# US 8,771,747 B2 · Microemulsions with adsorbed macromolecules and microparticles > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,771,747 B2 - Document ID: US8771747B2 - Status: Granted - Kind: B2 - Application number: 13/618,020 - Filed: 2012-09-14 - Published: 2013-08-01 - Granted: 2014-07-08 - Earliest claimed: 1999-02-26 - Assignees: Novartis Vaccines and Diagnostics, Inc. - Applicants: Derek O'Hagan; Gary S. Ott; John Donnelly; Jina Kazzaz; Mildred Ugozzoli; Manmohan Singh; John Barackman - Inventors: Derek O'Hagan; Gary S. Ott; John Donnelly; Jina Kazzaz; Mildred Ugozzoli; Manmohan Singh; John Barackman - Web page: https://patentgrep.com/patent/US8771747B2 ## CPC - A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants - 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 39/0208: {Specific bacteria not otherwise provided for} - A61K 39/21: Retroviridae, e.g. equine infectious anemia virus - A61K 39/245: Herpetoviridae, e.g. herpes simplex virus - A61K 39/29: Hepatitis virus - A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants - A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics - A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics - A61P 31/04: Antibacterial agents - A61P 31/12: Antivirals - A61P 31/14: for RNA viruses - A61P 31/16: for influenza or rhinoviruses - A61P 31/18: for HIV - A61P 31/20: for DNA viruses - A61P 31/22: for herpes viruses - A61P 33/00: Antiparasitic agents - A61P 33/06: Antimalarials - A61P 37/02: Immunomodulators - A61P 37/04: Immunostimulants - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - A61K 9/167: {with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface (with further drug-free outer coating A61K9/5073)} - 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 Microparticles with adsorbent surfaces, methods of making such microparticles, and uses thereof, are disclosed. The microparticles comprise a polymer, such as a poly(α-hydroxy acid), a polyhydroxy butyric acid, a polycaprolactone, a polyorthoester, a polyanhydride, and the like, and are formed using cationic, anionic, or nonionic detergents. The surface of the microparticles efficiently adsorb biologically active macromolecules, such as DNA, polypeptides, antigens, and adjuvants. Also provided are compositions of an oil droplet emulsion having a metabolizable oil and an emulsifying agent. Immunogenic compositions having an immunostimulating amount of an antigenic substance, and an immunostimulating amount of an adjuvant composition are also provided. Methods of stimulating an immune response, methods of immunizing a host animal against a viral, bacterial, or parasitic infection, and methods of increasing a Th1 immune response in a host animal by administering to the animal an immunogenic composition of the microparticles, and/or microemulsions of the invention, are also provided. ## Claims ### Claim 1 A microemulsion having an adsorbent surface, said microemulsion comprising a microdroplet emulsion wherein at least 80% (by number) of the microdroplets are less than 1 micron in diameter, said microdroplet emulsion comprising: (a) a metabolizable oil; (b) an emulsifying agent; and (c) at least one macromolecule, wherein, said emulsifying agent comprises a cationic detergent, wherein said macromolecule is an antigen, an adjuvant or a polynucleotide that encodes an antigen, and wherein said macromolecule is adsorbed on the surface of the microemulsion. ### Claim 2 (depends on 1) The microemulsion of claim 1 wherein said oil and said emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets, wherein at least 80% (by number) of the droplets are less than 1 micron, and wherein said composition exists in the absence of a polyoxypropylene-polyoxyethylene block copolymer. ### Claim 3 (depends on 2) The microemulsion of claim 2, wherein said oil is a member of the group consisting of an animal oil, an unsaturated hydrocarbon, a terpenoid, and a vegetable oil. ### Claim 4 (depends on 3) The microemulsion of claim 3 wherein said oil is a terpenoid which is squalene. ### Claim 5 (depends on 2) The microemulsion of claim 2 wherein said composition comprises 0.5 to 20% by volume of said oil in an aqueous medium. ### Claim 6 (depends on 1) The microemulsion of claim 1 wherein said composition comprises 0.01 to 0.5% by weight of said emulsifying agent. ### Claim 7 (depends on 1) The microemulsion of claim 1 wherein said emulsifying agent further comprises a non-ionic detergent. ### Claim 8 (depends on 7) The microemulsion of claim 7 wherein said emulsifying agent comprises a polyoxyethylene sorbitan mono-, di-, or triester or a sorbitan mono-, di-, or triether. ### Claim 9 (depends on 1) The microemulsion of claim 1 wherein said cationic detergent is selected from the group consisting of hexadecyltrimethylammonium bromide, benzalkonium chloride, dimethyl dioctodecyl ammonium bromide, dioleoyl-3-trimethylammonium propane (DOTAP), dodecyltrimethylammonium bromide, benzyldimethylhexadecyl ammonium chloride, cetylpyridinium chloride, methylbenzethonium chloride, and 4-picoline dodecyl sulfate. ### Claim 10 (depends on 1) The microemulsion of claim 1 wherein said composition comprises 0.01 to 0.5% by weight of said emulsifying agent. ### Claim 11 (depends on 1) The composition of claim 1 wherein said macromolecule is an adjuvant selected from the group consisting of a CpG oligonucleotide, alum, a bacterial cell wall component, and muramyl peptide. ### Claim 12 (depends on 1) The microemulsion of claim 1 wherein said antigen is from a virus, a bacterium or a parasite. ### Claim 13 (depends on 1) A composition comprising a microemulsion of claim 1 and a microparticle having an adsorbent surface, said microparticle comprising: a polymer selected from the group consisting of a poly(a-hydroxy acid), a polyhydroxy butyric acid, a polycaprolactone, a polyorthoester, a polyanhydride, and a polycyanoacrylate; and a second detergent. ### Claim 14 (depends on 13) The composition of claim 13, wherein said microparticle further comprises a first biologically active macromolecule adsorbed on the surface thereof; wherein the first biologically active macromolecule is at least one member selected from the group consisting of a polypeptide, a polynucleotide, a polynucleoside, an antigen, a pharmaceutical, a hormone, an enzyme, a transcription or translation mediator, an intermediate in a metabolic pathway, an immunomodulator, and an adjuvant. ### Claim 15 (depends on 13) The composition of claim 13, wherein said microparticle further comprises a second biologically active macromolecule encapsulated within said microparticle, wherein the second biologically active macromolecule is at least one member selected from the group consisting of a polypeptide, a polynucleotide, a polynucleoside, an antigen, an immunomodulator, and an adjuvant. ### Claim 16 (depends on 13) The composition of claim 13, wherein the microparticle comprises a poly(α-hydroxy acid) selected from the group consisting of poly(L-lactide), poly(D,L-lactide) and poly(D,L-lactide-co-glycolide). ### Claim 17 (depends on 13) The composition of claim 13, wherein the second detergent is a cationic detergent. ### Claim 18 (depends on 13) The composition of claim 13, wherein the second detergent is an anionic detergent. ### Claim 19 (depends on 13) The composition of claim 13, wherein the second detergent is an nonionic detergent. ### Claim 20 (depends on 15) The composition of claim 15, wherein the second biologically active macromolecule is an adjuvant. ### Claim 21 A microemulsion having an adsorbant surface, said microemulsion comprising an microdroplet emulsion wherein at least 80% (by number) of the microdroplets are less than 1 micron in diameter, said microdroplet emulsion comprising: (a) a metabolizable oil; (b) an emulsifying agent; and (c) at least one macromolecule, wherein said emulsifying agent comprises an ionic detergent, wherein said macromolecule is a polypeptide, an antigen or an adjuvant, and wherein said macromolecule is adsorbed on the surface of the microemulsion. ### Claim 22 (depends on 21) The microemulsion of claim 21 wherein said oil and said emulsifying agent are present in the form of an oil-in-water emulsion having oil droplets, wherein at least 80% (by number) of the droplets are less than 1 micron, and wherein said composition exists in the absence of a polyoxypropylene-polyoxyethylene block copolymer. ### Claim 23 (depends on 22) The microemulsion of claim 22, wherein said oil is a member of the group consisting of an animal oil, an unsaturated hydrocarbon, a terpenoid, and a vegetable oil. ### Claim 24 (depends on 23) The microemulsion of claim 23 wherein said oil is a terpenoid which is squalene. ### Claim 25 (depends on 22) The microemulsion of claim 22 wherein said composition comprises 0.5 to 20% by volume of said oil in an aqueous medium. ### Claim 26 (depends on 21) The microemulsion of claim 21 wherein said composition comprises 0.01 to 0.5% by weight of said emulsifying agent. ### Claim 27 (depends on 21) The microemulsion of claim 21 wherein said emulsifying agent further comprises a non-ionic detergent. ### Claim 28 (depends on 27) The microemulsion of claim 27 wherein said emulsifying agent comprises a polyoxyethylene sorbitan mono-, di-, or tri-ester or a sorbitan mono-, di-, or triether. ### Claim 29 (depends on 21) The microemulsion of claim 21 wherein said composition comprises 0.01 to 0.5% by weight of said emulsifying agent.