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Claims for Patent: 5,248,492

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Claims for Patent: 5,248,492

Title: Low molecular weight carbohydrates as additives to stabilize metal oxide compositions
Abstract:This invention relates to compositions comprising a colloidal or particulate metal oxide which are stabilized by low molecular weight carbohydrates. The carbohydrates are characterized by the fact that a) they are not retained on the surface of the metal oxide based on the equilibrium room temperature dialysis of about 2 ml of the metal oxide composition at 0.2M metal concentration against deionized water; and b) they impart sufficient stability to the metal oxide compositions such that the compositions can withstand heat stress without perceptible aggregation as determined by a prescribed test procedure.
Inventor(s): Groman; Ernest V. (Brookline, MA), Josephson; Lee (Arlington, MA)
Assignee: Advanced Magnetics, Inc. (Cambridge, MA)
Application Number:07/860,388
Patent Claims: 1. An improved parenterally administrable composition, comprising a colloidal or particulate biodegradable superparamagnetic metal oxide in a physiologically acceptable carrier, which metal oxide is capable of being biodegraded by a subject within about two weeks or less after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of said subject to preadministration levels, and is filterable through a 0.8 micron filter, wherein the improvement comprises the addition to said carrier of:

an effective amount of a physiologically acceptable, soluble, stabilizer, which stabilizer is selected from the group consisting of a low molecular weight carbohydrate, a low molecular weight linear polyalcohol, inositol and ascorbate; and which stabilizer

(a) is not retained on the surface of said metal oxide based on the equilibrium room temperature dialysis of about 2 ml of said composition at 0.2M metal concentration against deionized water; and

(b) imparts improved physical stability to said composition as determined by heating said composition at about 55.degree. C. for about 3 days and then filtering said composition through a 0.8 micron filter, whereafter substantially no precipitate is visible on said filter.

2. An improved parenterally administrable composition, comprising a colloidal or particulate biodegradable superparamagnetic metal oxide in a physiologically acceptable carrier, which metal oxide is capable of being biodegraded by a subject within about two weeks or less after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of said subject to preadministration levels, and is filterable through a 0.8 micron filter, wherein the improvement comprises the addition to said carrier of:

an effective amount of a physiologically acceptable, soluble, stabilizer, which stabilizer is selected from the group consisting of a low molecular weight carbohydrate, a low molecular weight linear polyalcohol, inositol and ascorbate; and which stabilizer

(a) is not retained on the surface of said metal oxide based on the equilibrium room temperature dialysis of about 2 ml of said composition at 0.2M metal concentration against deionized water; and

(b) imparts improved physical stability to said composition as determined by autoclaving said composition at about 121.degree. C. for about 30 minutes and then filtering said composition through a 0.8 micron filter, whereafter substantially no precipitate is visible on said filter.

3. The composition of claim 1 or 2 wherein said metal oxide is a transition metal oxide.

4. The composition of claim 1 or 2 wherein said metal is selected from the group consisting of iron, chromium, cobalt, manganese and mixed metals thereof.

5. The composition of claim 1 or 2 in which the stabilizer is present at a concentration of about 0.001M to about 2M.

6. The composition of claim 1 or 2 wherein said stabilizer has a molecular weight below 5.000 daltons.

7. The composition of claim 6 wherein said stabilizer is a low molecular weight linear polyalcohol.

8. The composition of claim 7 wherein said low molecular weight linear polyalcohol is selected from the group consisting of mannitol, sorbitol and glycerol.

9. The composition of claim 1 or 2 wherein said low molecular weight carbohydrate is dextran having a molecular weight of about 1,000 daltons.

10. The composition of claim 1 or 2 wherein said low molecular weight linear polyalcohol is mannitol.

11. The composition of claim 1 or 2 wherein said stabilizer is ascorbate.

12. The composition of claim 1 or 2 in which said carrier comprises a buffer.

13. The composition of claim 1 or 2 in which said carrier further comprises a preservative.

14. The composition of claim 1 or 2 wherein said stabilizer is inositol.

15. A method for obtaining an in vivo MR image of an organ or tissue of an animal or human subject which comprises:

(a) parenterally administering to such subject the composition of claim 1 or 2;

(b) imaging said organ or tissue.

16. A method for reducing anemia in an animal or human subject which comprises parenterally administering to such subject the composition of claim 1 or 2 wherein the metal in said composition is iron.

17. The composition of claim 1 or 2 in which the metal oxide comprises an uncoated biodegradable superparamagnetic metal oxide.

18. An improved water-based ferrofluid composition, comprising a colloidal or particulate biodegradable superparamagnetic metal oxide in an acceptable carrier, which metal oxide is capable of being biodegraded by a subject within about two weeks or less after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of said subject to preadministration levels, and an effective amount of a soluble, stabilizer, which stabilizer is selected from the group consisting of a low molecular weight carbohydrate, a low molecular weight linear polyalcohol, inositol and ascorbate; and which stabilizer

(a) is not retained on the surface of said metal oxide based on the equilibrium room temperature dialysis of about 2 ml of said composition at 0.2M metal concentration against deionized water; and

(b) imparts improved physical stability to said composition as determined by heating said composition at about 55.degree. C. for about 3 days and then filtering said composition through a 0.8 micron filter, whereafter substantially no precipitate is visible on said filter.

19. An improved water-based ferrofluid composition, comprising a colloidal or particulate biodegradable superparamagnetic metal oxide in an acceptable carrier, which metal oxide is capable of being biodegraded by a subject within about two weeks or less after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of said subject to preadministration levels, and an effective amount of a soluble, stabilizer, which stabilizer is selected from the group consisting of a low molecular weight carbohydrate, a low molecular weight linear polyalcohol, inositol and ascorbate; and which stabilizer

(a) is not retained on the surface of said metal oxide based on the equilibrium room temperature dialysis of about 2 ml of said composition at 0.2M metal concentration against deionized water; and

(b) imparts improved physical stability to said composition as determined by autoclaving said composition at about 121.degree. C. for about 30 minutes and then filtering said composition through a 0.8 micron filter, whereafter substantially no precipitate is visible on said filter.

20. A method for stabilizing a biodegradable superparamagnetic metal oxide composition comprising a colloidal or particulate metal oxide in a liquid carrier, which metal oxide is capable of being biodegraded by a subject within about two weeks or less after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of said subject to preadministration levels, which method comprises adding an effective amount of a soluble stabilizer to said carrier, which stabilizer is selected from the group consisting of a low molecular weight carbohydrate, a low molecular weight linear polyalcohol, inositol and ascorbate; and which stabilizer

(a) is not retained on the surface of said metal oxide based on the equilibrium room temperature dialysis of about 2 ml of said composition at 0.2M metal concentration against deionized water; and

(b) imparts stability to said composition as determined by heating said composition at about 55.degree. C. for about 3 days and then filtering said composition through a 0.8 micron filter, whereafter no precipitate is visible on said filter.

21. A method for stabilizing a biodegradable superparamagnetic metal oxide composition comprising a colloidal or particulate metal oxide in a liquid carrier, which metal oxide is capable of being biodegraded by a subject within about two weeks or less after administration, as evidenced by a return of proton relaxation rates of an affected organ or tissue of said subject to preadministration levels, which method comprises adding an effective amount of a soluble stabilizer to said carrier, which stabilizer is selected from the group consisting of a low molecular weight carbohydrate, a low molecular weight linear polyalcohol, inositol and ascorbate; and which stabilizer

(a) is not retained on the surface of said metal oxide based on the equilibrium room temperature dialysis of about 2 ml of said composition at 0.2M metal concentration against deionized water; and

(b) imparts stability to said composition as determined by autoclaving said composition at about 121.degree. C. for about 30 minutes and then filtering said composition through a 0.8 micron filter, whereafter no precipitate is visible on said filter.

22. The method of claim 20 or 21 wherein said composition is selected from the group consisting of parenterally administrable MR contrast agent compositions, parenterally administrable compositions for reducing anemia and ferrofluids.

23. The composition of claim 18 or 19 in which the metal oxide comprises an uncoated biodegradable superparamagnetic metal oxide.

24. The method of claim 20 or 21 in which the metal oxide comprises an uncoated biodegradable superparamagnetic metal oxide.
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