# US 5,705,196 A · Process of continuous preparation of disperse colloidal systems in the form of nanocapsules or nanoparticles > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,705,196 A - Document ID: US5705196A - Status: Granted - Kind: A - Application number: 08/309,797 - Filed: 1994-09-21 - Granted: 1998-01-06 - Earliest claimed: 1991-08-08 - Assignees: Laboratorios Cusi, S.A. - Inventors: Francisco Javier Galan Valdivia; Jose Alberto Vallet Mas; Michael Van Wie Bergamini - Web page: https://patentgrep.com/patent/US5705196A ## CPC - A61K 9/5138: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates} - A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)} - A61K 9/5192: {Processes} - Y10S 977/783: Organic host/matrix, e.g. lipid - Y10S 977/835: Chemical or nuclear reactivity/stability of composition or compound forming nanomaterial - Y10S 977/836: having biological reactive capability - Y10S 977/90: having step or means utilizing mechanical or thermal property, e.g. pressure, heat - 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) - Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS ## Abstract It comprises: (1) preparing an aqueous phase containing surface active suspensor agents and, optionally, a chemically or biologically active chemical substance; (2) preparing an organic phase containing a biocompatible polymer or monomer and, optionally, a lipid or chemically or biologically active chemical substance; (3) mixing both phases in a continuous manner in a constant average phase-volume ratio, continuously removing a recently formed colloidal suspension; (4) continuously eliminating the solvent from the colloidal suspension; and (5) completely eliminating the organic solvent and part or all of the water in order to obtain the desired concentration of nanospheres or dry product. Application in biomedicine, pharmacy, medicine, cosmetics, chemical industry, agriculture, veterinary science, etc. ## Claims ### Claim 1 A continuous method for preparing nanospheres comprising: (1) mixing under constant stirring and controlled temperature and pH (a) an aqueous phase comprising water, and optionally, one or more surface active agents and suspensor agents wherein said agents are, optionally, chemically or biologically active substances; and (b) an organic phase comprising a solve or a mixture of solvents each having a miscibility in water of greater than 10% or a dielectric point of greater than 15, a biocompatible polymer or monomer or a mixture thereof, and, optionally, a lipid product and a chemically or biologically active substance; (c) wherein the mixing continues until the desired phase ratio and reaction medium volume are obtained and a colloid suspension is formed; (2) continuously removing the colloid suspension and continuously adding further organic and aqueous phases such that the desired phase ratio and reaction medium volume are maintained; (3) introducing the removed colloidal suspension to an evaporator where the organic solvent is continuously removed; and (4) withdrawing the resultant organic solvent-free suspension including nanospheres from the evaporator. ### Claim 2 (depends on 1) The method according to claim 1, wherein the biocompatible polymer is a polyacrylic, polylactic, polyglycolic derivative, polylactic-glycolic copolymer, polyanhydride, polyamide, poly(alpha-amino acid), cellulosic polymers or natural polymers. ### Claim 3 (depends on 1) The method according to claim 1, wherein the biocompatible polymer is a polyalkylcyanoacrylate. ### Claim 4 (depends on 1) The method according to claim 1, wherein the chemically or biologically active substance is added in the aqueous phase. ### Claim 5 (depends on 1) The method according to claim 1, wherein the chemically or biologically active substance is added in the organic phase. ### Claim 6 (depends on 1) The method according to claim 1, wherein the ratio between the organic and aqueous phases is 0.1 to 1. ### Claim 7 (depends on 6) The method according to claim 6, wherein the ratio between the organic and aqueous phases is 0.1 to 0.5. ### Claim 8 (depends on 1) The method according to claim 1, wherein the organic and aqueous phases are mixed by magnetic stirring or with blades, homogenization or sonication. ### Claim 9 (depends on 1) The method according to claim 1, wherein the organic and aqueous phases are mixed at atmospheric pressure, reduced pressure or in an inert atmosphere. ### Claim 10 (depends on 1) The method according to claim 1, wherein the organic and aqueous phases are mixed at a temperature between 0 and 200 degrees Centigrade. ### Claim 11 (depends on 1) The method according to claim 1, wherein the concentration of biocompatible polymer or monomer in the organic phase is between 0.01 to 5% (w/v). ### Claim 12 (depends on 11) The method according to claim 11, wherein the concentration of biocompatible polymer or monomer in the organic phase is between 0.4 and 1% (w/v). ### Claim 13 (depends on 1) The method according to claim 1, wherein the concentration of the surface active agent included in the aqueous phase is between 0.01 and 10% (w/v). ### Claim 14 (depends on 13) The method according to claim 13, wherein the concentration of the surface active agent included in the aqueous phase is less than 5% (w/v). ### Claim 15 (depends on 1) The method according to claim 1, wherein the concentration of the suspensor agent in the aqueous phase is between 0.01 and 10% (w/v). ### Claim 16 (depends on 15) The method according to claim 15, wherein the concentration of the suspensor agent in the aqueous phase is less than 5% (w/v). ### Claim 17 (depends on 1) The method according to claim 1, wherein the chemically or biologically active substance is a pharmaceutically active compound or precursor, a reagent, a marker, a cosmetic product or a dye. ### Claim 18 (depends on 1) The method according to claim 1 wherein the organic phase contains a lipid substance selected from the group consisting of coconut oil derivatives, oleic glycerides, ethoxylates, diethylglycerol monoethyl ether, C.sub.8 -C.sub.10 ethoxylated glycerides, phospholipids, natural oils and petroleum derivatives, and mixtures thereof. ### Claim 19 (depends on 1) The method according to claim 1, wherein the colloidal suspension is includes nanocapsules having a lipid nucleus and a polymeric coating. ### Claim 20 (depends on 19) The method according to claim 19, wherein the chemically or biologically active substance is withheld in the lipid nucleus, in the polymeric coating or absorbed in the surface thereof. ### Claim 21 (depends on 1) The method according to claim 1, wherein the colloidal suspension is includes nanoparticles formed by a polymeric framework. ### Claim 22 (depends on 1) The method according to claim 1, wherein the nanospheres have a diameter of between 50 and 500 nm. ### Claim 23 (depends on 1) The method according to claim 1, wherein the nanospheres have a diameter of between 500 and 5000 nm. ### Claim 24 (depends on 1) The method according to claim 1, wherein the nanospheres have a polydispersity lower than 0.5. ### Claim 25 (depends on 1) The method according to claim 1, wherein the pH of the reaction medium is between 2 and 9. ### Claim 26 (depends on 25) The method according to claim 25, wherein the pH of the reaction medium is between 5 and 7. ### Claim 27 (depends on 1) The method according to claim 1, wherein the organic solvent-free suspension is lyophilized, isotonized, extruded or compressed. ### Claim 28 (depends on 1) The method according to claim 1, wherein the miscibility in water of the organic solvent or mixture of organic solvents is higher than 10%. ### Claim 29 (depends on 1) The method according to claim 1, wherein the dielectric constant of the organic solvent or mixture of organic solvents is higher than 15. ### Claim 30 (depends on 1) The method according to claim 1, wherein the organic solvent is acetone. ### Claim 31 (depends on 1) The method according to claim 1, wherein the organic solvent is ethanol. ### Claim 32 (depends on 1) The method according to claim 1, wherein the aqueous phase and the organic phase are sterilized prior to the mixing step and the process is carried out under sterile conditions.