ACUVAIL*: Corneal Wound Healing Model

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Ex Vivo Porcine Corneal Wound
Healing Following Exposure to
Ophthalmic Ketorolac Solutions
Mark McDermott, MD1; Linda Villanueva, COT2;
Rhett M. Schiffman, MD, MS, MHSA2; David A. Hollander, MD2
1The
Kresge Eye Institute, Department of Ophthalmology, Wayne State University School of
Medicine, Detroit, MI; 2Allergan, Inc., Irvine, CA
Study funded by Allergan, Inc.
Dr. Mark McDermott has received research funding Allergan Inc.
Ms. Linda Villanueva and Drs. Rhett M. Schiffman and David A. Hollander are employees of Allergan, Inc.
1
Background
• The ketorolac family of topical nonsteroidals is used to treat pain and/or
inflammation following cataract or corneal refractive surgery.1-3
• Ketorolac is potent inhibitor of prostaglandin production via suppression of
both cyclooxygenase-1 and -2 (COX-1) and (COX-2) enzymes.4
• In the past, topical NSAIDS have been associated with corneal toxicity and
delays in wound healing.5
• A novel formulation of preservative-free ketorolac 0.45% (Acuvail®; Allergan,
Inc.; Irvine, CA) was recently introduced that also contains
carboxymethylcellulose (CMC).1
• Previous formulations of ketorolac include a 0.5% aqueous solution
preserved with 0.01% benzalkonium chloride (BAK) (Acular®; Allergan, Inc.;
Irvine, CA)2 and a 0.4% aqueous solution preserved with 0.006% BAK
(Acular LS®; Allergan, Inc.; Irvine, CA).3 (see next slide)
• We hypothesized that the addition of CMC and removal of BAK in the
ketorolac 0.45% formulation would lead to improved corneal epithelial wound
healing compared to prior ketorolac formulations. We tested this hypothesis
using a porcine-derived, corneal organ culture model.
2
Ketorolac 0.45% Is the Only Preservative-Free
Formulation That Contains CMC
Brand Name
Active ingredient
Ketorolac 0.45%1
ACUVAIL®
Ketorolac 0.5%2
ACULAR®
Ketorolac 0.4%3
ACULAR LS®
Inactive ingredients
CMC, Na citrate
EDTA, octoxynol
EDTA, octoxynol
Preservative
No preservative
BAK (0.01%)
BAK (0.006%)
pH
6.8
7.4
7.4
CMC = carboxymethylcellulose;
BAK = benzalkonium chloride;
EDTA = ethylenediaminetetraacetic acid (sodium edetate).
3
Methods: Wound Healing Model
• 5 mm central epithelial wound made in
freshly isolated porcine cornea with a
trephine.
• After 24 hours, corneas were incubated
for 10 minutes in either:
– 50 µL Minimum Essential Medium (MEM)
(negative control)
– Triton X-100 (positive control)
– NSAID (ketorolac 0.45%, ketorolac 0.4%,
or ketorolac 0.5%)
• Corneas rinsed twice with 3 mL PBS, and
2 mL fresh MEM was added.
• Corneas allowed to heal for another 24
hours prior to staining with Richardson's
staining solutions.
• Remaining wound area was
photographed and the intensity of
staining was quantified using Adobe®
Photoshop® and expressed as area in
pixels.
4
Original Wound
Results: Ketorolac 0.45% Improved Wound Healing
Wound Healing Model (Porcine Eyes)
Ketorolac 0.45%–treated
corneas demonstrated
superior wound closure than
the MEM negative control
(no drug) (P < .05).
Control
MEM
Ketorolac
0.45%
Ketorolac 0.45%–treated
corneas showed greater
wound closure than the
Triton X-100 positive control
and prior ketorolac
formulations (Acular®, Acular
LS®) (P < .05).
Ketorolac
0.4%
Ketorolac
0.5%
5
Individual porcine corneas shown 48 hours after lesion
Results: Ketorolac 0.45% Improved Wound Healing
90,000
Quantification of Remaining Wound Area
48 hours
a
Area (Pixels)
80,000
70,000
60,000
bP
< .05 versus all other treatment groups.
50,000
40,000
30,000
20,000
10,000
0
n = 3-5 per group
aP
< .05 versus MEM control.
2,969
a,b
586
10,228
50,674
• Corneal wound area was significantly reduced in the ketorolac 0.45% group
compared to eyes that received no drug (P < .05).
• Wound area was also significantly reduced in the ketorolac 0.45% group compared
6 to previous formulations (P < .05).
Discussion
• Our results demonstrate that ketorolac 0.45% led to
more rapid wound healing than prior formulations of
ketorolac in an animal model.
 The addition of CMC to the active agent led to more rapid
wound healing than tissue culture medium alone.
 More rapid epithelial recovery was seen in ketorolac 0.45%treated corneas than those treated with ketorolac 0.4%.
 Additional studies are necessary to confirm that these results
translate to more rapid wound healing in a clinical setting.
• The speed in epithelial recovery may stem from both
the removal of BAK and the addition of CMC.
 CMC has been shown to promote epithelial cell migration and
re-epithelialization.6
7
Conclusions
• Ketorolac 0.45% exposure promoted corneal wound
healing in an animal model.
• Differences in wound healing may be due to the
presence of CMC and/or absence of BAK in
ketorolac 0.45%.
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References
1. ACUVAIL® [package insert]. Irvine, CA: Allergan, Inc.; 2009.
2. ACULAR® [package insert]. Irvine, CA: Allergan, Inc.; 1997.
3. ACULAR LS® [package insert]. Irvine, CA: Allergan, Inc.; 2003.
4. Waterbury LD, Silliman D, Jolas T. Comparison of cyclooxygenase
inhibitory activity and ocular anti-inflammatory effects of ketorolac
tromethamine and bromfenac sodium. Curr Med Res Opin.
2006;22(6):1133-1140.
5. Tomas-Barberan S, Fagerholm P. Influence of topical treatment on
epithelial wound healing and pain in the early postoperative period
following photorefractive keratectomy. Acta Ophthalmol Scand.
1999;77(2): 135-138.
6. Garrett Q, Simmons PA, Xu S, et al. Carboxymethylcellulose binds to
human corneal epithelial cells and is a modulator of corneal epithelial
wound healing. Invest Ophthalmol Vis Sci. 2007;48(4):1559-1567.
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Author Bio
Dr. McDermott graduated from the University of Wisconsin
Medical School with election to the medical honor society
Alpha Omega Alpha. He completed a residency in
Ophthalmology at the University of Wisconsin.
After receiving a training grant from the National Institutes of
Health; he completed a two year fellowship in Corneal
Surgery at the Medical College of Wisconsin. Dr. McDermott
is certified by the American Board of Ophthalmology. He is a
fellow of the American Academy of Ophthalmology.
For his efforts in education of practicing eye surgeons, Dr.
McDermott has been awarded an Honor Award by the
American Academy of Ophthalmology. He has published
over 90 papers, book chapters, and abstracts covering all
aspects of cataract and corneal surgery.
Dr. McDermott is a member of the American Society of
Cataract and Refractive Surgeons. He is a medical director
for the Midwest Eye Bank and Transplantation Center. He
holds a Masters in Business Administration from the
University of Michigan Ann Arbor and is an elected member
of the business honor society Beta Gamma Sigma.
Dr. McDermott’s research interests include endothelial
toxicology, endothelial response to phacoemulsification, and
viscoelastics.
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