# US 2013/0155802 A1 · Compositions and methods for preparing nanoformulations and systems for nano-delivery using focused acoustics

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- Number: US 2013/0155802 A1
- Document ID: US20130155802A1
- Status: Published application
- Kind: A1
- Application number: 13/724,796
- Filed: 2012-12-21
- Published: 2013-06-20
- Earliest claimed: 2010-07-01
- Assignees: Covaris, Inc.
- Inventors: Carl Beckett; James A. Laugharn, JR.; Srikanth Kakumanu
- Web page: https://patentgrep.com/patent/US20130155802A1

## CPC

- B01F 31/87: transmitting the vibratory energy by means of a fluid, e.g. by means of air shock waves
- B01J 2/18: using a vibrating apparatus
- B01F 23/41: Emulsifying
- B01F 2215/0431: Numerical size values, e.g. diameter of a hole or conduit, area, volume, length, width, or ratios thereof
- B01F 2215/0454: Numerical frequency values
- B01F 2215/0477: Numerical time values
- B01J 2219/00932: Sonic or ultrasonic vibrations
- B01F: MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING (mixing paints B44D3/06)
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS

## Abstract

Focused ultrasonic acoustic processing is used to prepare formulations particles ranging between approximately 10 nm and approximately 50 microns (e.g., between 1 micron and 20 microns), or between approximately 10 nm approximately 400 nm (e.g., between 10 nm and 100 nm). Formulations (e.g., nanoformulations) may include a suspension (e.g., nanosuspension), an emulsion (e.g., nanoemulsion) or another small particle system. Formulations may be used as delivery systems for therapeutic agents, e.g., a formulation may include a bioactive agent and a carrier compound such as a surfactant that encapsulates the bioactive agent.

## Claims

### Claim 1

A method of preparing a formulation, comprising:
providing a mixture in a vessel, the mixture comprising a first composition and a second composition;
transmitting focused acoustic energy having a frequency of between about 100 kilohertz and about 100 megahertz and a focal zone having a size of less than about 2 centimeters through a wall of the vessel such that the mixture is disposed at least partially in the focal zone;
selecting one or more parameters of the focused acoustic energy to achieve a desired particle size of an emulsion or liposome-containing formulation created by exposing the mixture to the focused acoustic energy, different parameters of the focused acoustic energy providing different particle sizes in the emulsion or liposome-containing formulation after exposure to the focused acoustic energy; and
forming a plurality of particles in the mixture to create an emulsion or liposome-containing formulation by, at least in part, exposure of the mixture to the focal zone of the focused acoustic energy having the selected one or more parameters, a plurality of liquid particles in the emulsion or plurality of liposome particles in the liposome-containing formulation having an average size of between approximately 10 nm and approximately 400 nm after exposure of the mixture to the focal zone.

### Claim 2 (depends on 1)

The method of claim 1, wherein the plurality of particles resulting from exposure of the mixture to the focal zone have an average size of between approximately 20 nm and approximately 100 nm.

### Claim 3 (depends on 1)

The method of claim 1, wherein the mixture comprises a volume of between about 1 mL and about 300 mL and a concentration of the first composition in the mixture is between approximately 1 mg/mL and approximately 100 mg/mL of the mixture.

### Claim 4 (depends on 1)

The method of claim 1, wherein transmitting focused acoustic energy to expose the mixture to the focal zone comprises operating an acoustic energy source to produce a unimodal distribution of the plurality of particles in the mixture.

### Claim 5 (depends on 1)

The method of claim 1, wherein transmitting focused acoustic energy to expose the mixture to the focal zone comprises operating an acoustic energy source to produce a polydispersity index of less than 0.1.

### Claim 6 (depends on 5)

The method of claim 5, wherein transmitting focused acoustic energy to expose the mixture to the focal zone comprises operating an acoustic energy source to produce a polydispersity index of between 0.05 and 0.1.

### Claim 7 (depends on 1)

The method of claim 1, wherein the first composition comprises a bioactive drug including at least one of a therapeutic agent, or a polynucleotide material such as DNA, siRNA, miRNA, or a plasmid.

### Claim 8 (depends on 7)

The method of claim 7, wherein the second composition comprises a surfactant.

### Claim 9 (depends on 8)

The method of claim 8, wherein the surfactant comprises sodium lauryl sulfate.

### Claim 10 (depends on 1)

The method of claim 1, wherein transmitting focused acoustic energy to expose the mixture to the focal zone comprises exposing the mixture to an isothermal environment.

### Claim 11 (depends on 1)

The method of claim 1, wherein the plurality of particles comprise a hydrophilic liquid material or a hydrophobic liquid material containing an active ingredient, each particle having a size between approximately 10 nanometers and approximately 400 nanometers, and further comprising a carrier that suspends the particles, the carrier including a liquid having a hydrophilicity that is opposite that of the particles.

### Claim 12 (depends on 11)

The method of claim 11, wherein the formulation lacks particles having a size larger than approximately 400 nanometers or smaller than approximately 10 nanometers.

### Claim 13 (depends on 11)

The method of claim 11, wherein the formulation exhibits longer shelf life than formulations created via other processes.

### Claim 14 (depends on 11)

The method of claim 11, wherein the formulation exhibits minimal contamination levels than formulations created via other processes, or wherein said formulation is sterile.

### Claim 15 (depends on 11)

The method of claim 11, wherein the formulation exhibits higher bioactivity (pharmacokinetic activity and lower renal clearance), resulting in lower dosing and lower side effects and developed resistance.

### Claim 16 (depends on 11)

The method of claim 11, wherein the particles are each a droplet of hydrophobic material that is suspended in a hydrophilic carrier liquid.

### Claim 17 (depends on 11)

The method of claim 11, wherein the particles are each a droplet of hydrophilic material that is suspended in a hydrophobic carrier liquid.

### Claim 18 (depends on 11)

The method of claim 11, wherein the active ingredient is a pharmaceutical, nutraceutical, or cosmeceutical.

### Claim 19 (depends on 11)

The method of claim 11, wherein the mixture comprises a liquid dispersion medium and a liquid carrier, wherein said active ingredient optionally has a solubility greater than 3 mg/ml in said medium.

### Claim 20 (depends on 19)

The method of claim 19, wherein the liquid dispersion medium is hydrophobic and the liquid carrier is hydrophilic.

### Claim 21 (depends on 19)

The method of claim 19, wherein the liquid dispersion medium is hydrophilic and the liquid carrier is hydrophobic.

### Claim 22 (depends on 19)

The method of claim 19, wherein the dispersion medium is selected from the group consisting of aqueous media and oil-based media.

### Claim 23 (depends on 19)

The method of claim 19, wherein the dispersion medium is an oil-based media selected from the group including saturated and unsaturated oils from vegetable and marine sources, silicone oils, mineral oils, and plant-derived oils.

### Claim 24 (depends on 1)

The method of claim 1, wherein the mixture includes a polynucleotide material, a lipid and a carrier, and after exposure of the mixture to the focused acoustic energy, the lipid and polynucleotide material form liposomes in the carrier and the carrier is substantially devoid of polynucleotide material.

### Claim 25 (depends on 24)

The method of claim 24, the polynucleotide material has a size of less than 1000 bp.

### Claim 26 (depends on 1)

The method of claim 1, wherein the step of forming a plurality of particles includes creating a liposome-containing formulation, and the mixture includes water and no organic solvent.

### Claim 27

A method of preparing a liposome-containing formulation, comprising:
providing a mixture in a vessel, the mixture comprising a lipid, an active ingredient to be encapsulated by the lipid and an aqueous solution with no organic solvent;
transmitting focused acoustic energy having a frequency of between about 100 kilohertz and about 100 megahertz and a focal zone having a size of less than about 2 centimeters through a wall of the vessel such that the mixture is disposed at least partially in the focal zone;
selecting one or more parameters of the focused acoustic energy to achieve a desired particle size of liposomes in the liposome-containing formulation created by exposing the mixture to the focused acoustic energy, different parameters of the focused acoustic energy providing different particle sizes in the liposome-containing formulation after exposure to the focused acoustic energy; and
forming a plurality of liposomes in the mixture to create the liposome-containing formulation by, at least in part, exposure of the mixture to the focal zone of the focused acoustic energy, the plurality of liposomes in the liposome-containing formulation having an average size of between approximately 10 nm and approximately 400 nm after exposure of the mixture to the focal zone.

### Claim 28 (depends on 27)

The method of claim 27, wherein the step of forming includes maintaining the mixture within 5 degrees C. of a starting temperature of the mixture before the mixture is exposed to acoustic energy.

### Claim 29 (depends on 27)

The method of claim 27, wherein step of forming includes maintaining the mixture within 5 degrees C. of 4 degrees C.

### Claim 30 (depends on 27)

The method of claim 27, wherein the step of forming includes sterilizing the mixture.

### Claim 31 (depends on 27)

The method of claim 27, further comprising adjusting the one or more parameters of the focused acoustic energy to achieve a desired particle size of liposomes in the formulation.

### Claim 32 (depends on 27)

The method of claim 27, wherein the one or more parameters includes a period of time that the mixture is exposed to the focused acoustic energy.

### Claim 33 (depends on 27)

The method of claim 27, wherein the active ingredient includes polynucleotide material.