BACKGROUND OF THE INVENTION During most of this century, glaucoma was defined as a blinding eye disease caused by an increased pressure within the eye. This pressure damaged the inner eye tissues leading to the loss of visual field. Science believed that if intraocular pressure (IOP) was lowered to a level under 21 mm on the Mercury Scale, the progression of the disease could be stopped. However, there are many cases where glaucoma occurs with IOP under 21 mm/Mercury, therefore, the level of IOP is not the only factor in producing this disease. 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 signal. After the light 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 brain function and sent back to the eye in order to form the visual picture. It is believed that the uninterrupted signal carried in the optic nerve fibers is the most crucial aspect in the prevention of blindness. 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.

It has now been found that drugs in the class of β- adrenergic blocking agents (β-blockers) when administered

⁵ intraocularly can maintain and improve the health of the optic nerve, β-blockers include such drugs as timolol, cartelol, levobunolol, betaxolol, atenolol, metoprolol, nadolol, pindolol, propanolol, labetalol and the like. Timolol, (S)-l-(t-butylamino)-3-[(4-mo holino- 1,2,5- thiadiazol-3-yl)-oxy]-2-propanol and the other β-blockers have been i ° used primarily for the treatment of glaucoma. They act by inhibiting the aqueous humor production and therefore lowering intraocular pressure. Research during the last decade indicates that the health of the optic nerve is crucial to prevent the loss of the visual field.

is DESCRIPTION OF THE INVENTION

The present invention is directed to a method for maximizing the health of the optic nerve by topical application of β- adrenergic blocking agents to the eye. Additionally, this invention is directed to a method for increasing and/or maintaining retinal nerve

20 fiber thickness by topical application of β-adrenergic blocking agents to the eye. This invention is also directed to a method for decreasing optic disc cupping and pallor by topical application of β-adrenergic blocking agents to the eye.

The present invention is based upon the discovery that β-

25 blockers can preserve or benefit vision by increasing or maintaining optic nerve fiber layer thickness. The maintenance or increase in optic nerve fiber layer thickness ensures that the consistency and form of the nerve is sufficient for adequate function of the nerve and to allow uninterrupted signal flow. It was also found that treatment with β- 0 blockers resulted in a significant decrease in optic disc cupping and pallor and a significant increase in retinal nerve fiber layer thickness.

Research was done using Timolol, a particular β- adrenergic blocking agent. It is a known compound useful as a β- adrenergic blocking agent and for the reduction of intraocular pressure

as is described in U.S. Pat. Nos. 3,655,663, 3,657,237, 3,729,469 and 4,195,085.

The β-blocker used is preferably administered in the form of ophthalmic pharmaceutical compositions adapted for topical

⁵ administration to the eye such as solutions, ointments or as a solid insert. Formulations of this compound may contain from 0.01 to 5% and especially 0.5 to 2% of medicament. Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in lowering intraocular pressure. As a unit dosage o from between 0.001 to 5.0 mg, preferably 0.005 to 2.0 mg, and especially 0.005 to 1.0 mg of the compound is generally applied to the human eye.

The pharmaceutical preparation which contains the compound may be conveniently admixed with a non-toxic i ⁵ pharmaceutical organic carrier, or with a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethyl-

20 cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally employed acceptable carriers. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes

25 1 ,000, 1 ,500, 4,000, 6,000 and 10,000, bacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium borate, sodium acetates, gluconate 0 buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetracetic acid, and the like. Additionally, suitable ophthalmic vehicles can be used as carrier media for the present

purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like. The pharmaceutical preparation may also be in the form of a solid insert. For example, one may use a solid water soluble polymer as the carrier for the medicament. The polymer used to form the insert may be any water soluble non-toxic polymer, for example, cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, (hydroxyloweralkyl cellulose), hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose; acrylates such as polyacrylic acid salts, ethylacrylates, polyactylamides; natural products such as gelatin, alginates, pectins, tragacanth, karaya, chondrus, agar, acacia; the starch derivatives such as starch acetate, hydroxymethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum, and mixtures of said polymer.

Preferably the solid insert is prepared from cellulose derivatives such as methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose or hydroxypropylmethyl cellulose or from other synthetic materials such as polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide or polyvinyl methylether. Hydroxypropyl cellulose, one of the preferred polymers for the preparation of the insert is available in several polymeric forms, all of which are suitable in the preparation of these inserts. Thus, the product sold by Hercules, Inc. of Wilmington, Delaware under the name

KLUCEL™ such as KLUCEL HF, HWF, MF, GF, JF, LF and EF which are intended for food of pharmaceutical use are particularly useful. The molecular weight of these polymers useful for the purposes described herein may be at least 30,000 to about 1,000,000 or more. Similarly, an ethylene oxide polymer having a molecular weight of up to 5,000,000 or greater, and preferably 100,000 to 5,000,000 can be employed. Further, for example, POLYOX™ a polymer supplied by Union Carbide Co. may be used having a molecular weight of about 50,000 to 5,000,000 or more and preferably 3,000,000 to 4,000,000.

Other specific polymers which are useful are polyvinyl pyrrolidine having a molecular weight of from about 10,000 to about 1 ,000,000 or more, preferably up to about 350,000 and especially about 20,000 to 60,000; polyvinyl alcohol having a molecular weight of from about

⁵ 30,000 to 1 ,000,000 or more, particularly about 400,000 and especially from about 100,000 to about 200,000; hydroxypropylmethyl cellulose having a molecular weight of from about 10,000 to 1 ,000,000 or more, particularly up to about 200,000 and especially about 80,000 to about 125,000; methyl cellulose having a molecular weight of from about ι° 10,000 to about 1 ,000,000 or more, preferably up to about 200,000 and especially about 50 to 100,000; and CARBOPOL™ (carboxyvinyl polymer) of B. F. Goodrich and Co. designated as grades 934,940 and 941.

It is clear that for the purpose of this invention the type and

¹⁵ molecular weight of the polymer is not critical. Any water soluble polymers can be used having an average molecular weight which will afford dissolution of the polymer and accordingly the medicament in any desired length of time. The inserts, therefore, can be prepared to allow for retention and accordingly effectiveness in the eye for any

2 ⁰ desired period. The insert can be in the form of a square, rectangle, oval, circle, doughnut, semi-circle, 1/4 moon shape, and the like. Preferably the insert is in the form of a rod, doughnut, oval or 1/4 moon. The insert can be readily prepared, for example, by dissolving the medicament and the polymer in a suitable solvent and the solution

25 evaporated to afford a thin film of the polymer which can then be subdivided to prepare inserts of appropriate size. Alternatively the insert can be prepared by warming the polymer and the medicament and the resulting mixture molded to form a thin film. Preferably, the inserts are prepared by molding or extrusion procedures well known in

30 the art. The molded or extruded product can then be subdivided to afford inserts of suitable size for administration in the eye. The insert can be of any suitable size to readily fit into the eye. For example, castings or compression molded films having a thickness of about 0.25 mm to 15.0 mm can be subdivided to obtain suitable inserts.

Rectangular segments of the cast or compressed film having a thickness between about 0.5 and 1.5 mm can be cut to afford shapes such as rectangular plates of 4x5-20 mm or ovals of comparable size. Similarly, extruded rods having a diameter between about 0.5 and 1.5

5 mm can be cut into suitable sections to provide the desired amount of polymer. For example, rods of 1.0 to 1.5 mm in diameter and about 20 mm long are found to be satisfactory. The inserts may also be directly formed by injection molding. It is preferred that the ophthalmic inserts containing the medicament of the present invention be formed so that i o they are smooth and do not have any sharp edges or corners which could cause damage to the eye. Since the term smooth and sharp edges or corners are subjective terms, in this application these terms are used to indicate that excessive irritation of the eye will not result from the use of the insert. 5 The ocular medicinal inserts can also contain plasticizers, buffering agents and preservatives. Plasticizers suitable for this purpose must, of course, also be completely soluble in the lacrimal fluids of the eye. Examples of suitable plasticizers that might be mentioned are water, polyethylene glycol, propylene glycol, glycerine, trimethylol

20 propane, di and tripropylene glycol, hydroxypropyl sucrose and the like. Typically, such plasticizers can be present in the ophthalmic insert in an amount ranging from up to 1 about 30% by weight. A particularly preferred plasticizer is water which is present in amounts of at least about 5% up to about 40%. In actual practice, a water

25 content of from about 10% to about 20% is preferred since it may be easily accomplished and adds the desired softness and pliability to the insert.

When plasticizing the solid medicinal product with water, the product is contacted with air having a relative humidity of at least

30 40% until said product picks up at least about 5% water and becomes softer and more pliable. In a preferred embodiment, the relative humidity of the air is from about 60% to about 99% and the contacting is continued until the water is present in the product in amounts of from about 10% to about 20%.

Suitable water soluble preservatives which may be employed in the insert are sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric borate, parabens, benzyl alcohol and phenylethanol. These agents may be present in amounts of from 0.001 to 5% by weight of solid insert, and preferably 0.1 to 2%.

Suitable water soluble buffering agents are alkali, alkali earth carbonates, phosphates, bicarbonates, citrates, borates, and the like, such as sodium phosphate, citrate, borate, acetate, bicarbonate and carbonate. These agents may be present in amounts sufficient to obtain a pH of the system of between 5.5 to 8.0 and especially 7-8; usually up to about 2% by weight of polymer. The insert may contain from about 1 mg to 100 mg of water soluble polymer, more particularly from 5 to 50 mg and especially from 5 to 20 mg. The medicament is present from about 0.1 to about 25% by weight of insert.

The claimed use of the compound to ensure optic nerve health has been the subject of a long term study to determine whether timolol drops compared to placebo drops had a significant effect on optic disc cupping and pallor and retinal nerve fiber layer thickness in ocular hypertensives.

In the study, 37 ocular hypertensives were randomly assigned to receive placebo or 0.5% timolol drops to both eyes for 18- 24 months in a double masked clinical trial. Measurements of ocular pressure, optic disc cupping and nerve fiber layer thickness by stereophotogrammetry and pallor by computerized image analysis from photographs of the optic disc were made at about 3 months intervals for 18-24 months of follow-up. The results demonstrated that subjects treated with the placebo showed no change in ocular pressure. Subjects treated with timolol exhibited a significant decrease in ocular pressure and a significant decrease in optic disc cupping and pallor with a significant increase in retinal nerve fiber layer thickness. However, it was determined that the decrease of optic disc cupping and pallor and the increase of retinal nerve fiber layer thickness were not associated

with the ocular pressure or the decrease in ocular pressure during the trial.

Measurements were made at the optic disc margin, therefore, it can be considered that the tissues measured are almost pure nerve fibers.

One theory to explain the increase in thickness of the nerve fibers is that there is a resumption of axoplasmic flow with the use of timolol therapy. It is theorized that the retinal ganglion cells are in a defective metabolic state which does not allow them to produce sufficient axoplasm to flow down the axons in the nerve fibers of the ganglion cells. Thus, the nerve fibers become thinner. Timolol or other β-blockers are believed to restore the metabolic state of the retinal ganglion cells and increase axoplasmic flow with a resultant increase of the size or thickness of the nerve fibers. It is believed that timolol acts directly on the ganglion cells and the nerve fibers.