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Ophthamological drugs

a technology of ophthamological drugs and ophthalmic drugs, which is applied in the field of ophthamological drugs, can solve the problems of loss of vision, elevated intraocular pressure, and elevated pressure, and achieve the effect of increasing their penetration through the cornea

Inactive Publication Date: 2006-06-22
DUKE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] The present invention relates generally to ophthamological drugs. More specifically, the inventon relates to a method of modifying (derivatizing) ophthamological drugs so as to increase their penetration through ...

Problems solved by technology

The neuronal death results in loss of vision once a sufficient number of individual nerves are destroyed.
Elevated intraocular pressure (IOP) is the leading cause of glaucoma.
Pressure is elevated because drainage of aqueous fluid from within the eye is impaired.
Glaucoma patients may also suffer reduced blood flow to the optic nerve and neuronal tissue, and diminished resistance of the nerve tissue to damage, and the compliance of connective tissue surrounding and supporting the optic nerve.
Unfortunately, many esters are too hydrophobic (non-polar) to diffuse out of the relatively non-polar external layer of the cornea (corneal epithelium) and into the aqueous humor.
Further complicating delivery, such compounds are often too insoluble to formulate in aqueous solutions.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0089] Preparation of 5-O-Ribitol[2,3-dichloro-4-(thiophene-2-carbonyl)]phenoxyacetate (Formula III), with reference to Scheme I.

[0090] To a stirring suspension of ticrynafen (0.40 g, 1.2 mmol) in anhydrous benzene (1.5 mL) was added thionyl chloride (0.18 mL, 2 equiv) at room temperature. The reaction was heated to reflux, at which time all ticrynafen dissolved. Reflux was maintained for 2.5 h and the reaction was cooled and concentrated at reduced pressure. The residual oil was resuspended in anhydrous THF (2 mL), and added dropwise at room temperature to a stirring solution of 1,2:3,4-di-O-isoproylideneribitol (0.28 g), triethylamine (0.57 mL) in THF (1 mL). The reaction was stirred at room temperature for 16 h, concentrated at reduced pressure and resuspended in EtOAc (100 mL). This solution was extracted with water (2×50 mL) and brine (50 mL), and dried (anhydrous MgSO4). The solvents were evaporated in vacuo, and the crude products were purified by flash chromatography (elut...

example 2

[0092] Ticrynafen (Formula IV) is a drug of known activity against glaucoma. The free acid, as the carboxylate salt, has little or no activity presumably because penetration through the cornea into the anterior chamber is negligible. Simple esters of ticrynafen are highly insoluble and also show little or no activity. In contrast, the ribitol ester of ticrynafen (Formula III) is completely soluble in petrolatum / lanolin mixtures. The compound reduces intraocular pressure (IOP) in a dose-dependent fashion in Dutch-Belted white rabbits (see Example 3 and FIGS. 1-4).

example 3

[0093] Ticrynafen-ribitol ester was formulated as an ointment in 5, 10, and 15% concentrations. The Dutch Belted rabbit model was used to test the formulation for both pressure lowering and side effects.

[0094] Baseline intraocular pressures were obtained by placing one drop of proparacaine in each eye followed by pressure measurements utilizing a Pneumotonometer®. One eye of each rabbit was then given 0.1 mg of ticrynafen-ribitol ester ointment topically in the inferior conjunctival sac. The second eye was used as a control with application of lanolin ointment without drug. Repeat doses were given at 24 hour intervals for a total of three doses (0, 24, and 48 hours). Intraocular pressures were recorded every 12 hours for one week. A total of twelve rabbits received the 5% ointment, eight rabbits the 10% ointment, and eight rabbits the 15% ointment.

[0095] Pressure reduction for each concentration is shown in FIGS. 1, 2 and 3. FIG. 4 presents the 10% data with statistically signific...

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Abstract

The present invention relates generally to ophthamological drugs. More specifically, the inventon relates to a method of modifying (derivatizing) ophthamological drugs so as to increase their penetration through the cornea. The invention also relates to drugs modified (derivatized) in accordance with the instant method and to the use of same in treating conditions associated with elevated intraocular pressure, particularly, glaucoma.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 60 / 620,320 filed Oct. 21, 2004, the entire content of which is hereby incorporated by reference.TECHNICAL FIELD [0002] The present invention relates, in general, to ophthamological drugs, and, in particular, to a method of modifying ophthamological drugs so as to increase their penetration through the cornea into the anterior chamber. The invention further relates to such modified drugs and to the use of same in treating diseases / disorders of the eye, such as glaucoma and other conditions related to elevated intraocular pressure. BACKGROUND [0003] Glaucoma is one of the three leading causes of blindness in the United States and a leading cause of blindness in the world. Over 2.2 million people in the United States have glaucoma, and several million more are at risk of developing the disease. As the population ages, the number of individua...

Claims

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Application Information

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IPC IPC(8): A61K31/225
CPCA61K31/225A61K31/712C07C69/712C07C69/738C07H13/04A61P27/02A61P27/06
Inventor TOONE, ERIC J.EPSTEIN, DAVID L.CHALLA, PRATAPSNYDER, PHILLIP W.CHEN, XINDELONG, MITCHELL A.
Owner DUKE UNIV
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