MXPA99004069A - Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma - Google Patents

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 CARBON ANHYDRIDE AND PROSTAGLANDIN INHIBITORS FOR THE TREATMENT OF (- AUCOMA BACKGROUND OF THE INVENTION The present invention relates to the field of ophthalmology. In particular, the present invention relates to the treatment of people suffering from glaucoma and associated elevations of intraocular pressure (IOP) and / or ocular hypertension. Although the underlying causes of glaucoma are not understood, their symptoms often include a high POOP, which may be caused by excessive production or inadequate flow of aqueous humor. If left untreated, or treated inappropriately, glaucoma can cause blindness or significant loss of sight. Therefore, there is a continuing need for therapies that control the elevated intraocular pressure associated with glaucoma. At present there are a number of drugs used in the treatment of glaucoma and ocular hypertension, which include: miotics (e.g., pilocarpine, carbacol and acetylcholinester inhibitors); ethical sympathomics (e.g., epinephrine, dipivallypinephrine and para-aminoclonidine); beta- REF .: 30160 blockers (e.g., betaxolol, levobunolol and timolol); and carbonic anhydrase inhibitors (CAI), for example, acetazolamide, etazolamide and etoxolamide administered systemically, and dorzolamide applied topically. Currently, prostaglandins (PG) are being developed for use in the treatment of people with glaucoma and PG latanoprost, marketed as Xalatan ©, is available at Pharmacia-Upjohn Laboratories. It is believed that miotics and sympathomimetics decrease IOP by increasing the outflow of aqueous humor, whereas beta-blockers and carbonic anhydrase inhibitors are believed to decrease IOP by decreasing aqueous humor formation. All four types of drugs have potentially serious side effects. Myotics, such as pilocarpine, can cause forehead pain, blurred vision and other visual side effects, which can cause either minor compliance on the part of the patient, or the conclusion of therapy. Carbonic anhydrase inhibitors administered systemically also cause serious side effects that may affect patient compliance and / or require discontinuation of treatment. Beta-blockers can be irritants. Sympathomimetics can cause allergic responses and sedative effects. The Side effects associated with PG include edema, and sensation of foreign bodies. A significant number of patients with glaucoma requires the administration of more than one type of drug in order to achieve therapeutic control over the IOP, because a single drug does not provide adequate control of it. The use of two drugs, each of which affects IOPO by a different mechanism, would be useful for the treatment of these patients. The present invention relates to such use, either by administering the drugs separately, or in combination. BRIEF DESCRIPTION OF THE INVENTION The present invention relates to methods for the treatment of patients with glaucoma or ocular hypertension, where their IOP can only be controlled by the use of two drugs that decrease the IOPO; that is, inhibitors of the carbonic anhydrase enzyme and prostaglandins. These drugs can be dosed simultaneously or at different times and can also be formulated in a single composition, for convenience and for patient compliance. DETAILED DESCRIPTION OF THE INVENTION Prostaglandins are metabolic derivatives of arachidonic acid. The arachidonic acid cascade is initiated by the transformation of arachidonic acid into prostaglandin G2 and its subsequent conversion into prostaglandin H2. Other prostaglandins of natural origin are derived from prostaglandin H2. A number of different types of prostaglandins have been discovered, including prostaglandins A, B, D, E, F and Series I. Prostaglandins that are useful in accordance with the present invention include all prostaglandins that exhibit diminishing mechanisms of the PIÓ similar to PGD2 (I) or PGF2a (II): While the Applicants do not wish to be bound by any theory, it is believed that D-prostaglandins ("DP agonists") inhibit the formation of aqueous humor and can have an effect on their outflow. It is believed that F-prostaglandins ("FP agonists") increase the outflow of the aqueous humor of the eye. The DP agonists of the present invention are useful for decreasing IOP in humans and other mammals. The DP agonists of the present invention are functionally defined by their ability to bind to the prostaglandin-D2 receptors of the cells and induce similar responses to those obtained when PGD2 binds to these receptors, thus inducing the decrease in the PIÓ. Several assays can be used for the determination of DP agonists. Binding assays can be used to elucidate the DP agonists of the present invention. Sharif, et al. , have described a receptor binding assay in: Sharif, NA, Williams, GW and DeSantis, LM, Neurochem-istry Research, volume 20, pages 669-674 (1995), the content of which is incorporated herein by reference, and it can be modified in the manner described below for the detection of DP agonists of the present invention. Briefly, binding assays are performed in 25-mM Tris-HCl (pH 7.4) containing 138 mM NaCl, 5 mM MgCl 2 and 1 mM EDTA. Thawed human blood platelets (40-60 mg / ml stock) are incubated in a total volume of 500 ml with 2-10 nM [H] PGD2 in the absence and presence of unlabeled 100 mM PGD2, to define the binding total and union and non-specific, respectively. Incubations (20 minutes at 23 ° C) are concluded by rapid vacuum filtration, using a Whatman GF / B glass fiber filter previously moistened with 1% polyethyleneimine and 0.1% ASB (ASB = serum albumin). bovine) and then the radioactivity bound to the receptors is determined by scintillation spectrometry. The binding data is analyzed using an iterative non-linear curve fitting computer program, to define the receptor binding affinity (Ki) of the compounds. Compounds that exhibit Ki values in this assay, less than or equal to about 20 μM, fall within the definition of DP agonists of the present invention. The DP agonists of the present invention can also be functionally defined by their ability to stimulate the activity of the enzyme adenylate cyclase. Sharif e al. , have described this type of functional assay in: Sharif, NA, Xu, S. and Yanni, JM, Journal of Ocular Pharmacology, volume 10, pages 653-664 (1994), the content of which is incorporated herein by reference and the which can be modified in the manner described below for the determination of DP agonists of the present invention. In short, functional adenylate cyclase activity is determined using bovine embryo trachea (EbTr) cells. The cultured cells are stimulated with the test compound for 15 minutes at 23 ° C. Subsequently, the reaction is stopped and the -AMP generated with a radioimmunoassay package. The data is analyzed using an iterative nonlinear curve fitting computer program, to define the power ("ECso", concentration that produces 50% of the maximum response of the PGD2) and effectiveness of the compounds. Compounds that exhibit EC50 values less than or equal to about M, fall within the definition of DP agonists of the present invention. Preferred DP agonists include: [IR- [l.a. (Z), 2.ß. (1E, 3S), 3.a., 5.a.]] - [[4- [5-chloro-2- (3-cyclohexyl-3-hydroxypropyl) -3-hydroxycyclopentyl] -2-butenyl] -oxi ] -acetic (see EP0299 914B1) and isopropylester of the acid. { [1R- [l.a. (Z), 2.β. (3S), 3.a., 5.a.]] - [[4- [5-chloro-2- (3-cyclohexyl-3-hydroxypropyl) -3-hydroxycyclopentyl] -2-butyl] -oxi] - acetic) (see US Patent No. 5, 627,209 commonly assigned). Preferred FP agonists include: latanoprost (Xalatan®, available from Up ohn-Pharmacia) (see U.S. Patent No. 5,296,504) and the compounds described in U.S. Patent No. 5,510,383, particularly isopropyl esters of cloprostenol and fluprostenol, and their isomers Individuals, and the compounds described in WO International Publication 97/23223. The most preferred compounds are (+) - isopropylfluprostenol and compound VIII of page 9 of International Publication WO 97/23223 ([2R (1E, 3R), 3S- (4Z), 4R] -7- [tetrahydro- 2- [4- (3-chlorophenosi) -3-hydroxy-l-butenyl] -4-hydro? I-3-furanyl] -4-isopropyl heptanoate). IACs that are useful in the compositions and methods of the present invention include all thiophenesulfonamides and thienothiazines that decrease and control IOP by inhibiting carbonic anhydrase when administered topically. The representative IACs are described in: North American Patents Nos. 4,797,413 (Baldwin, et al.); 4, 847, 289 (Baldwin, et al.) And 4,731,368 (Hoffman, Jr., et al.); Patents North American Nos. 5,153,192 (Dean, et al.); 5,240,923 (Dean, et al.) And 5,378,703 (Dean, et al.); PCT / US91 / 02262 (filed on April 9, 1990); and the European Patent EP 452 151 (published on October 16, 1991). The complete content of each of the Patents and Requests for Patent mentioned above, is incorporated herein by reference. Preferred IACs of the present invention are those described in U.S. Patent No. 5,378,703, particularly R- (+) - 4-ethylamino-3,4-dihydro-2- (3-methoxypropyl) 1,1-dioxide. -2H-Thieno [3, 2, e] -1,2-thiazine-6-sulfonamia (brinzolamide).

The PGs and IACs of the present invention can be formulated either separately or in the same pharmaceutical composition. Thus, humans and other mammals suffering from glaucoma or ocular hypertension can be administered simultaneously or sequentially. When formulated separately, the drugs can be administered 1) concomitantly; 2) with a small delay between one agent and the other; or 3) out of phase with respect to each other. It is preferred that the PG be administered at night. In general, the concentration of PG in a formulation is between about 0.00005 and about 0.5% by weight (% by weight), preferably between about 0.0003 and 0.3% by weight, more preferably between about 0.0005 and 0.03% by weight. The concentration of IAC in a formulation is between about 0.1 and 10.0% by weight, preferably between about 0.25 and 3% by weight, more preferably between about 0.5 and 2.0% by weight. In a combination formulation, the concentration of PG can be between 0.0005 and 0.03% by weight and that of the IAC between 0.5 and 1.5% by weight. In addition to the main ingredients described above, the antiglaucoma compositions of the present invention may comprise various formulation ingredients, such as antimicrobial preservatives and tonicity agents. Examples of suitable antimicrobial preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, Onamer M® and other agents also 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% by weight. Examples of suitable agents that can be used to adjust the tonicity or osmolarity 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 and 10.0% by weight. Also, viscosity improvers such as hydroxyethylcellulose, hydroxypropylmethyl cellulose and carbomers can be used, and when used, the concentration of prostaglandin can be substantially reduced. Stabilizing agents such as polyethoxylated castor oil, such as crefor EL, may also be employed. As will be appreciated by those skilled in the art, the compositions may be formulated in various dosage forms suitable for topical ophthalmic administration, including erosion-free solutions, suspensions, emulsions, gels and solid eye inserts. The Preferred combination compositions are aqueous suspensions, having a pH between 5.0 and 7.8, preferably 6.5 to 7.6 and an osmolarity between 280 and 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 (% by weight) Brinzo1a-measure 1. 0 Isopropylester of ([1R- 0. 01 [la (Z), 2.β (3S), 3.a., 5.a.]] - [[4- [5- chloro-2- (3 -cyclohexyl-3-hydroxypropyl) -3- hydroxycyclopentyl] -2-butenyl] -oxy] -acetic acid) Hydroxypropylmethyl cellulose 0.5 Dibasic sodium phosphate 0.2 Disodium edetate 0.01 Sodium chloride 0.8 Purified water c.b.p. Benzalkonium Chloride 0.01 Cremafor 0.1 NaOH / HCl or H 7.1 EXAMPLE 2 Ophthalmic Suspension Ingredient Concentration (% by weight) Brinzolamide 1. .0 (+) -Isopropilf luprostenol 0. (TWO Hydroxypropylmethyl cellulose 0 .5 Sodium diphosphate 0 .2 Disodium edetate 0. 01 Sodium chloride 0 .8 Purified water cb > .p. Benzalkonium chloride 0. 01 Cremafor 0. 1 NaOH / HCl H 7.1 EXAMPLE 3 Ophthalmic Suspension Ingredient Concentration (% in DTSO) Brinzolamide 1 .0 [2R- (ÍE, 3R), 3S- (4Z), 4R] -7- [tetrahydro-2- 0. 01 [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl] - 4-hydroxy-3-furanyl] -4-isopropyl heptanoate Hydroxypropylmethyl cellulose 0.5 Dibasic sodium phosphate 0.2 Disodium edetate 0.01 Sodium chloride 0.8 Purified water c.b. p. Benzalkonium Chloride 0.01 Cremafor 0.1 NaOH / HCl pH 7.1 EXAMPLE 4 Example of two formulations to be used concomitantly, within a period of 30 minutes, or out of phase in more than 1 hour. Formulation A Ingredient Concentration (% by weight) (+) -Isopropilfluprostenol 0.005 Sodium monobasic phosphate 0.05 Dibasic sodium phosphate (anhydrous) 0.15 Sodium chloride 0.75 AEDT disodium (disodium edetate) 0.05 CREmafor EL 0.1 Benzalkonium Chloride 0.01 HCl and / or NaOH pH 7.3-7.4 Purified water c.b.p. 100% Formulation B Ingredient Concentration (% by weight) Brinzolamide 1.0 Hydroxypropylmethyl cellulose 0.5 Dibasic sodium phosphate (anhydrous) 0.2 Disodium edetate 0.01 Sodium chloride 0.8 Purified water c.b.p. Benzalkonium Chloride 0.01 Cremafor 0.1 NaOH / HCl H 7.1 EXAMPLE 5 The following two formulations can be used concomitantly within a period of 30 minutes, or out of phase in more than 1 hour. Formulation A Ingredient Concentration (% by weight) Brinzolamide 1.0 Hydroxypropylmethyl cellulose 0.5 Dibasic sodium phosphate 0.2 Disodium edetate 0.01 Sodium chloride 0.8 Purified water c.b.p. Benzalkonium Chloride 0.01 Cremafor 0.1 NaOH / HCl pH 7.1 Formulation B Ingredient Concentration (% by weight) (+) -Isopropylfluprostenol 0.001 Sodium monobasic phosphate 0.05 Sodium dibasic phosphate (anhydrous) 0.15 Sodium chloride 0.75 AEDT dx-sodium (disodium edetate) 0.05 EL cream 0.0 0.1 Benzalkonium chloride HCl and / or NaOH pH 7.3-7.4 Purified water c.b.p. 100% EXAMPLE 6 The following two formulations can be used concomitantly within a period of 30 minutes, or out of phase in more than 1 hour.

Formulation A Ingredient Concentration (% by weight) Brinzolamide 1. .0 Hydroxypropylmethyl cellulose 0, .5 Dibasic sodium phosphate 0. .2 Disodium edetate 0. 01 Sodium Chloride 0 .8 Purified water c.b i.p.

Benzalkonium Chloride 0. 01 Cremafor 0 .1 NaOH / HCl pH 7.1 Formulation B Ingredient Concentration (% by weight) [2R- (1E, 3R), 3S- (4Z), 4R] -7- [tetrahydro-2,001 [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl] -4-hydroxy-3- furanyl] -4-isopropyl heptanoate Sodium monobasic phosphate 0.05 Dibasic sodium phosphate (anhydrous) 0.15 Sodium chloride 0.75 AEDT disodium (disodium edetate) 0.05 Cremafor EL 0.1 Benzalkonium Chloride 0.01 HCl and / or NaOH pH 7.3-7.4 Purified water c.b.p. 100% EXAMPLE 7 The following two formulations can be used concomitantly within a period of 30 minutes, or out of phase in more than 1 hour. Formulation A Ingredient Concentration (% by weight) Brinzolamide 1.0 Mannitol 3.3 Carbopol 974P 0.4 Tyloxapol 0.025 Benzalkonium Chloride 0.1% + 5% xs Disodium AEDT (disodium edetate) 0.01 Sodium hydroxide pH 7.5 ± .2 Hydrochloric acid pH 7.5 ± .2 Sodium chloride 0.25 Purified water c.b.p. 100% Formulation B Ingredient Concentration (% by weight) [+) -Isopropilfluprostenol 0.005 Sodium monobasic phosphate 0.05 Dibasic sodium phosphate (anhydrous) 0.15 Sodium chloride 0.75 AEDT disodium (disodium edetate) 0.05 CREmafor EL 0.1 Benzalkonium Chloride 0.01 HCl and / or NaOK pH 7.3-7.4 Purified water c.b.p. 100% EXAMPLE 8 The following two formulations can be used concomitantly within a period of 30 minutes, or out of phase in more than 1 hour. Formulation A Ingredient Concentration (% by weight) Brinzolamide 1.0 Mannitol 3.3 Carbopol 974P 0.4 Tyloxapol 0.025 Benzalkonium Chloride 0.1% + 5% xs Disodium AEDT (disodium edetate) 0.01 Sodium hydroxide pH 7.5 ± .2 Hydrochloric acid pH 7.5 ± .2 Sodium chloride 0.25 Purified water c.b.p. 100% Formulation B Ingredient Concentration (% by weight) [2R- (1E, 3R), 3S- (4Z), 4R] -7- [tetrahydro-2- 0.01 [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl] -4-hydroxy-3- furanyl] -4-isopropyl heptanoate Sodium monobasic phosphate 0.05 Dibasic sodium phosphate (anhydrous) 0.15 Sodium chloride 0.75 AEDT disodium (disodium edetate) 0.05 CREmafor EL 0.1 Benzalkonium Chloride 0.01 HCl and / or NaOH pH 7.3-7.4 Purified water c.b.p. 100% It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (10)

2. Having described the invention as an antecedent, what is claimed as property is contained in the instruments 1. A method to decrease intraocular pressure (IOP) in people suffering from glaucoma or ocular hypertension, characterized in that it comprises administering topically to the eye, an amount pharmaceutically effective of a carbonic anhydrase inhibitor and a prostaglandin which is selected from the group consisting of (+) - isopropylfluprostenol and [2R- (ÍE, 3R), 3S- (4Z), R] -7- [tetrahydro-2] - [4- (3-chlorophenoxy) -3-hydroxy-l-butenyl] -4-hydroxy-3-furanyl] -4-isopropyl heptanoate. 2. A method according to claim 1, characterized in that the prostaglandin is (+) - isopropylfluprostenol.
3. 3. A method according to claim 1, characterized in that the prostaglandin is [2R- (1E, 3R), 3S- (4Z), 4R] -7- [tetrahydro-2- [4- (3-chlorophenoxy) 3-hydroxy-l-butenyl] -4-hydroxy-3-furanyl] -4-isopropyl heptanoate.
4. 4. A method according to any of claims 1 to 3, characterized in that the carbonic anhydrase inhibitor is brinzolamide.
5. 5. A method for decreasing the IOP in people suffering from glaucoma or ocular hypertension, characterized in that it comprises administering a pharmaceutically effective amount of an inhibitor of the drug administered topically to the eye. carbonic anhydrase and a prostaglandin, where the inhibitor of carbonic anhydrase is brinzolamide and the prostaglandin is (+) - isopropylfluprostenol.
6. 6. A product containing a pharmaceutically effective amount of a carbonic anhydrase inhibitor and a prostaglandin selected from the group consisting of (+) - isopropylfluprostenol and [2R- (ÍE, 3R), 3S- (4Z), 4R ] -7- [tetrahydro-2- [4- (3-chlorophenoxy) -3-hydroxy-l-butenyl] -4-hydroxy-3-furanyl] -4-isopropyl heptanoate, characterized in that it is a combined preparation for use simultaneously, separately or sequentially, to decrease the IOP in people suffering from glaucoma or ocular hypertension.
7. 7. A product according to claim 6, characterized in that the prostaglandin is (+) - isopropylfluprostenol.
8. 8. A product according to claim 6, characterized in that the prostaglandin is [2R- (ÍE, 3R), 3S- (4Z), 4R] -7- [tetrahydro-2- [4- (3-chlorophenoxy)) 3-hydroxy-l-butenyl] -4-hydroxy-3-furanyl] -4- isopropyl heptanoate.
9. 9. A product according to any of claims 6, 7 or 8, characterized in that the carbonic anhydrase inhibitor is brinzoiamide.
10. 10. A product that contains a quantity pharmaceutically effective of a carbonic anhydrase inhibitor and a prostaglandin, characterized in that the carbonic anhydrase inhibitor is brinzolamide and the prostaglandin is (+) - isopropylfluprostenol, in the form of a combined preparation for simultaneous administration, separately or sequentially, for used to decrease the IOP in people suffering from glaucoma or ocular hypertension.