ii 

 

 

 

 

 

 

Reformulation and Drop Size of Apraclonidine
Hydrochloride

 

Mark I. Vocci, M.D., Alan L. Robin, John C. Wahl, 
Phil Mayer, Adrienne Graves, Billie York, 
Cheryl Enger, M.S., and James Sutton, C.O.T.

We performed a prospective, dOuble-
masked, placebo?controlled, six-period, cross-
over study in which normal subjects were
randomly assigned to treatment and compared
three different formulations of apraclonidine
hydrochloride (the present commercially
available formulation, and formulations with
'or lysole?ci-
thin)..We also evaluated the ef?cacy of a 1611.1
and 30-511 drop size. The magnitude and dura-
tion of'decrease in intraocular pressure was
comparable for all formulations. Most sub-
jects tolerated all formulations well with only
a few reporting any side effects. The best-tol-
erated formulation was 0.5% apraclonidine
hydrochloride delivered with a 16-ul dr0p
size. Dry mouth developed frequently with
the commercially available 1% apraclonidine
solution. Blurred vision complicated the use
of the formulation containing hydroxypro-
Both dry mouth (P .05)
and blurred vision (P .004) were statistically
signi?cant side effects.

APRACLONIDINE HYDROCHLORIDE is a relatively
selective alphaz?adrenergic agonist and a cloni-
dine derivative. Topical 1.0% apraclonidine is
the only medication that consistently reduces
intraocular pressure increases accompanying
argon'laser trabeculoplasty and iridotomy?4
Various concentrations of apraclonidine have
reduced intraocular pressure in normal and
glaucomatous eyes.5'8 Dose-related7side effects,

 

Accepted for publication Oct. 25, 1991.
From the Sinai H05pital (Drs. Vocci, Robin, and Wahl
and Mr. Sutton) and Wilmer Institute of Johns Hopkins
School of Medicine, Baltimore, Maryland (Dr. Robin and
Ms. Enger); and Alcon Laboratories, Fort Worth, Texas
(Drs. Mayer, Graves, and York).

Reprint requests to Alan L. Robin, M.D., 6115 Falls
Rd? 3rd Floor, Baltimore, MD 21209-2226.

suth as dry mouth, might limit its long-term
usefulness. It would be ideal to minimize such
while not altering apraclonidine's
ability to reduce intraocular pressure.

These could possibly be reduced
by reformulation. and reduction in drop size.
Reformulation may allow greater adherence of
the medication to the cornea, better corneal
penetration, and IeSs systemic absorption. This
may allow for a comparable magnitude and
duration of intraocular pressure reduction seen
with the 1% solution, but with fewer side ef-
fects. A similar effect (a reduction in concentra-
tion from 0.5% to 0.25% with a comparable
intraocular pressure reduction) has been seen
with the reformulation of betaxolol hydrochlor-
ide.9

Previous studies with topical alpha-agonists10
and beta-blockers11 suggest that reducing the
drop size affects intraocular pressure reduction
minimally. The eyelid fornix normally holds
less than 20 pl of solution.12 A smaller eyedrop
decreases the amount of medication reaching

.the and may allow for decreased eyelid

pumping of the eyedrop and decreased system?
ic absorption. A smaller eyedrop may deliver a
bigger effective dose because washout'of medi?
cation through tearing would be minimal.

We evaluated the intraocular pressure reduc?
tion activity and systemic side effects of various
eyedrop sizes, concentrations, and formula?
tions of apraclonidine.

 

Subiects and Methods

 

We recruited 29 healthy volunteers who were

?21 years of age or older. Subject mean age was

33 i 10.1 years (range, 21 to 55 years). Five
were men, 24 were women, 15 were black, and
14 were white. Subjects were excluded if they
had any of the following: recent history of
ocular trauma, infection, or inflammatory dis?

154 JOURNAL OF 113:154?160, FEBRUARY, 1992

VOL 113, N0. 2



Reformulation and Drop Size of Apraclonidine 155

 

ease; any abnormality preventing reliable to-
nometry; previous intraocular or laser Opera-
tions; contact?lens wear during the study;
monocular vision; unstable cardiopulmonary
disease; chronic renal failure; received systemic
alpha-agonists within 30 days before the study;
or had a history of hypersensitivity to apraclo?
nidine or clonidine. We also excluded women
who were pregnant, nursing, or of childbearing
potential. The hospital's investigational review
board approved the study, and written in-
formed consent was obtained from each sub?
ject.

We performed a double-masked, six-period
crossover study in which subjects were ran-
domly assigned to treatment using three con-
trols, each with a 30-ul drop size (Table 1). The
?rst was the vehicle of the commercially avail-
able 1% solution (placebo). The second was 1%
apraclonidine solution. The third was a 30?p.1
solution Of 0.5% apraclonidine with conven-
tional formulation. We compared these to the
three following different formulations of apra-
clonidine using a 16-p.l drop size: a 0.5% solu-
tion of apraclonidine with hydroxypro?
added; a 0.5% solution of
apraclonidine with both hydroxypropylmethyl-
cellulose and the corneal penetration enhancer,
lysolecithin, added; and a 1611.1 0.5% Ophthal?
mic solution formulated identically to the com-
mercially available 1% solution. Each subject
randomly received all six medications with a
one-week washout between periods.

On the ?rst day of each crossover period we
measured visual acuity, resting blood pressure,
and heart rate, and performed slit?lamp biomi-
croscopy. We carefully placed only a single
drop of study medication in both eyes of each
subject. We examined the subjects one, three,
eight, and 12 hours later. No topical anesthetic
was given or intraocular pressure was mea?
sured before instillation Of the study medica-
tion. This allowed us to evaluate better the
efficacy of the corneal penetration enhancer,
lysolecithin. Applanation tonometry can
abrade the cornea, enhancing the penetration
of a t0pical medication. Applanation tonometry
before the administration of a glaucoma medi-
cation also does not mimic its use in a clinical
situation. By instilling medication in subjects
before applanation tonometry, there was no
confusion between the effects of the penetra-
tion enhancer that we evaluated and the effects
of topical anesthetic (proparacaine or its
preservative (benzalkonium chloride) on the
cornea.13

TABLE 1
DIFFERENCES IN FORMULATION AND DROP SIZE OF
APRACLONIDINE MEDICATIONS FOR THE SIX STUDY

 

 

ARMS
CONCENTRATION DROP SIZE
OF APRACLONIOINE on.) FORMULATION
None 30 Conventional
0.5% 30 Conventional
1% 30 Conventional
0.5% 16 Conventional
0.5% 16 
0.5% 16 

with lysolecithin

 

At each subsequent interval, intraocular
pressure was measured with Goldmann appla?
nation tonometry. We also measured resting
blood pressure and heart rate. Subjects estimat?
ed side effects and on an arbitrary
scale from 0 to 9. Mild side effects were rated 1
to 3, moderate side effects were rated 4 tO 6, and
severe side effects were rated 7 to 9. These
were subjective and we did not at-
tempt to measure their severity objectively. The
following were actively elicited: ocu-
lar burning, ocular stinging, ocular itching,
ocular dryness, excessive tearing, blurred vi-
sion, dry mouth, bad taste in mouth, unusually
dry nose, systemic tiredness, and systemic
drowsiness.

After the 12-hour examination, we instilled a
second drop of study medication in both eyes.
Each subject was then given the bottles of study
medication and asked to instill one drop in each
twice daily over the next six days. Each
subject was seen again one week later, 12 hours
after the last eyedrop instillation. We again
carefully instilled only one drop of the same
study medication into both eyes Of each indi-
vidual. Subjects were examined at one, three,
eight, and 12 hours later as on the ?rst day. The

. identical sequence of examinations was repeat-

ed for the next study phase, after the washout.

We averaged the intraocular pressure read-
ings from both eyes of each volunteer, treating
each subject as a unit. Results were reported as
mean i 1 standard deviation. The Bonferroni

paired t-test was used to evaluate data.

 

Results

 

Only one subject did not complete all study
visits. This subject completed ?ve of the six

 

 

 

 

 

11151111711131". tam

 

 

 

156 AMERICAN JOURNAL OF OPHTHALMOLOGY

February, 1992

 

study phases and was eliminated during the
?nal day of the last study phase because of an
adverse reaction. No change in the visual acuity
of any subject was found at any time during the
study.

Baseline intraocular pressure was not mea-
sured on any study date. We used the placebo-
treatment phase as a baseline value. This repre?
sented a normal diurnal curve for each subject.
At each interval, we compared the results ob-
tained for each study medication with those
obtained during placebo treatment at the same
interval (Table 2, Figure). All formulations of
apraclonidine signi?cantly reduced intraocular
pressure, compared to placebo (P .05). The
maximal intraocular pressure reduction effect
from placebo for all agents was observed at
three hours (21.9% i? 16.6% to 26.0% 1' 15.6%)
and decreased to the range of 10% i 19.6% to
16% 18-2% by 12 hours. Statistical analysis
comparing each formulation to all other formu-
lations showed no signi?cant differences for
any formulation. A similar intraocular pressure
reduction was seen on Day 7 for all formula-
tions. Comparison of intraocular pressure re-
duction ef?cacy of all formulations on Day 1
compared with Day 7 yielded no signi?cant
differences at all intervals.

The number of subjects whose intraocular
pressure was reduced 20% by the placebo for
all formulations was determined (Table 3). The
3011.1 drOp 0.5% apraclonidine solution with
conventional formulation reduced intraocular
pressure signi?cantly more than the formula-
tion containing both 
lulose and lysolecithin on Day 7 at three hours.
Although no other signi?cant difference was
observed, the 30-p.l drop 0.5% apraclonidine

with conventional formulation appeared to re-
duce intraocular pressure better than all other
medications at this interval. No difference was
found for any other formulations at any time
point.

The percent change of mean systolic blood
pressure ranged from i 10.4% to
+50% 1' 15.0% and the percent change of
mean diastolic blood pressure ranged from
i 12.3% to +58% i 18.1%. No statisti-
cally signi?cant differences (P .05) were ob-
served in the percent change from baseline
value for systolic and diastolic blood pressure
for any agent.

Data for the following side effects were not
statistically different (nor did they approach
signi?cance) from placebo: burning, stinging,
itching, tearing, dry nose, and bad taste. Data
for side effects that were signi?cantly different
than those of the placebo were also determined
(Tables 4Ithrough 7). The formulation contain-
ing induced sig-
ni?cantly more blurred vision than all other
formulations (P .004). The placebo induced
signi?cantly less (P .05) dry mouth than
apraclonidine 1% (P .002), 1641.1 0.5% apra-
clonidine with conventional formulation (P 
.032), and 30?111 0.5% apraclonidine with con-
ventional formulation (P .032) but neither
formulation with 
lose. Apraclonidine 1% induced signi?cantly
(P .022) more dry mouth than both formula-
tions with Fa-
tigue and drowsiness were more signi?cant
(P .016) with apraclonidine 1% than with
placebo. Tiredness was also less frequent (P 
.04) with placebo when compared with the
solution containing 

TABLE 2
MEAN INTRAOCULAR PRESSURE VALUES (1 ONE STANDARD DEVIATION)

 

APRACLONIDINE

 

 



WITH CONVENTIONAL 
FORMULATION 
WITH
TIME 30.? 1 .094. 164.1. 0.5% 30-1.; 0.5% LYSOLECITHIN PLACEBO
Day 1
Hour 1 11.6 i- 2.6 12.4 i 2.2 12.5 i 2.8 12.9 i 3.1 12.4 i 2.7 14.7 i 2.5
Hour 3 10.5 i 2.5 10.9 2.0 10.9 i 2.4 10.9 1* 2.0 10.5 i 2.1 14.3 i 2.3
Hour 8 10.6 i 2.8 11.7 2.1 11.0 i 1.9 11.2 i 2.3 10.8 i 2.1 13.3 i 2.2
Hour 12 11.1 2.2 11.7 I 2.5- 11-3 2.6 11.9 i 2.2 11.4 i 2.4 13.5 i 2.6
Day 7
Hour 1 11.2 2.4 12.5 3.1 11.4 I 2.8 11.6 i 2.3 11.9 1 2.9 14.4 i 2.3
Hour 3 9.9 2.1 11.1 2.7 10.2 1- 2.5 10-7 1- 1.8 10.9 i 2.5 13.7 3.0
Hour 8 10.7 i 2.7 11.8 2.1 11.5 2.2 11.7 2.2 11.4 I 2.8 13.3 a: 2.8
Hour 12 11.3 i 2.5 12.0 :t 1.9 12.2 I 2.3 11.8 I 2.0 11.9 2.3 13.7 2.3

 

 

Vol. 113, No. 2

Reformulation and Drop Size of Apraclonidine 157

 

Figure (Vocci and associates). Line
graph comparing the percent change
in mean intraocular pressure from the
placebo?treatment phase for all for-
mulations and drop sizes. The open
triangles represent the 30-p.l eyedrop

 

 

 

 

 

 

 

0 of the standard formulation of 1%

'2 apraclonidine. The solid squares rep-

'4 resent 3011.1 eyedrops of 0.5% apra?

?5 clonidine with the standard formula?

'8 tion. The open squares represent

?10 standard formulation of 0.5% apraclo-

42 nidine with a smaller 16-9.] eyedrop
2 .14 size. Both the solid and open circles
.16 represent formulations of 0.5% apra-
0 48 clonidine using the smaller 16-ul eye-
39 20 drop size. The solid circles represent
.22 formulations to which hydroxypro-

- was added. The

'24 open circles represent the formulation

?26 to which lysolecithin was also added.

'33 No signi?cant difference at any inter?
mealtime 1itr 12;? a? 3% egg 12 L?s val was observed between groups. No
signi?cant difference was observed in

De)? TIME 950'" any group between mean percent in-

lulose and lysolecithin. Although the differenc-
es in drowsiness and tiredness between the
16-p.l 0.5% apraclonidine with conventional
formulation and apraclonidine 1% were not
statistically signi?cant at the -05 level,
eight of the 29 subjects reported moder-
ate to severe reactions with 1% apraclonidine
compared to three of the subjects re-
porting the same level with the 1611.1 0.5%
apraclonidine with conventional formulation.
This trend might be signi?cant if a larger sam-
ple size is used.

The one subject who was discontinued from
the study reported the most severe side effect at
Day 7 of her ?nal study visit while receiving
apraclonidine Before instillation of the
medication on the last day of the study, this
subject reported mildly blurred vision, burn?
ing, and photophobia. Slit-lamp biomicroscopy
disclosed bilateral mild corneal punctate stain-
ing, mild conjunctival injection, and trace cell
and ?are in the anterior chamber. Two addition-
al subjects receiving apraclonidine 1% had
sparse corneal punctate staining but were
A mild headache was reported
by two subjects receiving the 30?51.} 0.5% apra-

traocular pressure change from place-
bo at comparable times on Days 1 and
7. indicates hydroxypro-
and lysolecithin.
HPMC indicates hydroxypropylmeth-
ylcellulose.

clonidine with conventional formulation on
Day 1. Nine subjects-reported subjective mild
blurring of vision after the instillation of both
solutions containing 
lulose. Five of these nine subjects reported that
the blurring was transient, lasting less than one
minute. Headache was reported by two subjects
while using the formulation containing hy-
with lysolecithin.

 

Discussion

 

This study used a potentially commercially
available eyedrop bottle that delivers a 16-p.l
drop size. Previous studies of other medica-
tions that used minidrops used either pipettes10
or a prototype drop bottle.? We also evaluated
multiple formulations and concentrations.
Baseline intraocular pressure was not measured
and the intraocular pressure data were ana-
lyzed as percent change from placebo. The data
obtained from the placebo-treated group sepa-
rated the pharmacologic effects of apracloni?
dine from diurnal variation and placebo effects.



 

 

 

 

 

158 AMERICAN JOURNAL OF OPHTHALMOLOGY February, 1992

1

TABLE 3

I NUMBER OF SUBJECTS WITH A 20% REDUCTION 1N INTRAOCULAR PRESSURE

APRACLONIDINE WITH

FORMULATION 

TIME 301.1. 1.0% 15% 0.5% 30-11:. 0.5% WITH LYSOLECITHIN 
Day 1

Hour 1 16 11 12 13 12

Hour 3 20 19 19 21 19

Hour 8 16 11 14 12 13

Hour Hour Hour Hour Hour 12 13 7 10 10 11

 

*SO-pl 0.5% apraclonidine with conventional formulation signi?cantly reduced intraocular pressure in more volunteers by 20%

 

ga-emM-TI?

?ux

'l



i compared to with lysolecithin.

In
.

nit."

I 

 

 

This method was important because statistical-
ly signi?cant decreases in intraocular pressure
have been observed in eyes in which placebo
drops have been instilled??16

The data regarding the effect of the corneal
penetration enhancer, lysolecithin, would have
been confounded by the previous applanation
of an anesthetized cornea had a baseline intra-
ocular pressure been obtained. However, the
main disadvantage of this study was that the
data were calculated as a percent change from
placebo rather than from baseline value. This
may under- or overestimate the intraocular
pressure-reducing ability of various formula-
tions. 

This study was conducted to determine
whether reformulation or reduction in drop
size, or both, of topically administered apraclo-

TABLE 4
NUMBER OF SUBJECTS BLURRED
VISION AS A SIDE EFFECT (N 29)

nidine would affect its ocular hypotensive ef-
fects and its side effect pro?le. All formulations
signi?cantly reduced intraocular pressure com-
pared to placebo. No signi?cant differences in
the average maximal intraocular pressure re-
duction were found for any formulation at any
time point in the study compared to any other
formulation. The maximal intraocular pres-
sure?reducing effect was observed at three
hours for all formulations. This was consistent
with ?ndings of previous studies.5'7'l7 The range
of maximal response in this study varied from
21.9% i 16.6% to 26.1% 15.6%. This range

of maximal response was similar to previous

apraclonidine studies}17 which reported a
22.4% and 28.6% maximal response with 1%
and 0.5% apraclonidine, respectively. Al?
though our study used healthy adult volun-

TABLE 5
NUMBER OF SUBJECTS EXPERIENCING DRY MOUTH
AS A EFFECT (N 29)

 

OF SIDE EFFECT

 

 

NONE
OR
MILD MODERATE SEVERE
Placebo 29 0 
Apraclonidine 1% 29 0 0
161d 0.5% apraclonidine
with conventional formulation 29 
30-,ul 0.5% apraclonidine
with conventional formulation 29 0 0
Hydroxypropylmethyloeliulose
with lysolecithin 24 5 
20 6 3

 

 

RATING OF SIDE EFFECT

 

 

NONE
on
MILD MODERATE SEVERE
Placebo 29 0 0
Apraclonidine 1% 16 9 4
16?p.l 0.5% apraclonidine
with conventional formulation 23 4 2
3041.1 0.5% apraclonidine
with conventional formulation 23 6 - 0
Hydroxypropylmemylcellulose
with lysolecithin 25 2 2
Hydroxypropylmethyloellulose 25 3 1

 

Vol. 113, No.2

Reformulation and Drop Size Of Apraclonidine 159

 

TABLE 6
NUMBER OF SUBJECTS EXPERIENCING DROWSINESS
AS A SIDE EFFECT (N 29)

 

RATING 0F SIDE EFFECT

 

 

NONE
0R
MILD MODERATE SEVERE
Placebo 29 0 0
Apraclonidine 1% 23 2 4
161d 0.5% apraclonidine
with conventional formulation 28 1 0
30m 0.5% apraclonidine
with conventional formulation 27 1 1

with Iysolecithin 26 3
27 1 1

 

teers, these results probably corresponded to
potential short-term results seen in glaucoma-
tous eyes as the results of our study were
similar to those seen when t0pical apracloni?
dine was instilled in both healthy and glauco-
matous eyes.?5

The effective dose of all formulations of 0.5%
apraclonidine with a reduced (16?p.l) drop size
is approximately one drop of a 0.25% solution.
A previous dose-response study7 that used con-
centrations of 0.125%, 0.25%, and 0.5% apra-
clonidine in subjects with ocular hypertension
and glaucoma found no statistically signi?cant
differences between 0.25% and 0.5% solutions.
The previous dose?response study"1 did ?nd a
difference in the percentage of patients with a
greater than 20% reduction in intraocular pres-
sure at eight hours for the 0.25% and 0.50%
solutions. However, as in our present study,
this difference did not attain signi?cance with
the exception of the formulation with hydroxy?
and the conventional
30?31.] 0.5% apraclonidine solution. Hydroxy?
might lessen the effec?
tive concentration of apraclonidine.

The magnitude and duration of responses
was similar for Day 1 and Day 7. The range of
magnitude and duration of response was simi?
lar to that in previous studies using. similar
concentrations of apraclonidine?l7 This may
indicate that short-term studies of apracloni?
dine could be as brief as 24 hours.

We detected no clinically or statistically sig?
nificant differences in resting systolic or diastol-
ic blood pressure or pulse rate in this study.
Similar ?ndings have been reported in several
studiesd?ds

TABLE 7
NUMBER OF SUBJECTS EXPERIENCING TIREDNESS
AS A SIDE EFFECT (N 29)

 

RATING 0F SIDE EFFECT

 

 

NONE
0R
MILD MODERATE SEVERE
Placebo 28 1 0
Apraclonidine 1% 21 2 6
16-pl 0.5% apraclonidine
with conventional formulation 26 2 1
3010 0.5% apraclonidine
with conventional formulation 26 2 1
Hydroxypropylmethyloellulose
with Iysolecithin 21 7 1
25 3 1

 

The most commonly elicited side effects in
our study were dry mouth, dry nose, fatigue,
drowsiness, and burning on instillation. Fewer
subjects reported side effects while taking 16?
[3.1 0.5% apraclonidine with conventional for-
mulation, the 30?p.l 0.5% apraclonidine with
conventional formulation, and both formula-
tions containing 
lose when compared to apraclonidine 1% for
fatigue, dry mouth, and bad taste. However, the
decrease in side effects was not entirely dose?
dependent. The trend was as might be expect?
ed; lower doses of apraclonidine were associat-
ed with a decrease in the number of subjects
reporting complications, and the complications
that were reported were milder. The only ex-
ception was transient blurring of vision in-
duced by the formulations containing hydroxy?
This was subjective and
visual acuity was not measured after the instil?
lation of apraclonidine. This was most likely
caused by the increased viscosity of hydroxy?
The addition of hy-
offered no appar?
ent advantages, but had the disadvantage of
blurred vision.

All subjects spontaneously volunteered in?
formation about the new (16?ul) eyedrop bot-

tle. They agreed it was easier to squeeze and

deliver one drop with this bottle and therefore
preferred the new eyedrop bottle to the conven-
tional eyedr0p bottle.

Although the side effects were tolerable for
the subject group as a whole, some of these side
effects may limit the future applications of the
drug in susceptible individuals. One subject
developed mild ocular irritation and anterior

 

 

 

Wr'tf?i?i

?1

 

 

160 AMERICAN JOURNAL OF OPHTHALMOLOGY

February, 199 2

 

chamber inflammation representative of an al?
lergic reaction during the one?week instillation
period with the apraclonidine 1% formulation.
This reaction developed during the subject?s
sixth study phase and did not develop with any
other formulation or drop size. This unusual
reaction has been previously reported with 1%
apraclonidine17 and may represent a problem
when used for long-term treatment of glauco-
ma. It is noteworthy that this reaction devel-
oped during the ?nal phase (Week 6) of the
study and may be related to the total duration
of apraclonidine exposure.

This study demonstrated that reformulation
or reduction in drop size, or both, is associated
with a similar duration and magnitude of intra-
ocular pressure reduction but can also be asso?
ciated with a decrease in local and systemic side
effects. Decreased eyelid pumping of a smaller
drop volume contributed to the effects found in
this study. These short-term results augur well
for the future long-term instillation of apraclo-
nidine hydrochloride as an ocular hypotensive
agent in the management of glaucoma. Apra?
clonidine, when used in long-term treatment,
may be most effective in a smaller drop size. A
new long?term agent for the treatment of glau-
coma must not only be safe and effective, but
also have tolerable side effects. Apraclonidine
in the form of the 0.5% solution with a 1611.1
drop size was both effective and well-tolerated.

 

References

 

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