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1. 发明授权

US06858225B2 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：US06858225B2
公开(公告)日：2005-02-22
申请号：US09895480
申请日：2001-06-29
申请人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter Cullis , Peter Scherrer , Dan Debeyer
发明人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter Cullis , Peter Scherrer , Dan Debeyer
IPC分类号： A61K9/127 , A61K9/50 , A61K31/7105 , A61K31/711 , A61K47/28 , A61K47/44 , A61K48/00 , A61K31/70 , C07H21/00 , C12N11/02 , C12N15/88
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。

2. 发明授权

US07341738B2 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：US07341738B2
公开(公告)日：2008-03-11
申请号：US10658947
申请日：2003-09-09
申请人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter Cullis , Peter Scherrer , Dan Debeyer
发明人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter 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。

3. 发明申请

US20120114831A1 HIGH EFFICIENCY ENCAPSULATION OF CHARGED THERAPEUTIC AGENTS IN LIPID VESICLES 审中-公开
标题翻译：脂质体内充电治疗药物的高效包扎
公开(公告)号：US20120114831A1
公开(公告)日：2012-05-10
申请号：US13195692
申请日：2011-08-01
申请人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter Cullis , Peter Scherrer , Dan Debeyer
发明人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter Cullis , Peter Scherrer , Dan Debeyer
IPC分类号： B05D3/10
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。

4. 发明申请

US20080200417A1 HIGH EFFICIENCY ENCAPSULATION OF CHARGED THERAPEUTIC AGENTS IN LIPID VESICLES 有权
标题翻译：脂质体内充电治疗药物的高效包扎
公开(公告)号：US20080200417A1
公开(公告)日：2008-08-21
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 Cullis , Peter Scherrer , Dan Debeyer
发明人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter Cullis , Peter Scherrer , Dan Debeyer
IPC分类号： A61K31/70 , C07H21/00 , C12N15/87 , A61P43/00
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。

5. 发明授权

US06835395B1 Composition containing small multilamellar oligodeoxynucleotide-containing lipid vesicles 失效
标题翻译：含有小的多层寡脱氧核苷酸的脂质囊泡的组合物
公开(公告)号：US06835395B1
公开(公告)日：2004-12-28
申请号：US09654373
申请日：2000-09-01
申请人： Sean C. Semple , Sandra K. Klimuk , Troy O. Harasym , Nancy Dos Santos , Steven M. Ansell , Pieter R Cullis , Michael J. Hope , Peter Scherrer , Deirdre McIntosh , Kim F. Wong , Norbert Maurer
发明人： Sean C. Semple , Sandra K. Klimuk , Troy O. Harasym , Nancy Dos Santos , Steven M. Ansell , Pieter R Cullis , Michael J. Hope , Peter Scherrer , Deirdre McIntosh , Kim F. Wong , Norbert Maurer
IPC分类号： A61K9127
CPC分类号： A61K9/1272 , Y10T428/2984
摘要： Lipidic compositions with superior characteristics for in vivo delivery of oligodeoxynucleotides (ODN) can easily and efficiently be made in the form of small multilamellar vesicles. The compositions contain a population of nucleic acid-containing lipid vesicles in a liquid carrier, and at least a portion of the lipid vesicles are small multilamellar vesicles. The small multilamellar vesicles are made from a lipid component including 20-30 mol % of an ionizable amino lipid such as DODAP, and a steric barrier lipid such as PEG-CerC14; and an oligodeoxynucleotide contained in the lumen or interlamellar spaces of the small multilamellar vesicles. The ODN and lipid components are preferably present in the small multilamellar vesicles in a mole ratio of from 0.15 to 0.25. The compositions of the invention can be made by preparing two solutions: a lipid mixture with 20-30 mol % of the ionizable amino lipid, the steric barrier lipid and additional lipid components selected from among neutral lipids and sterols in an ethanolic solvent; and a solution of oligodeoxynucleotide in an aqueous solvent having a pH at which the ionizable amino lipid is positively charged. The lipid mixture is added to the solution of oligodeoxynucleotide to form a mixture containing lipid vesicles which is then massed through a filter to produce sized lipid vesicles in a solution containing ethanol. The ethanol is then removed, for example by dialysis. Then, the pH of the solution surrounding the sized lipid vesicles is increased to reduce the net positive charge on the exterior of the sized lipid vesicles.
摘要翻译：寡脱氧核苷酸（ODN）的体内递送具有优异特性的脂质体组合物可以容易且有效地以小的多层囊泡的形式进行。组合物在液体载体中含有含有核酸的脂质囊泡，并且至少一部分脂质囊泡是小的多层囊泡。小的多层泡囊由包含20-30mol％的可离子化氨基脂质如DODAP和空间屏障脂质如PEG-CerC14的脂质组分制成; 和包含在小多层囊泡的内腔或层间空间中的寡脱氧核苷酸。 ODN和脂质组分优选以0.15至0.25的摩尔比存在于小多层囊泡中。本发明的组合物可以通过制备两种溶液：在乙醇溶剂中具有20-30mol％的可电离氨基脂质的脂质混合物，空间屏障脂质和选自中性脂质和甾醇中的另外的脂质组分; 和寡脱氧核苷酸在具有可电离氨基脂质带正电荷的pH的水性溶剂中的溶液。将脂质混合物加入到寡脱氧核苷酸的溶液中以形成含有脂质囊泡的混合物，然后通过过滤器将其混合，以在含有乙醇的溶液中产生大小的脂质囊泡。然后例如通过透析除去乙醇。然后，增加围绕大小的脂质囊泡的溶液的pH以降低大小的脂质囊泡外部的净正电荷。

6. 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。

7. 发明授权

US07311924B2 Compositions and methods for treating cancer 有权
标题翻译：用于治疗癌症的组合物和方法
公开(公告)号：US07311924B2
公开(公告)日：2007-12-25
申请号：US10407864
申请日：2003-04-03
申请人： Andreas H Sarris , Fernando Cabanillas , Patricia M Logan , Clive T R Burge , James H Goldie , Murray S Webb , Thomas D Madden , Sean C Semple , Quet F Ahkong , Sandra K Klimuk
发明人： Andreas H Sarris , Fernando Cabanillas , Patricia M Logan , Clive T R Burge , James H Goldie , Murray S Webb , Thomas D Madden , Sean C Semple , Quet F Ahkong , Sandra K Klimuk
IPC分类号： A61K9/127
CPC分类号： A61K45/06 , A61K9/127 , A61K9/1272 , A61K9/1278 , A61K31/4745 , A61K31/475 , A61K31/704 , A61K2300/00
摘要： This invention provides compositions and methods for treating neoplasias in a mammal. In particular, the invention provides liposome-encapsulated vinca alkaloids, e.g., vinorelbine, and methods of treating a mammal using such compositions.
摘要翻译：本发明提供用于治疗哺乳动物的肿瘤的组合物和方法。特别地，本发明提供脂质体包封的长春花生物碱，例如长春瑞滨，以及使用这种组合物治疗哺乳动物的方法。

8. 发明授权

US06287591B1 Charged therapeutic agents encapsulated in lipid particles containing four lipid components 失效
标题翻译：包含在含有四种脂质组分的脂质颗粒中的带电治疗剂
公开(公告)号：US06287591B1
公开(公告)日：2001-09-11
申请号：US09078954
申请日：1998-05-14
申请人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter Cullis , Peter Scherrer , Dan Debeyer
发明人： Sean C. Semple , Sandra K. Klimuk , Troy Harasym , Michael J. Hope , Steven M. Ansell , Pieter Cullis , Peter Scherrer , Dan Debeyer
IPC分类号： A61K9127
CPC分类号： A61K9/1277 , A61K9/1272 , Y10T428/2984
摘要： Lipid-therapeutic agent particles are prepared containing a charged therapeutic agent encapsulated in lipid portion containing at least two lipid components including a protonatable or deprotonatable lipid such as an amino lipid and a lipid that prevents particle aggregation during lipid-therapeutic agent particle formation such as a PEG-modified or polyamide oligomer-modified lipid. Other lipid components may also be present and these include a neutral lipid such as DSPC, POPC, DOPE or SM, and a sterol such as Chol. The therapeutic agent is encapsulated by combining a mixture of the lipids with a buffered aqueous solution of a charged therapeutic agent to form an intermediate mixture containing lipid-encapsulated therapeutic agent particles, and changing the pH of the intermediate mixture to neutralize at least some surface charges on the particles. The method permits high ratios of therapeutic agent to lipid and encapsulation efficiencies in excess of 50%. The method is particularly useful for preparing lipid-encapsulated nucleic acids such as an antisense polyanionic nucleic acid having exclusively phosphodiester linkages. The encapsulated nucleic acid can be contacted with a cell to introduce the nucleic acid into the cell such as for treatment or prevention of a disease characterized by aberrant expression of a gene. A pharmaceutical composition may be prepared containing the lipid-encapsulated therapeutic agent particles and a carrier.
摘要翻译：制备包含含有至少两种脂质组分的脂质部分的带电治疗剂的脂质治疗剂颗粒，所述脂质组分包括可质子化或可去质子化的脂质如氨基脂质和防止脂质治疗剂颗粒形成期间的颗粒聚集的脂质，例如 PEG修饰或聚酰胺低聚物修饰的脂质。其他脂质组分也可以存在，它们包括中性脂质如DSPC，POPC，DOPE或SM，以及甾醇如Chol。通过将所述脂质的混合物与带电治疗剂的缓冲水溶液组合以形成含有脂质包封的治疗剂颗粒的中间体混合物并改变中间体混合物的pH以中和至少一些表面电荷来封装治疗剂在颗粒上。该方法允许高比例的治疗剂与脂质和包封效率超过50％。该方法特别可用于制备脂质包封的核酸，例如仅具有磷酸二酯键的反义聚阴离子核酸。封装的核酸可以与细胞接触以将核酸引入细胞，例如用于治疗或预防以基因异常表达为特征的疾病。可以制备含有脂质包封的治疗剂颗粒和载体的药物组合物。

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