US5204112A
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Induction of asymmetry in vesicles
Assignee: Elan Pharmaceuticals LLC
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Filing: 1987-06-12
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Granted: 1993-04-20
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Expires: 2007-06-12
Abstract
Abstract 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.
Inventors
- 👤 Michael J. Hope
- 👤 Pieter R. Cullis
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 12:16
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/10; A61K9/127; A61K9/1277; A61K9/1278; Y; Y10; Y10S; Y10S436/00; Y10S436/829; Y10T; Y10T428/00; Y10T428/29; Y10T428/2982; Y10T428/2984
Claims Analysis
Total Claims: 31
Claim 1
Independent Claim
56 words
An asymmetric liposome having an outer bilayer which comprises an ionizable lipid or an ionizable protein wherein the outer bilayer has an asymmetric distribution of the ionizable lipid or ionizable protein within the two monolayers which comprise the outer bilayer, said asymmetric distribution induced by a transmembrane concentration gradient wherein the gradient is a pH gradient.
Claim 2
Dependent Claim
56 words
An asymmetric liposome having an outer bilayer which comprises an ionizable lipid or an ionizable protein wherein the outer bilayer has an asymmetric distribution of the ionizable lipid or ionizable protein within the two monolayers which comprise the outer bilayer, said asymmetric distribution induced by a transmembrane concentration gradient wherein the gradient is a pH gradient.
Claim 3
Dependent Claim
11 words
The liposomes of claim 1 wherein the ionizable lipis is basic.
Claim 4
Dependent Claim
12 words
The liposomes of claim 2 wherein the ionizable lipid is an amine.
Claim 5
Dependent Claim
12 words
The liposomes of claim 3 wherein the amine is sphingosine or stearylamine.
Claim 6
Dependent Claim
11 words
The liposomes of claim 1 wherein the ionizable lipid is acidic.
Claim 7
Dependent Claim
13 words
The liposomes of claim 5 wherein the ionizable lipid is a fatty acid.
Claim 8
Dependent Claim
15 words
The liposomes of claim 6 wherein the fatty acid is oleic acid or stearic acid.
Claim 9
Dependent Claim
12 words
The liposomes of claim 5 wherein the ionizable lipid is a phospholipid.
Claim 10
Dependent Claim
12 words
The liposomes of claim 5 wherein the ionizable lipid is a prostaglandin.
Claim 11
Dependent Claim
13 words
The liposomes of claim 8 wherein the phospholipid is phosphatidylglycerol, phosphatidylinositol, or cardiolipin.
Claim 12
Dependent Claim
11 words
The liposomes of claim 1 wherein the ionizable protein is basic.
Claim 13
Dependent Claim
19 words
The liposomes of claim 11 wherein the ionizable protein is oxytocin, vasopressin, arginine vasopressin, calcitonin, or alpha-atrial natriuritic factor.
Claim 14
Dependent Claim
11 words
The liposomes of claim 1 wherein the liposomes are multilamellar liposomes.
Claim 15
Dependent Claim
13 words
The liposomes of claim 11 wherein the liposomes are FATMLVs, MPVs, or SPLVs.
Claim 16
Dependent Claim
10 words
The liposomes of claim 14 wherein the liposomes are FATMLVs.
Claim 17
Dependent Claim
14 words
The liposomes of claim 13 wherein the liposome's aqueous layers have equal solute distribution.
Claim 18
Dependent Claim
11 words
The liposomes of claim 1 wherein the liposomes are unilamellar liposomes.
Claim 19
Dependent Claim
13 words
The liposomes of claim 1 wherein the liposomes additionally comprise a bioactive agent.
Claim 20
Dependent Claim
13 words
The liposomes of claim 18 wherein the bioactive agent is an ionizable drug.
Claim 21
Dependent Claim
57 words
An asymmetric liposome wherein the liposome is a large unilamellar liposome or a liposome having two or more bilayers, the liposome having an outer bilayer which comprises an ionizable lipid or an ionizable protein wherein the outer bilayer has asymmetric distribution of the ionizable lipid or ionizable protein within the two monolayers which comprise the outer bilayer.
Claim 22
Dependent Claim
57 words
An asymmetric liposome wherein the liposome is a large unilamellar liposome or a liposome having two or more bilayers, the liposome having an outer bilayer which comprises an ionizable lipid or an ionizable protein wherein the outer bilayer has asymmetric distribution of the ionizable lipid or ionizable protein within the two monolayers which comprise the outer bilayer.
Claim 23
Dependent Claim
11 words
The liposomes of claim 20 wherein the ionizable lipid is basic.
Claim 24
Dependent Claim
11 words
The liposomes of claim 20 wherein the ionizable lipid is acidic.
Claim 25
Dependent Claim
12 words
The liposomes of claim 20 wherein the ionizable lipid is a phospholipid.
Claim 26
Dependent Claim
13 words
The liposomes of claim 23 wherein the phospholipid is phosphatidylglycerol, phosphatidylinositol, or cardiolipin.
Claim 27
Dependent Claim
11 words
The liposomes of claim 20 wherein the ionizable protein is basic.
Claim 28
Dependent Claim
14 words
The liposomes of claim 20 wherein the liposome's aqueous layers have equal solute distribution.
Claim 29
Dependent Claim
13 words
The liposomes of claim 20 wherein the liposome additionally comprises a bioactive agent.
Claim 30
Dependent Claim
87 words
An asymmetric liposome having an outer bilayer which comprises an ionizable lipid or an ionizable protein wherein the outer bilayer has an asymmetric distrubution of the ionizable lipid or ionizable protein within the two monolayers which comprise the outer bilayer, made by a transmembrane concentration gradient process comprising the steps of: (a) preparing liposomes with an internal buffer at a first pH; and (b) exposing the liposomes of step (a) to an external aqueous buffer at a second, relatively acidic or basic pH, to obtain asymmetric liposomes.
Claim 31
Dependent Claim
87 words
An asymmetric liposome having an outer bilayer which comprises an ionizable lipid or an ionizable protein wherein the outer bilayer has an asymmetric distrubution of the ionizable lipid or ionizable protein within the two monolayers which comprise the outer bilayer, made by a transmembrane concentration gradient process comprising the steps of: (a) preparing liposomes with an internal buffer at a first pH; and (b) exposing the liposomes of step (a) to an external aqueous buffer at a second, relatively acidic or basic pH, to obtain asymmetric liposomes.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1996-04-19 | 1996-10-19 | 1997-04-20 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2000-04-19 | 2000-10-19 | 2001-04-20 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2004-04-19 | 2004-10-19 | 2005-04-20 | $7700.00 | Window Closed / Lapsed |