# US 10,500,227 B2 · Bioactive gas-encapsulated echogenic liposomes and methods for treating cardiovascular disease

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- Number: US 10,500,227 B2
- Document ID: US10500227B2
- Status: Granted
- Kind: B2
- Application number: 14/957,705
- Filed: 2015-12-03
- Published: 2016-09-01
- Granted: 2019-12-10
- Earliest claimed: 2014-12-03
- Assignees: University of Cincinnati
- Applicants: University of Cincinnati
- Inventors: Christy Holland; Jason Raymond; Jonathan Sutton
- Web page: https://patentgrep.com/patent/US10500227B2

## CPC

- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61K 9/0009: {involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis}
- A61K 41/0028: {Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds}
- A61K 47/6911: {the form being a liposome}
- A61K 49/227: {Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric}
- G01N 33/5082: {Supracellular entities, e.g. tissue, organisms}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- A61K 9/1278: Post-loading, e.g. by ion or pH gradient
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Echogenic liposomes (ELIP) formulated with an at least partially pegylated phospholipid bi-layer shell, encapsulated nitric oxide, and encapsulated perfluorocarbon of the formula CxFy in a ratio of about 1:1 by volume, wherein X is greater than or equal to 3, are disclosed, along with methods for treating a patients suffering from cardiovascular disease by administering the ELIP at a site remote from the target diseased section, monitoring presence of the ELIP at the target diseased section, and administering ultrasound upon detection of presence such that bioactive NO is released at the target diseased section.

## Claims

### Claim 1

A microbubble comprising an at least partially pegylated phospholipid shell, encapsulated nitric oxide, and encapsulated perfluorocarbon of the formula CxFy, wherein X is 3 and Y is 8, wherein the ratio of NO to CxFy is about 1:1 or about 1:9 by volume.

### Claim 2 (depends on 1)

The microbubble according to claim 1, wherein the at least partially pegylated phospholipid shell comprises dipalmitoylphosphatidylcholine (DPPC), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000), and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-750] (DSPE-PEG750) in a molar ratio of 79:15:3:3.

### Claim 3 (depends on 1)

A method of manufacturing the microbubble according to claim 1, the method comprising:
providing an emulsion comprising phospholipids;
injecting a volume ratio of nitric oxide and C3F8 into the emulsion;
agitating the emulsion; and
adjusting the temperature of the emulsion to room temperature, wherein freezing of the emulsion is avoided,
wherein at least some of the phospholipids are pegylated,
wherein the volume ratio of nitric oxide and the perfluorocarbon is about 1:1 or about 1:9.

### Claim 4 (depends on 3)

The method according to claim 3 wherein the phospholipids consist of one or more of nonionic and anionic phospholipids.

### Claim 5 (depends on 1)

A method comprising administering the composition of claim 1 to a patient.

### Claim 6 (depends on 5)

The method of claim 5, wherein the patient suffers from cardiovascular disease.