Methods and compositions for treatment of macular and retinal disease
The present invention describes linking a therapeutic agent to a compound which is known to be naturally concentrated in a tissue affected by, or that is causing, a disease, to create a prodrug for treatment of the disease. Embodiments of the present invention include a new class of carotenoid-linked drugs to treat such blinding retinal disease such as age-related macular degeneration, retinoblastoma, and diabetic macular edema. For example, the present invention comprises a method for the treatment of a disorder of the eye comprising linking a therapeutic agent to a xanthophyll carotenoid to create a prodrug, and administering a therapeutically effective amount of the prodrug to an individual in need of treatment. Provided are prodrugs for treatment of retinoblastoma, cystoid macular edema (CME), exudative age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, or inflammatory disorders.
1. A method for the treatment of an inflammatory disorder of the eye comprising linking a therapeutic agent comprising an anti-inflammatory agent comprising at least one of a steroid or a non-steroidal anti-inflammatory drug (NSAID) to a xanthophyll carotenoid to create a prodrug, and administering a pharmaceutically effective amount of the prodrug to an individual in need of treatment, wherein a pharmaceutically effective amount of the prodrug comprises an amount sufficient to ameliorate, said eye disorder.
2. The method of claim 1 , wherein the therapeutic agent comprises ketorolac, triamcinolone, or fluocinolone.
3. The method of claim 1 , wherein the xanthophyll comprises lutein.
4. The method of claim 1 , wherein the xanthophyll comprises zeaxanthini.
5. the method of claim 1 , wherein the xanthophyll carotenoid comprises either (3R, 3′R, 6′R)-lutein or (3R, 3′R)-zeaxanthin.
6. The method of claim 1 , wherein the therapeutic agent comprises at least one of a cyclooxygenase inhibitor or a prostaglandin inhibitor.
7. The method of claim 1 , wherein the xanthophyll carotenoid comprises at least one of 3′-epilutein, meso-zeaxanthin, or 3-hydroxy-beta epsilon-caroten-3′ one.
8. The method of claim 1 , wherein the therapeutic agent is effective for treatment of at least one of cystoid macular edema (CME), posterior uveitis, exudative age-related macular degeneration (AMD), diabetic retinopathy, or diabetic macular edema.
9. The method of claim 1 , wherein the linkage between the therapeutic agent and the carotenoid comprises a biologically cleavable bond.
10. The method of claim 1 , wherein there is a direct bond linking the therapeutic agent to the carotenoid.
11. The method of claim 1 , wherein a spacer molecule is used to link the therapeutic agent to the carotenoid.
12. The method of claim 1 , wherein the linkage between the therapeutic agent and the carotenoid comprises an amino acid spacer, a carbonate spacer, an ester bond, an amide bond, or a dicarboxylic amino acid.
13. The method of claim 1 , comprising systemic administration of the prodrug.
14. The method of claim 1 , comprising intravenous administration of the prodrug.
15. The method of claim 1 , comprising subcutaneous or topical administration of the prodrug.
16. The method of claim 1 , comprising intramuscular administration of the prodrug.
17. The method of claim 1 , comprising oral administration of the prodrug.
18. The method of claim 1 , further comprising having the individual reduce their intake of dietary carotenoids prior to application of the prodrug.
19. The method of claim 1 , wherein the prodrug is administered in a dosage amount that ranges from 100 mg/kg q.d. to 0.01 mg/kg q.d.
20. A method for the treatment of a disease of the eye comprising linking a therapeutic agent comprising at least one of ketorolac, triameinolone, or fluocinolone to a xanthophyll carotenoid comprising at least one of a zeaxanthin or a lutein compound to create a prodrug, and administering a pharmaceutically effective amount of the prodrug to an individual in need of treatment, wherein a pharmaceutically effective amount of the prodrug comprises an amount sufficient to ameliorate disease, wherein the disease comprises at least one of cystoid macular edema (CME), posterior uveitis, exudative age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, or inflammation.
21. The method of claim 20 , wherein a spacer molecule is used to link the therapeutic agent to the xanthophyll carotenoid.
22. The method of claim 20 , wherein the linkage between the therapeutic agent and the xanthophyll carotenoid comprises a biologically cleavable bond.
23. The method of claim 20 , wherein the linkage between the therapeutic agent and the xanthophyll carotenoid comprises an amino acid spacer, a carbonate spacer, an ester bond, an amide bond, or a dicarboxylic amino acid.
24. The method of claim 20 , wherein the prodrug is administered by at least one of topical administration, systemic administration, intravenous administration, subcutaneous administration, oral administration, or intramuscular administration.
25. The method of claim 20 , wherein the xanthophyll carotenoid comprises at least one of (3R, 3′R, 6′R)-lutein, (3R, 3′R)-zeaxanthin, 3′-epilutein, meso-zeaxanthin, or 3-hydroxy-beta epsilon-caroten-3′ one.
26. The method of claim 20 , wherein there is a direct bond linking the therapeutic agent to the xanthophyll carotenoid.