# US 11,305,013 B2 · Surfactant microbubbles and process for preparing and methods of using the same

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- Number: US 11,305,013 B2
- Document ID: US11305013B2
- Status: Granted
- Kind: B2
- Application number: 14/835,636
- Filed: 2015-08-25
- Published: 2016-03-03
- Granted: 2022-04-19
- Earliest claimed: 2014-08-26
- Assignees: Drexel University; Thomas Jefferson University
- Applicants: Drexel University; Thomas Jefferson University
- Inventors: John Robert Eisenbrey; Margaret Alison Wheatley; Patrick O'Kane; Lorenzo Albala; Flemming Forsberg
- Web page: https://patentgrep.com/patent/US11305013B2

## CPC

- 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 9/0009: {involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis}
- A61K 9/5015: {Organic compounds, e.g. fats, sugars}
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61K 41/0038: {Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy (radiotherapy per se A61N5/10)}
- A61K 49/223: {Microbubbles, hollow microspheres, free gas bubbles, gas microspheres}
- A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device}
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)

## Abstract

The invention relates to an ultrasound contrast agent (UCA) comprising an outer shell and a gas core. The gas core is filled with oxygen, and the outer shell comprises a first surfactant and a second surfactant. The invention also relates to a method of making an oxygen-filled UCA and delivering oxygen to a local area of a subject's body. The method comprises injecting a composition comprising an oxygen-filled UCA of the invention into the subject's body; directing ultrasound radiation to the local area in an intensity sufficient to rupture the UCA.

## Claims

### Claim 1

An ultrasound contrast agent (UCA) comprising:
an outer shell, and
a gas core,
wherein said gas core is filled with between 98% and 100% pure oxygen without a perfluorocarbon, and
wherein said outer shell comprises:
a first surfactant, and
a second surfactant,
wherein the first surfactant comprises d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS),
wherein the UCA induces a statistically significant increase in oxygen concentration when in solution and insonated relative to in solution without insonation, and
wherein the insonated UCA has a half-life under 5 MHz ultrasound of from about 5 minutes to about 20 minutes.

### Claim 2 (depends on 1)

The UCA of claim 1, wherein the second surfactant is selected from the group consisting of: sorbitan esters, alkylphenol ethoxylate-based surfactants, alcohol ethoxylate-based surfactants, silicone-based surfactants, alkyl polyethylene oxide), alkylphenol poly(ethylene oxide), copolymers of polyethylene oxide) and polypropylene oxide), alkyl polyglucosides, fatty alcohols, cocamide MEA, cocamide DEA, and polysorbates.

### Claim 3 (depends on 1)

The UCA of claim 1, wherein the mean diameter of the UCA is in the range of 1 μm to 10 μm.

### Claim 4 (depends on 1)

The UCA of claim 1, wherein the mean diameter of the UCA is in the range of 2 μm to 7 μm.

### Claim 5 (depends on 1)

The UCA of claim 1, wherein the mean diameter of the UCA is about 3 μm.

### Claim 6 (depends on 1)

The UCA of claim 1, wherein the half-life of the UCA under 5 MHz ultrasound is in the range of 10 to 20 minutes.

### Claim 7 (depends on 1)

The UCA of claim 1, wherein the half-life of the UCA under 5 MHz ultrasound is about 15 minutes.

### Claim 8 (depends on 1)

The UCA of claim 1, wherein:
the second surfactant is sorbitan monostearate.

### Claim 9 (depends on 8)

The UCA of claim 8, wherein the mean diameter of the UCA is about 3 μm.

### Claim 10 (depends on 1)

A method of delivering oxygen to a local area of a subject's body, comprising
a. injecting a composition comprising a UCA of claim 1 into the subject's body; and
b. directing ultrasound radiation to the local area in an intensity sufficient to rupture the UCA.

### Claim 11 (depends on 1)

A method of improving effectiveness of radiotherapy and chemotherapy against cancer, comprising the steps of:
a. injecting a composition comprising a UCA of claim 1 into a subject suffering from cancer;
b. directing ultrasound radiation to a location of said cancer in an intensity sufficient to rupture the UCA; and
c. applying radiotherapy and/or chemotherapy.

### Claim 12 (depends on 1)

The UCA of claim 1, wherein the UCA is stable long enough to pass through a circulatory system of a large animal.