428/2984
摘要： Methods and compositions are described for nonliposomal lipid complexes in association with toxic hydrophobic drugs such as the polyene antibiotic amphotericin B. Lipid compositions are preferably a combination of the phospholipids dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG) in about a 7:3 mole ratio. The lipid complexes contain a bioactive agent, and may be made by a number of procedures, at high drug:lipid ratios. These compositions of high drug:lipid complexes (HDLCs) may be administered to mammals such as humans for the treatment of infections, with substantially equivalent or greater efficacy and reduced drug toxicities as compared to the drugs in their free form. Also disclosed is a novel liposome-loading procedure, which may also be used in the formation of the HDLCs.
摘要翻译：描述了与毒性疏水性药物如多烯抗生素两性霉素B相关的非脂质体脂质复合物的方法和组合物。脂质组合物优选以约7:3摩尔比组合磷脂二肉豆蔻酰磷脂酰胆碱（DMPC）和二肉豆蔻酰磷脂酰甘油（DMPG）。脂质复合物含有生物活性剂，并且可以以高药物：脂质比例通过多种方法制备。与其游离形式的药物相比，高药物：脂质复合物（HDLC）的这些组合物可以施用于哺乳动物例如人以治疗感染，具有基本相同或更大的功效和降低的药物毒性。还公开了一种新的脂质体加载程序，其也可用于HDLC的形成。

3. 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。

4. 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。

5. 发明授权

US5578320A Method of dehydrating liposomes using protective sugars 失效
标题翻译：使用保护性糖脱水脂质体的方法
公开(公告)号：US5578320A
公开(公告)日：1996-11-26
申请号：US22819
申请日：1993-02-24
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

US4880635A Dehydrated liposomes 失效
标题翻译：脱水脂质体
公开(公告)号：US4880635A
公开(公告)日：1989-11-14
申请号：US759419
申请日：1985-07-26
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。

7. 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。

8. 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。

9. 发明授权

US5885613A Bilayer stabilizing components and their use in forming programmable fusogenic liposomes 失效
标题翻译：双层稳定组分及其在形成可编程融合脂质体中的应用
公开(公告)号：US5885613A
公开(公告)日：1999-03-23
申请号：US485608
申请日：1995-06-07
申请人： John W. Holland , Thomas D. Madden , Pieter R. Cullis
发明人： John W. Holland , Thomas D. Madden , Pieter R. Cullis
IPC分类号： A61K9/127 , A61K47/18 , B01J13/02
CPC分类号： A61K9/1272 , Y10T428/2984
摘要： The present invention provides a fusogenic liposome comprising a lipid capable of adopting a non-lamellar phase, yet capable of assuming a bilayer structure in the presence of a bilayer stabilizing component; and a bilayer stabilizing component reversibly associated with the lipid to stabilize the lipid in a bilayer structure. Such fusogenic liposomes are extremely advantageous because the rate at which they become fusogenic can be not only predetermined, but varied as required over a time scale ranging from minutes to days. Control of liposome fusion can be achieved by modulating the chemical stability and/or exchangeability of the bilayer stabilizing component(s). The fusogenic liposomes of the present invention can be used to deliver drugs, peptide, proteins, RNA, DNA or other bioactive molecules to the target cells of interest.
摘要翻译：本发明提供了一种融合脂质体，其包含能够采用非层状相的脂质，但能够在双层稳定成分存在下具有双层结构; 和与脂质可逆地相关的双层稳定组分以稳定双层结构中的脂质。这种融合脂质体是非常有利的，因为它们变得融合的速率不仅可以预先确定，而且可以在数分钟到数天的时间范围内根据需要而变化。脂质体融合的控制可通过调节双层稳定化组分的化学稳定性和/或可交换性来实现。本发明的融合脂质体可用于将药物，肽，蛋白质，RNA，DNA或其他生物活性分子递送至感兴趣的靶细胞。

10. 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。

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