WO1998056379A1

WO1998056379A1 - Compositions and methods for treating glaucoma

Info

Publication number: WO1998056379A1
Application number: PCT/US1998/010779
Authority: WO
Inventors: Billie M. York
Original assignee: Alcon Laboratories, Inc.
Priority date: 1997-06-11
Filing date: 1998-06-09
Publication date: 1998-12-17
Also published as: AU7799898A

Abstract

Compositions and methods for lowering and controlling elevated IOP are disclosed.

Description

COMPOSITIONS AND METHODS FOR TREATING GLAUCOMA

The invention is directed to the use of a reversible cholinesterase inhibitor to lower and control the elevated intraocular pressure (IOP) associated with primary open angle glaucoma or ocular hypertension. The reversible cholinesterase inhibitor can also be used in closed angle glaucoma because it induces miosis which reduces angle crowding.

Background of the Invention

U.S. Patent No. 4,895,841 is directed to certain cyclic amine compounds and their pharmaceutical use, in particular, for the treatment of senile dementia. The compounds are acetylcholinesterase inhibitors. The patent discloses the compound, l-benzyl-4-[(5,6- dimethoxy-l-indanon-2yl)methyl]piperidine, also known as E 2020. U.S. Patent No. 5,100,901 and European Patent Application Nos. 0 579 263 Al and 0 296 560 A2 also disclose the compound and are related applications. None of the patents or applications disclose the compounds for use in lowering elevated IOP or treating glaucoma or ocular hypertension.

Cholinesterase inhibitors have been used to lower IOP, for example, echothiophate iodide (Phospholine Iodide^®, Wyeth Ayerst) and demecarium bromide (Humorsol^®, Merck and Co., Inc.). Both of these compounds are strong, or long acting, cholinesterase inhibitors which, although effective in lowering IOP, cause significant side effects, such as miosis, nearsightedness, and brow ache.

The compound, l-benzyl-4-[(5,6-dimethoxy-l-indanon-2yl)methyl]piperidine, is a reversible cholinesterase inhibitor and is effective in lowering IOP, but without the severe side effects associated with prior cholinesterase inhibitors. Summary of the Invention

This invention is directed to compositions of E2020 and its isomers and methods for its use in lowering and controlling the elevated IOP associated with glaucoma and ocular hypertension.

Description of Preferred Embodiments

The present invention is directed to using l-benzyl-4-[(5,6-dimethoxy-l-indanon- 2yl)methyl]piperidine (E 2020), and its stereo and optical isomers, hereinafter "Compound," to lower and control the elevated IOP associated with glaucoma or ocular hypertension.

The Compound can be administered systemically or topically to the eye, preferably topically in pharmaceutically acceptable formulations at concentrations from about 0.01 to 1.0 weight percent (wt.%), preferably .05 to 0.5 wt.%.

Various types of formulations are suitable for topical delivery to the eye. The Compound may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving the Compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the Compound. Furthermore, the ophthalmic solution may contain a thickener such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. In order to prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-940, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated. A formulation containing the Compound is administered to the eye of a person suffering from glaucoma or ocular hypertension 1-4 times per day according to the discretion of a skilled clinician.

The following example is illustrative, but not limiting.

Example 1

Wt.% Based

Ingredient on Free Base

Compound (free base or 0.1 hydrochloride salt) Dibasic Sodium Phosphate (Anhydrous) 0.50 Sodium Chloride 0.60

Benzalkonium Chloride Solution (10%) 0.01 + 3% XS Hydrochloric Acid or Sodium Hydroxide Adj. pH 6.8-7.2 Purified Water Q.S.

Example 2

Wt.% Based

Ingredient on Free Base

Compound (free base or 0.1 hydrochloride salt) Benzalkonium Chloride 0.01 + 5% XS Tris (Hydroxymethyl) Aminomethane 0.5 Sodium Chloride 0.68 Hydroxypropyl Methylcellulose 0.25 Sodium Hydroxide or Hydrochloric Acid Adj. pH 7.4 Purified Water Q.S.

Claims

I Claim:

1. A method for lowering and controlling the elevated intraocular pressure associated with glaucoma or ocular hypertension, which comprises, administering a pharmaceutically effective amount ofthe compound, l-benzyl-4-[(5,6-dimethoxy-l-indanon-

2yl)methyl]piperidine or an isomer thereof.

2. The method of claim 1 wherein the compound is administered topically to the affected eye.

3. The method of claim 2 wherein the compound is administered at a concentration of 0.01 to 1.0 wt.%.

4. The method of claim 3 wherein the compound is administered at a concentration of .05 to 0.5 wt.%).

5. A composition for lowering and controlling the elevated intraocular pressure associated with glaucoma or ocular hypertension, comprising, a pharmaceutically effective amount ofthe compound, l-benzyl-4-[(5,6-dimethoxy-l-indanon-2yl)methyl]piperidine or an isomer thereof.

6. The composition of claim 5 wherein the concentration ofthe compound is 0.01 to 1.0 wt.%.

7. The composition of claim 6 wherein the concentration ofthe compound is administered at a concentration of .05 to 0.5 wt.%.