# US 8,541,023 B2 · Immunogenic compositions containing phospholipid

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,541,023 B2
- Document ID: US8541023B2
- Status: Granted
- Kind: B2
- Application number: 13/270,107
- Filed: 2011-10-10
- Published: 2012-05-10
- Granted: 2013-09-24
- Earliest claimed: 2002-12-27
- Assignees: Novartis Vaccines and Diagnostics, Inc.
- Applicants: Derek O'Hagan
- Inventors: Derek O'Hagan
- Web page: https://patentgrep.com/patent/US8541023B2

## CPC

- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- 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 9/10: Dispersions; Emulsions
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 39/095: Neisseria
- A61K 39/12: Viral antigens
- A61K 39/21: Retroviridae, e.g. equine infectious anemia virus
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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 9/1676: {having a drug-free core with discrete complete coating layer containing drug (adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921)}
- A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/55555: {Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers}
- A61K 2039/55561: {CpG containing adjuvants; Oligonucleotide containing adjuvants}
- A61K 2039/55566: {Emulsions, e.g. Freund's adjuvant, MF59}
- A61K 2039/6093: {Synthetic polymers, e.g. polyethyleneglycol [PEG], Polymers or copolymers of (D) glutamate and (D) lysine}
- A61K 2039/622: {non-covalent binding}
- C12N 2740/16234: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Immunogenic compositions containing phospholipid adjuvants, including microparticle and emulsion compositions. According to one aspect of the invention, an immunogenic microparticle composition is provided comprising: water; a polymer microparticle; an antigen adsorbed to the microparticle; and a phospholipid compound, e.g., a synthetic phospholipid compound comprising: (i) one or more phosphoryl groups independently selected from a phosphato group and a phosphodiester group; (ii) a plurality of linear alkane groups. According to another aspect of the invention an immunogenic emulsion composition is provided that comprises: water; a metabolizable oil; an emulsifying agent; an antigen; and a phospholipid compound, e.g., a synthetic phospholipid compound like that above. The emulsion composition is an oil-in-water emulsion having oil and aqueous phases, in which the oil phase is in the form of oil droplets, substantially all of which are less than 1 micron in diameter.

## Claims

### Claim 1

An immunogenic composition comprising: (a) water; (b) a metabolizable oil; (c) an emulsifying agent; (d) an antigen; and (e) a phospholipid compound comprising: (i) one or more
groups; (ii) 3 to 10 linear alkane groups,
in which n is independently an integer ranging from 6 to 20, or a pharmaceutically acceptable salt thereof,
wherein the composition is an oil-in-water emulsion having oil and aqueous phases, and
wherein the oil phase is in the form of oil droplets substantially all of which are less than 1 micron in diameter.

### Claim 2 (depends on 1)

The immunogenic composition of claim 1, wherein the phospholipid compound comprises
groups.

### Claim 3 (depends on 1)

The immunogenic composition of claim 1, wherein the phospholipid compound comprises four to eight of said
groups.

### Claim 4 (depends on 1)

The immunogenic composition of claim 1, wherein the phospholipid compound comprises six of said
groups.

### Claim 5 (depends on 1)

The immunogenic composition of claim 1, wherein the phospholipid compound does not comprise a saccharide group.

### Claim 6 (depends on 1)

The immunogenic composition of claim 1, wherein the phospholipid compound is a compound having the following formula:
wherein:
R1 is selected from the group consisting of
(a) C(O);
(b) C(O)—C1-14 alkyl-C(O), wherein the C1-14 alkyl is optionally substituted with hydroxy, C1-5 alkoxy, C1-5 alkylenedioxy, C1-5 alkylamino, or C1-5-alkyl-aryl, wherein the aryl moiety of the C1-5-alkyl-aryl is optionally substituted with C1-5 alkoxy, C1-5 alkylamino, C1-5 alkoxy-amino, C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C1-5 alkoxy, —O—C1-5 alkylamino-C(O)—C1-5 alkyl C(O)OH, —O—C1-5 alkylamino-C(O)—C1-5 alkyl-C(O)—C1-5 alkyl;
(c) C2 to C15 straight or branched chain alkyl optionally substituted with hydroxyl or alkoxy; and
(d) —C(O)—C6-12 arylene-C(O)— wherein the arylene is optionally substituted with hydroxy, halogen, nitro or amino;
a and b are independently 0, 1, 2, 3 or 4;
d, d′, d″, e, e′ and e″ are independently an integer from 1 to 4;
X1, X2, Y1 and Y2 are independently selected from the group consisting of a null, oxygen, NH and N(C(O)C1-4 alkyl), and N(C1-4 alkyl)2;
W1 and W2 are independently selected from the group consisting of carbonyl, methylene, sulfone and sulfoxide;
R2 and R5 are independently selected from the group consisting of:
(a) C2 to C20 straight chain or branched chain alkyl which is optionally substituted with oxo, hydroxy or alkoxy,
(b) C2 to C20 straight chain or branched chain alkenyl or dialkenyl which is Optionally substituted with oxo, hydroxy or alkoxy;
(c) C2 to C20 straight chain or branched chain alkoxy which is optionally substituted with oxo, hydroxy or alkoxy;
(d) —NH—C2 to C20 straight chain or branched chain alkyl, wherein the alkyl group is optionally substituted with oxo, hydroxy or alkoxy; and
(e)
wherein Z is selected from the group consisting of O and NH, and M and N are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl, alkenyl, alkoxy, acyloxy, alkylamino, and acylamino;
R3 and R6 are independently selected from the group consisting of C2 to C20 straight chain or branched chain alkyl or alkenyl, optionally substituted with fluoro or oxo;
R4 and R7 are independently selected from the group consisting of C(O)C2 to C20 straight chain or branched chain alkyl or alkenyl; C2 to C20 straight chain or branched chain alkyl; C2 to C20 straight chain or branched chain alkoxy; C2 to C20 straight chain or branched chain alkenyl; wherein the alkyl, alkenyl or alkoxy groups are independently and optionally substituted with hydroxy, fluoro or C1 to C5 alkoxy;
G1, G2, G3 and G4 are independently selected from the group consisting of oxygen, methylene, amino, thiol, —NHC(O)—, and —N(C(O)C1-4 alkyl)-; or G2 R4 or G4 R7 may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 6)

The immunogenic composition of claim 6, wherein R1is C(O); a, b, d, d′, d″, e, e′ and e″ are independently 1 or 2; X1, X2, Y1 and Y2 are NH; W1 and W2 are carbonyl; R2 and R5 are C10 to C20 straight chain alkyl which is substituted with oxo; R3 and R6 are C5-C10 straight chain alkyl; R4 and R7 are C(O)C8-C14 straight chain alkyl or alkenyl; and G1, G2, G3 and G4 are oxygen.

### Claim 8 (depends on 6)

The immunogenic composition of claim 6, wherein R1is C(O); a and b are 2; d, d′, e and e′ are 1; d″ and e″ are 2; X1, X2, Y1 and Y2 are NH; W1 and W2 are carbonyl; R2 and R5 are C13 straight chain alkyl which is substituted with oxo at the 2 position; R3 and R6 are C7 straight chain alkyl; R4 and R7 are C(O)C11 straight chain alkyl; G1, G2, G3 and G4 are oxygen.

### Claim 9 (depends on 1)

The immunogenic composition of claim 1, wherein substantially all of the oil droplets are less than 500 nm in diameter.

### Claim 10 (depends on 1)

The immunogenic composition of claim 1, wherein substantially all of the oil droplets are less than 250 nm in diameter.

### Claim 11 (depends on 1)

The immunogenic composition of claim 1, wherein the metabolizable oil is selected from an animal oil and a vegetable oil.

### Claim 12 (depends on 1)

The immunogenic composition of claim 1, wherein the metabolizable oil is a Fish oil.

### Claim 13 (depends on 1)

The immunogenic composition of claim 1, wherein the metabolizable oil is a branched, polyunsaturated hydrocarbon having from 20-40 carbon atoms.

### Claim 14 (depends on 1)

The immunogenic composition of claim 1, wherein the metabolizable oil is a terpenoid.

### Claim 15 (depends on 1)

The immunogenic composition of claim 1, wherein the metabolizable oil is squalene.

### Claim 16 (depends on 1)

The immunogenic composition of claim 1, wherein the emulsifying agent comprises a sorbitan derivative.

### Claim 17 (depends on 16)

The immunogenic composition of claim 16, wherein the sorbitan derivative is selected sorbitan fatty acid monoesters, sorbitan fatty acid sesquiesters, sorbitan fatty acid triesters, polyoxyethylene sorbitan fatty acid monoesters and polyoxyethylene sorbitan fatty acid triesters.

### Claim 18 (depends on 1)

The immunogenic composition of claim 1, wherein the composition comprises a plurality of emulsifying agents.

### Claim 19 (depends on 18)

The immunogenic composition of claim 18, wherein the composition comprises a sorbitan ester and a polyoxyethylene sorbitan ester.

### Claim 20 (depends on 19)

The immunogenic composition of claim 19, wherein the composition comprises polyoxyethylene sorbitan monooleate and sorbitan trioleate.

### Claim 21 (depends on 18)

The immunogenic composition of claim 18, wherein the composition comprises a first emulsifying agent having an HLB value ranging from 1 to 9 and a second emulsifying agent having an HLB value ranging from 10 to 20.

### Claim 22 (depends on 18)

The immunogenic composition of claim 18, wherein the composition comprises a first emulsifying agent having an HLB value ranging from 1 to 4 and a second emulsifying agent having an HLB value ranging from 12 to 17.

### Claim 23 (depends on 1)

The immunogenic composition of claim 1, wherein the phospholipid is dissolved or dispersed in the oil phase.

### Claim 24 (depends on 1)

The immunogenic composition of claim 1, wherein the phospholipid is dispersed in the aqueous phase.

### Claim 25 (depends on 1)

The immunogenic composition of claim 1, wherein the antigen is dissolved or dispersed in the aqueous phase.

### Claim 26 (depends on 1)

The immunogenic composition of claim 1, wherein the antigen is a polypeptide-containing antigen.

### Claim 27 (depends on 1)

The immunogenic composition of claim 1, wherein the antigen is a polynucleotide-containing antigen.

### Claim 28 (depends on 1)

The immunogenic composition of claim 1, wherein the antigen is derived from a tumor cell.

### Claim 29 (depends on 1)

The immunogenic composition of claim 1, wherein the antigen is derived from a pathogenic organism.

### Claim 30 (depends on 29)

The immunogenic composition of claim 29, wherein the pathogenic organism is selected from a virus, a bacterium, a fungus and a parasite.

### Claim 31 (depends on 29)

The immunogenic composition of claim 29, wherein the pathogenic organism is selected from HIV, hepatitis B virus, hepatitis C virus, meningitis B, Haemophilus influenza type B, pertussis, diphtheria, tetanus, and influenza A virus.

### Claim 32 (depends on 29)

The immunogenic composition of claim 29, wherein the pathogenic organism is selected from human immunodeficiency virus, Neisseria meningitidis, and hepatitis virus.

### Claim 33 (depends on 1)

The immunogenic composition of claim 1, further comprising a supplemental immunological adjuvant.

### Claim 34 (depends on 1)

The immunogenic composition of claim 1, wherein the immunogenic composition is an injectable composition.

### Claim 35 (depends on 1)

A method of delivering a therapeutic amount of an antigen to a vertebrate host animal, comprising administering to the host animal the immunogenic composition of claim 1.

### Claim 36 (depends on 1)

A method of treating a host animal having a pathogenic organism infection or tumor comprising administering to the animal the immunogenic composition of claim 1.

### Claim 37 (depends on 1)

A method of immunizing a host animal against a tumor or infection by a pathogenic organism comprising administering to the animal the immunogenic composition of claim 1.

### Claim 38 (depends on 1)

A method of stimulating an immune response in a host animal, comprising administering to the host animal the immunogenic composition of claim 1.

### Claim 39 (depends on 38)

The method of claim 38, wherein the immune response comprises a humoral immune response.

### Claim 40 (depends on 38)

The method of claim 38, wherein the immune response comprises a cellular immune response.

### Claim 41 (depends on 38)

The method of claim 38, wherein the immune response is raised against a viral, bacterial, or parasitic infection.

### Claim 42 (depends on 38)

The method of claim 38, wherein the immune response is raised against a tumor.

### Claim 43 (depends on 38)

The method of claim 38, wherein the host animal is a vertebrate animal.

### Claim 44 (depends on 38)

The method of claim 38, wherein the host animal is a mammal.

### Claim 45 (depends on 38)

The method of claim 38, wherein the host animal is a human.