METHOD FOR OPTIMIZING RETINAL AND OPTIC NERVE HEALTH

Abstract: There is disclosed a method for increasing retinal and optic nerve head blood velocity by topical application of a composition comprising carbonic anhydrase inhibitors and hypotonic xanthan gum to the eye.

Description: TITLE OF THE INVENTION METHOD FOR OPTIMIZING RETINAL AND OPTIC NERVE HEALTH BACKGROUND OF THE INVENTION Glaucoma is a degenerative disease of the eye wherein the intraocular pressure is too high to permit normal eye function. As a result, damage may occur to the optic nerve head and result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e., the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by the majority of ophthalmologists to represent merely the earliest phase in the onset of glaucoma. Normal tension glaucoma is the condition where there is no elevated intraocular pressure. Additionally, evidence suggests that glaucoma may have a vascular component, possibly vasospastic. New scientific technologies allow us to look more at the back of the eye and evaluate glaucoma from a circulatory, metabolic and hematological angle, therefore, being better able to determine the cause of the disease. In order to be able to see, light enters through the cornea and the lens; penetrates the back of the eye through the retina; passes the ganglion cells and bipolar cells; then goes down to the outer plexiform layers through the synaptic vesicle, the inner fiber, the nucleus, the outer fibers, the terminal bars, the cilium and finally reaches the photoreceptors which can be considered the instant film processing of the visual light beam. After the light beam has been processed in the photoreceptor disks, it passes back through the cilium, the ellipsoid, myoid, Mueller cells, outer fiber, nucleus, inner fiber, synaptic vesicle, the other plexiform layer, inner nuclear layer, the bipolar cells, the inner plexiform layer, finally reaching the ganglion cells where it is processed into an axon signal. After it reaches the ganglion cells, the signal is transported through the optic nerve fibers to the brain where it is assessed and compounded by the visual brain lobes to form the visual picture. It is believed that the uninterrupted signal carried by the retina, the optic nerve head and the optic nerve fibers is the most crucial aspect to create the visual picture and adequate blood flow which nurtures tissue and therefore assures axon flow. Glaucoma is seen as the progressive loss of optic nerve axons which leads to an interrupted signal flow, therefore, the result is visual field damage which leads over longer periods of time to blindness. Recently, a topically effective carbonic anhydrase inhibitor has become available for clinical use in treating glaucoma and ocular hypertension. (S,S)-(-)-5,6-Dihydro-4-ethylamino-6-methyl-4H- thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride TM (dorzolamide HC1; MK507) is the active ingredient in TRUSOPT which is prescribed for the treatment of elevated intraocular pressure in ocular hypertension, open-angle glaucoma and pseudo-exfoliative glaucoma. TRUSOPT (R) Ophthalmic Solution is applied as an isotonic, buffered, slightly viscous, aqueous solution of dorzolamide HC1. Each ml of TRUSOPT® 2% contains 20 mg dorzolamide (22.3mg dorzolamide HC1). When used as monotherapy, the dose is one drop of TRUSOPT (R) Ophthalmic Solution in the conjunctival sac of each affected eye three times daily. SUMMARY OF THE INVENTION The present invention is directed to a method for increasing retinal and optic nerve head blood velocity in a patient in need thereof by topical application of a composition comprising a hypotonic solution of xanthan gum and a topical carbonic anhydrase inhibitor. The present invention is also directed to a method for maximizing the health of the optic nerve and retina by topical application of a composition comprising a hypotonic solution of xanthan gum and a topical carbonic anhydrase inhibitor. The present invention is also directed to a method for treating normal tension glaucoma by topical application of a composition comprising a hypotonic solution of xanthan gum and a topical carbonic anhydrase inhibitor. Particularly, the invention relates to a method for increasing retinal and optic nerve head blood velocity by topical application of a composition comprising a topical carbonic anhydrase inhibitor(TCAI) such as those which are described in U.S. Patent Nos. 4,797,413, 4,386,098, 4,416,890, 4,426,388, 5,378,703, 5,240,923 and 5,153,192; and the like. Particularly preferred topical carbonic anhydrase inhibitors is the class of compounds of the structural formula (I): an individual diastereomer, an individual enantiomer or mixture thereof, or an ophthalmologically acceptable salt thereof, wherein: A is carbon or nitrogen, preferably carbon; Z is -NHR or -OR, preferably -NHR; R is C 1-6 alkyl, either straight or branched chain, preferably C 2 . 4 alkyl such as ethyl, propyl or isobutyl; R 1 is (a) hydrogen, (b) C 1-3 alkyl, preferably methyl, ethyl or n-propyl, or (c) C 1-4 alkoxy-C ι _ 4 alkyl, preferably 3-methoxypropyl or ethoxymethyl; and X is -S(O) 2 - or -C(O)-, preferably -S(O) 2 -. The carbon atoms to which Z and R 1 are bonded may be chiral. When named according to absolute configuration, e.g., (R,S) or (S,S), the first letter represents the chirality the carbon atom to which Z is bonded and the second letter represents the chirality of A when A is carbon. The carbonic anhydrase inhibitors of this invention accordingly may be used as diastereomeric mixtures or single enantiomers or as racemic mixtures. More preferred carbonic anhydrase inhibitors are dorzolamide, brinzolamide, acetazolamide, metazolamide described in U.S. Patent Nos., 4,797,413, 4,386,098, 4,416,890, 4,426,388, 5,378,703, 5,240,923 and 5,153,192; and the like . Dorzolamide, which has recently been approved under the trademark, TRUSOPT®, is the first topically effective CAI for clinical use. More particularly, the invention relates to a method for increasing retinal and optic nerve head blood velocity by topical application of a composition wherein the topical carbonic anhydrase inhibitor is (S,S)-(-)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno[2,3- b]thiopyran-2-sulphonamide-7,7-dioxide, or an ophthalmologically acceptable salt thereof or 2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide-4- (ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-l,l-dioxide or an ophthalmologically acceptable salt thereof. Other aspects of the invention will become apparent upon review of the complete application. DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to a method for increasing retinal and optic nerve head blood velocity by topical application of a composition comprising a hypotonic solution of xanthan gum and a topical carbonic anhydrase inhibitor. It is also directed to a method for treating normal tension glaucoma by topical application of a composition comprising a hypotonic solution of xanthan gum and a topical carbonic anhydrase inhibitor. The present invention is based upon the finding that CAIs can preserve or benefit vision by increasing both retinal and optic nerve head blood flow velocity. The increase in blood flow velocities was attained without any change in retinal vessel width which might have been the expected reason for the increase in flow velocity. Research was done using TRUSOPT (S) , as the carbonic anhydrase inhibitor. It is a known compound useful as a carbonic anhydrase inhibitor and for the reduction of intraocular pressure as is described in U.S. Pat. No. 4,797,413. In the compositions of the present invention the concentration of xanthan gum comprises about 0.1 to 2% (w/w), preferably 0.4 to 0.7% (w/w). Particularly preferred is KELTROL™ T xanthan gum from Monsanto Performance Materials. Xanthan gum is a high molecular weight polysaccharide gum obtainable from the aerobic fermentation of a carbohydrate with bacteria of the genus Xanthomonas, especially Xanthomonas campestris. Each xanthan gum repeat unit contains five sugar residues: two glucose, two mannose and one glucuronic acid. The polymer backbone consists of four β-D-glucose units linked at the 1 and 4 positions. Trisaccharide side chains on alternating anhydroglucose units distinguish xanthan gum from cellulose. Each side chain comprises a glucuronic acid residue between two mannose units. At most of the terminal mannose units is a pyruvate moiety. Xanthan gum solutions are pseudoplastic. In other words, when shear stress is increased, the viscosity is progressively reduced. Upon reduction of the shear, total viscosity is recovered almost instantaneously. This behaviour results from the high-molecular- weight molecule which forms complex molecular aggregates through hydrogen bonds and polymer entanglement. Also, this highly ordered network of entangled, stiff molecules accounts for the high viscosity observed at low shear rates. Shear thinning results from disaggregation of this network and alignment of individual polymer molecules in the direction of shear force. However, when the shearing ceases, aggregates re-form rapidly. As a result of its helical conformation, xanthan gum viscosity is relatively insensitive to temperature changes below the transition temperatures and to differences in ionic strength and pH. Xanthan gum solutions do not therefore have any liquid-gel phase transition properties, hence xanthan gum is not suitable for use in the formulation of in situ gelling solutions. The results of the present invention suggest that the high degree of pseudoplasticity, which is independent of concentration, appears to be important in contributing to the unusual ocular penetration properties of the hypotonic formulation of xanthan gum. Xanthan gum is commercially available, for example, under the tradename KELTROL™ from Monsanto Performance Materials, a unit of Monsanto Company, St. Louis, MO 63167, USA. Following administration of the composition to the conjunctival sac of a patient's eye, there is no liquid-gel phase transition. The advantageous enhancement in ocular bioavailability of the topical carbonic anhydrase inhibitor is achieved through the unique combination of the properties of the hypotonic solution of xanthan gum. The topical carbonic anhydrase inhibitors of use in the present invention include those compounds described in U.S. Patent Nos. 4,797,413, 4,386,098, 4,416,890, 4,426,388, 5,378,703, 5,240,923 and 5,153,192; and the like. Preferred topical carbonic anhydrase inhibitors are the class of compounds of the structural formula (I): an individual diastereomer, an individual enantiomer or mixture thereof, or an ophthalmologically acceptable salt thereof, wherein: A is carbon or nitrogen, preferably carbon; Z is -NHR or -OR, preferably -NHR; R is C 1-6 alkyl, either straight or branched chain, preferably C 2-4 alkyl such as ethyl, propyl or isobutyl; R ! is (a) hydrogen, (b) C ι-3 alkyl, preferably methyl, ethyl or n-propyl, or (c) C, -4 alkoxy-C ι-4 alkyl, preferably 3-methoxypropyl or ethoxymethyl; and X is -S(0) 2 - or -C(O)-, preferably -S(O) 2 -. The carbon atoms to which Z and R 1 are bonded may be chiral. When named according to absolute configuration, e.g., (R,S) or (S,S), the first letter represents the chirality the carbon atom to which Z is bonded and the second letter represents the chirality of A when A is carbon. The carbonic anhydrase inhibitors of this invention accordingly may be used as diastereomeric mixtures or single enantiomers or as racemic mixtures. Preferred topical carbonic anhydrase inhibitors for use in the present invention are compounds of formula (I), above, wherein A is carbon; and wherein R is -CH 2 CH 3 and R 1 is -CH 3 ; or R is -CH 2 CH 2 CH 3 and R 1 is -CH 2 CH 2 CH 2 OCH 3 ; or R is -CH 2 CH 3 and R 1 is -CH 2 CH 2 CH 3 ; or R is -CH 2 CH 2 (CH 3 ) 2 and R 1 is hydrogen; or R is -CH 2 CH 3 and R 1 is -CH 2 OCH 2 CH 3 ; and carbons 4 and 6 of the topical carbonic anhydrase inhibitor both have S absolute stereochemical configuration. More preferred carbonic anhydrase inhibitors are dorzolamide, brinzolamide, acetazolamide, metazolamide described in U.S. Patent Nos., 4,797,413, 4,386,098, 4,416,890, 4,426,388, 5,378,703, 5,240,923 and 5,153,192; and the like . Dorzolamide, which has recently been approved under the trademark, TRUSOPT®, is the first topically effective CAI for clinical use. Most preferred topical carbonic anhydrase inhibitors are (S,S)-(-)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno[2,3- b]thiopyran-2-sulphonamide-7,7-dioxide, or an ophthalmologically acceptable salt thereof and 2H-thieno[3,2-e]-l,2-thiazine-6-sulfonamide- 4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-l,l-dioxide or an ophthalmologically acceptable salt thereof. A particularly preferred topical carbonic anhydrase inhibitor is dorzolamide, especially as its hydrochloride salt. The concentration of TCAI in the present invention is about 0.05 to 5% (w/w), usually about 0.5 to 3% (w/w), and is administered once or twice daily, to each affected eye. The novel method of this invention comprises the topical ocular administration of about 0.025 to 5 mg per day, preferably about 0.25 to 3 mg per day, of the topical carbonic anhydrase inhibitor to each eye. 8 As a unit dosage, between 0.025 and 2.5 mg, preferably between 0.25 and 1.5 mg, of the topical carbonic anhydrase inhibitor is applied to each eye. Conventional ophthalmic solutions are usually prepared as isotonic solutions using tonicity adjusting agents such as potassium chloride, sodium chloride, mannitol, dextrose and glycerin. An isotonic solution will have a freezing point depression of approximately -0.54°C. Tonicity may also be measured by the osmolality of the solution, an isotonic solution having an osmolality of about 290 milliosmoles per kilogram (mOs/kg). It is a characteristic of the ophthalmic compositions of the present invention that they are hypotonic solutions, with a freezing point depression between about -0.28°C and -0.4°C, and preferably between about -0.31°C and -0.37°C. Alternatively, the hypotonicity of the ophthalmic solutions of the present invention is between about 150 and 215 mOs/kg, and preferably between 170 and 200 mOs/kg. According to a further aspect of the present invention, there is provided a novel method for increasing retinal and optic nerve head blood velocity by topical application of a composition comprising a hypotonic solution of xanthan gum, a therapeutically effective amount of a topical carbonic anhydrase inhibitor and a therapeutically effective amount of a β-adrenergic receptor blocking agent. Suitable β-adrenergic receptor blocking agents include betaxolol, bufetolol, carteolol, levobunolol, metipranolol, and timolol, or an ophthalmologically acceptable salt thereof. A particularly preferred β-adrenergic receptor blocking agent is timolol maleate. Such compositions preferably comprise about 0.05 to 5% (w/w) of the topical carbonic anhydrase inhibitor, usually about 0.5 to 3% (w/w), and about 0.01 to 1% (w/w) of the β-adrenergic receptor blocking agent, preferably about 0.1 to 0.5% (w/w) to be administered once or twice a day to each affected eye. Thus, a further novel method of this invention comprises the topical ocular administration of about 0.025 to 5 mg per day, preferably about 0.25 to 3 mg per day, of the topical carbonic anhydrase inhibitor and about 0.005 to 1 mg per day, preferably about 0.05 to 0.5 mg per day, of the β-adrenergic receptor blocking agent to each eye. As a unit dosage, between 0.005 and 0.5 mg of the β- adrenergic receptor blocking agent, and preferably between 0.05 and 0.25 mg of the β-adrenergic receptor blocking agent, is applied to each eye. The pH of the composition ranges from about 5.0 to about 7.5, preferably about 5.5 to about 7.0. Suitable subjects for the administration of the formulation of the present invention include primates, man and other animals, particularly man and domesticated animals such as cats and dogs. The pharmaceutical preparation may contain non-toxic auxiliary substances such as antibacterial components which are non- injurious in use, for example, thimerosal, benzalkonium chloride, methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol, or phenylethanol; buffering ingredients such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffers; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraacetic acid, and the like. The following examples of ophthalmic compositions are given by way of illustration. EXAMPLE 1 SOLUTION COMPOSITION A B (S,S)-(-)-5,6-Dihydro-4-ethylamino-6- 2.226% 2.226% methyl-4i -thieno[2,3-b]thiopyran-2- sulfonamide-7,7-dioxide monohydrochloride Xanthan Gum 0.5% 0.7% Sodium Chloride 0.2% 0.2% Benzalkonium Chloride 0.0075% 0.0075% Sodium hydroxide QS pH 5.6 pH 5.6 Purified Water QS 100% 100% The active compound, sodium chloride and benzalkonium chloride were dissolved in water for injection. The pH of the composition was adjusted to 5.6 by addition of 0.2 N sodium hydroxide solution, and water for injection was added until the weight of composition was equal to 75 parts of the final weight (Example 1 A) or 65 parts of the final weight (Example IB). The composition was sterilised by filtration, and the solution flushed with sterile nitrogen. Then a clarified, steam sterilised concentrate of 2% xanthan gum was added to the solution of drug and the obtained solution was homogenised by stirring. The solution was aseptically subdivided into sterile vials and sealed. EXAMPLE 2 SOLUTION COMPOSITION (S,S)-(-)-5,6-Dihydro-4-ethylamino-6- 0.88% (n-propyl)-4H-thieno [2,3 -b] thiopyran- 2-sulfonamide-7,7-dioxide monohydrochloride Xanthan Gum 0.5% Sodium Citrate 0.147% Hydrochloric Acid QS pH 5.0 Sorbitol 1.5% Benzalkonium Chloride 0.0075% Purified Water QS 100% The active compound, sodium citrate, benzalkonium chloride and sorbitol are dissolved in water for injection. The pH of the composition is adjusted to pH 5.0 by addition of hydrochloric acid, and water for injection is added until the weight of the composition is equal to 75 parts of the final weight. The composition is sterilised by filtration, flushing with sterile nitrogen. Then a clarified, steam sterilised concentrate of 2% xanthan gum is added to the solution of the drug and the obtained solution is homogenised by stirring. The solution is aseptically subdivided into sterile vials and sealed. EXAMPLE 3 SOLUTION COMPOSITION (±)-5,6-dihydro-4-[(2- 1.662% methylpropyl)amino]-4H-thieno[2,3- b]thiopyran-2-sulfonamide-7,7-dioxide monohydrochloride Xanthan Gum 0.5% Sodium Citrate 0.22% Sodium Hydroxide QS pH 5.6 Mannitol 0.50% Benzalkonium Chloride 0.0075% Purified Water QS 100% The active compound, sodium citrate, benzalkonium chloride and mannitol are dissolved in water for injection. The pH of the composition is adjusted to pH 5.6 by addition of sodium hydroxide, and water for injection is added until the weight of the composition was equal to 75 parts of the final weight. The composition is sterilised by filtration, flushing with sterile nitrogen. Then a clarified, steam sterilised concentrate of 2% xanthan gum is added to the solution of the drug and the obtained solution is homogenised by stirring. The solution is aseptically subdivided into sterile vials and sealed. EXAMPLE 4 SOLUTION COMPOSITION (S,S)-(-)-5,6-dihydro-4-ethylamino-6- 1.6695% methyl-4H-thieno[2,3-b]thiopyran-2- sulfonamide-7 ,7-dioxide monohydrochloride Xanthan Gum 0.7% Sodium Chloride 0.25% Sodium Hydroxide QS pH 5.8 Benzalkonium Chloride 0.0075% Purified Water QS 100% The active compound, sodium chloride and benzalkonium chloride were dissolved in water for injection. The pH of the composition was adjusted to pH 5.8 by addition of sodium hydroxide, and water for injection was added until the weight of the composition was equal to 65 parts of the final weight. The composition was sterilised by filtration, flushing with sterile nitrogen. Then a clarified, steam sterilised concentrate of 2% xanthan gum was added to the solution of the drug and the obtained solution was homogenised by stirring. The solution was aseptically subdivided into sterile vials and sealed. EXAMPLE 5 SOLUTION COMPOSITION (S,S)-(-)-5,6-dihydro-4-ethylamino-6- 1.113% methyl-4H-thieno[2,3-b]thiopyran-2- sulfonamide-7,7-dioxide monohydrochloride Xanthan Gum 0.7% Sodium Hydroxide QS pH 6.0 Sodium Chloride 0.32% Benzalkonium Chloride 0.0075% Purified Water QS 100% The active compound, sodium chloride and benzalkonium chloride were dissolved in water for injection. The pH of the composition was adjusted to pH 6.0 by addition of sodium hydroxide, and water for injection was added until the weight of the composition was equal to 65 parts of the final weight. The composition was sterilised by filtration, flushing with sterile nitrogen. Then a clarified, steam sterilised concentrate of 2% xanthan gum was added to the solution of the drug and the obtained solution was homogenised by stirring. The solution was aseptically subdivided into sterile vials and sealed. EXAMPLE 6 SOLUTION COMPOSITION (S,S)-(-)-5,6-dihydro-4-ethylamino-6- 1.113% methyl-4H-thieno[2,3-b]thiopyran-2- sulfonamide-7,7-dioxide monohydrochloride Xanthan Gum 0.7% Sodium Hydroxide QS pH 6.5 Sodium Chloride 0.32% Benzalkonium Chloride 0.0075% Purified Water QS 100% The active compound, sodium chloride and benzalkonium chloride were dissolved in water for injection. The pH of the composition was adjusted to pH 6.5 by addition of sodium hydroxide, and water for injection was added until the weight of the composition was equal to 65 parts of the final weight. The composition was sterilised by filtration, flushing with sterile nitrogen. Then a clarified, steam sterilised concentrate of 2% xanthan gum was added to the solution of the drug and the obtained solution was homogenised by stirring. The solution was aseptically subdivided into sterile vials and sealed. EXAMPLE 7 SOLUTION COMPOSITION (S,5)-(-)-5,6-dihydro-4-ethylamino-6- 2.226% methyl-4 -thieno[2,3-b]thiopyran-2- sulfonamide-7 ,7-dioxide monohydrochloride (S)-(-)-l-(rert-butylamino)-3-[(4- 0,684% morpholino-l,2,5-thiadiazol-3-yl)oxy]-2- propanol maleate Xanthan Gum 0.5% Sodium Chloride 0.15% Sodium Hydroxide QS pH 5.6 Benzalkonium Chloride 0.0075% Purified Water QS 100% The active compounds, sodium chloride and benzalkonium chloride are dissolved in water for injection. The pH of the composition is adjusted to pH 5.6 by addition of sodium hydroxide, and water for injection is added until the weight of the composition was equal to 75 parts of the final weight. The composition is sterilised by filtration, flushing with sterile nitrogen. Then a clarified, steam sterilised concentrate of 2% xanthan gum is added to the solution of the drug and the obtained solution is homogenised by stirring. The solution is aseptically subdivided into sterile vials and sealed. RESULTS Concentrations of 2% dorzolamide(TRUSOPT®) or 2% dorzolamide in hypotonic xanthan gum formulation were measured by HPLC in various fluids and tissues of pigmented rabbit eye at 1, 2, 4 and 8 hours after dosing. The instillation of the 2% dorzolamide in hypotonic xanthan gum formulation resulted in, for example approximately 2.8-fold higher concentration of dorzolamide in the aqueous humor and iris-ciliary body at 2 hours than the 2% dorzolamide . Likewise, the retinal, choroidal and scleral concentrations were approximately 2.2-fold higher at 2 hours. Moreover, the concentration of dorzolamide in the red blood cell and plasma were very similar after dosing with either the 2% dorzolamide (TRUSOPT ® ) or 2% dorzolamide in hypotonic xanthan gum formulations. This suggests that the penetration of dorzolamide into the anterior and posterior portions of the eye is enhanced by the instillation of dorzolamide in the hypotonic xanthan gum formulation and is independent of drug concentrations in the blood. The claimed use of the compound to increase retinal and optic nerve head blood flow velocity has been the subject of a study to determine whether TRUSOPT drops compared to placebo drops had a significant effect on retinal and optic nerve head blood flow velocity in healthy subjects. In the study, normal, healthy subjects were randomly assigned to receive placebo or 2.0%TRUSOPT ® drops to both eyes in a double masked clinical trial. Intraocular pressure and scanning laser video fluorescin angiography were evaluated at baseline and 120 minutes following application. Subjects treated with TRUSOPT exhibited an accelerated arteriovenous passage time as well as an increase in optic nerve head velocity. Additionally, the expected decrease in intraocular pressure was found.

Claims: WHAT IS CLAIMED IS: 1. A method for maximizing the health of the optic nerve and retina which comprises applying to the eye an effective amount of a composition comprising a hypotonic solution of 0.1 to 2% (w/w) of xanthan gum and 0.5 to 5% (w/w) of a topical carbonic anhydrase inhibitor. 2. The method according to Claim 1 wherein the composition is applied topically. 3. The method according to Claim 2 wherein the carbonic anhydrase inhibitor is a compounds of the structural formula (I): an individual diastereomer, an individual enantiomer or mixture thereof, or an ophthalmologically acceptable salt thereof, wherein: A is carbon or nitrogen, preferably carbon; Z is -NHR or -OR, preferably -NHR; R is C 1-6 alkyl, either straight or branched chain, preferably C 2-4 alkyl such as ethyl, propyl or isobutyl; R' is (a) hydrogen, (b) C 1-3 alkyl, preferably methyl, ethyl or n-propyl, or (c) C ι-4 alkoxy-C 1-4 alkyl, preferably 3-methoxypropyl or ethoxymethyl; and X is -S(O) 2 - or -C(O)-, preferably -S(O) 2 -. 4. The method according to Claim 3 wherein A is carbon; and wherein R is -CH 2 CH 3 and R 1 is -CH 3 ; or R is -CH 2 CH 2 CH 3 and R 1 is -CH 2 CH 2 CH 2 OCH 3 ; or R is -CH 2 CH 3 and R 1 is -CH 2 CH 2 CH 3 ; or R is -CH 2 CH 2 (CH 3 ) 2 and R 1 is hydrogen; or R is -CH 2 CH 3 and R 1 is -CH 2 OCH 2 CH 3 ; and carbons 4 and 6 of the topical carbonic anhydrase inhibitor both have S absolute stereochemical configuration. 5. The method according to Claim 3 wherein the carbonic anhydrase inhibitor is selected from the group consisting of dorzolamide, brinzolamide, acetazolamide, metazolamide and the like. 6. The method according to Claim 5 wherein the carbonic anhydrase inhibitor is dorzolamide. 7. The method according to Claim 6 wherein the dorzolamide is (S,S)-(-)-5,6-dihydro-4-ethylamino-6-methyl-4H- thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride. 8. The method of claim 1 wherein the concentration of carbonic anhydrase inhibitor is about 0.5 to about 2.0% (w/w) and the concentration of xanthan gum is 0.4 to 0.7% (w/w). 9. The method of claim 1 wherein the composition wherein the hypotonic solution has a freezing point depression of between -0.28°C and -0.4°C and the hypotonicity of the solution is between 150 and 215 mOs/kg. 9. The method of claim 7 wherein the composition wherein the hypotonic solution has a freezing point depression of between -0.28°C and -0.4°C and the hypotonicity of the solution is between 150 and 215 mOs/kg. 10. The method according to claim 1 which additionally comprises about 0.01 to 1% (w/w) of a β-adrenergic receptor blocking agent, or an ophthalmologically acceptable salt thereof. 11. The method according to Claim 10 wherein the concentration of β-adrenergic receptor blocking agent is about 0.1 to 0.5% (w/w). 12. The method according to Claim 10 wherein the β- adrenergic receptor is timolol maleate. 13. The method according to claim 9 which additionally comprises about 0.01 to 1% (w/w) of a β-adrenergic receptor blocking agent, or an ophthalmologically acceptable salt thereof. 14. The method according to Claim 13 wherein the concentration of β-adrenergic receptor blocking agent is about 0.1 to 0.5% (w/w). 15. The method according to Claim 14 wherein the β- adrenergic receptor is timolol maleate. 16. A method for increasing retinal blood flow velocity which comprises topically applying to the eye an effective amount of a composition comprising a hypotonic solution of 0.1 to 2% (w/w) of xanthan gum and 0.5 to 5% (w/w) of a topical carbonic anhydrase inhibitor. 17. The method according to Claim 16 wherein the carbonic anhydrase inhibitor is selected from the group consisting of dorzolamide, brinzolamide, acetazolamide, metazolamide and the like. 18. The method according to Claim 17 wherein the dorzolamide is (S,S)-(-)-5,6-dihydro-4-ethylamino-6-methyl-4H- thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride. 19. The method of claim 16 wherein the concentration of carbonic anhydrase inhibitor is about 0.5 to about 2.0% (w/w) and the concentration of xanthan gum is 0.4 to 0.7% (w/w). 20. The method of claim 16 wherein the composition wherein the hypotonic solution has a freezing point depression of between -0.28°C and -0.4°C and the hypotonicity of the solution is between 150 and 215 mOs/kg. 21. The method of claim 20 wherein the composition wherein the hypotonic solution has a freezing point depression of between -0.28°C and -0.4°C and the hypotonicity of the solution is between 150 and 215 mOs/kg. 22. The method according to claim 16 which additionally comprises about 0.01 to 1% (w/w) of a β-adrenergic receptor blocking agent, or an ophthalmologically acceptable salt thereof. 23. The method according to Claim 22 wherein the concentration of β-adrenergic receptor blocking agent is about 0.1 to 0.5% (w/w). 24. The method according to Claim 23 wherein the β- adrenergic receptor is timolol maleate. 25. The method according to claim 18 which additionally comprises about 0.01 to 1% (w/w) of a β-adrenergic receptor blocking agent, or an ophthalmologically acceptable salt thereof. 26. The method according to Claim 25 wherein the concentration of β-adrenergic receptor blocking agent is about 0.1 to 0.5% (w/w). 27. The method according to Claim 26 wherein the β- adrenergic receptor is timolol maleate. 28. A method for increasing optic nerve head blood velocity which comprises topically applying to the eye an effective amount of a composition comprising a hypotonic solution of 0.1 to 2% (w/w) of xanthan gum and 0.5 to 5% (w/w) of a topical carbonic anhydrase inhibitor. 29. The method according to Claim 28 wherein the carbonic anhydrase inhibitor is selected from the group consisting of dorzolamide, brinzolamide, acetazolamide, metazolamide and the like. 30. The method according to Claim 28 wherein the dorzolamide is (5 , ,.S')-(-)-5,6-dihydro-4-ethylamino-6-methyl-4H- thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride. 31. The method of claim 28 wherein the concentration of carbonic anhydrase inhibitor is about 0.5 to about 2.0% (w/w) and the concentration of xanthan gum is 0.4 to 0.7% (w/w). 32. The method of claim 28 wherein the composition wherein the hypotonic solution has a freezing point depression of between -0.28°C and -0.4°C and the hypotonicity of the solution is between 150 and 215 mOs/kg. 33. The method of claim 32 wherein the composition wherein the hypotonic solution has a freezing point depression of between -0.28°C and -0.4°C and the hypotonicity of the solution is between 150 and 215 mOs/kg. 34. The method according to claim 28 which additionally comprises about 0.01 to 1% (w/w) of a β-adrenergic receptor blocking agent, or an ophthalmologically acceptable salt thereof. 35. The method according to Claim 34 wherein the concentration of β-adrenergic receptor blocking agent is about 0.1 to 0.5% (w/w). 36. The method according to Claim 35 wherein the β- adrenergic receptor is timolol maleate. 37. The method according to claim 30 which additionally comprises about 0.01 to 1% (w/w) of a β-adrenergic receptor blocking agent, or an ophthalmologically acceptable salt thereof. 38. The method according to Claim 37 wherein the concentration of β-adrenergic receptor blocking agent is about 0.1 to 0.5% (w/w). 39. The method according to Claim 38 wherein the β- adrenergic receptor is timolol maleate. 40. A method for treating normal tension glaucoma by topical application of a composition comprising a hypotonic solution of xanthan gum and a topical carbonic anhydrase inhibitor.

Inventors: SUGRUE MICHAEL S, SUGRUE, MICHAEL, S.
Applicants: MERCK & CO INC, SUGRUE MICHAEL S, MERCK & CO., INC., SUGRUE, MICHAEL, S.
Application year: 1998
Main classification: A61K31
IPC codes: A61K31, A61K45, A61P25, A61P27, C07D279, C07D285, C07D495, C07D513