Treatment of Dry Eye

Field of the Invention

In many situations, it is found that the lachrymal film is discontinuous. This can be a result of weak lachrymal films, as inadequate rate of blinking, or with some users, wearing of contact lenses. There is, therefore, a need to provide a synthetic tear which can act as a tear substitute for dry eye syndromes. In addition, solutions which would provide stable ocular films could be used for prolonging the precorneal tear film retention of drugs instilled in liquid ophthalmic vehicles and for the wetting and cushioning of contact lenses.

Description of the Prior Art

Benedetto, Shah and Kaufman, Investigative Ophthalmology 14, 887 (1975) describes testing of hydroxypropylmethylcellulose and polyvinyl alcohol to prolong precorneal tear films.

A combination of hydroxyalkylcellulose and polyvinyl alcohol in about a 4 to 1 weight ratio is provided for use in aqueous solutions for treatment of dry eye and maintenance of stable lachrymal films. The aqueous compositions are preferably employed as isotonic solutions, having a viscosity in the range of about 5-70cs at 25.degree. C.

Novel compositions are provided employing in combination hydroxyalkylcellulose and polyvinyl alcohol, with the hydroxyalkylcellulose in the range of about 70 to 85 weight percent, preferably 75 to 85 weight percent, and more preferably 80 weight percent and reciprocally the polyvinyl alcohol in about 15 to 30, more usually 15 to 25 and preferably 20 weight percent. The polymer combination is normally employed as a uniform aqueous dispersion, normally a solution, which may be provided as a concentrate or as a solution for physiological use. The weight percent of the polymer combination will therefore vary from about 0.1 to 10, more usually from about 0.2 to 6 weight percent. For use in the eye, the concentration will generally vary from about 0.1 to 2.5 weight percent, more usually from about 0.5 to 2 weight percent, preferably from about 0.75 to 1.5 weight percent. Generally, those solutions which find use in the eye will have viscosities in the range of about 5-70cs, more usually 5-60cs and preferably from about 10 to 50cs at 25.degree. C. The solutions employed for treatment, when instilled into the conjunctival sac stabilizes or maintains a continuous lachrymal fluid film covering the eye.

In addition to the active ingredients of this invention, other materials will normally be included in the aqueous vehicle. Preferably, the composition is provided as isotonic, particularly employing sodium chloride. Generally, from about 0.4 to 1.4 weight percent sodium chloride, normally from about 0.7 to 1.1 weight percent sodium chloride will be employed.

Other additives may also be included, such as physiologically acceptable preservatives, disinfectants, buffers, and the like, depending upon the function of the medium and the presence of drugs for eye medication.

Illustrative preservatives and disinfectants include chlorobutanol, thimerosal, chlorhexidine, benzalkonium chloride, phenylmercuric acetate, phenylmercuric nitrate and methyl and propylparabens. The total amount of disinfectants and preservatives will generally be in the range of about 0.0005 to 1 weight percent, more usually from about 0.001 to 0.5 weight percent.

The pH of the medium will generally be within an acceptable physiological range from about 5.5 to 8.5 usually from about 6.5 to 7.5. This can be achieved by the addition of a physiologically acceptable base or acid, e.g. sodium hydroxide or hydrochloric acid, or by employing such buffers as carbonate, borate, etc. When the solution is provided as a concentrate, all of the amounts will normally be increased from about 1.5 to 6 times, more usually from about 1.5 to 4 times the amount desired in the final solution.

The hydroxylalkylcellulose which is employed will have alkylene groups of from 2 to 3 carbon atoms, more usually of 2 carbon atoms, i.e. ethylene. Normally, there will be on the average from about 1 to 3 hydroxyalkyl per anhydroglucosidemoiety, more usually from about 1.5 to 3.0 groups, and preferably from about 2.25 to 2.75 groups, and more preferably 2.5 groups. The viscosity average molecule weight of the hydroxyalkylcellulose will generally be in the range of about 1 to 10.times.10.sup.5. The viscosity of the polymer will generally be in the range of about 3,000 to 8,000, more usually about 4,500 to 6,500 cps (2 wt % aqueous solution, Brookfield Viscosity, 25.degree. C.).

The polyvinyl alcohol which is employed will generally have not more than about 20, preferably not more than about 15 mole percent vinyl acetate momoner, and usually at least about 2 mole percent vinyl acetate monomer. The polyvinyl alcohol polymer will normally have a viscosity of about 1 to 20, usually about 2 to 10 and preferably about 4 to 6 cs using a 4% w/v solution, (ASTM 882). The viscosity average molecular weight will usually be in the range of about 3 to 30.times.10.sup.4.

A number of tests were performed which relate to the stability of ocular films. The following tables indicates the results obtained with aqueous solutions of polyvinyl alcohol and hydroxyethylcellulose in varying proportions, both within and without the ranges of the subject invention.

It is evident from the above results, that desirable film properties such as film thickness, drainage time, and dewetting are not directly related to solution viscosity, but rather are very sensitive to variations in the proportions of the hydroxyethylcellulose and polyvinyl alcohol. The aqueous compositions of this invention provide for a thick stable lachrymal film, as well as wetting and cushioning for contact lenses. In addition, the subject compositions can be used as vehicles for a wide variety of drugs. Illustrative drugs include epinephrine, norepinephrine, phenylephrine, atropine, scopolamine, benoxinate, sodium fluorescein, pilocarpine, dexamethasone phosphate, prednisolone, proparacaine, sodium sulfacetamide, sulfisoxazole, cyclopentolate, homatropine, rose bengal, tetracaine, polymyxin B, neomycin, gramicidin, dichlorphenamide, isofluorophate, demecarium bromide, chloramphenicol, napazoline, idoxuridine and carbachol. The concentration of the drugs will vary widely depending on the individual drug. The concentration will generally range from about 0.001 weight percent to 5 weight percent, more usually from about 0.002 weight percent to 2 weight percent of the ophthalmic solution. For individual drugs, concentrations will generally be in the range of about 0.001 to 1 weight percent, more usually from 0.005 to 1 weight percent. Antibiotics and steroids will generally range from about 0.05 to 1 weight percent while alkaloids, epinephrines and their derivatives will generally range from about 0.1 to 2 weight percent.

By employing the subject compositions as vehicles for drugs, a uniform stable film containing the drug is maintained for relatively long periods of time on the eye. Thus, greater effectiveness can be achieved with a wide variety of drugs.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.