Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-07
2001-07-24
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S603000, C514S912000
Reexamination Certificate
active
06265435
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the field of ophthalmic drug delivery and more particularly, to enhanced penetration of corneal membranes of the eye by water soluble therapeutic agents.
BACKGROUND OF THE INVENTION
In order for an ophthalmic drug to be therapeutically effective, it is generally necessary for the drug to penetrate the cornea, where it may be taken up in the aqueous humor and other tissues in the inner eye. Drugs or drug products which act on the exterior surface of the cornea for treating dryness or irritation. Thus, the treatment of physiological conditions within the eye requires the movement of topically applied ophthalmic drugs through the cornea.
To pass through the cornea, a drug must penetrate three layers of tissue, namely, the epithelium, stroma and endothelium. Lipid soluble compounds more easily penetrate such membrane barriers that are rich in lipids, while water soluble compounds more easily penetrate water rich membrane barriers. The epithelial and endothelial cell membranes are relatively lipid rich, while the stroma has a relatively high water content. Since topically applied drugs must penetrate these differently structured barriers, it would appear that an ideal drug compound should be both lipid and water soluble.
The stroma and endothelium together are approximately 360 microns thick and these layers allow penetration by aqueous solutions through a process of inter-cellular diffusion. There is no particular need for enhancing the aqueous diffusion rate through the stroma or endothelium, since the epithelium is the only operative barrier to aqueous penetration of the cornea. Therefore, enhanced penetration of topically applied aqueous drugs through the corneal epithelium would proportionately increase the total drug dosage absorbed into the eye as is obviously desirable.
Prior to the present invention, there have been attempts to enhance the penetration of drugs through the corneal epithelium to an optimal point at which the stroma alone controls drug transport through the cornea. These attempts have included use of chemical agents to enhance drug penetration of the epithelium. It has been reported that benzalkonium chloride (BAC), bile salts, dimethyl sulfoxide (DMSO), ethylenediamine tetraacetate (EDTA) and 1-dodecylazayl-cycloheptan-2-one (AZONE<<)enhance the corneal penetration of certain drugs. The following publications may be referred to for further background concerning the use of such agents to enhance corneal penetration:
Acta Ophthalmological,
Vol. 53, p. 365 (1975);
J. Phar. Pharmacol.
Vol. 39, p. 124 (1987);
Chem. Abstracts,
Vol. 106, 125934t, p. 402 (1987);
Journal of Pharmaceutical Sciences,
Vol. 77, No. 1 (January, 1988); and
Investigative Ophthalmology and Visual Science,
Vol. 29, No. 2 (February, 1988). Notwithstanding such prior attempts, there continues to be a need for a means of safely and effectively enhancing the penetration of the cornea by ophthalmic drugs in aqueous solution.
A first object of the present invention therefore, is to provide an improved rate of epithelium penetration by topical ophthalmic drugs in aqueous solution. A second object is that this improved penetration rate be achieved in a completely safe manner, without ocular irritation or other undesirable side effects. A third object is that methods of the present invention be simple and readily accomplished without the need of clinical oversight.
SUMMARY OF THE INVENTION
The present inventions contemplate a unique utilization of electrochemical mechanisms for penetration of the epithelium by ophthalmic drugs in aqueous solution. Practice of the present inventions uses some steps, compounds and apparatus well known in the biological and ophthalmological arts and therefore, not the subject of detailed discussion herein.
A topical loop diuretic applied to the corneal epithelium blocks outwardly directed ion movement of the Na
+
2Cl
−
K
+
cotransporter in the baso-lateral membrane so that the net inwardly directed ion movement is increased. In this circumstance, transport through the corneal epithelium of a topical ophthalmic drug in aqueous solution is facilitated by inwardly directed solvent drag. This enhancement of the transport rate through the corneal epithelium makes it more nearly consistent with the normal aqueous diffusion rate through the stroma and endothelium and increases total drug penetration of the cornea. Thus, the addition of a loop diuretic to an aqueous, non-ionic ophthalmic drug solution provides more efficient and more effective treatment for internal eye conditions in either clinical or non-clinical circumstances.
REFERENCES:
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patent: 5182258 (1993-01-01), Chiou
patent: 5221696 (1993-06-01), Ke et al.
patent: 5227372 (1993-07-01), Folkman
patent: 5258374 (1993-11-01), Bianco
patent: 5585401 (1996-12-01), Brandt et al.
patent: 5661130 (1997-08-01), Meezan et al.
patent: 5763491 (1998-06-01), Brandt et al.
patent: 5814655 (1998-09-01), Patel et al.
Current Eye Research, vol. 4 No. 4, 1985 “Transport Processes Across the Rabbit Corneal Epithelium” by Klyce & Crosson.
Journal of Membrane Biology, 66, 133-144, “Effects of At+on Ion Transport by Corneal Epithelium of the Rabbit”, by Klyce & Marshall.
Journal of Membrane Biology, 95, 229-240, 1987 “Intracellular Ion Concentrations in the Frog Corneal Epithelium During Stimulation and Inhibition of Ion Secretion” by Roger Rick et al.
Bryan John F.
Fay Zohreh
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