Claims for Patent: 4,416,992

Summary for Patent: 4,416,992

Title:	Support matrices and immobilized enzyme systems
Abstract:	Support matrices are prepared by titanating the surface hydroxyl groups of refractory inorganic oxides with a titanium tetrahalide, such as TiCl.sub.4, reacting each of the remaining halogens of the surface-titanated oxide with one of the amino groups of diamine, and thereafter reacting the remaining amino group with one of the functional groups of a dialdehyde or diisocyanate. Titanating is carried out by contacting a refractory inorganic oxide with titanium tetrahalide, preferably in the absence of a solvent for the titanium tetrahalide, removing excess and unreacted titanium tetrahalide and heating the titanated inorganic oxide at a temperature of from about 80.degree. C. to about 200.degree. C. in an inert atmosphere of nitrogen, argon or helium, or in a vacuum. Such support matrices may be used to bind enzymes, affording effective immobilized enzyme systems.
Inventor(s):	Arena; Blaise J. (Des Plaines, IL), Rohrbach; Ronald P. (Forest Lake, IL)
Assignee:	UOP Inc. (Des Plaines, IL)
Application Number:	06/362,206
Patent Claims:	1. A method of preparing a support matrix comprising contacting a porous, refractory inorganic oxide selected from the group consisting of alumina, silica, titania, thoria, and combinations thereof, with titanium tetrahalide in the absence of a solvent for the titanium tetrahalide so as to produce a surface titanated inorganic oxide, removing excess and unreacted titanium tetrahalide, heating the titanated inorganic oxide at a temperature from about 80.degree. to about 200.degree. C. in an inert atmosphere of nitrogen, argon, helium, or in a vacuum, for a time sufficient to volatilize any remaining unreacted titanium tetrahalide, contacting the resulting material with a diamine, selected from the group of alkylene diamines containing from 2 to about 10 carbon atoms and phenylene diamine, or a polyamine of formula H.sub.2 N(CH.sub.2 CH.sub.2 NH).sub.x H, where x is an integer from 2 to about 2300, removing excess amine, treating the resulting material with an excess of a bifunctional reagent selected from the group consisting of phthalaldehyde, toluene diisocyanate, and X(CH.sub.2).sub.p X, where X is an aldehyde, CHO, or isocyanate, NCO, functional group and p is an integer from 2 to about 8, removing the excess and unreacted bifunctional reagent, and recovering the resulting support matrix. 2. The method of claim 1 where the oxide is alumina. 3. The method of claim 1 where the diamine is an alkylene diamine whose formula is H.sub.2 N(CH.sub.2).sub.n NH.sub.2, where n is an integer from 2 to about 10. 4. The method of claim 3 where the diamine is selected from the group consisting of 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane. 5. The method of claim 1 where the diamine is a phenylenediamine. 6. The method of claim 1 where the bifunctional reagent is selected from the group consisting of succindialdehyde, glutaraldehyde, adipaldehyde, phthalaldehyde, and phenylisocyanate. 7. The method of claim 1 where the halide of titanium tetrahalide is selected from the group consisting of fluorine, chlorine, and bromine. 8. The method of claim 7 where the halide of titanium tetrahalide is chlorine. 9. The method of preparing an immobilized enzyme system comprising contacting a porous, refractory inorganic oxide selected from the group consisting of alumina, silica, titania, thoria, and combinations thereof, with titanium tetrahalide in the absence of a solvent for the titanium tetrahalide so as to produce a surface-titanated inorganic oxide, removing excess and unreacted titanium tetrahalide, heating the titanated inorganic oxide at a temperature from about 80.degree. to about 200.degree. C. in an inert atmosphere of nitrogen, argon, helium, or in a vacuum, for a time sufficient to volatilize any remaining unreacted titanium tetrahalide, contacting the resulting material with a diamine selected from the group of alkylene diamines containing from 2 to about 10 carbon atoms and phenylene diamine, or a polyamine of formula H.sub.2 N(CH.sub.2 CH.sub.2 NH).sub.x H, where x is an integer from 2 to about 2300, removing excess amine, treating the resulting material with an excess of a bifunctional reagent selected from the group consisting of phthalaldehyde, toluene diisocyanate, and X(CH.sub.2).sub.p X, where X is an aldehyde, CHO, or isocyanate, NCO, functional group and p is an integer from z to about 8, removing the excess and unreacted bifunctional reagent, contacting the resulting mass with an enzyme solution, and recovering the formed immobilized enzyme system. 10. The method of claim 9 where the oxide is alumina. 11. The method of claim 9 where the diamine is an alkylene diamine whose formula is H.sub.2 N(CH.sub.2).sub.n NH.sub.2, where n is an integer from 2 to about 10. 12. The method of claim 11 where the diamine is selected from the group consisting of 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane. 13. The method of claim 9 where the diamine is a phenylenediamine. 14. The method of claim 9 where the bifunctional reagent is selected from the group consisting of succindialdehyde, glutaraldehyde, adipaldehyde, phthalaldehyde, and phenylisocyanate. 15. The method of claim 9 where the halide of titanium tetrahalide is selected from the group consisting of fluorine, chlorine, and bromine. 16. The method of claim 15 where the halide of titanium tetrahalide is chlorine. 17. The method of claim 9 where the enzyme is selected from the group consisting of glucose isomerase, glucoamylase, cholesteroloxidase, alcohol dehydrogenase, amino acid oxidase, arginase, asparaginase, catalase, chymotrypsin, cellulase, collagenase, deoxyribonuclease, ficin, histidase, glucose oxidase, lactase, peroxidase, lysozyme, amylase, papain, rennin, ribonuclease, and urease. 18. The support matrix prepared by the method of claim 1. 19. The support matrix of claim 18 where the oxide is alumina. 20. The support matrix of claim 18 where the diamine is an alkylene diamine whose formula is H.sub.2 N(CH.sub.2).sub.n NH.sub.2, where n is an integer from 2 to about 10. 21. The support matrix of claim 20 where the diamine is selected from the group consisting of 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane. 22. The support matrix of claim 18 where the diamine is a phenylenediamine. 23. The support matrix of claim 18 where the bifunctional reagent is selected from the group consisting of succindialdehyde, glutaraldehyde, adipaldehyde, phthalaldehyde, and phenylisocyanate. 24. The support matrix of claim 18 where the halide of titanium tetrahalide is selected from the group consisting of fluorine, chlorine, and bromine. 25. The support matrix of claim 24 where the halide of titanium tetrahalide is chlorine. 26. The immobilized enzyme system prepared by the method of claim 9. 27. The immobilized enzyme system of claim 26 where the oxide is alumina. 28. The immobilized enzyme system of claim 26 where the diamine is an alkylene diamine whose formula is H.sub.2 N(CH.sub.2).sub.n NH.sub.2, where n is an integer from 2 to about 10. 29. The immobilized enzyme system of claim 28 where the diamine is selected from the group consisting of 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane. 30. The immobilized enzyme system of claim 26 where the diamine is a phenylenediamine. 31. The immobilized enzyme system of claim 26 where the bifunctional reagent is selected from the group consisting of succindialdehyde, glutaraldehyde, adipaldehyde, phthalaldehyde, and phenylisocyanate. 32. The immobilized enzyme system of claim 26 where the halide of titanium tetrahalide is selected from the group consisting of fluorine, chlorine, and bromine. 33. The immobilized enzyme system of claim 32 where the halide of titanium tetrahalide is chlorine. 34. The immobilized enzyme system of claim 26 where the enzyme is selected from the group consisting of glucose isomerase, glucoamylase, cholesteroloxidase, alcohol dehydrogenase, amino acid oxidase, arginase, asparaginase, catalase, chymotrypsin, cellulase, collagenase, deoxyribonuclease, ficin, histidase, glucose oxidase, lactase, peroxidase, lysozyme, amylase, papain, rennin, ribonuclease, and urease.

Details for Patent 4,416,992

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2039-03-29
Smith & Nephew, Inc.	SANTYL	collagenase	Ointment	101995	06/04/1965		2039-03-29