Dry eye treatment process and solution

A method and composition for reducing evaporation of an aqueous layer from the surface of the eye. The method comprises applying a gel of oil and wax over the eye, preferably in the form of a meta-stable oil in water emulsion in a dosage not exceeding 100 microliters. The gel is formed by gelling a hydrocarbon oil with a wax, preferably dispersed in aqueous medium at a pH of at least about 8.0.

BACKGROUND OF THE INVENTION 
I. Introduction 
This invention relates to wetting the surface of the eye and/or an ocular 
prosthesis, providing mechanical lubrication therefor, reducing the 
evaporation of fluid from the surface of the eye and delivering a 
medicament to the ocular surface. In a preferred embodiment of the 
invention, the invention relates to an ophthalmic composition for dry eye 
treatment. 
II. Description of the Prior Art 
It is known that an aqueous tear film extends over the ocular surfaces and 
maintains the ocular surface moist and lubricated. It is also known that 
dehydration of moisture from the eye may result in discomfort. Further, it 
is known that compositions are available in the market intended for dry 
eye treatment. These compositions are primarily aqueous materials that 
supplement the tear film. 
The most common treatment for dry eye involves temporary alleviation of dry 
eye symptoms by topical application of a tear substitute that adds a large 
volume of liquid to the anterior surface of the eye and related adnexa. 
Typical tear substitute compositions comprise water soluble polymer 
solutions. Examples of such solutions include saline solutions of 
polyvinyl alcohol, hydroxypropylmethyl cellulose or carboxymethyl 
celluloses. U.S. Pat. No. 4,421,748 teaches an artificial tear composition 
comprising an aqueous hypotonic solution of lecithin and a viscosity 
adjusting agent such as a solution soluble cellulose. 
Methods used to quantify the effectiveness of tear substitutes for dry eye 
treatment solutions have not been standardized, and many methods used to 
quantify the results obtained using such tear substitute compositions are 
often inaccurate. For this reason, it is known that reported relief of dry 
eye symptoms using known tear substitutes varies considerably from subject 
to subject, and regardless of the method used to quantify relief using a 
tear substitute, relief often does not exceed several minutes. 
The symptoms associated with dry eye are often exacerbated with subjects 
using ocular prostheses such as contact lenses. In some cases, contact 
lens intolerance is caused by the condition of dry eye and its symptoms. 
Further, the rate of evaporation from the eye is accelerated by the nature 
of the contact lens surface, and the physical presence of the contact lens 
results in menisci formation with additional physical and evaporative 
effects, even with subjects having an adequate tear film. For many 
subjects, contact lens intolerance is not overcome by topical application 
of tear substitutes. Therefore, there is a continuing need for improved 
compositions and processes for treatment of the dry eye condition and for 
improving tolerance to ocular prostheses. 
An improved composition for dry eye treatment is the subject of U.S. Pat. 
No. 4,914,088 incorporated herein by reference. This patent teaches the 
use of charged phospholipids for the treatment of dry eye symptoms. In 
accordance with the patent, a phospholipid composition, preferably in the 
form of an aqueous emulsion, is topically applied to the eye where it is 
believed to disperse over the ocular surface and form a film that 
replicates a lipid layer formed by spreading a naturally occurring lipid 
secreted principally from the Meibomian glands during blinking. Because 
the phospholipid, when applied to the eye, carries a net charge, it is 
believed that aligned molecules repel each other preventing complex 
aggregate formation thereby resulting in a stable phospholipid film. 
In copending U.S. patent applications Ser. Nos. 07/529,657 and 07/638,215, 
filed respectively May 29, 1990 and Jan. 7, 1991, assigned to the same 
assignee as the subject application (hereafter the "copending 
applications") and incorporated herein by reference, further improvements 
in dry eye treatment are disclosed. In accordance with the disclosures of 
the copending applications, the dry eye treatment composition of U.S. Pat. 
No. 4,914,088 is improved by use of an essentially non-polar oil as a 
component of a dry eye treatment composition. The oil increases the 
longevity of the tear film formed on the eye following addition of the dry 
eye treatment solution, presumably by providing and/or thickening the 
dehydration barrier (the layer) on the outer surface of the tear film. 
Thus, the oil increases the efficacy of the dry eye treatment solution and 
reduces performance variability from subject to subject. In addition, it 
is a further discovery of the copending applications that for many 
patients, the use of oil alone is efficacious in treatment of the dry eye 
condition. 
The copending applications also teach the desirability of regulating the 
dosage of the oil applied to the eye. In accordance with the inventions 
disclosed in the copending applications, the total amount of oil available 
for formation of a film does not exceed that amount that would cause 
blurring and preferably does not exceed 25 ul. As the amount of oil 
exceeds a desired amount, the oil film formed over the eye becomes 
excessively thick or, alternatively, oil globules may form on the surface 
of the eye and not spread evenly over the eye. In either case, a thick oil 
layer is likely to contribute to patient blurring. The amount of oil 
beyond which blurring will occur varies from patient to patient and is 
dependent upon the specific oil used. 
To understand how the treatment compositions of the above cited patent and 
copending applications function, and how the compositions disclosed herein 
function, the mechanism by which a barrier film over the eye is capable of 
alleviating dry eye symptoms should be understood. 
It is reported that a naturally occurring tear film comprises a complex 
coating with three separate layers. The inner layer in contact with the 
ocular surface of the eye is said to be composed primarily of mucous, and 
renders the hydrophobic epithelial cell plasma membrane surface 
hydrophilic. The middle layer of the tear film is an aqueous layer. This 
layer is the thickest portion of the tear film, which is a source of 
moisture and lubrication for the eye and functions as an optical 
planarizing layer. The outer layer of the tear film, at the interface with 
the atmosphere, is a non-polar oily, naturally occurring lipid layer. This 
oily lipid layer is reported to act as a barrier that prevents evaporation 
of the aqueous layer (Mishima and Maurice: "The oily layer of the tear 
film and evaporation from the corneal surface," Exp. Eye Res. 1961; 
1:39-45). Finally, the oily layer is bound to the aqueous layer through a 
polar interfacial lipid layer containing phospholipids. 
The polar lipids which include the phospholipids, and the non-polar oily 
lipid components of the tear film are thought to originate primarily from 
secretions of the Meibomian glands. The oily layer of the tear film is 
formed from these secretions and is constantly replenished during blinking 
by expression of the secretions from the Meibomian glands and then 
spreading of the same over the surface of the eye by the eyelids. By 
constantly spreading the polar and non-polar lipids over the eye during 
blinking, the tear film is maintained and evaporation of the aqueous 
middle layer of the tear film is minimized. 
A cause of dry eye is believed to be a deficiency in the quantity or 
quality of secretions from the Meibomian glands. It is postulated that a 
cause of dry eye is a deficiency in the polar lipid layer of the tear 
film, the non-polar oily lipid layer, or both. Regardless of the cause of 
the deficiency, the compromised lipid layer fails to act as an adequate 
barrier against evaporation of the aqueous portion of the tear film 
resulting in one form of the dry eye condition. 
In accordance with the invention of U.S. Pat. No. 4,914,088, a charged 
phospholipid added to the eye is believed to disperse over the ocular 
surface to form a film replicating the lipid layer formed by spreading a 
naturally occurring lipid secreted from the Meibomian glands during 
blinking. Where the phospholipid applied to the eye carries a net charge, 
it is believed that the aligned molecules repel each other such that 
complex aggregate formation is prevented and the integrity of the 
phospholipid film is maintained. 
The above-referenced copending applications involve adding a non-polar oil 
to the eye alone or in combination with the charged phospholipid, 
preferably in the form of an oil-in-water emulsion. Upon application of 
the treatment composition to the eye, it was postulated that the 
negatively charged phospholipid layer forms an aligned film over the 
aqueous tear film with charged ends dissolved in the aqueous layer and 
hydrophobic ends furthest removed from the aqueous layer available to bond 
with the non-polar oil layer. This causes the oil layer to disperse over 
the top surface of the eye as a thin, continuous and stable layer that 
functions as an evaporation barrier. Recognizing that the tear film 
naturally occurring in the eye may be deficient in the phospholipid 
component, the oil component, or both, the preferred embodiment of the 
treatment composition of said applications replenished both components of 
the tear film, thereby reducing variations in efficacy from patient to 
patient. 
In the second of the copending applications, it is disclosed that to avoid 
blurred vision, the total amount of oil comprising the film over the 
ocular surface had to be controlled, the treatment composition is 
desirably added to the eye in the form of a meta-stable emulsion to 
enhance differentiation of the emulsion on the ocular surface, and the 
treatment composition desirably contains a surfactant that permits an 
increase in the oil content of an emulsion enabling rapid formation of a 
film of the efficacious components of the treatment composition over the 
ocular surface. 
The use of the dry eye treatment of the referenced patent and copending 
applications assist in overcoming dry eye symptoms as reported therein. 
However, with time, the thick oil film formed using the compositions of 
the copending applications thins and dissipates and consequently, there is 
a continuing need to prolong the presence of the replicated tear film on 
the ocular surface beyond that disclosed in the copending applications. 
SUMMARY OF THE INVENTION 
The invention disclosed herein is a further improvement over the inventions 
disclosed in the above-referenced copending applications. In accordance 
with this invention, it has been found that the residence time of the oil 
layer on the eye formed by the procedures disclosed in the copending 
applications can be further prolonged if a wax is present in the treatment 
composition, preferably at least partially dissolved with the oil to form 
a composition having the appearance of a gel. Dissolution or gelation of 
the wax with the oil may be readily accomplished by blending the oil with 
a wax at a temperature above the melting point of the wax, preferably in 
the presence of alkali, and then permitting the mixture to cool. By 
addition of the solution of the oil and wax to the eye, a replicated tear 
film will form on the ocular surface of the eye which is believed to be 
strengthened and better organized over the ocular surface. Accordingly, 
the residence time of the oil layer on the ocular surface is significantly 
prolonged. Moreover, and unexpectedly, the layer appears to contribute to 
blur reduction and thereby is believed to permit somewhat larger doses of 
treatment composition to be applied to the eye. 
Based upon the above, the invention comprises treatment of the eye with a 
composition that is a sterile solution or gel of oil and wax free of 
additives pharmaceutically unacceptable to the eye and preferably formed 
from a non-polar oil and a wax in the presence of a strong alkali in 
amounts and in a form that avoids blurring while extending the residence 
time of an artificially formed tear film on the eye. The invention also 
comprises methods for making the oil and wax gel in a form suitable for 
use as an eye treatment composition. The treatment composition of the 
invention is especially useful for the treatment of dry eye symptoms, 
lubricating an ocular prosthesis and delivering a medicament to the eye 
over a prolonged period of time.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The term "solution" and "gel" as used herein refer to a mixture of an oil 
and wax formed by heating the same together at a temperature in excess of 
the melting point of the wax. Though not wishing to be bound by theory, it 
is believed that all or a major portion of the wax dissolves in the oil 
when following the procedures of the invention though it is possible that 
some fraction of the wax is present in a treatment composition as a 
discrete phase as will be described in greater detail below. 
The term "treatment composition" as used herein refers to the oil and wax 
solution described above dispersed in a pharmaceutically acceptable 
carrier. 
The treatment material of the invention comprises the solution formed from 
an oil and a wax that is sterile and pharmaceutically suitable for 
addition to the eye. The treatment composition comprises the solution 
dispersed in a carrier, preferably water, together with other treatment 
components such as a charged phospholipid, stabilizers, pH adjustors, etc. 
The treatment composition is applied to the ocular surface by topical 
application, by application to an optical prosthesis which is then 
inserted into the eye or by topical application to the eye containing an 
optical prosthesis. Whether applied directly to the eye or by application 
to a prosthesis, treatment is preferably by application of the oil and wax 
gel in a liquid vehicle. More preferably, the treatment composition is in 
the form of an aqueous, meta-stable colloid or emulsion where the gel 
comprises the dispersed (organic) phase. 
The oil component used to form a gel may be derived from animals, plants, 
nuts, petroleum, etc. Oils derived from petroleum are usually aliphatic or 
aromatic hydrocarbons that are essentially free of polar substitution and 
are most preferred for purposes of the present invention provided the oil 
is refined so as to be compatible with human tissue such as the ocular 
surface. Preferably, the oil is a liquid hydrocarbon oil at room 
temperature having from 10 to 50 carbon atoms and more preferably, the oil 
is a saturated n-alkane or isoalkane hydrocarbon having from 14 to 26 
carbon atoms. Unsaturated alkene hydrocarbons may be used but are less 
chemically stable as the double bonds tend to oxidize. Aromatic oils are 
lesser preferred because it is known that aromatic compounds are for the 
most part unsuitable for application to the ocular surface. Those oils 
derived from animals, plant seeds, and nuts are similar to fats and are 
primarily glycerides or fatty acids and consequently, contain a 
significant number of acid and/or ester groups rendering the same polar. 
Such oils are least preferred for purposes of the invention but may be 
used if used in concentrations not exceeding about 5 microliters of the 
oil. 
The wax dissolved into the oil is a wax as typically used in cosmetics and 
may be of animal, vegetable or mineral origin or may be synthetically 
derived though mineral waxes are lesser preferred. Regardless of the 
origin of the wax, it should possess good film forming capability, be 
compatible with the oil and other components of the treatment composition 
in the concentration used, and be capable of dissolving into or gelling 
with the oil, be compatible with the ocular surface, preferably have a 
melting point between about 30.degree. C. and 95.degree. C. and more 
preferably between about 30.degree. C. and 65.degree. C. and most 
preferably, should be essentially free of triglycerides. A discussion of 
waxes and their properties can be found in the Encyclopedia of Polymer 
Science and Engineering, published by John Wiley and Sons, Volume 17, pp. 
784-794, New York, 1989 and Kirk Othmer, Encyclopedia of Chemical 
Technology, 3rd edition, Volume 24, John Wiley and Sons, pp. 466-480, 
1984, both incorporated herein by reference. 
With respect to the above requirements for the wax, compatibility with the 
oil and other components of the formulation means that the wax component 
is capable of dissolving into or gelling with the oil in the concentration 
range in which it is used and otherwise, is chemically non-reactive with 
components of the treatment composition. Compatibility with the ocular 
surface means that the wax component of the treatment material is 
non-toxic and preferably does not cause stinging when administered to the 
ocular surface. The melting point limitation is to assure that the gel 
formed from the oil and wax is not unduly hard and is desirably liquid on 
the ocular surface of the eye (at body temperature). Otherwise, 
particulates might be present on the ocular surface that could cause 
blurring, a feeling of grittiness on the eye and discomfort. The freedom 
from triglycerides assists in film formation and the procedure to rid the 
wax of the triglycerides results in the in situ formation of dispersants 
that aid in dispersing the organic phase through an aqueous carrier. 
Suitable waxes for purposes of the invention are esters of a long chain 
fatty alcohol and a long chain fatty acid having a chain length preferably 
within the range of from 12 to 50 carbon atoms. Examples of suitable waxes 
include carnauba wax, spermaceti wax, beeswax, bayberry (myrtyl) wax, 
candelilla wax, cetyl ester waxes such a ceryl certoate inclusive of 
Chinese wax, montan wax, cerbellina wax, etc. A preferred wax is beeswax. 
A lesser preferred wax is jojoba wax which is liquid at room temperature. 
In accordance with a preferred embodiment of the invention, the wax is 
treated to remove triglycerides using procedures to be described in 
greater detail below. 
A generalized method for forming what is believed to be a solution or gel 
of the oil and wax is by blending the oil and wax together in a desired 
ratio. The mixture is then heated to a temperature above the melting point 
of the wax with stirring. A solution of the wax in the oil is obtained, 
that upon cooling, results in a composition that has the consistency of a 
gel of the two components. The gel formed may vary in hardness from a 
soft, viscous fluid to a hard material that appears to be solid dependent 
upon the ratio of oil to wax and the melting point of the wax. Larger 
concentrations of the wax, and/or higher melting point waxes form harder 
gels. Hence, the ratio of oil to wax and melting point of the wax must be 
controlled so as to form a gel capable of rapidly spreading over the 
ocular surface. In this respect, the weight ratio of the oil to the wax 
preferably varies between 200:1 and 5:1 and more preferably varies between 
100:1 and 10:1. 
If the gel is formed by the above procedure, it has been found that to form 
a sustained tear film over the eye, it is desirable if the gel is hydrated 
prior to addition to the eye. Hydration can be accomplished by wetting the 
gel with an aqueous solution, preferably containing a surfactant, for at 
least several hours before adding the same to the eye. Preferably, the gel 
is left in contact with the aqueous solution for a time sufficient for the 
particle to adsorb at least one quarter and preferably one-half of its 
weight in water. 
In a preferred embodiment of the invention, where the gel is dispersed in 
an aqueous carrier, the gel is formed by separately adding the oil and wax 
to water and heating the aqueous dispersion so formed with stirring to an 
elevated temperature for an extended time. A preferred temperature is at 
least 50.degree. C. and more preferably, from 75.degree. to 90.degree. C. 
Heating is continued for at least several minutes and more preferably for 
at least two hours. Further in accordance with the preferred embodiment of 
the invention, a base such as sodium or potassium hydroxide is added to 
the reaction mixture in an amount sufficient to raise the pH to between 
about 8 and 9 prior to the step of heating and to hydrolize from about 10 
to 20 percent of the wax which amount represents the amount of 
triglycerides typically found in the wax. The hydrolysis of triglycerides 
present as impurities in either the wax or the oil converts the same to 
long chain fatty alcohols which assist in dispersing of the resultant gel 
throughout the aqueous medium. Following the reaction, the product is 
desirably neutralized to reduce the pH to between about 7.0 and 7.5 by 
addition of an acid such as hydrochloric acid. The removal of the 
triglycerides from the wax by alkali saponification substantially improves 
the ability of the composition to form a long lasting film over the eye. 
The total amount of treatment material added to the eye preferably does not 
exceed 25 microliters (ul), more preferably varies between about 1 and 10 
ul and most preferably varies between about 1 and 5 ul. In accordance with 
the subject invention, the total quantity of the gel added to the eye is 
desirably maintained within these concentration ranges. If the amount of 
gel on the ocular surface is in excess of 25 ul, and with most patients, 
in excess of 10 ul, the film formed on the surface of the eye may be too 
thick with formation of globules on the surface of the eye. This is likely 
to cause prolonged blurring. Consequently, to avoid blurring, the dose of 
the gel added to the eye most desirably does not exceed 10 ul though it 
should be understood that for some applications, such as application of 
medicaments to the ocular surface, larger doses may be desired 
notwithstanding that such doses may cause blurring. 
The gel can be added directly to the eye. If the gel is added directly, 
recognizing that it is desirable to control dosage, a suitable method of 
application comprises placing a small quantity of the gel on a glass rod 
dispenser. The quantity of the gel preferably does not exceed the 10 ul 
dosage indicated above. The rod is then placed against the inside of the 
lower lid lining (conjunctiva) and rotated to transfer the gel to the eye. 
With blinking, the gel rapidly forms a film over the eye. 
For self-administration of the gel of the invention to the eye, it is 
desirably admixed with a carrier and added to the eye in the form of a 
treatment composition, most preferably in the form of a colloid or 
emulsion of the gel in an aqueous carrier. Again, to avoid blurring, as 
described above, the total volume of gel available for formation of the 
tear film desirably does not exceed 25 ul and more preferably, does not 
exceed 10 ul. 
It is known that the eye cannot accommodate a volume of more than about 10 
ul of liquid. It is also known that excess liquid will be discharged or 
expressed from the eye during blinking immediately following addition of a 
liquid to the eye. Treatment composition added to the eye and discharged 
from the eye will carry treatment material with it. Consequently, 
following addition of a treatment composition to the eye, a portion of the 
efficacious component is immediately lost by blinking and discharge 
together with its liquid carrier. If a treatment composition added to the 
eye is in the form of a stable colloid or emulsion that differentiates 
slowly on the ocular surface, a volume of treatment material lost by 
discharge will be greater than the volume lost using a colloid or emulsion 
that rapidly differentiates on the ocular surface. For this reason, the 
treatment composition of the invention is preferably in the form of a 
meta-stable emulsion or colloid which is defined as a composition that is 
sufficiently stable to provide a uniform dose to the eye but is relatively 
unstable and rapidly differentiates upon contact with the eye, preferably 
differentiating within about 5 blinks following application of the 
composition to the eye or within about 30 seconds. A meta-stable emulsion 
or colloid is likely to separate on standing with formation of a layer 
containing agglomerated gel particles. An emulsion suitable for 
application to the eye is readily formed by shaking the treatment 
composition prior to administering the same to the eye to reform the 
meta-stable emulsion. 
In view of the above, the total amount of a treatment composition 
containing the gel in a carrier added to the eye per treatment per eye 
preferably does not exceed 100 ul (about 2 drops) and more preferably 
varies between about 25 and 50 ul. This dose can be readily controlled and 
administered using a dispenser such as an eye dropper that permits 
addition of a single drop of treatment material to the eye. 
Since it is desired to limit the total volume of treatment composition 
added to the eye while recognizing excess is discharged from the eye by 
blinking, and further recognizing that the total volume of treatment 
material available to form the tear film is desirably controlled so as not 
to exceed 25 ul, and preferably does not exceed 10 ul, it is apparent that 
the concentration of the gel in the treatment composition should be 
adjusted to provide the desired small dose of the gel while compensating 
for that lost due to discharge of excess treatment composition by 
blinking. 
For reasons stated above, rapid differentiation of an emulsion and 
formation of the film over the corneal surface is desirable. The formation 
of the film is desirably assisted by use of a surfactant in the treatment 
composition which assists in spreading the gel over the eye. The 
surfactant should be one that enables rapid phase differentiation and 
further, should be one compatible with composition components and 
physiologically compatible with the eye--i.e., it should not be toxic nor 
cause stinging. Preferred surfactants are polyoxyethylene fatty acid 
ethers and esters. The surfactant is added to the composition in minor 
amount, preferably in an amount of less than 1.0 percent by weight and 
preferably within a range of from 1.10 to 0.35 percent by weight. 
In a treatment composition, the gel may vary within reasonable limits 
provided the amount of gel retained on the eye is within the controlled 
volumes set forth above. A treatment composition containing the treatment 
material, the gel, in a concentration of at least 0.5 percent by weight of 
the total treatment composition provides some benefits. A preferred 
concentration for the gel is at least 1.0 percent of the weight of the 
total weight of the treatment composition. Preferably, the gel content of 
the treatment composition varies between about 2.5 and 12.5 percent by 
weight of the total treatment composition. 
A phospholipid may be included in the treatment composition of the 
invention if desired. Suitable phospholipids are those carrying a net 
positive or negative charge under conditions of use. The preferred 
materials are those carrying a net negative charge because the negatively 
charged material will be repelled by the negatively charged ocular surface 
thereby permitting the maintenance of a relatively thick aqueous layer. 
The most preferred phospholipid is a polyol with a net negative charge, 
such as a phosphatidylglycerol or a phosphatidylinositol. The positively 
charged phospholipid is lesser preferred because it would be attracted to 
the negatively charged ocular surface thus compressing the tear film. 
Hence the positively charged phospholipids operate in a different manner 
than the negatively charged phospholipids and are lesser preferred. 
Suitable phospholipid additives are fully disclosed in the above-cited 
U.S. Pat. No. 4,914,088. 
Other additives may be present in the treatment composition including minor 
amounts of neutral lipids and oils such as one or more triglycerides, 
cholesterol esters, and cholesterol; high molecular weight isoprenoids; 
stabilizers, surfactants; preservatives; pH adjusters to provide a 
composition preferably having a pH between about 5.0 and 8.5 and more 
preferably, between 6.0 and 7.4 and most preferably, between about 6.4 and 
7.2; salt, glycerol or sugar in sufficient concentration to form an 
isotonic or mildly hypotonic composition; etc., all as would be obvious to 
those skilled in the art. 
An especially useful class of additives are medicaments because the 
long-term stability of the film formed over the surface of the eye using 
the compositions of the invention results in improved delivery of the 
medicament to the eye due to increased contact time of the medicament with 
the eye. Medicaments suitable for delivery to the eye using the film 
forming compositions of the invention are those soluble in either the 
aqueous or oil phase of the composition. Illustrative medicaments include 
antibiotics, antiviral agents, anti-inflammatory agents, anti-fungal 
agents and anti-glaucoma agents such as illustrated in part in U.S. Pat. 
No. 4,522,803, Section 5.3.1 and 5.3.2, column incorporated herein by 
reference. 
The treatment compositions of the invention are also desirably used with 
subjects requiring ocular prostheses. In this instance, the treatment 
composition enhances the tear film layer and lubricates the boundary 
between the prosthesis and the ocular surface. When used with an ocular 
prosthesis, the treatment composition may be applied to the inner or both 
the inner and outer surfaces of the prosthesis prior to insertion of the 
same into the eye. Alternatively, the treatment composition may be added 
directly to an eye in which an ocular prosthesis has previously been 
added. Regardless of how added, the amount available to form the oil layer 
should be within the limits set forth above. 
Since the treatment compositions of the invention are to be added to the 
eye, the compositions should be sterile and should be packaged in sterile 
containers. Moreover, the treatment compositions must be pharmaceutically 
acceptable for addition to the eye. In this respect, they should be free 
of components incompatible with the ocular surface. For example, the 
treatment compositions should be free of solid particulates such as 
fillers, dyes, pigments and other components such as components that might 
cause stinging and irritation in contact with the ocular surface. 
The invention will be better understood by reference to the examples which 
follow. In many of the examples that follow, a tear film is formed over an 
ocular surface by either adding one standard drop of treatment solution 
(40 to 50 ul) or by adding the gel directly to the eye by means of the 
glass rod. Thereafter, the tear film formed is evaluated by projecting a 
light source onto the ocular surface and viewing the reflected images from 
the light source on a video screen. The light source and its location is 
one that illuminates a surface area on the ocular surface of approximately 
10 mm.sup.2. Interference patterns are formed, the color(s) of which are 
indicative of the thickness of the oil layer over the ocular surface. The 
color of the waves is correlated with a protocol of known film thickness. 
In this way, tear film is evaluated over a period of real time and first 
rated in accordance with the following scale: 
______________________________________ 
Rating 
Film Characteristics Quality 
______________________________________ 
A Colored waves - particularly greens 
Excellent 
and blues. Waves extend from lower lid 
to above the lower pupillary border. 
Film thickness is in excess of 170 nm. 
B Colored waves - reds, browns, yellows, 
Very Good 
but no blues. Waves extend from lower 
lid to above the lower pupillary border. 
Film thickness of approximately 140 nm. 
C Colored waves - only yellow is present. 
Good 
Waves extend from lower lid to lower 
pupillary border. Film thickness of 
approximately 90 nm. 
D Waves visible but no color present 
Fair 
or no color other than grayish white. 
Waves extend from lower lid to lower 
pupillary border. Film thickness of 
less than 55 nm. 
F No waves and no color. An absence of 
Poor 
any observable tear film movement. 
Film thickness of less than 25 nm. 
______________________________________ 
With respect to the above categories, it should be recognized that because 
of the thin films evaluated for the D and F categories, the film thickness 
is a rough approximation. 
Having rated the tear film as described above, a numerical format is then 
utilized to express change in tear film thickness. A numerical grade of 
1.0 indicates a change of one letter grade--e.g., if a C baseline finding 
prior to the application of a drop of treatment composition improved the 
tear film to a B rating, a numerical grade of 1.0 would be given. A 2.0 
numerical grade would indicate a two letter grade improvement; and a 3.0 
numerical grade would indicate a three letter grade improvement. For many 
of the following examples: a 3.0 numerical grade represents an improvement 
from a D to an A, the maximum improvement in accordance with the testing 
method used because subjects with a grade of F were screened and 
eliminated from testing. In some of the examples, a rating in excess of 
3.0 is given. In such instances, the films formed were exceptional and off 
scale. 
In most examples, the evaluation of the tear films formed using the 
treatment composition was over a period of four hours to determine 
residence time of the film on the eye. Therefore, with time, the numerical 
rating decreases but in all cases, the numerical rating is based upon the 
baseline tear film prior to addition of the treatment composition. 
EXAMPLES 1 TO 26 
The following examples illustrate preparation of a gel in accordance with 
one embodiment of the invention and the physical appearance of the same 
following cooling. In all cases, gels of oil and wax were prepared by 
mixing the oil and wax together at a temperature above the melting point 
of the wax. In Examples 1 to 9, Drakeol 35 hydrocarbon oil was used, a 
hydrocarbon oil available from Penreco Corporation of Butler, Pa. In 
Examples 10 to 17, Drakeol 15 was used. The difference between the oils is 
molecular weight. The wax used was white bleached beeswax flakes in 
Examples 1 to 17, cetyl ester wax in Examples 18 to 20, carnauba wax in 
Examples 21 to 23 and jojoba wax in Examples 24 to 26. The following 
formulations were prepared. 
______________________________________ 
Example No. 
Oil Wt. % Wax Gel Characteristics 
______________________________________ 
Beeswax Formulations 
1 Drakeol 35 
15.09 Milky white soft solid 
that melts on body 
contact. 
2 Drakeol 35 
10.04 Substantially the same 
as gel formed in 
Example 1. 
3 Drakeol 35 
5.02 Softer, less white 
viscous liquid and has 
oil-like feeling in hand. 
4 Drakeol 35 
2.51 Shiney, very viscous 
liquid. 
5 Drakeol 35 
1.24 Viscous liquid that will 
slowly flow when 
contaner is tipped. 
6 Drakeol 35 
0.62 Almost completely 
transparent viscous 
liquid that flows as 
a liquid. 
7 Drakeol 35 
0.31 Viscous liquid that flows 
readily 
8 Drakeol 35 
0.16 Water white liquid 
having viscosity 
essentially of oil. 
9 Drakeol 35 
0.08 Water white liquid 
having viscosity 
essentially of oil. 
10 Drakeol 15 
10.16 Solid white material soft 
to the touch and capable 
of melting on hand. 
11 Drakeol 15 
5.14 Essentially same as 
formulation of Example 
10. 
12 Drakeol 15 
2.63 Similar to formulation of 
Example 10 but less 
opaque and softer. 
13 Drakeol 15 
1.31 Opaque, viscous liquid. 
14 Drakeol 15 
0.66 Opaque viscous liquid 
but less opaque than 
Example 13. 
15 Drakeol 15 
0.33 Thin liquid that remains 
opaque. 
16 Drakeol 15 
0.17 Thin liquid somewhat 
opaque with viscosity 
essentially that of oil. 
17 Drakeol 15 
0.09 Thin liquid somewhat 
opaque with viscosity 
essentially that of oil. 
Cetyl Ester Wax Formulations 
18 Drakeol 15 
15.16 Cloudy vaseline-like 
liquid. 
19 Drakeol 15 
9.92 Cloudy vaseline-like 
liquid somewhat less 
viscous than gel of 
Example 18. 
20 Drakeol 15 
4.98 Mildly turbid viscous 
liquid. 
Carnauba Wax Formulations 
21 Drakeol 15 
14.98 Yellow, hard waxy-like 
material. 
22 Drakeol 15 
10.16 Similar to Example 21 
but softer. 
23 Drakeol 15 
5.07 Yellow cloudy vaseline- 
like material. 
Jojoba Wax Formulations 
24 Drakeol 15 
14.91 Yellow, liquid material 
having viscosity 
essentially that of 
Drakeol. 
25 Drakeol 15 
9.66 Same as for Example 24. 
26 Drakeol 15 
4.90 Same as for Example 24. 
______________________________________ 
In all cases, the wax and oil were mixed together and heated to a 
temperature above the melting point of the wax, typically in excess of 
70.degree. C., and then cooled. The jojoba wax was liquid at room 
temperature and had a viscosity essentially equivalent to that of the oil 
and therefore, did not require heating. 
Examples 27-36 
In the following examples, a number of the gels were administered to the 
eye using a glass rod having a bulbous end and compared to neat Drakeol 
oil. In all examples, the treatment material was applied to the end of the 
glass rod and applied to the eye in a dose of from 3 to 10 microliters. It 
is believed that approximately equal amounts of treatment material were 
applied to the eye in each of the examples. 
Example 27 represents the neat Drakeol oil. Examples 31, 34 and 35 
exemplify the use of hydrated gels obtained by forming emulsions of the 
gel and permitting the emulsions to coagulate. The hydrated coagulant from 
the emulsions was then removed from its container on the end of a glass 
rod and applied to the eye. In these examples, the wax content of the 
hydrated gel was 0.5 percent of the total of the treatment material and 
the oil used was Drakeol 35. In Example 31, the wax was from beeswax, in 
Example 34, the wax was cetyl ester wax and in Example 35, the wax was 
carnauba wax. 
For the remaining examples, selected gels from Examples 1 to 26 were used 
and the designation "Comp. of" in the following table refers to the 
examples. The designation "0" in the table under rating means immediately 
following instillation of the treatment material to the eye followed by 
about 30 seconds to permit film formation. The designation "nm" in the 
table means that for that data point, a measurement was not taken. 
______________________________________ 
Ex. Rating After Time on Ocular Surface (hours) 
No. Comp. of 0 0.5 1 2 3 4 5 6 
______________________________________ 
27 neat oil 3.4 2.8 2.3 1.6 1.1 0.6 0.4 0.3 
28 5 3.4 2.9 2.3 1.7 1.2 0.6 0.4 0.3 
29 3 3.2 2.9 2.7 1.3 0.5 nm nm nm 
30 1 3.2 3.0 2.7 13 0.6 nm nm nm 
31 -- 3.3 3.0 2.4 2.0 1.3 1.0 0.7 0.4 
32 20 3.2 2.7 2.1 0.9 0.4 0.2 0.0 -- 
33 18 3.2 2.7 2.1 1.2 0.6 0.3 0.0 -- 
34 -- 3.3 2.7 2.0 1.6 0.9 0.7 0.5 0.3 
35 -- 3.4 3.3 2.7 1.9 1.4 1.2 nm nm 
36 26 3.1 3.0 2.3 1.3 0.5 0.5 0.2 nm 
______________________________________ 
The gel of the carnauba wax and oil (Example 35) is more dense than the gel 
formed using beeswax. Upon insertion of coagulant of the gel onto the 
ocular surface, an excellent tear film is formed, though a mild grittiness 
on the eye following instillation of the particle onto the eye is 
experienced by the subject. The gel of this example was difficult to 
disperse in an aqueous phase. As with the carnauba wax, the gel formed 
using cetyl ester wax (Example 34) was difficult to disperse in an aqueous 
phase. 
EXAMPLES 37-41 
In these examples, a treatment solution was made by dissolving a stabilizer 
and preservative as indicated and sodium chloride in water and adjusting 
pH and osmolarity. Thereafter, a surfactant is added and the solution is 
heated to a temperature of from 70.degree. to 80.degree. C. A gel is then 
made in a separate container using the procedures of Examples 1 to 26. The 
heated aqueous phase is then added to a homogenizer. While the homogenizer 
is running, the heated gel is added to the aqueous phase. Following 
addition of the gel, homogenization is continued for about two minutes and 
then the mixture is permitted to cool to room temperature with stirring. 
In the formulation chart below, the concentration of oil and wax is the 
concentration in the total of the treatment composition recognizing that 
the oil and wax are gelled prior to addition to admixture with the 
carrier. 
______________________________________ 
Formultion 
Component Amount (% by Wt.) 
______________________________________ 
Ethylenediaminetetraacetic acid 
0.10 
Sodium Chloride to 250 m.o. 
Alkane Oil 10.00 
Surfactant 0.19 
Beeswax variable 
Preservative 0.10 
Water to 1 liter 
______________________________________ 
In the above formulation, the alkane oil was Drakeol 35 as identified 
above, the surfactant was a polyoxyethylene sorbitan monooleate sold under 
the tradename Tween 80 used in the quantity indicated except for Example 
37 where the concentration was 0.10 percent, the preservative was 
benzalkonium chloride, and the beeswax was as identified above. 
In the following presentation of data, the baseline for comparison is 
treatment with an oil containing emulsion free of a wax (Example 37). The 
treatment composition for Example 37 was prepared in the same manner as 
those containing the gel except for the step of adding the wax and the 
formation of the gel. The following results were obtained upon 
instillation of a standard drop of treatment composition to the eye (40 to 
50 ul): 
______________________________________ 
Ex. Beeswax Rating After Time on Ocular Surface (hours) 
No. Content 0 0.5 1 2 3 4 5 6 
______________________________________ 
37 0.00 3.0 1.4 0.6 1.1 0.0 -- -- -- 
38 0.10 3.0 1.9 1.1 0.6 0.2 nm 0.1 -- 
39 0.25 3.1 1.7 1.1 0.7 0.4 0.3 0.0 -- 
40 0.50 3.3 2.5 2.3 1.6 1.1 0.7 0.4 0.3 
41 1.00 3.3 3.3 3.2 2.6 2.0 1.5 1.1 0.7 
______________________________________ 
EXAMPLES 42 AND 43 
These examples compare the film forming capability of treatment materials 
of the invention with wax alone and a commercially available ocular 
treatment material. The film forming capability is determined immediately 
following instillation of the material to the eye. For comparison 
purposes, the hydrated gel of Example 31 and emulsion of Example 41 are 
compared to (1) an emulsion having the formulation of Examples 41 from 
which the oil was omitted leaving only wax component of the gel (Example 
42) and (2) a commercially available ointment identified as Lacri-Lube 
sold by Allergan Pharmaceutical, Inc. consisting of white petrolatum in an 
amount of 56.8% and mineral oil in an amount of 42.5% (Example 43). The 
hydrated gel of Example 31 was applied with the glass rod. The emulsion of 
Example 41 was applied as a standard drop. The wax in the emulsion 
(Example 42) was applied by removing a particle of the wax from the 
emulsion with a glass rod and applying the particle to the eye. Lacri-Lube 
was applied with the glass rod. 
The following results were obtained. 
Film Formation: For the composition of the invention (Examples 31 and 41), 
prior to blinking, a thickened fluid with small droplets could be seen. 
With one and then two blinks, the fluid spread with heavy color formation. 
The droplets disappeared within three of four blinks. By the fifth blink, 
a uniform, heavy film was present on the eye without particles or 
irregularities. For the wax (Example 42), the particle remained beneath 
the lower lid and a film did not form over the ocular surface. Upon 
application of Lacri-Lube ointment (Example 43), a heavy, irregular film 
or slick formed with large globules present after instillation of the 
formulation onto the eye. With one or two blinks, this film was slowly 
moved so that it covered 20 to 40% of the exposed portions of the eye and 
sclera. It did not substantially spread with further blinking though after 
approximately 10 minutes, the film had significantly thinned. Small 
droplets, uniformly present over the entire surface of the cornea, were 
still visible. 
Blur: With the formulations of Examples 31 and 41, there was no blur 
following addition of the treatment composition. No blur was experienced 
following the addition of the wax as would be expected in the absence of 
film formation. Considerable blur was experienced following the addition 
of Lacri-Lube. The blur continued for over ten minutes. 
EXAMPLE 44 
Since jojoba wax is liquid at room temperature, it was added neat to the 
eye using the glass rod procedure. It was found that initially an 
excellent film formed but the film did not sustain itself for in excess of 
about 1 hour. 
EXAMPLES 45 TO 48 
The following examples illustrate the currently preferred embodiment of the 
invention and describe an alternative procedure for formation of a gel. 
______________________________________ 
Final Formulation 
Component Amount (% by wt 
______________________________________ 
Ethylenediaminetetraacetic acid 
0.10 
Alkane Oil 4.75 
Surfactant 0.19 
Beeswax 0.25 
Boric Acid 1.86 
Sodium Chloride to 260 mo 
Water one liter 
pH to 7.5 
______________________________________ 
In the above formulation, the alkane oil was Drakeol 21 as identified 
above, the surfactant was a polyoxyethylene sorbitan monooleate sold under 
the tradename Tween 80, the preservative was sorbic acid and the beeswax 
was as identified above. The procedure used to make the above formulation 
comprised the following steps: 
The above formulation was made by preparing a first solution containing the 
EDTA, sodium chloride and boric acid dissolved in 875 ml of water. Sodium 
hydroxide was added to bring the pH of the solution to about 8.0. The 
solution was heated to 85.degree. C. with constant stirring using a stir 
bar. The surfactant and beeswax were added to the solution while 
maintaining the solution at 85.degree. C. In a separate vessel, the alkane 
oil was heated to 75.degree. C. The first solution was then added to a 
homogenizer and the heated alkane oil was slowly added while homogenizing 
the mixture over a period of time of 2 minutes with the mixture held at 
80.degree. C. to form an emulsion. The emulsion was then removed from the 
homogenizer and permitted to cool to ambient temperature with constant 
stirring using a stir bar. The so prepared composition was then autoclaved 
for 30 minutes at a temperature of about 120.degree. C. While held at 
elevated temperature, it is believed that the wax and oil formed a 
solution in each other and triglycerides were hydrolized. Thereafter, a 
solution identical to the first solution was prepared to which 1 percent 
by weight sorbic acid was added. This newly prepared solution was added to 
the autoclaved solution in an amount of 1 part sorbic acid solution per 
nine parts of the emulsion. The pH was then adjusted to 7.5 with 
hydrochloric acid and the volume was adjusted to 1 liter. 
A second formulation was made identical to the first with the beeswax 
content increased to 0.5%. 
The formulations so prepared were then evaluated using four groups of 
patients on two different days. The results are set forth as numerical 
averages for each group where group 1 comprised 4 patients, group 2 
comprised 5 patients, group 3 comprised 4 patients and group 4 comprised 5 
patients. The results are set forth below: 
______________________________________ 
Rating After Time on 
Ex. Beeswax Ocular Surface (hours) 
No. Content 0 0.5 1 2 3 4 5 6 7 
______________________________________ 
45 0.25 3.1 2.5 1.6 1.1 0.6 0.5 0.4 0.1 0.3 
46 0.25 2.4 2.5 1.9 1.6 1.6 1.5 0.6 0.4 0.2 
47 0.50 2.7 2.4 1.6 1.3 1.3 1.2 1.0 0.6 1.0 
48 0.50 2.4 2.5 2.1 1.6 1.6 1.6 1.4 1.4 1.3 
______________________________________