Claims for Patent: 5,501,863

Summary for Patent: 5,501,863

Title:	Contrast media synthesized from polyaldehydes
Abstract:	Microparticles comprising biodegradable polymers, characterized in that they are synthesized from polymerizable aldehydes, which optionally contain additives and/or crosslinkers capable of copolymerization, optionally surfactants or surfactant mixtures, gases and/or highly volatile liquids in free or bound form, coupling agents, optionally biomolecules or macromolecules bound by these coupling agents as well as optionally diagnostically or therapeutically effective components, are suitable as ultrasonic contrast media.
Inventor(s):	Rossling; Georg (Berlin, DE), Albayrak; Celal (Berlin, DE), Rothe; Matthias (Berlin, DE), Siegert; Joachim (Berlin, DE)
Assignee:	Schering Aktiengesellschaft (Berlin, DE)
Application Number:	08/373,467
Patent Claims:	1. Microparticles consisting essentially of (a) a biodegradable polymer having a molecular weight of 1-30 Kd, obtainable by polymerizing a polymerizable aldehyde, and (b) 0.01-2 wt % of a gas and/or liquid with a boiling point below 60.degree. C. relative to the amount of polymer, said microparticles having a diameter of 0.1 to 40 .mu.m and said aldehyde having been polymerized in the presence of said gas and/or liquid. 2. Microparticles according to claim 1, wherein the biodegradable polymer is a copolymer comprising a polymerizable aldehyde and a copolymerizable additive. 3. Microparticles according to claim 1 further containing 0-5 wt % of crosslinkers and, wherein the biodegradable polymer is crosslinked. 4. Microparticles according to claim 1, wherein a bio- or macromolecule is bound to said polymer. 5. Microparticles according to claim 4 further containing 1-95 wt % of a coupling agent based on the amount of polyaldehyde, and, wherein the bio- or macromolecule is bound to the polymer via said coupling agent. 6. Microparticles according to claim 1, wherein said biodegradable polymer contains 0.01-1 wt % relative to the weight of said polyaldehyde of a surfactant or a mixture of surfactants. 7. Microparticles according to claim 1, wherein the polymerizable aldehyde monomer is an alpha,beta-unsaturated aldehyde, an alpha-substituted acrolein derivative, and/or a dialdehyde. 8. Microparticles according to claim 7, wherein the .alpha.-substituted acrolein derivative is .alpha.-methylacrolein, .alpha.-chloroacrolein, .alpha.-phenylacrolein, .alpha.-ethylacrolein, .alpha.-isopropylacrolein, .alpha.-n-butylacrolein, or .alpha.-n-propylacrolein. 9. Microparticles according to claim 7, wherein the dialdehyde is glutaraldehyde, succinaldehyde, or a derivative thereof. 10. Microparticles according to claim 2, wherein the additive capable of copolymerization is .alpha.-substituted acrolein, .beta.-substituted acrolein, ethyl cyanoacrylate, methyl cyanoacrylate, butyl cyanoacrylate, hexyl cyanoacrylate, methyl methacrylate, a vinyl alcohol, an acrylic acid, a methacrylic acid, an acrylic acid chloride, a methacrylic acid chloride, acrylonitrile, methacrylonitrile, an acrylamide, a substituted acrylamide, an hydroxy methyl methacrylate, mesityl oxide, a dimethylaminoethylmethacrylate-2-vinylpyridine, and/or N-vinyl-2-pyrrolidinone. 11. A process for the production of microparticles according to claim 1, consisting essentially of: reacting, with mixing, the desired polymerizable aldehyde(s), with an aqueous solution saturated with the desired gas and/or containing the desired liquid with a boiling point below 60.degree. C., at a temperature of -5.degree. C. to +80.degree. C. and a pH of 7 to 14, within 1 minute to 24 hours, wherein the concentration of the aldehyde relative to the reaction mixture is 0.1 to 50 w/v; after the polymerization has finished, separating particles containing said gas or liquid below 60.degree. C. from particles not containing said gas or liquid; and optionally, purifying the particles containing said gas or liquid below 60.degree. C. 12. A process for the production of microparticles according to claim 11, further comprising: reacting the microparticles thus obtained with an aqueous solution which contains, relative to the mount of aldehyde, up to an equimolar amount of a coupling agent, with stirring, for up to 3 days, at temperatures of 0.degree. C. to 60.degree. C., and a pH of 3 to 9, and binding a bio- or macromolecule to the resultant microparticles. 13. A process for the production of microparticles according to claim 12, further comprising binding a bio- or macromolecule to the resultant microparticles. 14. A process for the production of microparticles according to claim 11, wherein the polymerizable aldehyde reactant contains a crosslinking agent in a concentration of up to 20% w/v. 15. A process for the production of microparticles according to claim 11, wherein the polymerizable aldehyde reactant contains a crosslinking agent in a concentration of up to 5 % w/v. 16. A process for the production of microparticles according to claim 11, wherein the reaction mixture contains a surfactant in a concentration of from 0.01 to 10% w/v. 17. A process for the production of microparticles according to claim 11, wherein the desired gas is passed through the reaction mixture. 18. Microparticles according to claim 7, wherein the .alpha.,.beta.-unsaturated aldehyde is acrolein, crotonaldehyde, or propynoicaldehyde. 19. A pharmaceutical composition comprising microparticles according to claim 1 and a pharmaceutically acceptable adjuvant. 20. A method of obtaining an ultrasonic image comprising administering to a patient microparticles of claim 1 and taking an ultrasonic image of the patient. 21. Microparticles of claim 2, wherein the surfactant is polyethylene oxide; a carboxylic acid salt; a polyoxyethylene fatty acid ester; sodium dioctyl sulfosuccinate; polyglutaraldehyde sodium hydrogen sulfite adduct; polyethylene glycol, a polyoxyethylene polyoxypropylene, sodium oleate, or polyoxyethylene stearate. 22. Microparticles of claim 1, wherein the gas or highly volatile liquid is ammonia, air, helium, neon, argon, xenon, krypton, a sulfur halide, sulfur hexalfluoride, nitrogen, carbon oxides, oxygen, hydrogen, methane, ethane, propane, butane, pentane, neopentane, isopentane, cyclopentane, ethylene, propylene, acetylene, 3,3-dimethyl-1-butyne, 2,3-pentadiene, 2-methyl-2-butene, 2-methyl-1,3-butadiene, 2-butyne, 2-methyl-1-butene, 3-methyl-1-butene, methylene chloride, 1,1-dichloroethylene, isopropyl chloride, dibromodifluoromethane, bromomethane, dimethyl ether, diethyl ether, a fluorinated ether, dimethylaminoacetone, propylene oxide, N-ethylmethylamine, N-ethyldimethylamine, and/or furan. 23. Microparticles of claim 5, wherein said coupling agent is hydroxylamine, butylamine, allylamine, ethanolamine, trishydroxymethylaminomethane, 3-amino-1-propanesulfonic acid, 5-aminovaleric acid, 8-aminooctanoic acid, D-glucosamine hydrochloride, aminogalactose, aminosorbitol, aminomannitol, diethylaminoethylamine, an aniline, sulfonyl acid amide, choline, N-methylglucamine, piperazine, 1,6-hexanediamine, urea, hydrazine, glycine, alanine, lysine, serine, valine, leucine, a peptide, a protein, albumin, human serum albumin, polylysine, gelatin, a polyglycolamine, an aminopolyalcohol, a dextran sulfate with amino groups, N-aminopolyethylene glycol (HO-PEG-NH.sub.2), N,N"-diaminopolyethylene glycol (NH.sub.2 -PEG-NH.sub.2), an antibody, an immunoglobulin, PEG linker asparaginic acid, PEG linker glutaminic acid, PEG linker DTPA, PEG linker EDTA, 1,3-propanediol, glycerol, or pentaerythritol. 24. Microparticles of claim 1, wherein said biomolecule is a monoclonal antibody. 25. A pharmaceutical composition according to claim 19, wherein the concentration of microparticles is 1 microgram to 100 mg per ml the composition.

Details for Patent 5,501,863

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Grifols Therapeutics Llc	ALBUKED, PLASBUMIN-20, PLASBUMIN-25, PLASBUMIN-5	albumin (human)	For Injection	101138	10/21/1942		2013-03-26
Baxalta Us Inc.	BUMINATE, FLEXBUMIN	albumin (human)	Injection	101452	03/03/1954		2013-03-26
Csl Behring Ag	ALBURX	albumin (human)	Injection	102366	07/23/1976		2013-03-26