Treatment of dry eye

Methods and compositions are provided for the treatment of dry eye and discontinuous tear films. The ophthalmic solution for maintaining a continuous tear film employs a combination of hydroxyalkylcellulose and polyvinyl alcohol in a predetermined ratio in an aqueous isotonic medium.

BACKGROUND OF THE INVENTION 
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. 
SUMMARY OF THE INVENTION 
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. 
DESCRIPTION OF THE SPECIFIC EMBODIMENTS 
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.

EXPERIMENTAL 
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. 
__________________________________________________________________________ 
Film Film 
Thickness 
Thickness Vertical 
Aqueous 1% (w/v) 
Weight 
by Draining 
Drainage 
Dewetting 
Surface 
Relative 
Film Surface 
PVA-HEC Mixtures 
Technique.sup.3 
Technique.sup.4 
Time.sup.4 
Time.sup.5 
Viscosity.sup.6 
Viscosity.sup.7 
Climbing 
Tension 
%PVA(w/w).sup.1 
%HEC(w/w).sup.2 
.mu. .mu. min hr (poise) 
(t/t.sub.o) 
Rate.sup.8 
(dyne/cm.) 
__________________________________________________________________________ 
100 0 10.4 10.3 3.65 
5.0 0.0093 
1.45 11.8 42.0 
80 20 11.6 -- -- -- -- 1.75 -- 42.0 
60 40 12.5 11.7 -- -- -- 2.1 -- 42.0 
40 60 13.2 -- 4.1 5.0 0.024 2.45 -- 43.0 
20 80 13.9 15.0 6.0 5.0 0.04 2.9 -- 44.5 
10 90 15.6 16.0 6.6 0.15 -- -- -- -- 
5 95 15.7 16.0 5.6 0.1 0.0455 
-- 8.2 45.1 
1 99 17.6 -- 5.8 -- -- -- -- 50.0 
0 100 10.0 8.0 &lt;0.1 &lt;0.1 0.052 3.7 4.9 59.0 
__________________________________________________________________________ 
.sup.1 PVA - polyvinyl alcohol, Goshenol GL-05, supplied by Hercules Corp 
.sup.2 HEC - hydroxyethylcellulose, Natrosol 250, supplied by DuPont Co. 
.sup.3 Film Thickness: Weight Technique 
Take a clean Plexiglas (Polymethyl methacrylate) slide having dimensions 
7.5 cm .times. 2.5 cm .times. 0.2 cm, and measure its dry weight on a 
Sartorius balance (accuracy 0.001 gm). Make a mark on the edge of the 
slide at a height of 5 cm from the bottom. The solution to be tested is 
taken in a beaker and is raised (at a constant speed of 1.0 cm/sec) so as 
to cover the Plexiglas slide up to the 5 cm mark. The total wetted area 
(if the solution does wet the Plexiglas surface) is 52 cm.sup.2. Lower th 
beaker at the same speed. Blot excess solution from the bottom of the 
slide for 5 seconds using a piece of filter paper. Allow drainage for one 
minute and then measure the weight of the slide plus the attached 
solution. Calculate the weight of solution adhering to the Plexiglas. The 
calculate the average film thickness 
##STR1## 
The average of 5 - 10 measurements is the reported value (S.D. = .+-. 5%) 
.sup.4 Film Thickness Using the SLFP 
The instruments used was a Slit Lamp Fluorophotometer (SLFP) [Waltman, S. 
R., and Kaufman, H. E., Invest. Ophthalmol., 14 (12), 887 (1975)]. All 
solutions used in measurements made with the SLFP had a Sodium Fluorescei 
(water soluble Fluorescent dye) concentration of 5 .times. 10.sup.-4 
gm/ml. The procedure is identical to that described in the previous 
section. The solution is raised at a constant speed to wet 5 cm of the 
slide and then lowered at the same speed. The slit of light from the SLFP 
is focused at the mid point of the wetted area, 2.5 cm from the bottom of 
the slide, and fluorescent intensity recorded. The intensity after one 
minute of drainage is noted and the corresponding thickness calculated 
from a calibration curve. The average of two readings is taken. After 
lowering the solution from the slide, a continuous recording of the 
fluorescent intensity is made. The calibration curve shows a linear 
dependance between film thickness and fluorescent intensity for thickness 
in the range of 0 - 75 .mu.m. The drainage time (td) is defined as the 
time elapsed before the film thickness (.delta.) reaches 5% its initial 
value (.delta..sub.o). 
.sup.5 Dewetting Time 
A clean Plexiglas slide (7.5 cm .times. 2.5 cm .times. 0.2 cm) was 
immersed in the solution being tested and allowed to soak for at least 24 
hours so absorption equilibrium, if any, would be achieved. Such 
adsorption allows the solution to wet the low energy (critical surface 
tension = 38 - 40 dynes/cm) Plexiglas surface. The slide is then clamped 
to a horizontal bar which can move up and down (dipping) at the rate of 5 
dips/minute. Excess solution was allowed to drain from the slide and the 
"dipping machine" was started. At the bottom of every downstroke, the 
slide dipped into a beaker containing 100 ml. isotonic saline. "Dewetting 
time" was defined as the dipping time required for the first dry spot to 
appear on the slide, indicating desorption of adsorbed molecules with 
consequent unwettability of the slide. It should be noted that each 
experiment was run for only five hours. Consequently a result of "5 hours 
should be taken to indicate that the slide was still wettable at the end 
of five hours, and this value is therefore a lower limit of dewetting tim 
for this solution. 
.sup.6 Surface Viscosity [Ref. Karam, J. App. Polymer Sci., 18, 1693-1709 
(1974)]- 
Measurements of surface viscosity were carried out using a Knife Edge 
Surface Viscometer. A fixed amount of solution is pipetted into a cup tha 
is mounted on a turntable capable of rotating at variable speeds. A 
circular knife edge bob, suspended from a torsion wire, is adjusted with 
the aid of leveling screws so it is centered with the cup. The bob is 
slowly lowered until its knife edge just touches the surface of the 
solution in the cup. The motor is started and the rotation speed of the 
turntable fixed. The rotation of the solution in the cup causes a 
deflection of the bob. This deflection from its rest position is measured 
with the aid of a telescope. The speed of the turntable (.OMEGA.) is 
changed to a new value and the deflection (.theta.) measured again. The 
corresponding surface viscosities are calculated from 
##STR2## 
##STR3## 
- 
where 
.eta..sub.5 = surface viscosity in surface poise (s/p) 
.theta. = angular deflection of bob for a given w 
.theta..sub.w = corresponding deflection of bob for pure water - air 
surface 
w = angular velocity 
R.sub.b,R.sub.c = Radii of bob and cup 
K = Wire Torsion constant 
The wire torsion constant, K, was determined by first measuring the perio 
(T.sub.o) of the chuck and dampening ring, then adding a mass of known 
moment of inertia (.DELTA.I) and measuring a new period of oscillation 
(T.sub.1). Then 
##STR4## 
All readings were taken at least twice and were reproducible to within 5% 
.sup.7 Relative Viscosity 
Relative viscosities were measured with a capillary viscometer of the 
Cannon-Fenske type. The size of the viscometer was either No. 25 or No. 
50. The temperature was held constant at 25 .+-. 0.1C.degree.. All 
measurements were repeated at least three times with excellent 
reproducibility. 
.sup.8 Benedetto et al, Investigative Ophthalmology 14, 887 (1975) 
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.