Download The effect of tear substitutes on tear film break-up time.

Volume I -I
Numhrr 3
Prednisolone
phosphate
1.0%
solution
18.2
±7.1|
33.1 + 7.2
Reports
Dcxamethasone
alcohol
0.1%
suspension
Dexamethasone
phosphate
0.1%
solution
20.9 t 3.8
3.8 ± 2.2f
30.0 t 6.1
N.I ± 4.1
10.
255
Symposium on Glaucoma. Transactions of the
New Orleans Academy of Ophthalmology,
St. Louis, 1967, The C. V. Mosby Company,
p. 123.
Podos, S. M., Kolker, A. M., and Becker, B.:
Topical corticosteroids: Dissociation of effects,
in: Ocular Anti-Inflammatory Therapy, Kaufman, M. L\, editor. Springfield, III'., 1970,
Charles C Thomas, Publisher, p. 108.
The effect of lenr substitutes on tear
film break-up time. MICHAEL A. LKMP,
MICHAEL GOLDHEHC, AND MAMCAHKT R.
RODDY.
46.0 ± 8.1
oxprcssi'tl
us pi'iri'iit
•11.8 + 7.1
ilillrri'iifc
from
22.4 ± 6.1
tin." m e n u
of 1 2 i m t r c i i t c i l
truiilini-iit p r o t o c o l ( p < 0 . 0 5 ) .
trc.itmcnt protocol ( p < 0 . 0 5 ).
Leibowitz, Boston University School or Medicine,
80 E. Concord St., Boston, Mass. 02118.
Key words: cornea, conical inflammation, corticosteioid, steroid, prednisolonc, dexaiiiethasone,
polymorplionuclear leukocytes, cornea.
KEFEKENCES
1. Leibowitz, II. M., and Kupferman, A,:
Pharmacology of topically applied dcxamethasone, Trans. Amur. Acad. Ophthalmol. Otolaryngol. 79: 78, 1975.
2. Leibowitz, II. M., and K'upferman, A.: Antiinllammatory effectiveness in the cornea of
topically administered prednisolone, INVEST.
OI'IITIIALMOI.. i:J: 757,
1974.
3. Cox, W. V., Kupferman, A., and Leibowitz,
II. M.: Topically applied steroids in conical
disease. I. The role of inflammation in
stronial absorption of dexaniethasone, Arch.
Ophthalmol. 88: 308, 1972.
4. Cox, VV. V., Kupferman, A., and Leibowitz,
II. M.: Topically applied steroids in cornea I
disease. II. The role of drug vehicle in stronial
absorption of devunethasone, Arch. Ophthalmol. 88: 549, 1972.
5. Leibowitz, II. M., Lass, |. H., and Kupferinan, A.: Oiiantitation of iiiHammation in the
cornea, Arch. Ophthalmol. 92: 427, 1974.
6. Kupferman, A., and Leibowitz, II. M.: Topically applied steioids in corneal disease. IV.
The role of drug concentration in the stronial
absorption of prednisolone acetate, Arch.
Ophthalmol. 9 1 : 377, 1974.
7. Kupfernian, A., and Leibowitz, II. M.: Topically applied steroids in conical disease. VI.
Kinetics of prednisolone phosphate., Arch.
Ophthalmol. 92: 331, 1974.
8 Kupferman, A., and Leibowitz, II. M.: Topically applied steroids in corneal disease. V.
Dexametliasone alcohol, Arch. Ophthalmol.
92: 329, 1974.
7
9. Arnialy, M. I .: Steroids and glaucoma, in:
Twelve commercial artificial tear solutions and
a newly developed one were evaluated, as to their
effect. O)i tear film breakup time (BUT) in ten
normal subjects. Instillation of one drop of these
solutions altered the BUT in such a way that serial
BUT measurements
could be used as an index
of retention
time.
Results demonstrated
significantly longer retention time for three related
products (Adapt, Adapcttc, and Adsorbotear) and
a newly developed product (Aleon 0413) [Tears
Naturale (Alcon T")]. This method appears to be
an accurate nonirritative way of assessing retention time of tear substitute/vehicles
ami demonstrate values much longer than previously reported
hi/ other
miihods.
Artificial tear solutions are used as replacement therapy in dry eye states: virtually identical
lormulations form the vehicles for the delivery of
locally instilled medications to the eye. These
solutions contain water-soluble polymers incorporated with the intent of prolonging retention
in the conjunctiva! sac. In practice, however, their
elh'eaev is limited by their short duration. 1 Studies
attempting to assess their stay in the conjnnctival
sac (retention time, contact time) have employed
visible markers, e.g., argyrol, nickel chloride,- and
have shown retention times of about 3 to 10
minutes; alternatively, excretion of instilled solutions through the nasolacrinial duct has been
studied and found to occur within minutes.'
Other studies have measured intiaoeular penetration of dyes1' and uptake of radioactive substances, but are only an indirect indication of
relative efficacy of dillcrent solutions in facilitating
incorporation or substances into the cornea.
If normal blinking is prevented, the precorneal
tear film will break up, i.e., develop random dry
spots. The interval between the last complete
blink and the appearance of the first dry spot—
breakup Mine (BUT)—lias been found to be
abnormally rapid in dry eye states. 0 ' i; This is
a reflection of decreased tear film stability. As
part of a larger study of BUT in normal subjects,
it was noted that after instillation of an artificial
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256
Reports
Ophthalmology
March 1975
E fftC I
O F IEAR
SUBSTITUTES
O N B U I
i!
I
Bdseline BUI
laveraqpi
^ B U I post instillation
•
I.
!
I II . .I I I . I
II II
Ii
I J I iI I
I 1pIJ
I II
I
1I
II
?0
Fig. 1. This graph illustrates the magnitude of the effect of the solutions on the BUT.
tear solution, a subject's BUT was altered over
a period of time. Since this might provide a
convenient nonirritative marker for duration o\
tear substitutes in the conjunctival sac, this study
was undertaken.
Methods. Twelve subjects with no evidence of
ocular disease and with normal BUT, between
15 and 25 seconds, were chosen for this study.
Twelve commercially available artificial tear solutions were studied; in addition, a new tear substitute developed in our laboratory with the cooperation of Alcon Laboratories was studied.
These solutions were studied in a randomized
order and in a double-blind fashion. All studies
were carried out in a room monitored for temperature and humidity and with no discernible air
currents. Baseline BUT values were measured
at each visit; one 50 /<l drop of artificial tear
was instilled in an eye and BUT was determined
at 5, 10, 15, and at approximately 15 minute
intervals thereafter until three successive measurements returned to baseline values. Return
to baseline values was interpreted as meaning the
solution was no longer present in significant
quantity. BUT measurements were performed
without anesthesia or holding the eye lids as
previously described.7 No more than one solution
was instilled on any single day.
Statistical methods. The maximum time of duration (length of time an observable effect on the
BUT was noted) was defined as the time until
the last BUT value was greater than the baseline
BUT (if the BUT was greater than baseline)
or until the last BUT value was less than baseline BUT (if the observable effect was to decrease BUT). This duration time was analyzed
to determine if there were any significant differences due to vehicle used, sex, age, or baseline
BUT. The observations for each eye were analyzed
separately.
Left eye. There was a significant dillerence
(p 0.01) (\y\t to vehicle but no significant ilillerences due to sex or age. Since there was a significant difference due to the stinting baseline
BUT, the means for vehicles were adjusted lor
these initial differences.
Right ci/c. There was a significant difference
(p 0.01) due to vehicle but neither the sex,
age, nor baseline values differed significantly.
Results. Two quantitative measurements could
be determined. The first of these was the magnitude of the effect of the solution on BUT.
Fig. 1 shows the average change from baseline
BUT noted alter instillation of solution. All solutions significantly lengthened BUT with the exception of one. A lengthened BUT is interpreted
as a reflection of enhanced tear film stability.
The second measurement was that of duration
of effect noted. Fig. 2 shows this in graphic form.
Interestingly, BUT values were altered after
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I ON B U I 0 1 I I A R S U B S I I I IJI ( S
100
80
60
40
?0
Fig. 2. This graph illustrates the duration over which the effect of solution instillation on BUT
was seen.
instillation of solution and remained altered lor
a given time, reverting to baseline values without an intermediate period permitting accurate
assessment of duration. In general, two groupings
of duration are discernible: those lorinulations
employing cellulose ethers or polyvinyl alcohol
tended to last about 35 to 6'0 minutes. The
lorinulations employing B1J polymer and the newly
developed tear substitute (Alcon 0413) were
noted to last about 90 minutes.
Discussion. Attempts to measure duration ot
tear substitute/vehicles have been hampered by
the difficulty in finding a suitable way of marking
and measuring the solution without inducing reIlex tearing. While currently available tear substitutes are limited by their short retention time,
clinical experience suggests they last much longer
than the few minutes reported in previous studies.
The rationale for using polymers in solutions
has been one primarily of increasing viscosity. Hecent studies show that viscosity seems to have
little ellect on retention time*; it has been stated
that the rate of tear secretion is the primary
determinant. If this is true, then solutions should
show longer retention time in dry eyes than in
normal eyes.
An alternative approach in the development
of tear substitutes would lie the use of watersoluble macromolecular compounds with an adsorptive affinity for the ocular surface. In this
way an ellective stitching action could be effected, promoting retention. Such an approach was
used in developing the new tear substitutes
tested here (Alcon 0413), using methods de-
scribed elsewhere." Evidence has been presented
showing that the solutions containing B1J polymer
(Adapt, Adapette, and Adsoibotear) display some
absorptive, properties. These solutions, therefore,
might be expected to show longer retention times.
The instillation of a drop of solution into the
tear system results, however, in a complex series
of interactions involving tear miicin, lipid, and
inorganic salts with the constituents of the instilled solution. It is interesting that all but one
solution resulted in prolonging BUT, indicating
an enhancement of tear film stability. The one
solution (Tearisol) that decreased BUT employs
hvdroxypropylmethyl cellulose as do a number
of other solutions. Complete formulations, however, are complex mixtures of polymers, preservatives, and salts. Laboratory experience has
demonstrated that seemingly small changes in
inorganic salts can profoundly influence polymer
behavior. Therefore, adverse efleets on tear film
stability might be the result of formulation
dillerences in salt content.
It has also been suggested that drop size is an
important determinant of retention time 1 "; in
tin's connection, all drops were of the same size
to eliminate a possible source of error.
An interesting finding in this study concerns
the baseline BUT values. Because of the study
design we were able to determine serial BUT's
in a given subject over a several week period.
Results indicate that this value is remarkably
constant in an individual. Table I shows the mean
BUT determined for each of the 12 participating
subjects with standard deviations.
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Reports
C Ophthalmology
March 1975
Table I. Serial hascline B i n ' s on ten subjects
taken on twelve dillerent days. Tlie mean BUT's
are listed with one standard deviation (S.D.).
OD
Subject
ID
number
Mean
BUT
01
02
03
04
05
06
07
08
09
010
23.66
17.83
27.50
24.91
23.00
29.16
18.50
22.50
25.00
25.85
.S.D.
±4
±3
±5
±6
±5
±6
±5
±4
±3
±7
OS
Mean
BUT
22.16
20.16
28.00
25.66
24.00
29.58
17.75
23.25
23.33
28.50
S.D.
i3
±5
±6
±8
±3
±8
±4
±4
i3
i8
The results ol the study indieate that the instillation of a drop ol an artificial tear solution
into the eonjunetival sae a Meets the BUT in such
a way that a definite, reproducible alteration in
BUT occurs over a certain period of time. While
the mechanism by which this change is ellected
is unknown, the measurement of serial BUT's
alter instillation ol a tear substitute seems to
provide an efficient convenient nonirritative method of assessing retention time. This assumes that
the observable eMects of the solution or the BUT
are an indication of the remaining piesence in
the conjuctival sac. Values reported are much
longer than those reported with previous methods
and are consistent with clinical experience. This
method seems to be sufficiently discriminatory to
define significant dillerences in duration and indeed elficacy (positive effect on tear film stability) between different tear substitutes. The
results demonstrate greater retention times for
tour products: these results are consistent with
laboratory data suggesting greater absorptive properties for their constituents. 1 ' It would seem that
this method oilers an excellent means of assessing
new tear substitute/vehicle solutions.
in part by United States Public Health Seivice
Grants 5R01 EY00988-02, and a grant from
Alcon Laboratories, Inc. Submitted for publication Oct. 1, 1974. Heprint requests: Dr. M. A.
Lemp, Director, Cornea Service Georgetown University Medical Center, 3800 Reservoir Rd., N.W.,
Washington, D. C. 20007.
Key words: tear film break up time, retention time,
tear substitutes, ophthalmic polymers.
REFERENCES
1. Lemp, M. A.: Artificial tear solutions, in:
The Preocular Tear Film and Dry Eye Syndromes, Holly, F. |., and Lemp, M. A.,
editors. Inteniat. Ohpthalmol. Clin. l.'J: 221,
1973.
2. Krishna, N., and Brow, F.: Polyvinyl alcohol
as an ophthalmic vehicle, Am. |. Ophthalmol.
57: 99, 1964.
3. Linn, M. L., and Jones, L. T.: Rale of lacrimal excretion of ophthalmic vehicles, Am. |.
Ophthalmol. (15: 76, 1968.
4. Waltman, S. R., and Patiowicz, T. C : Ellects
of hydroxypropyl.methylcelliilo.se and polyvinyl
alcohol on intraocular penetration ol topical
fluorescein
5.
6.
7.
8.
9.
10.
in
man,
INVEST.
OIMITIIALMOL.
9: 966, 1970.
Lemp, M. A., Dohlman, C. II., and Holly,
F. (.: Corneal desiccation despite normal tear
volume, Ann. Ophthalmol. 2: 258, 1970.
Lemp, M. A., Dohlman, C. H., Kuwabara,
T., et al.: Dry eye secondary to mucus deficiency, Trans. Am. Acacl. Ophthalmol. Otolaryngol. 75: 1223, 1971.
Lemp, M. A., and Hamill, |.: Factors allecting tear film breakup in normals, Arch.
Ophthalmol. 89: 103, 1973.
Acller, C. A., Marnier, D. M., and Peterson,
M. E.: The el feet of viscosity on the penetration of lluorescein into the human eye,
Exp. Eye Res. 11: 34, 1971.
Lemp, M. A., and Szyman.ski, E. S.: Adsorption at the ocular surface, Arch. Ophthalmol.
In press.
Chrai, S. S., Patton, T. F., Mehla, A., et al.:
Lacrimal and instilled Huid dynamics in
rabbit eves, I. Pharm. Sci. f>2: 1112, 1973.
From the Georgetown University Medical Center, Washington, D. C. This study was supported
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