AU734789B2

AU734789B2 - Use of a combination of carbonic anhydrease inhibitors and prostaglandins for treating glaucoma

Info

Publication number: AU734789B2
Application number: AU42573/97A
Authority: AU
Inventors: Thomas R. Dean; Jesse A. May
Original assignee: Alcon Laboratories Inc
Current assignee: Alcon Vision LLC
Priority date: 1996-11-01
Filing date: 1997-09-05
Publication date: 2001-06-21
Anticipated expiration: 2017-09-05
Also published as: WO1998019680A1; CA2270349A1; EP0948333A1; AU4257397A; JP2001504100A

Description

WO 98/19680 PCTIUS97/15793 USE OF A COMBINATION OF CARBONIC ANHYDRASE INHIBITORS AND PROSTAGLANDINS FOR TREATING

GLAUCOMA

Background of the Invention The present invention relates to the field of ophthalmology. In particular, the invention relates to the treatment of persons suffering from glaucoma and associated elevations of intraocular pressure (IOP) and/or ocular hypertension.

Although the underlying causes of glaucoma are not understood, its symptoms often include elevated IOP, which may be caused either by over-production or inadequate outflow of aqueous humor. If left untreated, or if inadequately treated, glaucoma can lead to blindness or significant loss of vision. There is therefore a continuing need for therapies which control the elevated intraocular pressure associated with glaucoma.

There are currently a number of drugs used in the treatment of glaucoma and ocular hypertension, including: miotics pilocarpine, carbachol, and acetylcholinesterase inhibitors); sympathomimetics epinephrine, dipivalylepinephrine, and para-amino clonidine); beta-blockers betaxolol, levobunolol, and timolol); and carbonic anhydrase inhibitors (CAls) acetazolamide, methazolamide and ethoxzolamide systemically and dorzolamide topically. Prostaglandins (PGs) are currently being developed for use in treating persons with glaucoma and the PG, latanoprost, marketed as Xalatan®, is available from Pharmacia-Upjohn.

Miotics and sympathomimetics are believed to lower IOP by increasing the outflow of aqueous humor, while beta-blockers and carbonic anhydrase inhibitors are believed to lower IOP by decreasing the formation of aqueous humor. All four types of drugs have potentially serious side effects. Miotics, such as pilocarpine, can cause brow ache, blurring of vision, and other visual side effects, which may lead either to decreased patient compliance or to therapy termination. Systemically administered carbonic anhvdrase inhibitors can also cause serious side effects which affect patient compliance and/or necessitate the withdrawal of treatment. Beta-blockers can be irritating.

Sympathomimetics can cause allergic responses and sedation. Side effects associated with PGs include edema, hyperemia, and foreign body sensation.

A significant number of glaucoma patients require the administration of more than one type of drug in order to achieve therapeutic control over their lOP because a single drug does not provide adequate IOP control. The use of two drugs, each of which affects lOP by a different mechanism, would be useful in treating these patients. The present invention is directed to such use, either by administration of the drugs separately or in combination.

Summary of the Invention is The present invention is directed to methods for treating patients with glaucoma or ocular hypertension wherein their IOP can only be controlled by the use of two IOP lowering drugs, namely, carbonic anhydrase inhibitors and prostaglandins. These drugs may be dosed simultaneously or at different times and may also be formulated in a single composition to provide for convenience and patient compliance.

According to one embodiment of this invention there is provided a method for lowering lOP in persons suffering from glaucoma or ocular hypertension, which comprises administering topically to the eye a pharmaceutically effective amount of a carbonic anhydrase inhibitor selected from the group consisting of brinzolamide, dorzolamide and a mixture of brinzolamide and dorzolamide, and a prostaglandin selected 25 from (+)-isopropyl fluprostenol and isopropyl [2R( E,3R),3 S(4Z),4R]-7-[tetrahydro-2-[4- (3-chlorophenoxy)-3-hydroxy- 1 -butenyl]-4-hydroxy-3-furanyl]-4-heptenoate.

According to another embodiment of this invention there is provided a carbonic anhydrase inhibitor selected from the group consisting of brinzolamide, dorzolamide and a mixture of brinzolamide and dorzolamide, and a prostaglandin selected from isopropyl fluprostenol and isopropyl [2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3chlorophenoxy)-3-hydroxy-l-butenyl]-4-hydroxy-3-furanyl]-4-heptenoate when used in lowering IOP in persons suffering from glaucoma or ocular hypertension.

According to a further embodiment of this invention there is provided the use of a carbonic anhydrase inhibitor selected from the group consisting of brinzolamide, dorzolamide and a mixture of brinzolamide and dorzolamide, and a prostaglandin selected [R:\LIBXX]02501 .doc:aak 2a from (+)-isopropyl fluprostenol and isopropyl [2R(1 E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4- (3-chlorophenoxy)-3-hydroxy- -butenyl]-4-hydroxy-3-furanyl]-4-heptenoate for the manufacture of a medicament for lowering IOP in persons suffering from glaucoma or ocular hypertension.

According to yet a further embodiment of this invention there is provided a method for lowering IOP in persons suffering from glaucoma or ocular hypertension, which comprises administering topically to the eye a pharmaceutically effective amount of a carbonic anhydrase inhibitor and a prostaglandin, wherein the carbonic anhydrase inhibitor is brinzolamide and the prostaglandin is (+)-isopropyl fluprostenol.

According to yet another embodiment of this invention there is provided a carbonic .anhydrase inhibitor and a prostaglandin, wherein the carbonic anhydrase inhibitor is brinzolamide and the prostaglandin is (+)-isopropyl fluprostenol when used in lowering IOP in persons suffering from glaucoma or ocular hypertension.

According to another embodiment of this invention there is provided the use of a 15 carbonic anhydrase inhibitor and a prostaglandin, wherein the carbonic anhydrase inhibitor is brinzolamide and the prostaglandin is (+)-isopropyl fluprostenol for the manufacture of a medicament for lowering IOP in persons suffering from glaucoma or ocular hypertension.

Disclosed is a product containing a pharmaceutically effective amount of a carbonic anhydrase inhibitor and a prostaglandin selected from (+)-isopropyl fluprostenol and isopropyl [2R(1E,3R),3S( 4

Z),

4

R]-

7 -[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1butenyl]- 4 -hydroxy-3-furanyl]-4-heptenoate, as a combined preparation for simultaneous, separate or sequential use in lowering IOP in persons suffering from glaucoma or ocular hypertension.

Also disclosed is a product containing a pharmaceutically effective amount of a carbonic anhydrase inhibitor and a prostaglandin, wherein the carbonic anhydrase inhibitor is brinzolamide and the prostaglandin is (+)-isopropyl fluprostenol, as a combined preparation for simultaneous, separate or sequential use in lowering IOP in persons suffering from glaucoma or ocular hypertension.

[R:\LIBXX]02501 .doc:aak 2b Detailed Description of the Invention Prostaglandins are metabolic derivatives of arachiidonic acid. The arachidonic acid cascade is initiated by the conv'ersion of aracidonic acid to prostaglandin G 2 and its SUbsequent conversion to prostaglandin Othier naturally occurringpotgadn r deri\'atves of p~rostaglandin A number of different types of prostaglandins have been discovered incIluding A, B, D, E, F and I-Series p)rostaglandinls.

[R:\LIBXX]02501 speci.docmaak 1f WO 98/19680 PCT/US97/15793 The prostaglandins which are useful according to the present invention include all prostaglandins which exhibit similar IOP lowering mechanisms as PGD 2 or PGF 2 (Il): HO

HO

COOH

0 OH HO OH (I While Applicants do not wish to be bound by any theory, the D-prostaglandins ("DP-agonist") are believed to inhibit aqueous humor formation and may have an affect on its outflow. F-prostaglandins ("FP-agonist") are believed to increase the outflow of aqueous humor from the eye.

The DP-agonists of the present invention are useful in lowering IOP in humans and other mammals. The DP-agonists of the present invention are functionally defined by their ability to bind to prostaglandin-D 2 receptors of cells and evoke similar responses as when

PGD

2 binds to these receptors inducing the lowering of IOP. Various assays may be used for the determination of DP-agonists.

Binding assays may be used to elucidate DP-agonists of the present invention.

Sharif, et al. have described a receptor binding assay in: Sharif, Williams, G.W. and DeSantis, L.M, Neurochemistry Research, volume 20, pages 669-674 (1995), the entire contents of which are incorporated herein by reference, and may be modified as described below, for the elucidation of DP-agonists of the present invention. Briefly, the binding assays are conducted in 25 mM Tris HCI (pH 7.4) containing 138 mM NaC1, 5 mM MgCl2, and 1 mM EDTA. Frozen-thawed expired human blood platelets (40-60 mg/ml stock) are incubated in a total volume of 500 ml with 2-10 nM 3 H]PGD2 in the absence WO 98/19680 PCT/US97/15793 and presence of 100 mM unlabeled PGD2 to define total and non-specific binding, respectively. The incubations (20 minutes at 23 0 C) are terminated by rapid vacuum filtration, using a Whatman GF/B glass fiber filter previously soaked in 1% polyethyleneimine and 0.1% BSA, and the receptor-bound radioactivity is then determined by scintillation spectrometry. The binding data are analyzed using a non-linear, iterative curve-fitting computer program to define the receptor binding affinity (Ki) of the compounds. Compounds which exhibit Ki values in this assay of less than or equal to about 20 tM are within the definition of DP-agonists of the present invention.

The DP-agonists of the present invention may also be defined functionally, by their ability to stimulate adenylate cyclase activity. Sharif, et al. have described this type of functional assay in: Sharif, Xu, S. and Yanni, Journal of Ocular Pharmacology, volume 10, pages 653-664 (1994), the entire contents of which are incorporated herein by reference, and which may be modified as described below, for the elucidation of DP-agonists of the present invention. Briefly, functional adenylate cyclase activity is determined using embryonic bovine tracheal cells (EbTr) cells. Cultured cells are stimulated with the test compound for 15 minutes at 23 0 C. The reaction is then stopped and the cAMP generated is determined by a radioimmunoassay kit. Data are analyzed using a non-linear, iterative curve-fitting computer program to define the potency ("ECso", concentration which produces 50% of the maximum response of PGD 2 and efficacy of the compounds. Compounds which exhibit EC 50 values of less than or equal to about 10 mM are within the DP-agonist definition of the present invention.

Preferred DP-agonists include: 2-(3-cyclohexyl-3-hydroxy-propyl)-3-hydroxycyclopentyl]-2-butenyl]oxy]-acetic acid, tbutyl ester (see EP0299 914B1) and cyclohexyl-3-hydroxy-propyl)-3-hydroxycyclopentyl]-2-butenyl]oxy]-acetic acid, isopropyl ester) (see commonly assigned U.S. Patent No. 5,627,209).

Preferred FP-agonists include: latanoprost (Xalatan®, available from Upjohn-Pharmacia) (see U.S. Patent No. 5,296,504), and the compounds disclosed in U.S. Patent No. 5,510,383, particularly isopropyl esters of cloprostenol and fluprostenol and their individual isomers and the compounds disclosed in WO 97/23223. Most preferred compounds are (+)-isopropyl fluprostenol and compound VIII on page 9 of WO 97/23223 (Isopropyl [2R(1E,3R),3S(4Z),4R]-7-[Tetrahydro-2-[4-(3-chlorophenoxy)3 hydroxy-l--butenyl]-4-hydroxy-3 -furanyl]-4-heptenoate).

The CAls which are useful in the compositions and methods of the present invention include dorzolamide and brinzolamide and mixtures thereof which lower and ia control IOP by inhibiting carbonic anhydrase when administered topically. CAls are disclosed in: U.S. Patent Nos. 4,797,413 (Baldwin, el 4,847,289 (Baldwin, et al.), and 4,731,368 (Hoffman, Jr., et U.S. Patent Nos. 5,153,192 (Dean, el 5,240,923 (Dean, el and 5,378,703 (Dean, el PCT/US91/02262 (filed 9 April 1990); EP 452 151 (published 16 October 1991) and U.S. 5,378,703. The entire contents of each of S) the above-mentioned patents and patent applications are incorporated herein by reference.

A particular CAI of the present invention is R-(+)-4-ethylamino-3,4-dihydro-2-(3methoxypropyl)-2H-thieno[3,2,e]-1,2-thiazine-6-sulfonamide-1,1-dioxide (brinzolamide).

The PGs and CAIs of the present invention may be formulated either separately or in the same pharmaceutical compositions. Thus, they can be administered simultaneously or sequentially to humans and other mammals suffering from glaucoma or ocular hypertension. When formulated separately the drugs may be administered 1) concomitantly; 2) within a short delay between one agent and the other; or 3) in an offset manner. It is preferred that the PG be dosed at night.

In general, the PG concentration in a formulation is between about 0.00005 and 25 about 0.5 percent by weight preferably between about 0.0003 and 0.3% wt.%,

LR

0- I R:\LIBXX]02501speci.doc:aak WO 98/19680 PCT/US97/15793 most preferably between about 0.0005 and 0.03 The CAI concentration in a formulation is between about 0.1 and 10.0 preferably between about 0.25 and 3 most preferably between about 0:5 and 2.0 In a combination formula, the PG concentration can be between 0.0005 and 0.03 wt.% and the CAI 0.5 and 1.5 wt.%.

In addition to the above-described principal ingredients, the anti-glaucoma compositions of the present invention may further comprise various formulatory ingredients, such as antimicrobial preservatives and tonicity agents. Examples of suitable antimicrobial preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Onamer M® and other agents equally well-known to those skilled in the art. Such preservatives, if used, will typically be employed in an amount between about 0.001 to Examples of suitable agents which may be used to adjust the tonicity or osmolality of the formulations include: sodium chloride, potassium chloride, mannitol, dextrose, glycerin, and propylene glycol. Such agents, if used, will typically be employed in an amount between about 0.1 to 10.0 wt%. Also, viscosity enhancers, such as hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and carbomers, may be used, and when they are, the prostaglandin concentration can be substantially reduced. Stabilizing agents may also be employed, such as, polyethoxylated castor oils like cremaphor EL.

As will be appreciated by those skilled in the art, the compositions may be formulated in various dosage forms suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, gels, and erodible solid ocular inserts. Combination compositions preferably are aqueous suspensions, have a pH between 5.0 to 7.8, preferably 6.5 to 7.6, and an osmolality between 280 to 320 milliOsmoles per kilogram (mOsm/kg).

The following examples further illustrate the anti-glaucoma compositions of the present invention, but are not limiting.

WO 98/19680 WO 9819680PCTIUS97/15793 Example 1 Ophthalmiic Suspension Lngredient Brinzolamide (1R )3 -chloro-2-(3-cyclohexyl-3 -bydroxy-propyl) -3 -hydroxycyclopentyl]-2-butenyl]oxy]-acefic acid, isopropyl ester) Hydroxypropylmethylcellulose Dibasic Sodium Phosphate Disodium Edetate Sodium Chloride Purified Water Benzalkoniumn Chloride Cremaphor NaOHIHC1 Concentration (wt 0.01 0.2 0.01 0.8 q. s 0.01 0.1 pH 7.1 WO 98/19680 WO 9819680PCTIUS97/15793 Example 2 Ophthalmic Suspension 1naredien Brinzolamide (+)-Isopropyl Fluprostenol Hydroxypropylmethylcellulose Dibasic Sodium Phosphate Disodium Edetate Sodium Chloride Purified Water Benzalkonium Chloride Cremaphor NaOHIIICl Concentration (wt 0.005 0.2 0.01 0.8 q. 0.01 0.1 pH 7.1 WO 98/19680 WO 9819680PCTIUS97/15793 Example 3 Ophthalmic Suspension Ingredien Brinzolamide Isopropyl [2R( lE,3R),3S(4Z),4R]-7- [Tetrahydro-2-[4-(3 -chlorophenoxy)-3 -hydroxy- 1 -butenyl]-4-hydroxy-3 -furanyl]-4-heptenoate Hydroxypropylniethylcellulose Dibasic Sodium Phosphate Disodium. Edetate Sodium Chloride Purified Water Benzalkonium Chloride Cremaphor 1s NaOH/HCl Concentration (wt 0.01 0.2 0.01 0.8 q. 0.01 0.1 pH 7.1 WO 98/19680 WO 9819680PCTIUS97/15793 Example 4 An example of two formulations to be used concomitantly, within 30 minutes, or offset by more than 1 hour.

Formulation A Ingredient (+)-Isopropyl Fluprostenol Monobasic sodium phosphate Dibasic sodium phosphate (anhydrous) Sodium chloride Disodium EDTA (Edetate disodium) Cremophor EL Benzalkonium chloride HCl and/or NaOH Purified water Amount 0.005 0.05 0.15 0.75 0.05 0.1 0.01 pH 7.3 7.4 q.s. to 100% Formulation B Inoxedient Brinzolainide Hydroxypropylmethylcellulose Dibasic Sodium Phosphate Disodium. Edetate Sodium Chloride Purified Water Benzalkonium Chloride Cremaphor NaOH/HCl Concentration (wt ON' 0.2 0.01 0.8 q. 0.01 0.1 pH 7.1 WO 98/19680 WO 9819680PCTIUS97/15793 Example The following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.

Formulation A 11 Ingredien Brinzolamide Hydroxypropylmethylcellulose Dibasic Sodium Phosphate Disodium Edetate Sodium Chloride Purified Water Benzalkonium Chloride Cremaphor NaOHIHCl Concentration (wt 0.2 0.01 0.8 q.s 0.01 0.1 pH 7.1 Formulation B Injuedient Amount (wt%/o) (+)-Isopropyl Fluprostenol 0.001 Monobasic sodium phosphate Dibasic sodium phosphate (anhydrous) Sodium chloride Disodium EDTA (Edetate disodium) Cremaphor EL Beuaknu chloride HCL and/or NaGH Purified water 0.05 0.15 0.75 0.05 0.1 0.01 pH 7.3 7.4 q.s. to 100% WO 98/19680 WO 9819680PCT/US97/15793 Example 6 The following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.

Formulation A Ingredien Brinzolamide Hydroxypropylinethylcellulose Dibasic Sodium Phosphate Disodium Edetate Sodium Chloride Purified Water Benzalkomium Chloride Cremaphor NaOHIHCl Concentration (wt 0.2 0.01 0.8 q. 0.01 0.1 pH 7.1 Formulation B Ingredient Amount Isopropyl [2R(1E,3R),3 S(4Z),4R]-7- [Tetrahydro-2-[4-(3 -chlorophenoxy)-3-hydroxy- 1 -butenyl]-4-hydroxy-3-fiuanyl]-4-heptenoate Monobasic sodium phosphate Dibasic sodium phosphate (anhydrous) Sodium chloride Disodium EDTA (Edetate disodium) Cremaphor EL Benzalkomium chloride HC1 and/or NaOH Purified water 0.01 0.05 0.15 0.75 0.05 0.1 0.01 pH17.3 -7.4 q.s. to 100% WO 98/19680 WO 9819680PCTIUS97/15793 Example 7 The following two formulations can be used concomitantly, within 3 0 minutes, or offset by more than 1 hour.

Formulation A Ingredien Brinzolamide Mannitol Carbopol 974P Tyloxapol Benzalkonium. Chloride Disodium EDTA (Edetate Disodium) Sodium Hydroxide Hydrochloric Acid Sodium Chloride Purified Water Concentration (wt 0%) 3.3 0.4 0.025 0.1% 0.01 pH 7.5 pH 7.5 0.25 q.s. to 100% Formulation B Ingredient Amount (+)-Isopropyl Fluprostenol 0.005 Monobasic sodium phosphate Dibasic sodium phosphate (anhydrous) Sodium chloride Disodium EDTA (Edetate disodium) Cremaphor EL Benzalkonium. chloride HC1 and/or NaOH Purified water 0.05 0.15 0.75 0.05 0.1 0.01 pH 7.3 7.4 q.s. to 100% WO 98/19680 WO 9819680PCTIUS97/15793 Example 8 The following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.

Formulation A Ingredient Brinzolamide Mannitol Carbopol 974P Tyloxapol Benzalkonium Chloride Disodium EDTA (Edetate Disodium) Sodium Hydroxide Hydrochloric Acid Sodium Chloride Purified Water Concentration (wt 3.3 0.4 0.025 0.1% 0.01 pH 7.5 pH 7.5 0.25 q.s. to 100% Formulation B Injredient Amount (wt%'o) Isopropyl [2R(1E,3 R),3 S(4Z),4R]-7- [Tetrahydro-2-[4-(3 -chlorophenoxy)-3 -hydroxy- 1 -butenyl]-4-hydroxy-3 -furanyl]-4-heptenoate Monobasic sodium phosphate Dibasic sodium phosphate (anhydrous) Sodium chloride Disodium. EDTA (Edetate disodium) Cremaphor EL Benzalkonium chloride HC1 and/or NaOH Purified water 0.01 0.05 0.15 0.75 0.05 0.1 0.01 pH 7.3 7.4 q.s. to 100%

Claims

2. A carbonic anhydrase inhibitor selected froill thle (1roup1 consisting of I hrinzolamnide. dorzolamnide and a mixture o[f brinzolamide and dorzolaide, and a prostagland in selected from (-i)-isoprop) I 11 uprosteniol and i sopropyl 1[2R( I F_3 S(4Z),4R]-7-[tetr-ahydro-2-[4-(3)-chlor-ophlenoxy,)-3)-hydr-oxl- I -bUtenyll-4- hvdriiox\v-3-furiianyl,]-4-hieptenioate when used in lowering 101" in1 persons Suffering from 111JUcomaI or- ocular hypertension. is 3 The use of a carbonic anhydrase iniibitor- selected fromn the group Consisting ol' brinzolamide, dorzolamide and a mixture of brinzolamnide and dorzolamide, and a prostaglandin selected fromn (+)-isopr-opyl flUprosteniol and isopropyl 2 R( I )S(4Z),4R1 -7-1-tetrahydro-2- -chilorophienoxy)-3 -hiydr-oxy- 1 -butenyl 1-4- hvdrlioxy-3)-fuLraniyl]-4-heptenioate for the manufacture of a medicament for lowering lOP 2 in persons Suffering from glaucoma or ocular hypertension.
4. A method according to claim 1 wherein the prostaglandin is (+)-isopropyl 1i uprostenlI. A method according to claim 1, wherein the prostaglandin is isopropyl 9 R( S(4Z),4R]-7- [tetrahydro-2-[4-(3 -chilorophenoxy)-3 -hiydroxy- 1 -butenyl]-4- 25 hy d roxy-3- Iliiranyl]-4-heptenoate.
6. A method according to claimn I whierein the carbonic anhydrase inhibitor is bri nzolamnide. a *aa.
7. A method for lowering IOP in persons suffering from glaucomla or ocular hlypertension, which comprises administering topically to the eye a pharmaceutically effective amount of a carbonic anhydrase Inhibitor and a prostaglandin, wherein the carbonic anhydrase inhibitor is brinzolamide and the prostaglandin is (+)-isopropyl IlUprostenol.
8. A carbonic anhydrase inhibitor and a prostaglandin, wherein the carbonic sr~iJ:. anhydrase inhibitor is brinzolamide and the prostaglandin is (+)-isopropyl fluprostenol 1 whIlenl used in lowering Lop in persons suffering from glaucoma or ocular hypertension. 270 R:\LI BXX]02501 .doc:aak
9. The use of a carbonic anhydrase inhibitor and a prostaglandin, wherein the carbonic anhydrase inhibitor is brinzolamide and the prostaglandin is (+)-isopropyl fluprostenol for the manufacture of a medicament for lowering IOP in persons suffering from glaucoma or ocular hypertension.
10. A method according to claim 1 wherein the carbonic anhydrase inhibitor is dorzolamide.
11. The carbonic anhydrase inhibitor and prostaglandin when used according to claim 2 wherein the carbonic anhydrase inhibitor is brinzolamide.
12. The carbonic anhydrase inhibitor and prostaglandin when used according to claim 2 wherein the carbonic anhydrase inhibitor is dorzolamide.
13. The use according to claim 3 wherein the carbonic anhydrase inhibitor is S* dorzolamide. ,14. The use according to claim 3 wherein the carbonic anhydrase inhibitor is brinzolamide. 0* i15 15. The method according to claim 10 wherein the prostaglandin is isopropyl [2R(1E,3R),3S( 4 Z), 4 R]- 7 -[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-l-butenyl]-4- hydroxy-3-furanyl]-4-heptenoate.
16. The method according to claim 10 wherein the prostaglandin is isopropyl fluprostenol. 20 17. The carbonic anhydrase inhibitor and prostaglandin when used according to claim 2, 11 or 12 wherein the prostaglandin is isopropyl fluprostenol.
18. The carbonic anhydrase inhibitor and prostaglandin when used according to Sclaim 2, 11 or 12 wherein the prostaglandin is isopropyl [2R(1E,3R),3S(4Z),4R]-7- [tetrahydro-2-[4-(3-chlorophenoxy)-3 -hydroxy-1 -butenyl]-4-hydroxy-3 -furanyl]-4- heptenoate.
19. The use according to claim 3, 13 or 14 wherein the prostaglandin is isopropyl fluprostenol. The use according to claim 3, 13 or 14 wherein the prostaglandin is isopropyl [2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-l-butenyl]-4- hydroxy-3-furanyl]-4-heptenoate.
21. A method of lowering IOP in a person suffering from glaucoma or ocular hypertension, which comprises administering topically to the eye of a person requiring such treatment, a therapeutically effective amount of a ophthalmic suspension substantially as herein described with reference to any one of Examples 1 to 3. [R:\LIBXX]02501 speci.doc:aak 17
22. An ophthalmic suspension substantially as herein described with reference to any one of Examples 1 to 3 when used to lower IOP in a person suffering from glaucoma or ocular hypertension.
23. A method of lowering IOP in a person suffering from glaucoma or ocular hypertension, which comprises administering topically to the eye of a person requiring such treatment, a therapeutically effective amount of formulations A and B substantially as herein described with reference to any one of Examples 4 to 8.
24. Formulations A and B substantially as herein described with reference to any one of Examples 4 to 8 when used to lower IOP in a person suffering from glaucoma or 0o ocular hypertension. Dated 24 April, 2001 Alcon Laboratories, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON a *°oo S oo o *000 j [R:\L[BXXJ02501 speci.doc:aak