JP2001504100A - Use of a combination of a carbonic anhydrase inhibitor and a prostaglandin to treat glaucoma - Google Patents

Abstract

  (57) [Summary] Disclosed are compositions and methods for treating a human suffering from glaucoma or intraocular hypertension. In particular, the humans are treated with prostaglandins and carbonic anhydrase inhibitors to control their intraocular pressure.

Description

DETAILED DESCRIPTION OF THE INVENTION Use of a Combination of Carbonic Anhydrase Inhibitor and Prostaglandin to Treat Glaucoma Background of the Invention The present invention has application in the field of ophthalmology. In particular, the present invention is applied to treat humans suffering from glaucoma and humans with elevated intraocular pressure (IOP) and / or intraocular hypertension. Although the underlying cause of glaucoma is unknown, its symptoms often include elevated IOP, which can be caused by either overproduction or inappropriate outflow of aqueous humor. If left untreated, or given inappropriate treatment, glaucoma can cause blindness or severe vision loss. Therefore, treatment to control the rise in intraocular pressure associated with glaucoma needs to be continued. Currently, there are many drugs used to treat glaucoma and intraocular hypertension: for example, miotics (eg, pilocarpine, carbachol and acetylcholinesterase inhibitors, etc.): sympathomimetics (eg, epinephrine) Beta-inhibitors such as betaxolol, levobunolol and timolol; and carbonic anhydrase inhibitors (CAIs) such as acetazolamide, methazolamide, and ethoxyzole for systemic administration Amides and dorzolamide for topical administration. Currently, prostaglandins (PGs) are being developed for the treatment of humans with glaucoma. Can be obtained from Pharmacia Upjohn. Miotics and sympathomimetics are thought to reduce IOP by increasing the outflow of aqueous humor, whereas beta inhibitors and carbonic anhydrase inhibitors inhibit aqueous humor. To reduce IOP by decreasing the production of All four drugs potentially have serious side effects. Miotics such as pilocarpine cause migraines, blurred eyes, and other visual side effects, which can lead to reduced patient compliance and discontinuation of treatment. Systemic administration of carbonic anhydrase inhibitors also causes severe side effects, which may affect patient compliance and / or withdrawal of treatment. Beta inhibitors are irritating. Sympathomimetics cause allergic reactions and sedation. Side effects associated with PGs include edema, hyperemia and foreign body sensation. Many patients with glaucoma need to take one or more drugs for successful treatment to control IOP, because one drug cannot provide adequate IOP control. The use of two drugs, each acting on IOP by a different mechanism, would be useful in treating such patients. The present invention directs the aforementioned uses, either by administering a plurality of drugs separately or in combination. SUMMARY OF THE INVENTION The present invention is directed to a method for treating a patient having glaucoma or intraocular hypertension, wherein the patient's IOP is comprised of two IOP lowering agents, a carbonic anhydrase inhibitor And prostaglandins can only be controlled. These drugs can be administered simultaneously or at different times, to provide convenience or patient compliance, or can be formulated in a single combination. DETAILED DESCRIPTION OF THE INVENTION Prostaglandins are metabolic derivatives of arachidonesan. The arachidone sun cascade begins with the conversion of arachidone sun to prostaglandin G ₂ and follows the conversion to prostaglandin H ₂ . Prostaglandins generated original other manner are derivatives of prostaglandin H _2. Many different types of prostaglandins have been discovered, including prostaglandins A, B, D, E, F and I. Prostaglandins useful according to the invention include all prostaglandins that exhibit a similar IOP lowering function as PGD ₂ (I) or PGF ₂ (II): Although Applicants do not wish to be bound by any hypothesis, prostaglandins D ("DP agonists") are believed to suppress the formation of aqueous humor and have an effect on their outflow. May also have. Prostaglandins F ("FP agonists") are believed to increase aqueous humor outflow from the eye. The DP agonists of the present invention are useful for 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 in cells and have a similar response to PGD ₂ binding to these receptors that induce IOP reduction. Provoke. A variety of tests can be used to determine DP agonists. A binding test can be performed to reveal the DP agonists of the present invention. Sharif et al. (Sharif et al.) Describe a receptor binding test (Sharif, NA, Williams, GW. And DeSantis, LM. Neurochemistry Research, vol. 20, p. 669-674 (1995)). Is incorporated herein by this reference, and the method is modified as follows to evaluate DP agonists of the invention. That is, the binding test is treated with 25 mM TrisHCl (pH 7.4) containing 138 mM NaCl, 5 mM MgCl ₂ and 1 mM EDTA. Freezing and human platelets completing thawing (40-60mg / ml stock), in ^[3 H] PGD ₂ and total 500m in l in 2-10NM, in the absence of unlabeled PGD ₂ in 100 mM, or in the presence Incubate to reveal total and non-specific binding, respectively. Incubation (23 minutes at 23 ° C.) was stopped by rapid suction filtration using Whatman GF / B glass fiber filter paper presoaked in 1% polyethyleneimine and 0.1% BSA, followed by receptor Bound radioactivity is measured by scintillation spectroscopy. The binding data is analyzed using a non-linear iterative curve fitting computer program to reveal the receptor binding affinity (Ki) of the compound. Compounds exhibiting a Ki value of about 20 μM or less in this test fall within the definition of DP agonists of the present invention. Also, the DP agonists of the present invention may be functionally defined by their ability to stimulate adenylate cyclase activity. Sharif et al. Describe a functional test of this type (Sharif, NA, Xu, S. and Yanni, JM, Journal of Ocular Pharmacology, vol. 10, p653-664 (1994)). The contents are incorporated herein by reference and the method is modified as follows to evaluate DP agonists of the present invention. That is, the functional adenylate cyclase activity is measured using fetal bovine tracheal cells (EbTr). The cultured cells are stimulated with the test compound for 15 minutes at 23 ° C. Subsequently, the reaction is stopped, and the generated cAMP is measured using a radioimmunoassay kit. Data to minute prayer using non-linear iterative curve fitting computer program reveals its efficacy ( "EC _50", the concentration at which 50% of the maximal response of PGD ₂ is obtained) and the efficacy of the compound. Compounds exhibiting an EC ₅₀ value of about 10 mM or less are defined as DP agonists of the present invention. A preferred DP agonist is [IR- [1.α (Z), 2.β. (1E, 3S), 3.α., 5.α.]]-[[4- [5-chloro-2- ( 3-cyclohexyl-3-hydroxy-propyl) -3-hydroxycyclopentyl] -2-butenyl] oxy] -acetic acid, t-butyl ester (see EP 0299 914B1) and ([IR- [1.α. (Z), 2.β. (3S), 3.α., 5.α]]-[[4- [5-Chloro-2 (3-cyclohexyl-3-hydroxy-propyl) -3-hydroxycyclopentyl] 2-butenyl] oxy] -acetic acid, isopropyl ester) (see commonly cited U.S. Pat. No. 5,627,209). Compounds disclosed in U.S. Pat.No. 5,296,504), and isopropyl esters of cloprostenol and fluprostenol , As well as their respective isomers, as well as the compounds disclosed in WO 97/22323. The most preferred compounds are (+)-isopropylfluprostenol and compound VIII on page 9 of WO 97/22323 (isopropyl [2R (1E, 3R), 3S (4Z), 4R] -7- [tetrahydro-2 -[4- (3-chlorophenoxy) -3-hydroxy-1-butenyl] -4-hydroxy-3-furanyl] -4-heptenoate). CAIs useful in the compounds and methods of the present invention include all thiophene sulfonamides and thienothiazines that, when administered topically, inhibit carbonic anhydrase and reduce and control IOP. Representative CAIs are U.S. Pat.Nos. 4,797,413 (Baldwin et al.), 4,847,289 (Baldwin et al.) And 4,731,368 (Hoffman, Jr., et al.), U.S. Pat.No. 5,153,192 (Dean et al.), Nos. 5,240,923 (Dean et al.) And 5,378,703 (Dean et al.), PCT / US91 / 02262 (filed on Apr. 9, 1990) and European Patent No. 4 52 151 (published on Oct. 16, 1991). It has been disclosed. The entire contents of each of the above patents and patent applications are incorporated herein by this reference. Preferred CAIs of the present invention are the compounds disclosed in U.S. Pat.No. 5,378,703, especially R-(+)-4-ethylamino-3,4-dihydro-2- (3-methoxypropyl) -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 separately or in the same pharmaceutical composition. Thus, they can be administered simultaneously or separately to humans and other mammals suffering from glaucoma or intraocular hypertension. When prescribed separately, the drugs can be administered 1) simultaneously; 2) within a short time interval of one drug and another; or 3) in an offset manner. . Preferably, the PG is taken at night. Generally, the concentration of the PG in the formulation will be between about 0.00005 and about 0.5% by weight (wt.%), Preferably between about 0.0003 and 0.3% by weight, particularly preferably about It is between 0.0005 and 0.03% by weight. The concentration of said CAI in the formulation is between about 0.1 and 10.0% by weight, preferably between about 0.25 and 3% by weight, most preferably between about 0.5 and 2.0% by weight. is there. In the formulation of the combination, the concentration of the PG is between 0.0005 and 0.03% by weight and the CAI is between 0.5 and 1.5% by weight. In addition to the above main components, the anti-glaucoma composition of the present invention may further contain various prescription components, for example, an antiseptic antibiotic and an isotonic agent. Examples of suitable preservative antibiotics include benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethylal Similar drugs known to the trader are included. If used, such preservatives will typically be used in an amount between about 0.001 and 1.0% by weight. Examples of suitable drugs that can be used to adjust the osmolality or osmolality of the formulation include sodium chloride, potassium chloride, mannitol, dextrose, glycerin and propylene glycol. If used, such drugs would typically be used in amounts between about 0.1 and 10.0% by weight. It is also possible to use thickeners such as hydroxyethylcellose, hydroxypropylmethylcellulose, carbomer and the like, and when they are used, the prostaglandin concentration can be substantially reduced. Further, as a stabilizer, for example, polyethoxylate castor oil such as Cremophor EL can be used. As will be appreciated by those skilled in the art, the compositions can be any of a variety of solutions suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, gels, and erodible solid ocular inserts. It can be formulated in a dosage form. The formulation composition has a pH between 5.0 and 7.8, preferably between pH 6.5 and 7.6, and an osmolality between 280 and 320 milliosmoles per kilogram of body weight (mOsm / kg). Aqueous suspensions are preferred. The following examples further illustrate, but do not limit, the anti-glaucoma composition of the present invention. Example 1 Ophthalmic Suspension Component Concentration (wt%) Brinzolamide 1.0 ([1R- [1.α. (Z), 2.β. (3S), 3.α., 5. α.]]-[[4- [5-Chloro-2- (3-cyclohexyl-3-hydroxy-propyl) -3-hydroxycyclopentyl] -2-butenyl] oxy] -acetic acid, isopropyl ester) 0.01 hydroxy Propylmethylcellulose 0.5 Sodium phosphate dibasic 0.2 Disodium edetate 0.01 Sodium chloride 0.8 Purified water qs Benzalkonium chloride 0.01 Cremophor 0.1 NaOH / HCl pH 7.1 Example 2 Eye suspension Suspension component concentration (wt%) Brinzolamide 1.0 (+)-Isopropylfluprostenol ((+)-Isopropyl Fluprostenol) 0.005 Hydroxypropylmethylserucose 0.5 Dibasic sodium phosphate 2 Disodium edetate 0.01 PH7.1 example sodium 0.8 Purified water qs Benzalkonium chloride 0.01 cremophor 0.1 NaOH / HCl 3 ophthalmic suspension component concentration (wt%) brine tetrazole amide 1.0 isopropyl [2R (1E, 3R), 3S (4Z), 4R] -7- [tetrahydro-2- [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl] -4-hydroxy-3-furanyl] -4-heptenoate 0 .01 hydroxypropyl methylcellulose 0.5 dibasic sodium phosphate 0.2 edetate disodium 0.01 sodium chloride 0.8 purified water qs benzalkonium chloride 0.01 cremophor 0.1 NaOH / HCl pH 7.1 Example 4 Example of two formulations to be used simultaneously, used within 30 minutes, or offset by 1 hour or more Formula A component concentration (wt%) (+)-isopropylfluprostenol 0.005 1 Basic sodium phosphate 0.05 Dibasic sodium phosphate (anhydride) 0.15 Sodium chloride 0.75 Disodium EDTA (disodium edetate) 0.05 Cremophor EL 0.1 Benzalkonium chloride 0.01 HCl And / or NaOH pH 7.3-7.4 purified water qs. Up to 100% Formulation B component concentration (wt%) Brinzolamide 1.0 Hydroxypropyl methylcellulose 0.5 Sodium phosphate dibasic 0.2 Disodium edetate 0.01 Sodium chloride 0.8 Purified water qs Benzalkonium chloride 0.01 Cremophor 0.1 NaOH / HCl pH 7.1 Example 5 The following two formulations can be used simultaneously, used within 30 minutes, or with an offset of 1 hour or more. Formulation A component concentration (wt%) brinzolamide 1.0 hydroxypropyl methylcellulose 0.5 dibasic sodium phosphate 0.2 edetate disodium 0.01 sodium chloride 0.8 purified water qs benzalkonium chloride 0.01 Cremophor 0.1 NaOH / HCl pH 7.1 Formulation B component concentration (wt%) (+)-isopropylfluprostenol 0.001 Monobasic sodium phosphate 0.05 Dibasic sodium phosphate (anhydrous) 15 Sodium chloride 0.75 Disodium EDTA (disodium edetate) 0.05 Cremophor EL 0.1 Benzalkonium chloride 0.01 HCl and / or NaOH pH 7.3-7.4 Purified water qs up to 100% Example 6 below Use the two formulations at the same time, within 30 minutes, or over 1 hour It can be used in the offset. Formulation A component concentration (wt%) brinzolamide 1.0 hydroxypropyl methylcellulose 0.5 dibasic sodium phosphate 0.2 edetate disodium 0.01 sodium chloride 0.8 purified water qs benzalkonium chloride 0.01 Cremophor 0.1 NaOH / HCl pH 7.1 Formulation B component concentration (wt%) Isopropyl [2R (1E, 3R), 3S (4Z), 4R] -7- [tetrahydro-2- [4- (3-chlorophenoxy) ) -3-Hydroxy-1-butenyl] -4-hydroxy-3-furanyl] -4-heptenoate 0.01 monobasic sodium phosphate 0.05 dibasic sodium phosphate (anhydrous) 0.15 sodium chloride 0.75 Disodium EDTA (edinate dinatium) 0.05 Cremophor EL 0.1 Benzalkonium chloride 0.01 HCl and / or NaOH pH 7.3-7.4 Water making qs up to 100% Example 7 The following two formulations can be used simultaneously, used within 30 minutes, or with an offset of 1 hour or more. Formulation A ingredient concentration (wt%) Brinzolamide 1.0 Mannitol 3.3 Carbopol 974P 0.4 Tyloxapol 0.025 Benzalkonium chloride 0.1% + 5% xs Disodium EDTA (disodium edetate) ) 0.01 Sodium hydroxide pH 7.5 ±. 2 Hydrochloric acid pH 7.5 ±. 2 Sodium chloride 0.25 Purified water qs. Up to 100% Formulation B component concentration (wt%) (+)-isopropylfluprostenol 0.005-basic sodium phosphate 0.05 dibasic sodium phosphate (anhydrous) 0.15 sodium chloride 0.75 EDTA Disodium (disodium edetate) 0.05 Cremophor EL 0.1 Benzalkonium chloride 0.01 HCl and / or NaOH pH 7.3-7.4 Purified water qs up to 100% Example 8 The following two formulations are: It can be used simultaneously, used within 30 minutes, or used with an offset of 1 hour or more. Formulation A component concentration (wt%) Brinzolamide 1.0 Mannitol 3.3 Carbopol 974P (Carbopol 1974P) 0.4 Tyloxapol 0.025 Benzalkonium chloride 0.1% + 5% xs Disodium EDTA (disodium edetate) ) 0.01 sodium hydroxide pH 7.5 ±. 2 Hydrochloric acid pH 7.5 ±. 2 Sodium chloride 0.25 Purified water qs up to 100% Formula B component concentration (wt%) Isopropyl [2R (1E, 3R), 3S (4Z), 4R] -7- [tetrahydro-2- [4- (3-chloro Phenoxy) -3-hydroxy-1-butenyl] -4-hydroxy-3-furanyl] -4-heptenoate 0.01 monobasic sodium phosphate 0.05 dibasic sodium phosphate (anhydrous) 0.15 chloride Sodium 0.75 Disodium EDTA (edinate dinatium) 0.05 Cremophor EL 0.1 Benzalkonium chloride 0.01 HCl and / or NaOH pH 7.3-7.4 Purified water qs up to 100%

[Procedure for Amendment] Article 184-8, Paragraph 1 of the Patent Act [Date of Submission] November 20, 1998 (1998.11.20) [Content of Amendment] Claims 1. A method of reducing IOP in a person suffering from glaucoma or intraocular hypertension, comprising topically applying a carbonic anhydrase inhibitor, (+)-isopropylfluprostenol and isopropyl [2R (1E , 3R), 3S (4Z), 4R] -7- [tetrahydro-2- [4- (3-chlorophenoxy) -3-hydroxy-1-butenyl] -4-hydroxy-3-furanyl] -4-heptenoate Administering a pharmaceutically effective amount of a prostaglandin selected from the group consisting of: 2. The method of claim 1, wherein the prostaglandin is (+)-isopropylfluprostenol. 3. The 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. The method according to any one of claims 1 to 3, wherein the carbonic anhydrase inhibitor is brinzolamide. 5. A method of lowering IOP in a human suffering from glaucoma and intraocular hypertension, comprising locally administering to the eye a pharmaceutically effective amount of a carbonic anhydrase inhibitor and a prostaglandin. The method wherein the carbonic anhydrase inhibitor is brinzolamide and the prostaglandin is (+)-isopropylfluprostenol. 6. Carbonic anhydrase inhibitor, (-)-isopropylfluprostenol and isopropyl [2R (1E, 3R), 3S (4Z), 4R] -7- [tetrahydro-2- [4- (3-chlorophenoxy) -A product containing a pharmaceutically effective amount of prostaglandin selected from 3-hydroxy-1-butenyl] -4-hydroxy-3-furanyl] -4-heptenoate, which suffers from glaucoma or intraocular hypertension A product that is a combined preparation for simultaneous, separate or sequential use to reduce IOP in a human. 7. 7. The product of claim 6, wherein the prostaglandin is (+)-isopropylfluprostenol. 8. 7. The product of 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-hebutenoate. 9. 9. The product according to any one of claims 6, 7 or 8, wherein the carbonic anhydrase inhibitor is brinzolamide. 10. A product comprising a pharmaceutically effective amount of a carbonic anhydrase inhibitor and a prostaglandin, wherein the carbonic anhydrase inhibitor is brinzolamide and the prostaglandin is (+)-isopropyl A product that is fluprostenol, a combination preparation for simultaneous, separate or sequential use to reduce IOP in a human suffering from glaucoma or ocular hypertension.

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Claims (1)

[Claims] 1. A method of reducing IOP in a human suffering from glaucoma or intraocular hypertension. A prostaglandin and carbonic anhydrase inhibitor Administering a pharmaceutically effective amount of 2. 2. The method of claim 1, wherein said prostaglandin is (+)-isopro A method that is pillfluprostenol. 3. 2. The method of claim 1, wherein said prostaglandin is isopropyl [2R (1E, 3R), 3S (4Z), 4R] -7- [tetrahydro-2- [4- (3-chlorophenoxy) -3-hydr Roxy-1-butenyl] -4-hydroxy-3-furanyl] -4-heptenoate. 4. 2. The method of claim 1, wherein the carbonic anhydrase inhibitor is Brinzow. A method that is luamide. 5. 2. The method of claim 1, wherein said prostaglandin is (+)-isopro Pilfluprostenol, and the carbonic anhydrase inhibitor is brinzol A method that is an amide. 6. 2. The method of claim 1, wherein the prostaglandin is isopropyl. [2R (1E, 3R), 3S (4Z), 4R] -7- [tetrahydro-2- [4- (3-chlorophenoxy) -3-hydro Xy-1-butenyl] -4-hydroxy-3-furanyl] -4-heptenoate The method wherein the carbonic anhydrase inhibitor is brinzolamide.