# US 8,771,727 B2 · Microfluidized oil-in-water emulsions and vaccine compositions

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- Number: US 8,771,727 B2
- Document ID: US8771727B2
- Status: Granted
- Kind: B2
- Application number: 12/650,715
- Filed: 2009-12-31
- Published: 2010-07-08
- Granted: 2014-07-08
- Earliest claimed: 2003-04-04
- Assignees: Zoetis LLC
- Applicants: Paul J. Dominowski; Ramasamy M. Mannan; Richard L. Krebs; Pamela K. Klose
- Inventors: Paul J. Dominowski; Ramasamy M. Mannan; Richard L. Krebs; Pamela K. Klose
- Web page: https://patentgrep.com/patent/US8771727B2

## CPC

- A61K 39/092: {Streptococcus}
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- A61K 39/0225: {Spirochetes, e.g. Treponema, Leptospira, Borrelia}
- A61K 39/0258: {Escherichia}
- A61K 39/12: Viral antigens
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61K 2039/521: {inactivated (killed)}
- A61K 2039/55505: {Inorganic adjuvants}
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/55555: {Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers}
- A61K 2039/55566: {Emulsions, e.g. Freund's adjuvant, MF59}
- A61K 2039/55577: {Saponins; Quil A; QS21; ISCOMS}
- A61K 2039/70: {Multivalent vaccine}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

This invention provides submicron oil-in-water emulsions useful as a vaccine adjuvant for enhancing the immunogenicity of antigens. The present invention also provides vaccine compositions containing an antigen combined with such emulsions intrinsically or extrinsically. Methods of preparing the emulsions and vaccines are also provided by the present invention.

## Claims

### Claim 1

A method of preparing a submicron oil-in-water emulsion, comprising:
(a) preparing a mixture by combining a light hydrocarbon non-metabolizable oil, one or more surfactants, and an aqueous component;
(b) subjecting said mixture to a primary emulsification process to produce an oil-in-water emulsion; and
(c) subjecting the oil-in-water emulsion prepared in (b) to microfluidization to produce said submicron oil-in-water emulsion, wherein the submicron emulsion has a mean oil droplet size of less than 1 μm, and wherein the distribution of droplet size is consistently from about 0.03 μm to about 1.0 μm.

### Claim 2 (depends on 1)

The method of claim 1, wherein said oil is in an amount of 1% to 50% v/v, and said surfactant is in an amount of 0.01% to 10% v/v.

### Claim 3 (depends on 2)

The method of claim 2 wherein said mean oil droplet size in said submicron oil-in-water emulsion is less than 0.8 μm.

### Claim 4 (depends on 3)

The method of claim 3 wherein said mean oil droplet size in said submicron oil-in-water emulsion is between 0.1-0.5 μm.

### Claim 5 (depends on 1)

The method of claim 1 wherein said light hydrocarbon non-metabolizable oil is light mineral oil.

### Claim 6 (depends on 1)

The method of claim 1 wherein said surfactant comprises a phospholipid compound or a mixture of phospholipid compounds.

### Claim 7 (depends on 6)

The method of claim 6 wherein said phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolmine, phosphatidylserine, phosphatidylethanolmine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, spingomyelin and cardiolipin.

### Claim 8 (depends on 6)

The method of claim 6 wherein said mixture of phospholipid compounds is lecithin.

### Claim 9 (depends on 1)

The method of claim 1 wherein said surfactant comprises at least one of polyoxyethylene sorbitan mono-oleate or sorbitan mono-oleate.

### Claim 10 (depends on 1)

The method of claim 1 wherein said microfluidization is conducted in a microfluidizer at an operating pressure in the range of about 1,000 to 15,000 psi.

### Claim 11 (depends on 1)

The method of claim 1, wherein the mixture formed in step (a) further includes an immunostimulatory molecule selected from Quil-A, GP-100, cholesterol or DDA.

### Claim 12 (depends on 1)

The method of claim 1, wherein the emulsion is stable for up to 24 months.