# US 9,750,690 B2 · Circulation of components during microfluidization and/or homogenization of emulsions > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,750,690 B2 - Document ID: US9750690B2 - Status: Granted - Kind: B2 - Application number: 14/478,818 - Filed: 2014-09-05 - Published: 2016-05-12 - Granted: 2017-09-05 - Earliest claimed: 2009-12-03 - Assignees: Novartis AG - Applicants: Novartis AG - Inventors: Harald Rueckl; Hanno Scheffczik; Barbara Santry - Web page: https://patentgrep.com/patent/US9750690B2 ## CPC - 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 9/107: Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)} - A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants - A61P 31/16: for influenza or rhinoviruses - B01F 23/41: Emulsifying - B01F 25/44: Mixers in which the components are pressed through slits - B01F 27/2711: {provided with intermeshing elements} - B01F 33/811: {in two or more consecutive, i.e. successive, mixing receptacles or being consecutively arranged} - A61K 2039/55566: {Emulsions, e.g. Freund's adjuvant, MF59} - 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 - B01F: MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING (mixing paints B44D3/06) ## Abstract An improved method for the manufacture of an oil-in-water emulsion involves circulation of emulsion components between a first container and a second container via a homogenizer and/or via a microfluidization device. Usefully, all of the emulsion components from the first container are emptied before being returned. ## Claims ### Claim 1 A method for a large-scale manufacture of a uniform oil-in-water emulsion, the method comprising steps of: providing a first emulsion; passing the first emulsion through a device at least two times, wherein the device operates under high pressure and high velocity sufficient to reduce the average size of oil droplets in the first emulsion so as to form a second emulsion; and, filtering the second emulsion with an asymmetric hydrophilic membrane so as to form a uniform oil-in-water emulsion, characterized in that the average oil droplet size is 220 nm or less and the number of oil droplets having a size>1.2 μm is 5×108/ml or less, and wherein the uniform oil-in-water emulsion has a volume more than or equal to 50 liters. ### Claim 2 (depends on 1) The method of claim 1, wherein the first emulsion has an average oil droplet size of 5000 nm or less, and wherein the number of oil droplets having a size>1.2 μm is 5×1011/ml or less. ### Claim 3 (depends on 1) The method of claim 1, wherein the second emulsion has an average oil droplet size of 500 nm or less, and wherein the number of oil droplets having a size>1.2 μm is 5×1010/ml or less. ### Claim 4 (depends on 1) The method of claim 1, wherein the device comprises an auxiliary processing module and an interaction chamber. ### Claim 5 (depends on 4) The method of claim 4, wherein the auxiliary processing module is positioned downstream of the interaction chamber. ### Claim 6 (depends on 4) The method of claim 4, wherein the auxiliary processing module comprises a Z-type channel. ### Claim 7 (depends on 6) The method of claim 6, wherein the auxiliary processing module comprises a plurality of Z-type channels. ### Claim 8 A method for a large-scale manufacture of a pharmaceutical composition, the method comprising steps of: providing a first emulsion; passing the first emulsion through a device at least two times, wherein the device operates under high pressure and high velocity sufficient to reduce the average size of oil droplets in the first emulsion so as to form a second emulsion; filtering the second emulsion with an asymmetric hydrophilic membrane so as to form a uniform oil-in-water emulsion, characterized in that the average oil droplet size is 220 nm or less and the number of oil droplets having a size>1.2 μm is 5×108/ml or less, and wherein the uniform oil-in-water emulsion has a volume more than or equal to 50 liters; adding to the uniform oil-in-water emulsion one or more components to form a pharmaceutical composition comprising the oil-in-water emulsion. ### Claim 9 (depends on 8) The method of claim 8, further comprising a step of sterilizing the pharmaceutical composition. ### Claim 10 (depends on 8) The method of claim 8, wherein the pharmaceutical composition comprises an antigen. ### Claim 11 (depends on 8) The method of claim 8, wherein the pharmaceutical composition is a vaccine. ### Claim 12 (depends on 8) The method of claim 8, wherein the pharmaceutical composition comprises squalene. ### Claim 13 (depends on 8) The method of claim 8, wherein the pharmaceutical composition comprises squalene, polysorbate 80 and sorbitan trioleate. ### Claim 14 (depends on 3) The method of claim 3, wherein the first emulsion is passed through the device at least five times.