Method of recovery of the optic nerve and retina


(57) Abstract:

The invention relates to medicine, in particular to ophthalmology, and for the health of the retina and optic nerve in various pathologies of the eye. I propose to introduce locally in the eye inhibitor carbonatehydroxide in a certain dosage. The method provides an improvement in the structure and functioning of these structures. 4 C.p. f-crystals.

Throughout the greater part of this century glaucoma was considered eye disease leading to blindness, caused by the high pressure inside the eye. This pressure was destroyed by internal eye tissues, leading to loss of sight. Science believed that if the intraocular pressure (RBI) to reduce to below 21 mm of mercury scale, the development of the disease could be stopped or slowed down. However, there are many cases of glaucoma occurs when the RBI below 21 mm of mercury scale, so the RBI is not an important factor in the origin of this disease. Recently, there have been evidence that glaucoma may be of vascular origin, and possibly vasospastic. New scientific methods allow us to more carefully look at the back of the eye and to assess glaucoma terms of cu is if his eyes could see, the light passes through the cornea and lens, enters the posterior part of the eye through the retina, passes through the ganglion cells and bipolar cells. Then he goes down to the outer reticular layer across the synaptic vesicle, inner fiber, the core, the outer fiber, the end of the arc, lash and finally reaches the visual receptors, which may be regarded as the film odnostebelnogo process, subjected to processing the visible light beam. After the light beam has been processed in the disks of the visual receptors, it passes back through the lash, ellipsoid, myid, Muller cells, outer fiber, the core, the inner fiber, synaptic vesicle, another reticular layer, inner nuclear layer, bipolar cell, the inner reticular layer and finally reaches the ganglion cells, where it is converted to axonomy signal. After he reaches the ganglion cells, the signal is transmitted via the optic nerve fibers in the brain, where it is evaluated and combined the optic lobes of the brain to create a visual image. It is believed that a continuous signal, which is the retina, the optic nerve head and optic nerve fibers are the most important asset axonomy stream. Glaucoma is treated as a progressive loss of axons in the optic nerve, which leads to intermittent signal flow, resulting in a violation of the field of view, which over long periods of time leads to blindness.

It was found that the drugs in the class of inhibitors of carbonatehydroxide (CAIs) when you enter them in the eye can lead to a significant increase in the speed of blood flow in the retina and the disc of the optic nerve. CAIs include such drugs as dorzolamide, acetazolamide, methazolamide and other compounds described in U.S. patents 4797413, 4386098, 4416890 and 4426388, and the like. Dorzolamide, S,S-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno-[2,3-b] thiopyran-2-sulfonamide-7,7-dioxygenase and his transnational were recently approved by the FDA for use in the treatment of ocular hypertension associated with glaucoma. CAIs has demonstrated its activity by inhibiting the enzymes, carbonatehydroxide, and promoting the formation of watery fluid, obtained by exchange carbonatehydroxide. CAIs block or delay the path sharing this influx through suppression carbonatehydroxide. Dorzolamide, which was recently adopted the ASS="ptx2">

The present invention is a method of increasing the speed of blood flow in the retina and disc of the optic nerve by local application of CAIs.

The present invention is based on the discovery that CAIs can save or improve vision by increasing the flow velocity as retinal and disc of the optic nerve. It was found that positive results were achieved without any change of the width of the retinal vessels, which could be the cause of the increase of the flow velocity.

Studies have been conducted using Trusopt, a specific inhibitor of carbonatehydroxide. This well-known compound used as the inhibitor carbonatehydroxide and to reduce intraocular pressure, as described in U.S. patent 4797413.

Used CAI preferably applied in the form of ophthalmic pharmaceutical compositions intended for local injection into the eye, types of solutions, ointments or solids. These compounds may contain from 0.01 to 5% and especially from 0.5% to 2% of the medicinal product. Higher doses (e.g., about 10% or below) can be used provided that the dose is effective to increase the flow velocity. As o 0 mg.

The pharmaceutical preparation which contains this compound can easily be mixed with non-toxic pharmaceutical organic carrier, or with a non-toxic pharmaceutical inorganic carrier. Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and aqueous solutions, such as lower alkanols or arcanely, vegetable oils, polyalkylene glycols, vaseline, ethylcellulose, etiloleat, carboxymethylcellulose, polyvinylpyrrolidone, isopropylmyristate and other commonly used acceptable carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, stabilizing, moisturizing, thickening agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbon paraffins 1 000, 1 500, 4 000, 6 000 and 10 000, bacterial components, Quaternary ammonium compounds, salts of finalstate, which is known for its properties of cold sterilization and which are harmless to use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenylethanol, buffering ingredients such as boracite sodium acetates of sodium, gluconate buffers, and other conventional ingredients such as monolaurate Corigliano, coorbital, etilendiamintetraatsetata acid, etc. are also acceptable eye fillers can be used as a carrier medium for this purpose including conventional phosphate buffer system filler, isotonic fillers boric acid, isotonic excipients sodium chloride, isotonic fillers, sodium borate, etc., the Pharmaceutical preparation can also be in the form of solids. For example, you can use a solid water-soluble polymer as a carrier of drugs. The polymer used in the form of inclusions, can be any water soluble non-toxic polymer, for example a derivative of cellulose, such as methylcellulose, carboxymethylated cellulose (cellulose hydroxy-lower alkyl), hydroxyethyloxy cellulose, hydroxypropionate cellulose, hydroxypropylmethyl cellulose; acrylates, such as salts of polyacrylic acid, ethylacrylate, polyacrylamide; natural products such as gelatin, alginates, pectins, tragakant, karaya, Chondrus, agar, acacia; the starch derivatives such as starch acetate, ethers hydroxymethylamino starch, hydroxypropionic starch, as well as other synthetic derivatives, such as polyvinylalcohol and xanthan gum, as well as mixtures of these polymers.

Preferably the solid inclusion is made from cellulose derivatives such as methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose or hypromellose, or other synthetic materials such as polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide or polivinilbutilovy ether. Hydroxypropylcellulose, one of the preferred polymers for the preparation of inclusion, there are a few polymer forms, all of which are acceptable for the preparation of these inclusions. Thus, the products sold by Hercules, Inc. of Wilmington, Delaware, under the name KLUCELTMsuch as KLUCEL HF, HWF, MF, GF, JF, LF and EF, which are intended for use as a source of ingredients for medicines, are particularly useful. The molecular weight of these polymers used for the purposes described here, can be at least 30,000 to about 1,000,000 or more. This way can be applied polymer of ethylene oxide having a molecular weight of up to 5 000 000 or more, and preferably from 100 000 to 5 000 000. Further, there may be used, for example, POLYOXTMpolymer, supplied by Union Carbide Co. with specific polymers are polyvinylpyrrolidine, having a molecular weight from about 10,000 to about 1,000,000 or more, preferably up to about 350,000, and especially from about 20 000 to 60 000; polyvinyl alcohol having a molecular weight from about 30,000 to 1,000,000 or more, preferably about 400 000 and, especially, from about 100,000 to about 200,000; hypromellose, having a molecular weight from about 10,000 to 1,000,000 or more, preferably up to 200,000, and particularly, from about 80,000 to about 125 000; the methylcellulose having a molecular weight from about 10,000 to about 1,000,000 or more, preferably up to about 200,000, and especially from about 50 to 100,000; and CARBOPOLTM(carboxyvinyl polymer) company B. F. Goodrich and Co., having denote 934, 940 and 941.

It is clear that to achieve the objectives of this invention, the type and molecular weight of the polymer is not decisive. Can be used any water-soluble polymers having an average molecular weight, which allows for the dissolution of the polymer and, consequently, the medicinal product within the required time period. Therefore, the inclusion can be prepared in such a way as to enable their preservation and, consequently, the efficiency in the eye within the required period vrigny etc. Preferably, the inclusion must be in the form of a rod, donut, oval, or quarters of the moon. Inclusion can be easily prepared, for example, by dissolving the drug and polymer in a suitable solvent and evaporating the solution to obtain a thin film of polymer, which can then be separated for the preparation of inclusions of a certain size. Alternatively, the inclusion can be prepared by heating the polymer and the drug and the formation of a thin film formed from the mixture. Preferably, the inclusion prepared by procedures molding or extruding, well known in this field. Molded or extruded product may then be separated to enable the desired size for introduction into the eye. For example, cast or obtained by molding under pressure a film having a thickness of from about 0.25 to 1.5 mm, can be separated to obtain the appropriate inclusions. Rectangular pieces are cast or molded film having a thickness of about 0.5 to 1.5 mm, can be cut with a rectangular receiving plate 4 x 5-20 mm or ovals about the same size. Similarly extruded rods, Diametro the example found that are acceptable to the rods with a diameter of 1.0 to 1.5 mm and about 20 mm in length. Inclusion can also be obtained directly by molding. Preferably, the ocular inclusion containing the drug in this invention, were made so that they had a smooth surface, would not have sharp edges or corners which could damage the eyes. Because concepts such as "smooth", "sharp edges and corners, are subjective, in this application, these terms are used to indicate that the introduction of inclusion in the eye will not cause any excessive irritation of the eyes.

Ocular drug incorporation may also contain plasticizers, buffering agents and stabilizers. Plasticizers used for this purpose must, of course, to be completely soluble in lacrimal fluid of the eye. Examples of acceptable plasticizers can serve water, polyethylene glycol, propylene glycol, glycerin, trimethylolpropane, di - and tripropyleneglycol, hydroxypropylcellulose, etc. Typically, these plasticizers can be presented in eye inclusion in the quantity constituting from 1 to about 30% by weight. Especially preferred platifina is sustained fashion is the water content from about 10% to 20%, because it can be easily obtained and provide the desired softness and flexibility enable.

When the plasticizing solid dosage product water product is in contact with air having a relative humidity of at least 40% until the specified product will not absorb at least about 5% water and become softer and more plastic. In a preferred embodiment of the invention the relative humidity is from about 60% to about 99%, and the communication continues until the water content in the product will be from about 10% to about 20%.

Acceptable water-soluble stabilizers that can be used in inclusion, are sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium, chlorobutanol, thimerosal, finalstate acetate, finalstate borate, parabens, benzyl alcohol and phenylethanol. These substances can be present in an amount of 0.001 to 5% by weight solids, and preferably from 0.1 to 2%.

Acceptable water soluble buffering agents are alkali, alkaline earth carbonates, phosphates, bicarbonates, citrates, borates, etc., substances such as sodium phosphate, citrate, borate, acesistem from 5.5 to 8.0, and, especially, 7-8; usually about 2% by weight of the polymer. This inclusion may contain from about 1 mg to 100 mg of water-soluble polymer, more preferably from 5 to 50 mg, and particularly from 5 to 20 mg of Drug substance is present in quantities of 0.1 to about 25% by weight of the inclusion.

The stated use of compounds to increase the speed of blood flow in the retina and the disc of the optic nerve was the subject of study with the purpose of definition, increase if the speed of blood flow in the retina and disc of the optic nerve Trusopt drops compared with drops of placebo in healthy individuals.

In the process, randomly selected normal healthy individuals were given a placebo or 2% Trusopt drops in both eyes in a double-masked clinical trial. Comparing the intraocular pressure and held laser scanning video fluorescent angiography in the initial stage and after 120 minutes after application. Individuals who have introduced Trusopt drops were observed acceleration of arterial-venous passage and increase the speed of blood flow in the optic nerve head. In addition, it was found the expected reduction of intraocular pressure.

2. The method according to p. 1, characterized in that the inhibitor carbonatehydroxide is selected from the group consisting of dorzolamida, acetazolamide, methazolamide, etc. substances.

3. The method according to p. 2, characterized in that the inhibitor carbonatehydroxide is dorzolamide.

4. The method according to p. 1, characterized in that the inhibitor carbonatehydroxide used in the form of 0.01 to 5.0% solution in ophthalmologist acceptable carrier.

5. The method according to p. 4, characterized in that the inhibitor carbonatehydroxide used in the form of 0.5-2.0%-aqueous solution of ophthalmologist acceptable carrier.


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