Formulation of acoustically activatable particles having low vaporization energy and methods for using same

• US 10,493,038 B2
• Filed: 01/25/2018
• Issued: 12/03/2019
• Est. Priority Date: 10/08/2010
• Status: Active Grant

• Current Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Original Assignee: University of North Carolina At Chapel Hill (University of North Carolina System)
• Inventors: Dayton, Paul Alexander, Sheeran, Paul Steven, Matsunaga, Terry Onichi, Borden, Mark A.
• Primary Examiner(s): Lamberski, Jennifer A.
• Application Number:
  US15/880,481
• Publication Number:
  US 20180221515A1
• Time in Patent Office: 677 Days
• Field of Search: None
• CPC Class Codes: 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
• CPC Class Codes: A61K 47/06 Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61K 49/0002 General or multifunctional contrast agents, e.g. chelated agents
• CPC Class Codes: A61K 49/221 characterised by the targeting agent or modifying agent linked to the acoustically-active agent
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/226 Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
• CPC Class Codes: A61K 9/51 Nanocapsules; Nanoparticles; nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61K 9/5192 Processes
• CPC Class Codes: B01J 13/02 Making microcapsules or microballoons for medical preparations A61K9/50

Abstract

An acoustically activatable particle of material includes a first substance that includes a component that is a gas 25° C. and atmospheric pressure. A second substance, different from the first substance, encapsulates the first substance to create a droplet or emulsion that is stable at room temperature and atmospheric pressure. At least some of the first substance exists in a gaseous phase at the time of encapsulation of the first substance within the second substance to form a bubble. After formation of the bubble, the bubble is condensed into a liquid phase, which causes the bubble to transform into the droplet or emulsion having a core consisting of a liquid. The droplet or emulsion is an activatable phase change agent having a core consisting of a liquid at 25° C. and atmospheric pressure. The first substance has a boiling point below 25° C. at atmospheric pressure.

Claims

1. A method of producing particles of materials for ultrasound activation, comprising:

condensing, from a gaseous phase to a liquid phase, a first substance comprising at least one component that is a perfluorocarbon or perfluorochemical having a boiling point below 25°

C. at atmospheric pressure;

extruding or emulsifying the first substance into or in the presence of a second substance to create a droplet having a diameter of less than one micron and in which the first substance is encapsulated by the second substance and wherein at least some of the first substance exists in the liquid phase at the time of encapsulation of the first substance within the second substance, and wherein the droplet is an activatable phase change agent that remains a droplet having a core that will remain in the liquid phase at a boiling point of the first substance and atmospheric pressure.

2. The method of claim 1 wherein the first substance comprises at least one of decafluorobutane (DFB) or octafluoropropane (OFP).

3. The method of claim 1 wherein causing the first substance to condense to a liquid phase comprises cooling the first substance.

4. The method of claim 3 wherein causing the first substance to condense to a liquid phase comprises cooling the first substance to a temperature that is below the liquid-to-gas phase transition temperature of a component of the first substance having the lowest liquid-to-gas phase transition temperature.

5. The method of claim 1 wherein causing the first substance to condense to a liquid phase comprises compressing the first substance.

6. The method of claim 5 wherein causing the first substance to condense to a liquid phase comprises compressing the first substance to a pressure that is above the gas-to-liquid phase transition pressure of a component of the first substance having the highest gas-to-liquid phase transition pressure.

7. The method of claim 1 wherein the second substance comprises at least one of a lipid, a protein, a polymer, a gel, a surfactant, a peptide, or a sugar.

8. The method of claim 1 wherein the second substance comprises lung surfactants, amphiphiles, proteins, or peptide components thereof in a sufficient quantity to fully encapsulate the liquid phase of the first substance.

9. The method of claim 1 wherein the amphiphiles comprise at least one of amphiphilic polymers and copolymers, amphiphilic peptides, amphiphilic dendrimers, or amphiphilic nucleic acids.

10. The method of claim 1 wherein the first substance consists of a single perfluorocarbon or perfluorochemical having a single activation energy.

11. The method of claim 1 wherein extruding or emulsifying the first substance into or in the presence of a second substance includes extruding the first substance through a filter.

12. The method of claim 11 wherein the filter has a pore size greater than a desired particle size.

13. The method of claim 1 wherein extruding or emulsifying the first substance into or in the presence of a second substance includes using a microfluidics technique to produce the droplet in which the first substance is encapsulated within the second substance.

14. The method of claim 13 wherein using the microfluidics technique includes using a flow focusing or T junction in a microfluidics device to produce the droplet in which the first substance is encapsulated within the second substance.