CA2270349A1

CA2270349A1 - Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma

Info

Publication number: CA2270349A1
Application number: CA002270349A
Authority: CA
Inventors: Jesse A. May; Thomas R. Dean
Original assignee: Individual
Current assignee: Alcon Vision LLC
Priority date: 1996-11-01
Filing date: 1997-09-05
Publication date: 1998-05-14
Also published as: AU4257397A; AU734789B2; JP2001504100A; WO1998019680A1; EP0948333A1

Abstract

Compositions and methods for treating persons suffering from glaucoma or ocular hypertension are disclosed. In particular, the persons are treated with prostaglandins and carbonic anhydrase inhibitors to control their intraocular pressure.

Description

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.
i s 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 (e.g., pilocarpine, carbachol, and a.cetylcholinesterase inhibitors); sympathomimetics (e.g., epinephrine, dipivalylepinephrine, and para-amino clonidine); beta-blockers (e.g., betaxolol, levobunolol, and timolol); and carbonic 2s anhydrase inhibitors (CAIs) e.g., acetazolamide, methazolamide and ethoxzolamide systemically and dorzolamide topically. Prostaglandins (PGs) are currently being developed for use in treating persons with giaucoma and the PG, latanoprost, marketed as Xalatari , is available from Pharmacia-Upjohn.
3o Miotics and sympathomimetics are believed to lower IOP by increasing the outflow of aqueous humor, while beta-Mockers and carbonic anhydrase inhibitors are believed to lower IOP by decreasing the formation of aqueous humor. All four types of drugs have WO 98/19680 PCT/~JS97/15793 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 anhydrase 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 IOP
because a single drug does not provide adequate IOP control. The use of two drugs, each of which affects IOP 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 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.
Detailed Description of the Invention Prostaglandins are metabolic derivatives of arachidonic acid. The arachidonic acid cascade is initiated by the conversion of arachidonic acid to prostaglandin G2 and its subsequent conversion to prostaglandin H2. Other naturally occurring prostaglandins are derivatives of prostaglandin H2. A number of different types of prostaglandins have been 3o discovered including A, B, D, E, F and I-Series prostaglandins.

The prostaglandins which are useful according to the present invention include all prostaglandins which exhibit similar IOP lowering mechanisms as PGDZ(I) or PGF2~(II):
HO HO
COOH
COOH
O OH ~n Ho OH
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 i o 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 i s ability to bind to prostaglandin-DZ receptors of cells and evoke similar responses as when PGDz 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.
Zo Sharif, et al. have described a receptor binding assay in: Sharif, N.A., Williasns, G.W. and DeSantis, L.M, Neurochemistry Research, volume 20, pages 669-674 (l995), 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 HCl (pH 7.4) containing 13 8 mM NaCI, 5 mM
zs 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 [3HJPGD2 in the absence and presence of 100 mM unlabeled PGD2 to define total and non-specific binding, respectively. The incubations (20 minutes at 23 ~ 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 (K;) of the compounds. Compounds which exhibit Ki values in this assay of less than or equal to about 20 ~.M 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, N.A., Xu, S. and Yanni, J.M., Journal of Ocular Pharmacoloay, 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 ~ s 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~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 so ("ECSO", concentration which produces 50% of the maximum response of PGDZ) and efficacy of the compounds. Compounds which exhibit ECso values of less than or equal to about 10 mM are within the DP-agonist definition of the present invention.
Preferred DP-agonists include: [1R-[1.oc.(~,2.13.(lE,3S),3.oc.,5.oc.]]-[[4-[5-chloro-zs 2-(3-cyclohexyl-3-hydroxy-propyl)-3-hydroxycyclopentyl]-2-butenyl]oxy]-acetic acid, t-butyl ester (see EP0299 914B 1 ) and ([ 1 R-[ 1. oc. (Z~,2. ~ . (3 S),3 . oc., 5. a. ] ]-[ [4-[ 5 -chloro-2-(3 -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 (Xalata~ , 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

{Isopropyl [2R(IE,3R),3S(4~,4R]-7-[Tetrahydro-2-(4-(3-chlorophenoxy)-3-hydroxy-butenyl]-4-hydroxy-3-furanyl]-4-heptenoate).
The CAIs which are useful in the compositions and methods of the present ~o invention include all thiophene sulfonamides and thienothiazines which lower and control IOP by inhibiting carbonic anhydrase when administered topically.
Representative CAIs are disclosed in: U.S. Patent Nos. 4,797,413 (Baldwin, et al.), 4,847,289 (Baldwin, et al.), and 4,731,368 (Hoffman, Jr., et al.); U. S. Patent Nos. 5,153,192 (Dean, et al.), 5,240,923 (Dean, et al.), and 5,378,703 (Dean, et al.); PCT/US91/02262 (filed 9 April 1990); and EP
~s 452 151 (published I6 October 1991). The entire contents of each of the above-mentioned patents and patent applications are incorporated herein by reference.
Preferred CAIs of the present invention are those disclosed in U. S. Patent No.

5,378,703, particularly, R-(+)-4-ethylamino-3,4-dihydro-2-(3-methoxypropyl)-2H-zo 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 zs hypertension. When formulated separately the drugs may be administered I) 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 3o about 0. 5 percent by weight (wt. %), preferably between about 0. 0003 and 0. 3 % wt. %, most preferably between about 0.0005 and 0.03 wt. %. The CAI concentration in a formulation is between about 0.1 and 10.0 wt. %, preferably between about 0.25 and 3 wt. %, most preferably between about 0: 5 and 2. 0 wt. %. 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, i o 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 1.0 wt.%. Examples of suitable agents which may be used to adjust the tonicity or osmolality of the formulations include: sodium chloride, potassium chloride, mannitol, dextrose, is 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 ophthalinic 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 2s 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.

Example 1 Ophthalmic Suspension Ingredient ~ Concentration (wt %) a Brinzolamide 1, 0 s ([1R-[1.oc.(2~,2.13.(3S),3.a.,5.oc.])-[[4-[5-chloro-2-(3-cyclohexyl-3-hydroxy-propyl) -3-hydroxycyclopentyl]-2-butenyl]oxy]-acetic acid, isopropyl ester) 0.01 Hydroxypropylmethylcellulose 0. 5 io Dibasic Sodium Phosphate 0.2 Disodium Edetate 0.01 Sodium Chloride 0.8 Purified Water q, s Benzalkonium Chloride 0.01 ~ s Cremaphor 0.1 NaOH/HCl pH 7.1 Example 2 Ophthalmic Suspension Ingredient - Concentration (wt %) Brinzolamide 1.0 s (+}-Isopropyl Fluprostenol 0.005 Hydroxypropyitnethylcellulose 0.5 Dibasic Sodium Phosphate 0.2 Disodium Edetate 0.01 Sodium Chloride 0.8 i o Purified Water q. s Benzalkonium Chloride 0.01 Cremaphor 0.1 NaOH/HCl pH 7.1 _g_ Eaample 3 Ophthalmic Suspension Ingredient - Concentration (wt %) Brinzolamide 1.0 s Isopropyl [2R(lE,3R),3S(4~,4R]-7-[Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3 -furanyl]-4-heptenoate0. 01 Hydroxypropylmethylcellulose 0.5 Dibasic Sodium Phosphate 0.2 Disodium Edetate 0.0l Sodium Chloride 0.8 Purified Water q.s Benzalkonium Chloride 0.01 Cremaphor 0.1 i s NaOH/HCl pH 7.1 Example 4 An example of two formulations to be used concomitantly, within 30 minutes, or offset by more than 1 hour.
s Formulation A
Ingredient Amount (wt%) (+)-Isopropyl Fluprostenol 0.005 Monobasic sodium phosphate 0.05 Dibasic sodium phosphate (anhydrous) 0.15 ~o Sodium chloride 0.75 Disodium EDTA (Edetate disodium) 0.05 Cremophor EL 0.1 Benzalkonium chloride 0.01 HCl and/or NaOH pH 7.3 - 7.4 i s Purified water q. s. to 100%

Formulation B
In egr dient Concentration (wt %) Brinzolamide 1.0 zo Hydroxypropylinethylcellulose 0.5 Dibasic Sodium Phosphate 0.2 Disodium Edetate 0.0l Sodium Chloride 0.8 Purified Water q, s is Benzallconium Chloride 0.01 Cremaphor 0.1 NaOH/HCl pH 7.1 Example 5 s The following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.
Formulation A
Ingredient Concentration (wt %) Brinzolamide 1.0 Hydroxypropylmethylcellulose 0. 5 i0 Dibasic Sodium Phosphate 0.2 Disodium Edetate 0.01 Sodium Chloride 0.8 Purified Water q,s Benzalkonium Chloride 0.01 is Cremaphor 0.1 NaOHCI pH 7.1 Formulation B
Ingredient Amount (wt%) (+)-Isopropyl Fluprostenol 0.001 Monobasic sodium phosphate 0.05 Dibasic sodium phosphate (anhydrous) 0.15 Sodium chloride 0.75 2s Disodium EDTA (Edetate disodium) 0.05 Cremaphor EL 0.1 Benzalkonium chloride 0.01 HCl and/or NaOH pH 7.3 - 7.4 Purified water q. s. to 100%

Example 6 The following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.
Formulation A
In~xedient Concentration (wt %) Brinzolamide 1.0 Hydroxypropylmethylcellulose 0. 5 Dibasic Sodium Phosphate 0.2 Disodium Edetate 0.01 Sodium Chloride 0.8 Purified Water q.s Benzalkonium Chloride 0.01 is Cremaphor 0.1 NaOH/HCl pH 7.1 Formulation B
In egg Amount (wt%) Isopropyl [2R(lE,3R),3S(4~,4R]-7-[Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl]-4-heptenoate 0.0l Monobasic sodium phosphate 0.05 zs Dibasic sodium phosphate (anhydrous)0.15 Sodium chloride 0.75 Disodium EDTA (Edetate disodium) 0.05 Cremaphor EL 0.1 Benzalkonium chloride 0.01 so HCl and/or NaOH pH 7.3 - 7.4 Purified water q. s. to 100%

Example 7 s The following two formulations can be used concomitantly, within 3 0 minutes, or offset by more than 1 hour.
Formulation A
Ingredient Concentration (wt %) Brinzolamide 1.0 Mannitol 3.3 io Carbopo1974P 0.4 Tyloxapol 0.025 Benzalkonium Chloride 0.1% + 5%xs Disodium EDTA (Edetate Disodium) 0.01 Sodium Hydroxide pH 7.5 +/- .2 is Hydrochloric Acid pH 7.5 +i- .2 Sodium Chloride 0.25 Purified Water q.s. to 100%

Formulation B
zo Ingredient Amount (wt%) (+)-Isopropyl Fluprostenol 0.005 Monobasic sodium phosphate 0.05 Dibasic sodium phosphate (anhydrous) 0.15 zs Sodium chloride 0.75 Disodium EDTA (Edetate disodium) 0.05 Cremaphor EL 0.1 Benzalkonium chloride 0.01 - HCl and/or NaOH pH 7.3 - 7.4 so Purified water q.s. to 100%

Eaample 8 The following two formulations can be used concomitantly, within 3 0 minutes, or offset by more than 1 hour.
s Formulation A
Ingredient Concentration (wt %) Brinzolamide 1.0 Mannitol 3 .3 Carbopol 974P 0.4 io Tyloxapol 0.025 Benzalkonium Chloride 0.1% + 5%xs Disodium EDTA (Edetate Disodium) 0.01 Sodium Hydroxide pH 7.5 +/ .2 Hydrochloric Acid pH 7.5 +/ .2 is Sodium Chloride 0.25 Purified Water q.s. to 100%

Formulation B
Ingredient Amount (wt%) Isopropyl [2R(lE,3R),3S(4~,4RJ-7-[Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl)-4-heptenoate 0.01 Monobasic sodium phosphate 0.05 2s Dibasic sodium phosphate {anhydrous)0.15 Sodium chloride 0.75 Disodium EDTA (Edetate disodium) 0.05 Cremaphor EL 0.1 Benzallconium chloride 0.01 3o HCl and/or NaOH pH 7.3 - 7.4 Purified water q.s. to 100%

Claims

CLAIMS:

1. 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 selected from (+)-isopropyl fluprostenol and isopropyl [2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl]-4-heptenoate.

2. A method according to claim 1, wherein the prostaglandin is (+)-isopropyl fluprostenol.

3. A method according to claim 1, 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.

4. A method according to any of claims 1 to 3, wherein the carbonic anhydrase inhibitor is brinzolamide.

5. 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.

6. 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(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-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.

7. A product according to claim 6, wherein the prostaglandin is (+)-isopropyl fluprostenol.

8. A product according to claim 6, 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.

9. A product according to any of claims 6, 7 or 8, wherein the carbonic anhydrase inhibitor is brinzolamide.

10. 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.