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Reports 1199

this generalization, however, at least one and prefera- Tono-Pen versus manometry in humans shortly after
bly several other units of this instrument should be deadi. Am J Ophthalmol. 1988; 105:678-682.
tested to determine how much inter-unit variability 4. Kao SF, Lichter PR, Bergstrom TJ, Rowe S, Musch DC.
exists. Presumably, there will be little. The exercise Clinical comparison of the Oculab Tono-Pen to the
is worthwhile because the TP is such a convenient Goldmann applanation tonometer. Ophthalmology.
1987;94:1541-1544.
instrument to use.
5. Frenkel REP, Hong YJ, Shin DH. Comparison of the
KeyWords Tono-Pen to the Goldmann applanation tonometer.
Arch Ophthalmol. 1988; 106:750-753.
cynomolgus monkey, glaucoma, intraocular pressure, to- 6. Armstrong TA. Evaluation of the Tono-Pen and the
nometry, Tono-Pen° Pulsair tonometers. Am J Ophthalmol. 1990; 109:716-
720.
Acknowledgments
7. Geyer O, Mayron Y, Loewenstein A, Neudorfer M,
The authors thank Paul Dederichs of Mentor O & O, Inc. Rothkoff L, Lazar M. Tono-Pen tonometry in normal
(Nowell, MA) for loaning them the Tono-Pen. and post-keratoplasty eyes. Br J Ophthalmol. 1992;
76:538-540.
8. Menage MJ, Kaufman PL, Croft MA, Landay SP. Intra-
References ocular pressure measurement after penetrating kera-
1. Minckler DS, Baerveldt G, Heuer DK, Quillen- toplasty: Minified Goldmann applanation tonometer,
Thomas B, Walonker AF, Weiner J. Clinical evaluation pneumatonometer, and Tono-Pen versus manometry.
of the Oculab Tono-Pen. Am J Ophthalmol. 1987; BrJ Ophthalmol. 1994; 78:671-676.
104:168-173. 9. Mendelsohn AD, Forster RK, Mendelsohn SL, et al.
2. Boothe WA, Lee DA, Panek WC, Pettit TH. The Tono- Comparative tonometric measurements of eye bank
Pen: A manometric and clinical study. Arch Ophthal- eyes. Cornea. 1987; 6:219-225.
mol. 1988; 106:1214-1217. 10. Moore CG, Milne ST, Morrison JC. Noninvasive mea-
3. Hessemer V, Rossler R, Jacobi KW. Comparison of surement of rat intraocular pressure with the Tono-
intraocular pressure measurements with the Oculab Pen. Invest Ophthalmol Vis Sd. 1993;34:363-369.

drug permeability into the eye, through drug-cyclodex-


Dexamethasone - Cyclodextrin- trin-polymer co-complexes.
Polymer Co-complexes in Aqueous Methods. 2-hydroxypropyl-/?-cyclodextrin is a water-solu-
Eye Drops ble oligosaccharide that can be used to dissolve lipo-
philic drugs, such as dexamethasone, in aqueous solu-
Aqueous Humor Pharmacokinetics in tions. Co-complexation with a polymer further in-
Humans creases the solubility and increases drug permeability
through biologic membranes. Eye drops containing
Johannes Kdri Kristinsson* Hafrun Fridriksddttir,\ dexamethasone (0.32% and 0.67%), 2-hydroxypropyl-
Sigridur Th&risdottir,* Anna M. Sigurdardottir,-f /3-cyclodextrin, and polymer were given to patients be-
Einar Stefdnsson,* and Thorsteinn Lofisson^ fore cataract surgery, and the resultant dexamethasone
concentration was measured from aqueous humor sam-
Purpose. To test an aqueous eye drop solution con- ples.
taining a high concentration of dexamethasone in a Results. The dexamethasone -cyclodextrin drops give a
cyclodextrin-based drug delivery system. This system in- significandy higher concentration of dexamethasone in
creases both drug solubility in aqueous eye drops and aqueous humor than dexamethasone alcohol 0.1%
(Maxidex). Heating of the dexamethasone-cyclodex-
trin-polymer co-complexes appears to enhance the per-
From the * Department of Ophthalmology, Landakolsspttali, and the -[Department of
Pharmacy, University of Iceland, Reykjavik, Iceland. meability of the drug into the eye.
Presented in part al the annual meeting of the Association for Research in Vision
and Ophthalmology, Sarasota, Florida, May 1994. Conclusions. The cyclodextrin-based drug delivery sys-
Supported by iMndakotsspitali Research Fund, the Helga Jonsdotlir and Sigurlidi tem enhances both the solubility of dexamethasone in
Kristjdnsson Memorial Fund, the University of Iceland Research Fund, and the aqueous eye drops and the permeability of the drug into
Icelandic Research Council.
Submitted for publication October 30, 1995; revised January 16, 1996; accepted the human eye. Dexamethasone concentration levels in
January 23, 1996. the human aqueous humor exceed those reported with
Proprietary interest category: P.
Reprint requests: Einar Stefdnsson, Professor of Ophthalmology, University of
currently available steroid eye drops. Invest Ophthal-
Iceland, Landakotsspitali, IS 101 Reykjavik, Iceland. mol Vis Sci. 1996; 37:1199-1203.

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1200 Investigative Ophthalmology & Visual Science, May 1996, Vol. 37, No. 6

aqueous dexamethasone-HP/?CD-HPMC co-com-


JLJexamethasone has been one of the most frequently
plex with a dexamethasone concentration up to
used topical ocular corticosteroids. 1 Topical cortico-
1.28%. In a previous study,10 we compared the admin-
steroids are used for diseases of the outer eye and
anterior segment of the eye. Inflammatory diseases istration of 1.28% dexamethasone eye drop solution
in the posterior segment of the eye usually require in rabbits to 0.1% dexamethasone alcohol suspension
systemic corticosteroids. Topical corticosteroids are li- (Maxidex; Alcon Laboratories (Fort Worth, TX).
pophilic water-insoluble compounds that are only sol- Dexamethasone concentration in aqueous humor
uble to a limited extent in aqueous eye drop formula- measured, on average, 4.7 times greater with 1.28%
tions and, thus, frequently are formulated as suspen- dexamethasone than with 0.1% dexamethasone. The
sions, such as 0.1% dexamethasone alcohol, or as purpose of this study was to determine the ocular bio-
hydrophilic water-soluble prodrugs, such as 0.1% dex- availability of 0.32% and 0.67% dexamethasone-
amethasone sodium phosphate. HP/3CD-HPMC by administrating the eye drops to
patients undergoing cataract surgery and comparing
To increase the bioavailability of topical ocular it to the bioavailability of the commercially available
steroids, it is desirable to increase the concentration dexamethasone 0.1% suspension (Maxidex). Further-
of the steroid drug in aqueous eye drops and the per-
more, we tested the effect of heating (i.e., forming
meability through the cornea or sclera. Our hypothe-
the co-complex) on the ocular bioavailability of 0.67%
sis is that both these aims can be accomplished with
dexamethasone.
the use of the cyclodextrin-based drug delivery system
for eye drops.
2-hydroxypropyl-/5-cyclodextrin (HP/3CD) is a hy- MATERIALS AND METHODS. Patients sched-
droxypropyl substituted /3-cyclodextrin.2'3 It is a cyclic uled to undergo cataract surgery were recruited to the
oligosaccharide with a hydrophilic outer surface. Al- study. Informed consent was obtained. Patients with
though soluble in water, it has a lipophilic cavity in corneal disease, inflammatory ocular disease, glau-
the center. HP/9CD forms inclusion complexes with coma, or with the only potentially seeing eye undergo-
many lipophilic drugs by taking up a drug molecule, ing surgery or receiving systemic or topical steroid
or part of it, into the cavity. In this way, it is possible to treatment were excluded.
form aqueous drug-HP/?CD complexes of lipophilic Dexamethasone was obtained from Sigma Chemi-
drugs. 4 The complexes are readily dissociated because cal (St. Louis, MO), HP/?CD of molar substitution 0.6
no covalent bonds are formed. As a rule, HP/3CD mol- was obtained from Wacker-Chemie (Munich, Ger-
ecules do not penetrate biologic membranes but act many), hydroxypropyl methylcellulose (HPMC) 4000
as penetration enhancers by assuring constant high was obtained from Mecobenzon (Copenhagen, Den-
concentration of dissolved drug at the membrane sur- mark), and Maxidex eye drops were obtained from
face. In topical drug formulations, HP/3CD keeps wa- Alcon Laboratories. The dexamethasone-HP/3CD-
ter-insoluble drug molecules in solution, delivering HPMC co-complex was produced by heating the dexa-
them to the surface of the barrier where they partition methasone -HP/3CD with 0.10% hydroxypropyl meth-
into the barrier. 5 ' 6 In doing so, HP/3CD improves ocu- ylcellulose in an autoclave (120°) for 20 minutes.
lar bioavailability of drugs by increasing their rate of
absorption through the corneal barrier. Complex-
ation of dexamethasone with HP/3CD increases the Four types of preparations were tested:
absorption of dexamethasone 0.1% through the rab-
bit cornea by 40%. 7 Preparation 1
We have discovered that in aqueous solutions, wa- 0.32% dexamethasone
ter-soluble polymers (hydroxypropyl methylcellulose 0.1% HPMC
[HPMC]) increase the solubilizing effect of cyclodex- 5% HP/3CD
trins on lipophilic drugs by increasing the stability 0.05% sodium edetate
constants of the drug-cyclodextrin complexes. The 0.7% sodium chloride
polymers form co-complexes with the drug and cyclo- 0.01% benzalconium chloride
dextrin molecules. At the cornea, the polymers may
adhere to the surface. This promotes the release of Preparation 2
drug molecules from the cyclodextrin inclusion com- 0.67% dexamethasone
plexes into the solution leading to a high concentra- 0.1% HPMC
tion of drug molecules at the corneal surface, resulting 10% HP/3CD
in permeability enhancement. However, the cyclodex- 0.05% sodium edetate
trin-based drug delivery system has not been found to 0.55% sodium chloride
alter the barrier function of the cornea. 89 0.01% benzalconium chloride
We have formed eye drops containing a novel Heated in an autoclave (120°) for 20 minutes

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Reports 1201

Preparation 3 200 n

0.67% dexamethasone 0.32% dexamethasone


0.1% HPMC
0.1% dexamethasone (Maxidex®)
11.5% HP/3CD
0.05% sodium edetate
0.55% sodium chloride
100-
0.01% benzalconium chloride ~ 6
Unheated
Preparation 4
0.1% dexamethasone alcohol (Maxidex)
Other preoperative procedures were routine and
included the administration of 1 drop of eye drop
solution containing 0.1% indomethacine 60 and 30 8 10
minutes before surgery and 1% cyclopentolate and
Time from application (hours)
10% phenylephrine, each 60, 45, and 30 minutes be-
fore surgery. FIGURE l. Dexamethasone concentration in aqueous humor
One drop (50 fA) of 0.32% dexamethasone- after the administration of 0.32% dexamethasone-2-hy-
droxypropyl-/?-cyclodextrin—hydroxypropyl methylcellulose
HP/?CD-HPMC or 0.67% dexamethasone-HP0CD- and 0.1% dexamethasone alcohol (Maxidex). Mean concen-
HPMC (heated or unheated) or 0.1% dexamethasone tration ± SEM is shown at appropriate time points after
alcohol (Maxidex) was administered into the lower administration of the eye drops.
conjunctival fornix of the eye prepared for cataract
surgery at predetermined time points before surgery.
Twelve patients acted as controls and received no dex- This research followed the tenets of the Declara-
amethasone preparation. The selection of prepara- tion of Helsinki. Approval was obtained from the eth-
tions to patients was randomized. ics committee of Landakotsspitali and the Icelandic
Before opening the anterior chamber, 0.1 ml of Drug Administration (Ministry of Health).
aqueous humor was withdrawn with a small needle
and syringe. The time interval between the topical RESULTS. One hundred twenty-five patients par-
administration of the dexamethasone eye drops and ticipated in the study. Of those, 47 received 0.32%
aspiration of the aqueous humor was recorded. Quan- dexamethasone-HP/?CD-HPMC, 26 patients re-
titative determination of dexamethasone concentra- ceived heated 0.67% dexamethasone—HP/3CD-
tion was performed by liquid chromatography on a HPMC, 18 patients received unheated dexametha-
high-performance liquid chromatography component sone 0.67%-HP/?CD, and 34 patients received Maxi-
system (ConstaMetric [Bie & Bernsten a/s, Denmark] dex. Two additional patients were excluded because
3200 solvent delivery system, Rheodyne [Cotati, CA] of abnormally high values of dexamethasone in the
7125 injector, a Beckman Ultrasphere [Caltech, Pasa- anterior chamber, one after receiving heated 0.67%
dena, CA] ODS 5 //m [4.6 X 150 mm] column and a dexamethasone-HP/?CD-HPMC (655 ng/ml after 4
Spectro Monitor [Bie & Bernsten] 3200 UV, Milton hours, mean concentration hours ± SEM = 50.5 ± 33.5
Roy [Spectronic Instruments, Rochester, NY], vari- ng/ml) and the other after receiving unheated 0.67%
able-wavelength detector operated at 242 nm). The dexamethasone-HP/?CD-HPMC (116 ng/ml after
mobile phase consisted of acetonitrite, tetrahydrofur- 1.9 hours, mean concentration] 9 hollIS ± SEM = 6.4 ±
ane, and water (30:1:69). The flow rate was 1.8 ml/ 6.4 ng/ml).
minute, and the retention time was 4.4 minutes. Aque- Dexamethasone concentration in the anterior
ous humor samples were injected direcdy into the col- chamber was higher after the administration of 0.32%
umn without pretreatment. The drug recovery from dexamethasone-HP/5CD-HPMC solution compared
aqueous humor samples that had been spiked with with Maxidex suspension (Fig. 1) or 2.6 times higher
dexamethasone was estimated to be approximately levels comparing AUC curves of the preparations (Ta-
100%. ble 1), which was a statistically significant difference
The area under the curve (AUC) for each prepa- ( P < 0.001).
ration was generated as a linear combination of means Administering dexamethasone solution contain-
from 0 through the last observation time. Statistical ing an approximately 2-fold higher concentration of
methods for demonstrating bioequivalence by com- dexamethasone, or 0.67% compared to 0.32%, did
paring the drug preparations were adopted from not result in a much higher dexamethasone concen-
Schoenwald et al." These included calculating the tration in the aqueous humor, with a 0.67% dexameth-
variance estimates for each AUC and using them to asone-0.32% dexamethasone concentration ratio of
construct 95% confidence limits on each area and 1.13. Conversely, the duration of activity seemed to be
calculating a Hest comparing two areas. longer with 0.67% dexamethasone because dexameth-

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1202 Investigative Ophthalmology & Visual Science, May 1996, Vol. 37, No. 6

TABLE i.Statistical Comparison of Dexamethasone Concentration


Curves After Administration of 0.1% Dexamethasone Alcohol
Suspension (Maxidex) and 0.32% Dexamethasone-HP/?CD-HPMC
(0.32%) Solution
AUC SE 95% a df
Maxidex 124.11 26.42 97.69-150.52 9.13
0.32% 327.57 34.53 293.03-362.10 26.64
AUC = area under the curve; SE = standard error of the estimate of AUC; 95% CI = 95 percent
confidence interval for AUC; df = approximate degrees of freedom for the standard error of the
estimate of the AUC.
0.32% vs. Maxidex (West): AUCdim,rence = 203.46; SEMdifTt;rence = 43.38; dfdinmnCK = 32.86; lvalue =
4.68; P < 0.001.

TABLE 2. Statistical Comparison of Dexamethasone Concentration


Curves After Administration of Unheated 0.67% Dexamethasone-
HP^CD-HPMC (Unheated) and Heated 0.67% Dexamethasone-
HP/3CD-HPMC (0.32%) Solution (Heated)
Group AUC Group SEM 95% df
Unheated 90.70 19.88 70.83-110.6 1.61
Heated 260.08 59.84 200.24-319.91 3.84
AUC = area under the curve; SE = standard error of the estimate of AUC; 95% CI = 95 percent
confidence interval for AUC; df = approximate degrees of freedom for the standard error of the
estimate of the AUC
Heated vs. unheated (Rest): AUCdim.rt.nce = 169.38; SEMdinerence = 63.05; dfdMe[cncc = 4.67; t value =
2.69; P < 0.05.

asone concentration was measurable in the aqueous ability of dexamethasone compared with the commer-
humor 9 hours after instillation with 0.67% dexameth- cially available 0.1% dexamethasone, Maxidex. No
asone, but not with 0.32% dexamethasone or Maxi- toxic effects were observed.
dex.
By heating the 0.67% dexamethasone-HP/?CD-
HPMC (i.e., formation of the cyclodextrin-polymer
2001
co-complex), a higher concentration was obtained in
the anterior chamber compared to unheated 0.67%
dexamethasone-HP/?CD-HPMC (Fig. 2) or 2.9 times
higher levels comparing AUC curves of the prepara-
tions (Table 2), which was statistically significant (P
Heated (co-complex)
< 0.05). 100 - Unheated (no co-complex)

DISCUSSION. This study shows that it is possible


to achieve effective trans-ocular delivery of lipophilic
corticosteroids, such as dexamethasone, by producing
a three-way co-complex consisting of the drug, 2-hy-
droxypropyl-/?-cyclodextrin, and hydroxypropyl meth- 2 4 6 10
ylcellulose. The drug delivery system produces a Time from application (hours)
higher concentration of dexamethasone in aqueous
FIGURE 2. Dexamethasone concentration in aqueous humor
eye drops than would otherwise be possible. Heating after the administration of heated 0.67% dexamethasone-
the dexamethasone-cyclodextrin-polymer co-com- 2-hydroxypropyl-/?-cyclodextrin-hydroxypropyl methylcel-
plexes seems to enhance permeability into the eye lulose and unheated 0.67% dexamethasone-2-hydroxypro-
regardless of the drug concentration. pyl-/5<yclodextrin. Mean concentration ± SEM is shown at
The cyclodextrin-based drug delivery system is as- appropriate time points after administration of the eye
sociated with a large increase in the intraocular avail- drops.

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Reports 1203

TABLE 3.Adjusted Mean Peak Concentrations References


(± SEM) of Corticosteroids in Aqueous 1. Gordon DM. Dexamethasone in ophthalmology. Am
Humor of Human Patients After Topical JOphthalmol. 1959; 48:656-660.
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Prednisolone acetate 1%10 95.7 ± 19.4* hydroxypropyl-/?-cyclodextrin: Properties and usage
in pharmaceutical formulations. Pharm Ztg Wisw.
*Prednisolone is a sevenfold weaker steroid than 1991; 136:5-10.
dexamethasone."12 The intraocular concentrations reported by 5. SzejdiJ. Cyclodextrin Technology. Dordrecht: Kluwer Ac-
McGhee et al'° are adjusted accordingly.
ademic; 1988:39-43,188-192.
6. Loftsson T, Olafsdottir BJ, Bodor N. The effects of
Watson and associates12 measured the dexametha- cyclodextrin on transdermal delivery of drugs. EurJ
sone in human aqueous humor after the administra- Pharmacol Biopharmacol. 1991;37:30-33.
tion of Maxidex with results that were similar to ours. 7. Usayapant A, Karara AH, Narurkar MM. Effect of 2-
Prednisolone concentration in the anterior chamber hydroxypropyl-/?-cyclodextrin on the ocular absorp-
tion of dexamethasone and dexamethasone acetate.
after the administration of prednisolone acetate 1 %
Pharmacol Res. 1991; 12:1495-1499.
is 20-fold higher than dexamethasone concentration
8. van Doorne H. Interactions between cyclodextrins
after the administration of Maxidex 0.1 %. 13 However, and ophthalmic drugs. EurJ Pharmacol Biopharmacol.
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amethasone preparations (Table 3). Results also show evaluation of their effects on rabbit corneal epithe-
that heating the dexamethasone-HP/?CD complex lium. Lens Eye Toxicity Res. 1990; 7:459-468.
with 0.10% hydroxypropyl methylcellulose increases 10. Loftsson T, Fridriksdottir H, Thorisdottir S, Stefans-
the delivery of dexamethasone into the human eye. son E. The effect of hydroxypropyl mediylcellulose
Our results indicate that by using a cyclodextrin- on the release of dexamethasone from aqueous 2-
hydroxypropyl-/?-cyclodextrin formulations. Int J Phar-
based drug delivery system, it is possible to raise the
macol. 1994; 104:181-184.
intraocular corticosteroid concentration from what is
11. Schoenwald RD, Harris RG, Turner D, Knowles W,
possible with currently available steroid eye drops, and Chien D-S. Ophthalmic bioequivalence of steroid/
presumably to exert a greater anti-inflammatory effect antibiotic combination formulations. Biopharm Drug
inside the eye. Further study is needed to establish Dispos. 1987; 8:527-548.
the clinical efficacy of these drug formulations. 12. Watson D, Noble MJ, Dutton GN, MidgleyJM, Healey
TM. Penetration of topically applied dexamethasone
Key Words
alcohol into human aqueous humor. Arch Ophthalmol.
aqueous humor, corticosteroids, cyclodextrin, dexametha- 1988; 106:686-687.
sone, drug penetration 13. McGhee CNJ, Watson DG, MidgleyJM, Noble MJ, Dut-
ton GN, Fern AI. Penetration of synthetic corticoste-
Acknowledgments
roids into human aqueous humour. Eye. 1990; 4:526-
The authors thank Drs. Fridbert Jonasson, OH Bjorn Han- 530.
nesson, Ingimundur Gislason, and Gudmundur Viggosson 14. Havener WH. Corticosteroid therapy. In: Havener
for their invaluable assistance in acquiring samples for analy- WH, ed. Ocular Pharmacology. 5th ed. St. Louis: CV
sis. They also thank Sigurborg Sigurjonsdottir, Sveinbjorg Mosby; 1983:433-500.
Gunnarsdottir, and other nurses at the Department of Oph- 15. Haynes RC, Murad F. Goodman and Gilman's The Phar-
thalmology, Landakot Hospital, for their critical contribu- macological Basis of Therapeutics. 7th ed. New York: Mac-
tion to the study. Millan; 1985:1475-1477.

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