Patent EA-004220-B1 (EA)
Title: Multi-stage method for producing gas-filled microcapsules
Inventor: BUDDE UWE
IPC: A61K49/18
Filed: 2000-05-23
Abstract: 1. Multi-stage process for the production of gas-filled microcapsules, characterized in that the following process steps are carried out separated in space and/or time: a) polymerization of the shell-forming substance with the formation of a primary dispersion that consists of colloidal polymer particles, b) structure-building aggregation of the colloidal polymer particles in gas-filled microcapsules. 2. Process according to claim 1, wherein the polymerization of the monomer in aqueous solution is carried out under stirring conditions such that the gas phase proportion in the stirring medium is < 1%. 3. Process according to claims 1 to 2, wherein the build-up of the microcapsule from a polymer primary dispersion is carried out under dispersing conditions such that the gas phase proportion in the dispersing medium is > 1%, preferably greater than 10%. 4. Process according to claims 1 to 3, wherein the polymerization of the monomer in an intermittent, semi-continuous or continuous stirring vessel is performed with a diameter to height ratio of 0.3 to 2.5. 5. Process according to claims 1 to 4, wherein the polymerization of the monomer in an intermittent, semi-continuous or continuous stirring vessel in a diameter to height ratio of 0.3 to 2.5 is performed with an outside loop (loop reactor), in which a single-stage or multi-stage dispersing unit is arranged, which is cut in at the beginning of the reaction or later. 6. Process according to claims 1 to 5, wherein the polymerization of the monomer is performed with a vertical, oblique or lateral stirring element, whose diameter in the ratio to the reactor diameter is in a range of 0.2 to 0.7. 7. Process according to claims 1 to 3, wherein the polymerization of the monomer is performed in a continuously operated tubular-flow reactor. 8. Process according to claims 1 to 7, wherein the polymerization of the monomer is performed in a hydraulically filled container that is externally encapsulated against the atmosphere. 9. Process according to claims 1 to 8, wherein the build-up of the microcapsule from a polymer primary dispersion is carried out with a dispersing unit. 10. Process according to claims 1 to 9, wherein the buildup of the microcapsule from a polymer primary dispersion is carried out with a rotor-stator system. 11. Process according to claims 1 to 10, wherein the buildup of the microcapsule from a polymer primary dispersion is carried out with a rotor-stator system such that the gas that covers the reaction mixture is introduced (self-gassing) and/or that active gas is introduced into the reaction mixture (external gassing). 12. Process according to claims 1 to 11, wherein the buildup of the microcapsule from a polymer primary dispersion is carried out with a rotor-stator system that is arranged in a stirring vessel with a diameter to height ratio of 0.3 to 2.5. 13. Process according to claims 1 to 12, wherein the buildup of the microcapsule from a polymer primary dispersion is carried out with a rotor-stator system, which is arranged in the outside loop of a loop reactor. 14. Process according to claims 1 to 13, wherein one or more of the following monomers are selected from the group consisting of lactides, alkyl esters of acrylic acid, alkyl esters of methacrylic acid, and preferably alkyl esters of cyanoacrylic acid. 15. Process according to claims 1 to 14, wherein one or more of the following monomers are used: butyl, ethyl and isopropylcyanoacrylic acid. 16. Process according to claims 1 to 15, wherein the monomer or monomers are added at a concentration of 0.1 to 60%, preferably 0.1 to 10%, to the acidic aqueous solution. 17. Process according to claims 1 to 16, wherein one or more of the following surfactants are used selected from the group comprising alkylarylpoly(oxyethylene)sulfate alkali salts, dextrans poly(oxyethylenes), poly(oxypropylene)-poly(oxyethylene)-block polymers, ethoxylated fatty alcohol (cetomacrogols), ethoxylated fatty acids, alkylphenolpoly(oxyethylenes), copolymers of alkylphenolpoly(oxyethylene)s and aldehydes, partial fatty acid esters of sorbitan, partial fatty acid esters of poly(oxyethylene)sorbitan, fatty acid esters of poly(oxyethylene), fatty alcohol ethers of poly(oxyethylene), fatty acid esters of saccharose or macrogol glycerol esters, polyvinyl alcohols, poly(oxyethylene)-hydroxy fatty acid esters, macrogols of multivalent alcohols, partial fatty acid esters. 18. Process according to claims 1 to 16, wherein one or more of the following surfactants are used selected from the group comprising ethoxylated nonylphenols, ethoxylated octylphenols, copolymers of aldehydes and octylphenolpoly(oxyethylene), ethoxylated glycerol-partial fatty acid esters, ethoxylated hydrogenated castor oil, poly(oxyethylene)-hydroxystearate, poly(oxypropylene)-poly(oxyethylene)-block polymers with a molecular weight of < 20,000. 19. Process according to claims 1 to 16, wherein one or more of the following surfactants are used selected from the group comprising para-octylphenol-poly-(oxyethylene) with 9-10 ethoxy groups on average (=octoxynol 9,10), para-nonylphenol-poly(oxyethylene) with 30/40 ethoxy groups on average (= e.g., Emulan<(RTM)> 30/Emulan<(RTM)>40), para-nonylphenol-poly(oxyethylene)-sulfate-Na salt with 28 ethoxy groups on average (= e.g., Disponil<(RTM)> AES), poly(oxyethylene)glycerol monostearate (= e.g., Tagat<(RTM)>S), polyvinyl alcohol with a degree of polymerization of 600-700 and a degree of hydrolysis of 85%-90% (= e.g., Mowiol<(RTM)> 4-88), poly(oxyethylene)-660-hydroxystearic acid ester (= e:g., Solutol<(RTM)> HS 15), copolymer of formaldehyde and paraoctylphenolpoly(oxyethylene) (= e.g., Triton<(RTM)> WR 1339), polyoxypropylene-polyoxyethylene-block polymers with a molecular weight of about 12,000 and a polyoxyethylene proportion of about 70% (= e.g., Lutrol<(RTM)> F127), ethoxylated cetylstearyl alcohol (= e.g., Cremophor<(RTM)> A25), ethoxylated castor oil (= e.g., Cremophor<(RTM)> EL). 20. Process according to claims 1 to 19, wherein the surfactant or surfactants are used at a concentration of 0.1 to 10%. 21. Process according to claims 1 to 20, wherein at least one of the process steps is performed in acidic, aqueous solution. 22. Process according to claims 1 to 21, wherein the following acids are used: hydrochloric acid, phosphoric acid and/or sulfuric acid. 23. Process according to claims 1 to 22, wherein the additive or additives is (are) used at a concentration of 0.1 to 10%. 24. Process according to claims 1 to 23, wherein the polymerization and the build-up of the microcapsule is carried out at temperatures of -10 degree C to 60 degree C, preferably in the range between 0 degree C and 50 degree C, especially preferably between 10 degree C and 35 degree C. 25. Process according to claims 1 to 24, wherein the gas-filled microcapsules from the reaction medium are separated, taken up in a physiologically compatible medium, and optionally are freeze-dried after a cryoprotector is added. 26. Process according to claims 1 to 25, wherein water or 0.9% common salt solution is used as a physiologically compatible medium to take up the floated material. 27. Process according to claims 1 to 26, wherein polyvinylpyrrolidone, polyvinyl alcohol, gelatin and/or human serum albumin are used as a cryoprotector. 28. Microparticles, wherein they can be obtained according to the process of claims 1 to 27.