MXPA97009063A - Use of carbonic anhydrase to prepare a composition to increase the blood flow of the retina and composition of the - Google Patents

Abstract

The present invention is referenced to: The use of carbonic anhydrase to prepare an enhancement to increase the blood velocity in the retina and in the head of the optic nerve is described by the local application of carbonic anhydrase inhibitors to

Description

USE OF CRRBONIC ANHYDRASE TO PREPARE A COMPOSITION TO INCREASE THE BLOOD FLUOXIDE OF THE RETINA AND COMPOSITION OF THE SAME BACKGROUND OF THE INVENTION T) uran + e the largest part of this century, gJaucorna was defined as a disease of the eyes that produced blindness caused by increased pressure inside the eye. It is + under pressure from the internal tissues < k- > l or which led to the loss ^ \ ^ 1 visual field »Science believed that if the blood pressure (PIÓ) was lowered to a level below 21 mm on the mercury scale, it could stop or slow down the course of the disease. However, there are many cases in which glaucoin with PEO occurs below 21 rnrn / rne curium, therefore, PEO is not the main factor in causing it + to disease. Recent evidence suggests that glaucoma may also have a vascular component, possibly ás vasospas. The new scientific technologies allow us to look behind the eye and value the glaucorna from a circulatory, metabolic and herbal angle, thus being able to better determine the cause of the disease. In order to see, light enters through the cornea and lens; penetrates the posterior part of the o or through the retina; it passes through ganglion cells and bipolar cells; then it is directed towards the external plastic layers through the synaptic vesicle, the inner fiber, the nucleus, the internal fibers, the terminal bars, the cilia and finally the endorsements that can be considered the instantaneous attachment of film?] the visual light beam. Then «what the beam of light h? • treated in the disc orrecoptor, it passes through the cilium, the psoid, myoid, Nueller cells, external fiber, nucleus, internal fiber, mapic vesicle, the other plexi layer, nuclear layer internally, the bipolar cells, the inner layer pl ex i form, finally reaching the ganglia cells in which it was converted to a neuraxial signal. After LU reaches the ganglonary cells, the serial is transposed by the optic nerve fibers to the brain where it is evaluated and composed by the visual cerebral globules for formal visual image. It is believed that the uninterrupted serial carried by the retina, the head of the nerve Optical L5 and optic nerve fibers is the most crucial aspect to croak the visual image and the adequate blood flow that nourishes the tissue and thus ensures the axi n flow co. Glaucoma is seen as the progressive loss of the axons of the optic nerve which leads to an interrupted flow of Therefore, the result is damage to the visual field, which leads to blindness for longer periods.

BRIEF DESCRIPTION OF THE INVENTION It has now been noted that the drugs in the class of carbonic anhydrase inhibitors (CABs) when they are described in FIG.

It has now been noted that drugs in the class of carbohydrate anhydrase inhibitors (CRFs) when administered intraocularly can cause a marked increase in blood velocity on the? In addition, at the top of the nerve, the IACs include drugs such as dopamine, acetazolamide, even azole, and other compounds described in ?? U.S. Patent No. 7, '17, 4 L 5, LU? , 'Jßb, p' -) U,? , 41F), 090 and 4,426,380; and similar. The ammonia solution, 7,7-dioxid hydrochloride of S, - 5, bd hi dro-4-et i lamí non-B-rneti 1 - 4H-t? Ene-f 2, 3 -bit? Op ? The first of these has been approved and its trans enant 1 has been recently approved by the FDA for use in the treatment of ocular hypertension associated with L5 glaucoin. The TACs manifest their activity by inhibiting the enzyme, carbonic anhydrase, and preventing s? contribution to the formation of aqueous humor produced through the carbonic anhydrase pathway. The lACs obstruct or hinder this afferent pathway by inhibiting carbonic anhydrase. The dorzola i da, la which has been recently approved with the name of factory 7RUS0PTR, is the first IAC Locally effective for clinical use.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the use of carbon anhydrase to prepare a co-operation to increase the blood velocity in the tina and the head of the optic nerve by means of the local application of IHOs < . «.! eye .. the present invention is based on the discovery of f? that IROs can preserve or benefit vision by increasing the speed of blood flow both in the retina and in the head of the optic nerve. It was observed that the results were achieved without any change in the width of the retained vessels which could have been the expected reason for the increase in the velocity of the flow. An investigation was made using Trusopt, a particular inhibitor of the carbonic anhydrase. It is a known compound useful as an inhibitor of carbonic anhydrase and for reduction of the pressure m + ratio as described in U.S. Patent No. 4,797,413. The EAC that is used is preferably administered in the form of ophthalmic pharmaceutical compositions adapted for local eye care, such as solutions, ointments or as solid insertion material. The 0 formulations of this compound can contain from 0.01 to 5% and especially from 0.5 to 2% of medicine. Higher doses, such as doses of 10% or lower, may be used as long as the dose is effective to increase the rate of blood flow. For a single dose, between 0.001 to 5.0 mg, preferably between 0.005 and 2.0 mg and especially between 0.005 to 1.0 mg of the compound or pharmaceutically acceptable are, for example, < (water mixtures and miscible solvents in water such as albandes and araleanolos interiors, vegetable oils pol? ot i Lcng 1 icoles, jelly based on oil, and Ice Luíosa, or Slow of ethyl, b carboximot i lcel ulosa LPI RROL i DON, ISOPROPIL MIPASSATE AND OTHER ACCEPTABLE VEHICLES CONVENIENTLY EMPLOYED The pharmaceutical preparation may also contain non-toxic auxiliary substances, such as oinulsing agents, preservatives, huinedecodores, ospesadoros and Similar LUs, as for example, pol et i lengl cabals 200, 7) 110, 400 and 600, cartridges L, 000, 1,500, 4,0 (10, 6,000 and LO, UOO bacterial components taLes as a quaternary ammonium compound, Phenolic salts that are known to have properties that are cold and that are not harmful to their use, imerosal, rnet L- and propylparaben, benzyl alcohol, phenylglycanol pH-regulating ingredients such as sodium borate, sodium acetate, gluconate pH regulators and other conventional ingredients such as sorbitan mono laurate, t riet anolarnin, oleate onopalm polyoxyethylene thiol, 20 -sodium sulphonate, sodium phosphate, sodium thioxide, ethylene diamine tetraacetic acid, and the like, suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional systems of pH regulating vehicles of phosphate, isotonic boric acid vehicles, isotonic sodium chloride vehicles, similar sodium borate sotonic vehicles. The pharmaceutical preparation may also be in the form of solid insertion material. For example, a water-soluble pain polymer may be used as a vehicle for the medicament. The polymer used to form the insertion material can be any non-toxic, water-soluble polymer, for example, cellulose derivatives such as methylcellulose, sodium hydrocarbyl cellulose, hydroxy- (lower alkyl) hydroxyethyl, Tylose, hydroxy propyl cellulose, hydrox propyl met 1 cel ul; Acts such as acid salts, polypeptides, polyacids, polylactics; natural products such as gelatin, alginates, pectones, tragacanth, karaya, chondro, agar, acacia; starch derivatives such as starch acetate, hydroxyrnethylamine ethers, hydroxypropyl Lalnunidon, as well as their synthetic derivatives such as polyvinyl alcohol, polypropylene glycol, polyvinyl ether, polyethylene oxide, neutralized carbopol and xanthan gum, and mixtures of said polymer. Preferably the solid insertion material is prepared from cellulose derivatives such as methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxypropyl ethyl cellulose or from other synthetic maternal materials such as polyvinyl alcohol, polyvinyl pyrrolidone, polyether oxide or polyvinyl etheric ester. Hydroxypropylcellulose, one of the preferred polymers for the preparation of the maternal insertion, is obtainable in various polymeric forms all of which are suitable in the preparation of these insertion inatepals. In this way, products sold by manufacturers, Ene. Or f- Wi lirunt ong, Delaware under the name KLUC I.TM, as well as KLUCEL Hl-, HUF, MF, ÜF, JF ", LF and FFs that are available for food use The pharmaceutical molecular weight of these polymers for the purposes described herein may be at least 30,000 to about 1, 000, 000 or more. a full-oxide polymer having a molecular weight of up to 5,000,000 or greater, and preferably from 100,000 to 5,000,000 can be used.Further, for example, P0LY0X ™, polymer supplied by Union Carbide O. which has a molecular weight of about 50,000 to 5,000,000 or more and preferably from 3,000,000 to 4,000,000 Other specific polymers that are useful are polyvinyl chloride or polypropylene with a molecular weight of from about 10,000. to approximately 1. (100,000 or more, preferably up to approximately 350,000 and especially from approximately 20,000 to 60,000; Polyvinyl alcohol having a molecular weight of from about 30,000 to 1. 000,000, particularly from approximately 400,000 especially from approximately 100,000 to approximately 200,000; hydroxypropylrnetylcellulose which has a molecular weight of from about 10,000 to 1,000,000 or more, particularly up to about 200,000 and especially from about 00,000 to about L 2b, () U 0; cellulose which is a molecular weight of from about 1U, 00 () to approximately 1,000.00 (1 or more, preferably up to about 200,000 and especially from about 50 to 100,000; and 0ARU0P0L ™ It is evident that for the purpose of this invention the type and molecular weight of the polymer is not critical, any soluble polymers can be used. in ag? a that have an average molecular weight that produce the dissolution of the polymer and therefore the drug in any desired time.The insert materials, therefore, can be prepared to allow retention and consequently the effectiveness in the eye During any desired period, the insertion material may be in the form of a square, rectangle, oval, circle, donut, semicircle, lunar quadrant and the like, preferably the insertion material is presented in the form of a vari 1 L a, thread, oval or lunar quadrant. The insertion material can be easily prepared, for example, by dissolving the medicament and the polymer in a suitable solvent and evaporating the solution to produce a thin film of the polymer which can be further subdivided to prepare the appropriate tarnishing insert materials. Alternatively, the insert material can be prepared by heating the polymer and the medicament and molding the resulting mixture to form a thin film. Preferably, the insert materials are repaired by molding or extrusion processes well known in the art. The molded product - noise can be subdivided afterwards? Overser material insertion of adequate size for your ad inis ration on the eye, b l-l insertion material can be of «, -quantity? A good fit to fit faciLmen or aJoo »For example, Cast parts or compression molded films have a thickness of approximately 0.25 mm or lb. or can be subdivided to obtain suitable materials from serción LO I O? Rectangular segments of the cast part or compressed film having a thickness of between about 0.5 and 1.5 mm can be cut to provide tall figures with rectangular plates of 4 x 5-20 mm and ovals of comparable size. Sirnily, clogged rods that have a diameter of L5 between approximately 0.5 and L.b inin can be cut into suitable sections to provide * the desired amount of polymer. For example, rod factories from 1.0 to 1.5 min in diameter and approximately 20 nm in length are considered to be rod factories. The insert materials can also be formed directly or by injection molding. It is preferred that the ophthalmic insertion materials having medicament of the present invention be formed so that they are smooth and have no sharp corners or edges that could cause damage to the eye. Since the terms corners and smooth and sharp edges are 5 subjective terms, in this application these terms are used to indicate that excessive irritation of the eye does not result from the use of inatoi? < \ L insertion. When the solid medicinal product is inca with water, does the product come into contact with the air? which has a relative humidity of at least 40% until said product absorbs less than about% water and becomes softer and more flexible. In a preferred embodiment, the relative humidity of the air is from about 60% to about 99% and the contact condition is continued until the water is present in the product in amounts of from about 1 U. % n approximately 20%. The suitable water-soluble preservatives that can be used in the insertion material are sodium bisulfate, sodium thiosulfate, ascorbate, benzalcomo chloride, ciorob? t anol, tyrosenal, acet atofemlrnercurico, borate ferulrnercupco, parabens, benzyl alcohol and phenylethanol. These agents can be present in amounts of from 0.001 to 5% by weight of the solid insertion material and preferably from 0.1 to 2%. Suitable water-soluble pH regulating agents are carbonates, phosphates, bicarbonates, cyanides, borates, alkalis, alkaline-earths and the like, such as phosphate, citrate, borate, acetate, bicarbonate and sodium bicarbonate. These agents can be present in sufficient quantities to obtain a pH of the system between 5.5 and 0.0 and specifically 7 - T; usually up to about 2% by weight of the polymer. The insertion material may suitably contain from 1 to LOO mg of soluble polymer on water, very particularly from 5 to 50 mu, and especially from 20 to 20%. The medicament is presently available from 0.1 to approximately 0.1. 25% by weight of the preservative material. The claimed use of the compound to increase the velocity of blood flow in the retina and in the head. The first nerve has been the subject of a study to detect if the Trusopt drops compared with placebo drops had a significant effect on the velocity of blood flow in the retina and on the head of the optic nerve in healthy individuals. In the study, normal and healthy individuals were randomly assigned to receive drops of placebo or 2.0% fripsil in both eyes in a doubly disguised clinical trial. The intraocular pressure and the deoang ography of the fluorescence were assessed with a sweep laser at the baseline and 120 minutes after the application. Individuals treated with h-usopt exhibited an accelerated arteriovenous passage time as well as an increase in velocity at the optic nerve head. Additionally, the expected decrease in intraocular pressure was observed.

Claims (1)

1. NOVELTY OF THE INVENTION CLAIMS L.- A pharmaceutical composition for maximally increasing the health of the optic nerve and La t na by local application to the eye that I understand an effective amount of a carbon anhydrase inhibitor and a carrier automatically accept it. A pharmacological composition according to claim 1, further characterized in that the carbonic anhydrase inhibitor is selected from the group consisting of dorzo Larn i da, acet azolarru da, metazolatnide and s i rn 11 ares. 3. A pharmaceutical composition according to claim 2, further characterized in that the inhibitor of car-bonica anhi rasa is dorzolamide. 4.- A pharmaceutical composition will increase the speed of the retinane blood flow < U eye through l? local application to the eye which comprises an effective amount of a carbonic anhydrase inhibitor and a pharmaceutically acceptable carrier. 5. A pharmaceutical composition according to claim 4, further characterized in that the carbonic anhydr-ase inhibitor is dorzoaryanide. 6. A pharmaceutical composition for increasing the blood velocity in the head of the optic nerve by means of the local application to the eye comprising an effective amount of a carbonic anhydride inhibitor and an acceptable pharmaceutical vehicle. 7. A pharmaceutical composition according to claim 6, further characterized in that the inhibitor of carbon anhydrase is dorzolamide., 0.- A pharmaceutical composition according to claim 1, characterized in that the anhydrase inhibitor car-bonica is a solution of 0.01 to 5% in a vehicle of taimo Log i ca acep acepb 1 e .. 9.- A pharmaceutical composition in accordance with The claim is further characterized in that the carcinogenic anhydrase inhibitor is a 0.5% to 2% solution in an ophthalmologically acceptable vehicle. 10. The use of a carbon anhydrase inhibitor to prepare a composition to increase the blood velocity in the retina and in the head of the optic nerve. 11. The use according to claim 10, further characterized in that the composition containing the carbonic anhydrase inhibitor is applied locally. 12. The use according to claim 11, further characterized in that the car- bonic anhydrase inhibitor is selected from the group consisting of dorzol amide, acetazo- lamide, rnetazolarnide and sirní Lares. 13. The use according to claim 10, further characterized in that the composition containing the carbonic anhydrase inhibitor is administered as a 0.01 solution < \ 1 5% in a vehicle or drug store. 14. The use according to re-indication 13, further characterized in that the composition containing the carbonic anhydrase inhibitor is administered as a 0.5% to 2% solution in an ophthalmologically acceptable vehicle.