US4944948A
Expired / Lapsed
US
⏱️ 0.0 years remaining
EGF/Liposome gel composition and method
Assignee: Liposome Technology Inc
•
Filing: 1989-02-24
•
Granted: 1990-07-31
•
Expires: 2009-02-24
Abstract
Abstract A composition and method for treating a wound or surgical incision, by sustained-released delivery of epidermal growth factor (EGF). The composition includes a high-viscosity aqueous dispersion of negatively charged liposomes with liposome-entrapped EGF. The EGF/liposome composition is formed, in one embodiment of the invention, by suspending a lipid mixture typically containing equimolar amounts of neutral and negatively charged phopholipids and cholesterol in a low-conductivity aqueous medium containing EGF and a zwitterionic compound whose isoelectric point is between pH 5.5 and 8.5 to form a gel-like composition. One embodiment of the invention contains EGF entrapped by surface adsorption to the liposomes, for slow release from the composition.
Inventors
- 👤 Paul S. Uster
- 👤 Robert M. Fielding
- 👤 Francis J. Martin
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 19:38
CPC Classifications
A; A61; A61K; A61K38/00; A61K38/16; A61K38/17; A61K38/18; A61K38/1808; A61K9/00; A61K9/10; A61K9/127
Claims Analysis
Total Claims: 34
Claim 1
Independent Claim
108 words
A high-viscosity liposome composition for use in administering a sustained release dose of epidermal growth factor (EGF) at a wound or surgical incision site, comprising (a) EGF/liposomes (i) containing neutral phospholipid, between 10-50 weight percent negatively charged phospholipid, and liposome-entrapped EGF; and (ii) having a lipid concentration of at least 50 mg/g composition and a pH between 5.5 and 8.5; and (b) means for imparting a high composition viscosity selected from the group consisting of: (i) a low-conductivity aqueous medium containing a zwitterionic compound having an isoelectric point between pH 5.5 and 8.5; and (ii) empty liposomes which are substantially free of negatively charged phospholipid and entrapped EGF.
Claim 2
Dependent Claim
108 words
A high-viscosity liposome composition for use in administering a sustained release dose of epidermal growth factor (EGF) at a wound or surgical incision site, comprising (a) EGF/liposomes (i) containing neutral phospholipid, between 10-50 weight percent negatively charged phospholipid, and liposome-entrapped EGF; and (ii) having a lipid concentration of at least 50 mg/g composition and a pH between 5.5 and 8.5; and (b) means for imparting a high composition viscosity selected from the group consisting of: (i) a low-conductivity aqueous medium containing a zwitterionic compound having an isoelectric point between pH 5.5 and 8.5; and (ii) empty liposomes which are substantially free of negatively charged phospholipid and entrapped EGF.
Claim 3
Dependent Claim
20 words
The composition of claim 1, wherein the neutral phospholipid is predominantly phophatidylcholine, and the negatively charged phospholipid is predominantly phophatidylglycerol.
Claim 4
Dependent Claim
18 words
The composition of claim 2, which contain at least about 25 mole percent of phosphatidylcholine, phosphatydylglycerol, and cholesterol.
Claim 5
Dependent Claim
32 words
The composition of claim 1, wherein the total concentration of liposomes in the composition is less than about 200 mg/g, and the aqueous medium is a conductivity medium containing a zwitterionic compound.
Claim 6
Dependent Claim
14 words
The composition of claim 5, wherein the zwitterionic compound is a neutral amino acid.
Claim 7
Dependent Claim
16 words
The composition of claim 5, wherein the concentration of zwitterionic compound is between 1-5 weight percent.
Claim 8
Dependent Claim
20 words
The composition of claim 6, wherein the concentration of the zwitterionic compound is adjusted to produce an substantially physiological osmolarity.
Claim 9
Dependent Claim
48 words
The composition of claim 1, wherein the high viscosity of the composition is produced by empty liposomes, the empty liposomes contain between about 20-50 mole percent cholesterol, and the total lipid concentration of both EGF/liposomes and empty liposomes in the composition is greater than about 400 mg/g composition.
Claim 10
Dependent Claim
20 words
The composition of claim 1, wherein the EGF is entrapped in the EGF/liposomes by surface adsorption to negatively charged liposomes.
Claim 11
Dependent Claim
24 words
The composition of claim 1, which is further characterized by a liposome size distribution in a selected size range less than about 2 microns.
Claim 12
Dependent Claim
63 words
An epidermal growth factor (EGF)/liposome composition having a gel-like consistency, comprising (a) liposomes containing between 20-50 mole percent each of phosphatidylcholine, phosphatidylglycerol, and cholesterol, at a total lipid concentration of between about 50-200 mg/g composition; (b) a low-conductivity aqueous medium containing a zwitterionic compound whose isoelectric point is between about pH 6-8; and (c) liposome-entrapped EFG, at a concentration between about 0.5-5 μg/ml.
Claim 13
Dependent Claim
63 words
An epidermal growth factor (EGF)/liposome composition having a gel-like consistency, comprising (a) liposomes containing between 20-50 mole percent each of phosphatidylcholine, phosphatidylglycerol, and cholesterol, at a total lipid concentration of between about 50-200 mg/g composition; (b) a low-conductivity aqueous medium containing a zwitterionic compound whose isoelectric point is between about pH 6-8; and (c) liposome-entrapped EFG, at a concentration between about 0.5-5 μg/ml.
Claim 14
Dependent Claim
25 words
The composition of claim 11, wherein the phosphatidylcholine and phosphatidylglycerol are egg phosphatidylcholine and phosphatidylglycerol, respectively, and the zwitterionic compound is a neutral amino acid.
Claim 15
Independent Claim
79 words
A method of forming an epidermal growth factor (EGF)/liposome composition having a gel-like consistency, comprising (a) providing a lipid mixture containing neutral phospholipid, between 10-50 weight percent negatively charged phospholipid and EGF; and (b) suspending (i) the lipid mixture to a final lipid concentration between about 50-200 mg/ml, and (ii) EGF, to a final EGF concentration of between about 0.1 and 10 μg/ml, in a low-conductivity aqueous medium containing a zwitterionic compound having an isoelectric point between pH 5.5-8.5.
Claim 16
Independent Claim
79 words
A method of forming an epidermal growth factor (EGF)/liposome composition having a gel-like consistency, comprising (a) providing a lipid mixture containing neutral phospholipid, between 10-50 weight percent negatively charged phospholipid and EGF; and (b) suspending (i) the lipid mixture to a final lipid concentration between about 50-200 mg/ml, and (ii) EGF, to a final EGF concentration of between about 0.1 and 10 μg/ml, in a low-conductivity aqueous medium containing a zwitterionic compound having an isoelectric point between pH 5.5-8.5.
Claim 17
Dependent Claim
27 words
The method of claim 13, wherein said mixing is carried out by adding said aqueous medium to a thin film of the lipid mixture in dried form.
Claim 18
Dependent Claim
37 words
The method of claim 14, which further includes extruding the composition through a defined-pore-size membrane which is effective to reduce the sizes of the liposomes in the composition to a selected size less than about 2 microns.
Claim 19
Dependent Claim
26 words
The method of claim 13, wherein said peptide is present in the aqueous medium at the time of liposome formation, to yield liposomes with encapsulated polypeptide.
Claim 20
Dependent Claim
28 words
The method of claim 13, wherein said peptide is added after formation of liposomes in the aqueous medium, and the polypeptide is predominantly adsorbed to the liposome surfaces.
Claim 21
Dependent Claim
66 words
The method of claim 13, wherein the aqueous medium initially is at a selected pH at which the zwitterionic compound is substantially charged, and which further includes rehydrating the lipid mixture at the selected pH, by said rehydrating, forming a relatively non-viscous suspension of liposomes, and adjusting the pH of the suspension to the isoelectric point of the zwitterionic compound, thereby to produce the gel-like composition.
Claim 22
Dependent Claim
97 words
The method of claim 18, wherein the lipid mixture is prepared by dehydrating a dispersion of liposomes which contain said zwitterionic compound in predominantly liposome encapsulated form, where the pH of the liposome suspension before dehydrating is such that mixing of the suspension with the aqueous medium produces, at equilibrium, a pH at which the zwitterionic compound is isoelectric, wherein adding said aqueous medium initially produces a liposome dispersion having such selected pH, and equilibration of the zwitterionic compound between inner and outer liposome spaces produces a final suspension pH at which the zwitterionic compound is isoelectric.
Claim 23
Independent Claim
121 words
A method of treating a wound or surgical incision with a sustained release dose of epidermal growth factor (EGF), providing a high-viscosity liposome composition comprising (a) EGF/liposomes (i) containing neutral phospholipid, at least about 10 weight percent negatively charged phospholipid, and liposome-entrapped EGF, and (ii) having a lipid concentration of less than about 200 mg/g composition and a pH between 5.5 and 8.5 and (b) means for imparting a high composition viscosity selected from the group consisting of (i) an low-conductivity aqueous medium containing a zwitterionic compound having an isoelectric point between 5.5 and 8.5; and (ii) empty liposomes which are substantially free of negatively charged phospholipid and liposome entrapped EGF, and applying the composition to the wound or incision site.
Claim 24
Independent Claim
121 words
A method of treating a wound or surgical incision with a sustained release dose of epidermal growth factor (EGF), providing a high-viscosity liposome composition comprising (a) EGF/liposomes (i) containing neutral phospholipid, at least about 10 weight percent negatively charged phospholipid, and liposome-entrapped EGF, and (ii) having a lipid concentration of less than about 200 mg/g composition and a pH between 5.5 and 8.5 and (b) means for imparting a high composition viscosity selected from the group consisting of (i) an low-conductivity aqueous medium containing a zwitterionic compound having an isoelectric point between 5.5 and 8.5; and (ii) empty liposomes which are substantially free of negatively charged phospholipid and liposome entrapped EGF, and applying the composition to the wound or incision site.
Claim 25
Dependent Claim
21 words
The method of claim 20, wherein the liposomes contain between 25-50 mole percent each of egg phosphatidylcholine, egg phosphatidylglycerol, and cholesterol.
Claim 26
Dependent Claim
37 words
The method of claim 20, wherein the aqueous medium contains wherein the total concentration of liposomes in the composition is less than about 200 mg/g and the aqueous medium is a low-conductivity medium containing a zwitterionic compound.
Claim 27
Dependent Claim
17 words
The method of claim 22, wherein the pH of the composition is substantially at such isoelectric point.
Claim 28
Dependent Claim
14 words
The method of claim 23, wherein the zwitterionic compound is a neutral amino acid.
Claim 29
Dependent Claim
38 words
The method of claim 20, wherein the high viscosity of the composition is produced by empty liposomes, and the total lipid concentration of both EGF/liposomes and empty liposomes in the composition is greater than about 400 mg/g composition.
Claim 30
Dependent Claim
32 words
The method of claim 20, wherein the amount of EGF released, over a several-day period, is at least about 1% per day of the total EGF originally present in the applied composition.
Claim 31
Dependent Claim
16 words
The method of claim 26, wherein the EGF is entrapped in the liposomes by surface adsorption.
Claim 32
Dependent Claim
20 words
The method of claim 20, for treatment of surface ulcers, wherein the composition is applied directly to the skin surface.
Claim 33
Dependent Claim
19 words
The method of claim 20, for treatment of surgical incision, wherein the composition is applied between surgical incision layers.
Claim 34
Dependent Claim
34 words
The method of claim 20, for treatment of ophthalmic surgical incisions involving both corneal and conjunctiva incisions, wherein the composition is injected to the space between the cornea and conjunctiva, after resuturing the conjunctiva.
References Cited (Backward Citations)
US4781871A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1993-07-30 | 1994-01-29 | 1994-07-31 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1997-07-30 | 1998-01-29 | 1998-07-31 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2001-07-30 | 2002-01-29 | 2002-07-31 | $7700.00 | Window Closed / Lapsed |