U.S. patent application number 13/081161 was filed with the patent office on 2011-11-10 for ketorolac compositions for corneal wound healing.
This patent application is currently assigned to ALLERGAN, INC.. Invention is credited to Mayssa ATTAR, Chin-Ming CHANG, Eldon Q. FARNES, Richard S. GRAHAM, David A. HOLLANDER, Rhett M. SCHIFFMAN, Linda VILLANUEVA, Devin F. WELTY.
Application Number | 20110275688 13/081161 |
Document ID | / |
Family ID | 40852460 |
Filed Date | 2011-11-10 |
United States Patent
Application |
20110275688 |
Kind Code |
A1 |
HOLLANDER; David A. ; et
al. |
November 10, 2011 |
KETOROLAC COMPOSITIONS FOR CORNEAL WOUND HEALING
Abstract
The present invention is directed to an aqueous ophthalmic
solution comprising an effective amount of ketorolac which
comprises carboxymethyl cellulose which promotes epithelial wound
healing in a patient's cornea.
Inventors: |
HOLLANDER; David A.;
(Irvine, CA) ; VILLANUEVA; Linda; (Huntington
Beach, CA) ; FARNES; Eldon Q.; (Laguna Beach, CA)
; ATTAR; Mayssa; (Placentia, CA) ; SCHIFFMAN;
Rhett M.; (Laguna Beach, CA) ; CHANG; Chin-Ming;
(Tustin, CA) ; GRAHAM; Richard S.; (Irvine,
CA) ; WELTY; Devin F.; (Foothill Ranch, CA) |
Assignee: |
ALLERGAN, INC.
Irvine
CA
|
Family ID: |
40852460 |
Appl. No.: |
13/081161 |
Filed: |
April 6, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12953622 |
Nov 24, 2010 |
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13081161 |
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12396131 |
Mar 2, 2009 |
7842714 |
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12953622 |
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61322628 |
Apr 9, 2010 |
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61329992 |
Apr 30, 2010 |
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61353723 |
Jun 11, 2010 |
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61067925 |
Mar 3, 2008 |
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61096096 |
Sep 11, 2008 |
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61111919 |
Nov 6, 2008 |
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Current U.S.
Class: |
514/413 |
Current CPC
Class: |
A61K 9/0048 20130101;
A61P 29/00 20180101; A61K 31/407 20130101; A61K 47/02 20130101;
A61P 27/02 20180101; A61K 47/12 20130101; A61K 47/10 20130101; A61K
47/186 20130101; A61K 31/14 20130101; A61K 47/38 20130101 |
Class at
Publication: |
514/413 |
International
Class: |
A61K 31/407 20060101
A61K031/407; A61P 27/02 20060101 A61P027/02 |
Claims
1. A composition for use in promoting corneal wound healing
comprising an aqueous solution of 0.35-0.45% w/v ketorolac.
2. The composition of claim 1 wherein the aqueous solution is 0.45%
w/v ketorolac tromethamine.
3. The composition of claim 2 wherein the composition further
comprising carboxymethyl cellulose and wherein the composition
contains no preservative.
4. The topical aqueous ophthalmic solution of claim 2 wherein the
carboxymethyl cellulose is a combination of medium and high
viscosity carboxymethyl cellulose.
5. The topical aqueous ophthalmic solution of claim 4 having a pH
between 6.8 and 7.4.
6. The topical aqueous ophthalmic solution of claim 4 wherein the
concentration of carboxymethyl cellulose is from 0.2 to 2 percent
by weight.
7. The topical aqueous ophthalmic solution of claim 5 having a pH
of approximately 6.8.
8. The topical aqueous solution of claim 4 wherein the solution is
surfactant and chelator free.
9. The topical aqueous solution of claim 4 further comprising a
mixture of medium and high viscosity sodium carboxymethyl
cellulose, sodium chloride, sodium citrate dehydrate, sodium
hydroxide, hydrochloric acid and purified water.
10. The topical aqueous solution of claim 9 wherein the combination
of carboxymethyl cellulose and keterolac increases the absorption
in the eye of a patient more than a solution of keterolac
alone.
11. The topical aqueous solution of claim 1 wherein the keterolac
tromethamine is present as a racemic mixture of R-(+) and
S-(-)-ketorolac tromethamine.
12. The topical aqueous solution of claim 1 wherein the keterolac
tromethamine is present in a mixture of crystal forms.
13. The topical aqueous solution of claim 4 wherein the viscosity
is from 10 to 30 cps.
14. The topical aqueous solution of claim 6 wherein the
carboxymethylcellulose is present in the amount of 0.5% percent by
weight.
15. The topical aqueous solution of claim 4 wherein the solution
may be administered at least once a day before or after eye surgery
to promote healing of epithelial cell growth.
16. The topical aqueous solution of claim 4 wherein the solution
administered to the eye accelerates corneal wound healing of the
eye after surgery in comparison to keterolac solutions containing
no carboxymethyl cellulose.
17. A method of accelerating healing of corneal epithelial tissues
in a patient after surgery by administering a composition
comprising 0.45% w/v ketorolac and carboxymethyl cellulose.
18. The method of claim 17 wherein the composition is a topical
aqueous solution and wherein the topical aqueous solution is
instilled twice daily to the patient's eyes.
19. The method of claim 17 wherein the carboxymethyl cellulose is a
combination of medium and high viscosity carboxymethyl
cellulose.
20. The method of claim 17 further comprising a mixture of medium
and high viscosity sodium carboxymethyl cellulose, sodium chloride,
sodium citrate dehydrate, sodium hydroxide, hydrochloric acid and
purified water.
Description
RELATED APPLICATION
[0001] This application claims priority under 35 U.S.C. .sctn.120
to U.S. Provisional Patent Application No. 61/322,628 filed on Apr.
9, 2010, Provisional Patent Application No. 61/329,992 filed on
Apr. 30, 2010, and Provisional Patent Application No. 61/353,723
filed on Jun. 11, 2010. This application also claims the benefit of
U.S. patent application Ser. No. 12,953,622 filed on Nov. 24, 2010
which is a Continuation of U.S. patent application Ser. No.
12/396,131 filed on Mar. 2, 2009 which is now U.S. Pat. No.
7,842,714 issued on Nov. 30, 2010 pursuant to 35 USC 120 which
application claims the benefit of and priority to U.S. provisional
application Ser. Nos. 61/067,925 filed Mar. 3, 2008, 61/096,096
filed Sep. 11, 2008, and 61/111,919 filed Nov. 6, 2008 all of which
prior applications are incorporated herein by reference in their
entireties.
FIELD OF THE INVENTION
[0002] This invention relates to pharmaceutical compositions. More
particularly, this invention relates to topical ophthalmic
solutions comprising
5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid, otherwise
known as ketorolac, and the use of ketorolac for corneal wound
healing and corneal repair.
BACKGROUND OF THE RELATED ART
[0003] Nonsteroidal anti-inflammatory drugs (NSAIDS) have
anti-inflammatory, analgesic, and antipyretic properties. NSAIDS
primarily act as cycloxygenase (COX) inhibitors and limit the
production of endogenous prostaglandins (PGs) in the arachidonic
acid cascade. Topical NSAIDS are commonly used in ophthalmology to
control postoperative inflammation, reduce pain following
refractive surgery, inhibit intraoperative miosis, and treat
allergic conjunctivitis. Commercially available topical NSAIDS may
differ in the type and concentration of the active agent,
concentration of preservative, pH, and/or additional
surfactants.
[0004] Topical NSAIDS have been associated with corneal
complications which include superficial punctate keratopathy,
subepithelial infiltrates, epithelial defects, delayed epithelial
healing, corneal anesthesia, ulceration and perforation. While
corneal epithelial toxicity has been attributed to both the active
agents and the preservatives within topical formulations as well as
preexisting systemic conditions, keratitis, corneal ulceration and
perforation have all been reported in patients using
preservative-free formulations. Animal studies have suggested that
the corneal toxicity of topical NSAIDS may result from an
upregulation of matrix metalloproteinases (MMPs), and
endopeptidases involved in the remodeling of the corneal
extracellular matrix.
[0005] As topical NSAIDs are commonly used in the perioperative
setting, it is critical to develop formulations that do not inhibit
epithelial healing but in fact enhance epithelial wound healing.
Topical ketorolac, first introduced in 1993, remains the most
commonly used ophthalmic NSAID. Ophthalmic ketorolac 0.45% solution
(Acuvail.RTM., Allergan, Inc; Irvine, Calif.) was developed to
maintain the efficacy of prior formulations of ketorolac while
enhancing tolerability and reducing the dosing regimen. Changes in
the new formulation, ketorolac 0.45%, include the removal of the
preservative (BAK) and the surfactant (octoxynal 40) and the
addition of carboxymethyl cellulose (CMC) which prolongs drug
retention on the eye, protects the ocular surface, and may also
promote corneal re-epithelialization
SUMMARY OF THE INVENTION
[0006] The present invention provides an aqueous ophthalmic
formulation comprising an effective amount of ketorolac but having
an optimized concentration of keterolac in comparison other
commercially available keterolac products. The aqueous ophthalmic
solution of the present invention comprises carboxymethyl
cellulose, e.g. sodium carboxymethyl cellulose, having a pH within
the range of from about 6.8 to 7.4, which is comfortable when
topically applied to the eye of a patient, wherein the
concentration of carboxymethyl cellulose and, preferably, the pH,
is selected to provide an increased absorption of ketorolac in the
eye of a patient as compared to a comparative keterolac solution
that differs in whole or in part in not including the carboxymethyl
cellulose. That is, the absorption of keterolac may be 130% or
greater than the absorption of a comparative aqueous ketorolac
ophthalmic solution having the same or higher concentration of
ketorolac.
[0007] More preferably, the aqueous ophthalmic solution of this
invention has a pH within the range of from 6.8 to 7.4,
particularly 6.8.
[0008] More preferably, the aqueous ophthalmic solution of the
present invention has a concentration of carboxymethyl cellulose of
from about 0.1 to about 2 percent, by weight, even more preferably
from about 0.5 to 1.5 percent, by weight, and most preferably about
0.5% w/v.
[0009] Even more preferably, the aqueous ophthalmic solution of the
present invention comprises a mixture of medium viscosity and high
viscosity sodium carboxymethyl cellulose.
[0010] More preferably, the aqueous ophthalmic solution of the
invention comprises an effective amount of ketorolac of from 0.25
to 0.50 percent, by weight, or about 0.45 percent, by weight.
[0011] More preferably, the aqueous ophthalmic solution of the
invention has a viscosity of from 5 to 50 cps, preferably from 10
to 30 cps.
[0012] It has been surprisingly discovered that optimizing the
concentration of ketorolac tromethamine reduces the occurrence of
adverse events while maintaining clinical efficacy. Additionally,
it has been discovered that the optimized concentration of
ketorolac tromethamine in combination with carboxymethyl cellulose
offers surprising and clear benefits in terms of formulation in
that no preservative, chelating agent, and surfactant are required
for formulation. Thus, finding a way to increase the absorption of
ketorolac benefits the patient who can use a solution having an
optimized concentration of ketorolac and obtain similar results in
terms of efficiency as compared to a ketorolac solution having a
higher concentration of ketorolac.
[0013] Thus, this invention relates to an aqueous topical
ophthalmic composition comprising 0.25 to 0.50 percent by weight,
more preferably from 0.35% to 0.45% w/v and most preferably about
0.45% ketorolac tromethamine by weight/volume for corneal wound
healing. The present invention also contains from 0.2 to 2 percent
by weight/volume, more preferably from 0.5 to 1.5 percent by
weight/volume and most preferably about 0.5% w/v percent of
mixtures of medium and high molecular weight sodium carboxymethyl
cellulose. Another aspect of this invention relates to a method of
treating or preventing ocular pain in a person while promoting
epithelial wound healing before and/or following surgery or a
corneal wound comprising topically administering (qd, bid, tid,
qid) to a patient a sterile composition comprising from 0.25 to
0.50 percent, by weight/volume, more particularly from 0.35% to
0.45% by weight/volume, or about 0.45% w/v ketorolac tromethamine
in combination with from 0.2 to 2 percent, by weight/volume,
preferably from 0.5 to 1.5 percent by weight/volume, and most
preferably 0.5% percent by weight/volume, sodium carboxymethyl
cellulose and mixtures thereof.
[0014] While not intending to limit the scope of this invention in
any way, of particular interest in relationship to this invention
is the use of aqueous topical ophthalmic compositions of 0.45%
(w/v) ketorolac tromethamine for the treatment of ocular pain,
especially for the treatment of ocular pain in postoperative
photorefractive keratectomy (PRK) surgery patients and cataract
surgery patients which improves corneal wound healing. It is
surprising that the lower concentration of ketorolac as compared to
the Acular.RTM. product, discussed herein, would reduce the
incidence of adverse events and enhance comfort while maintaining
clinical efficacy. Two drops (0.1 mL) of 0.5% ketorolac
tromethamine ophthalmic solution instilled into the eyes of
patients 12 hours and 1 hour prior to cataract extraction achieved
measurable levels in 8 of 9 patients' eyes (mean ketorolac
concentration 95 ng/mL aqueous humor, range 40 to 170 ng/mL).
Ocular administration of ketorolac tromethamine reduces
prostaglandin E.sub.2 (PGE.sub.2) levels in aqueous humor. The mean
concentration of PGE.sub.2 was 80 pg/mL in the aqueous humor of
eyes receiving vehicle and 28 pg/mL in the eyes receiving 0.5%
ketorolac tromethamine ophthalmic solution.
[0015] Ocular administration of 0.45% w/v ketorolac tromethamine
ophthalmic solution increases relative bioavailability of ketorolac
in the aqueous humor of rabbits to greater than 200% and in the
iris-ciliary body to nearly 300%, compared with 0.5% ketorolac
tromethamine ophthalmic solution. This enhanced ketorolac
bioavailability allows for a reduction in dosing frequency from QID
with 0.5% ketorolac tromethamine ophthalmic solution to BID with
0.45% keterolac solution. Preclinical data indicate systemic
ketorolac exposure levels achieved following ocular administration
of 0.45% keterolac solution are comparable to levels achieved with
0.5% ketorolac tromethamine ophthalmic solution.
[0016] Some embodiments of the invention are as follows:
[0017] 1. A composition for use in promoting corneal wound healing
comprising an aqueous solution of 0.35-0.45% w/v ketorolac.
[0018] 2. The composition of paragraph 1 wherein the aqueous
solution is 0.45% w/v ketorolac tromethamine.
[0019] 3. The composition of paragraph 2 wherein the composition
further comprising carboxymethyl cellulose and wherein the
composition contains no preservative.
[0020] 4. The topical aqueous ophthalmic solution of paragraphs 2
and 3 wherein the carboxymethyl cellulose is a combination of
medium and high viscosity carboxymethyl cellulose.
[0021] 5. The topical aqueous ophthalmic solution of paragraph 4
having a pH between 6.8 and 7.4.
[0022] 6. The topical aqueous ophthalmic solution of paragraphs 4
and 5 wherein the concentration of carboxymethylcellulose is from
0.2 to 2 percent by weight.
[0023] 7. The topical aqueous ophthalmic solution of paragraph 5
having a pH of approximately 6.8.
[0024] 8. The topical aqueous solution of paragraphs 1, 2, 3, 4, 5,
6 and 7 wherein the solution is surfactant, preservative and
chelator free.
[0025] 9. The topical aqueous solution of paragraphs 4, 7 and 8
further comprising a mixture of medium and high viscosity sodium
carboxymethyl cellulose, sodium chloride, sodium citrate dehydrate,
sodium hydroxide, hydrochloric acid and purified water.
[0026] 10) The topical aqueous solution of paragraph 9 wherein the
combination of carboxymethyl cellulose and keterolac increases the
absorption of ketorolac in the eye of a patient more than a
solution of keterolac alone without carboxymethyl cellulose.
[0027] 11) The topical aqueous solution of paragraphs 1, 2, 3, 4,
5, 8, 9 and 10 wherein the keterolac tromethamine is present as a
racemic mixture of R-(+) and S-(-)-ketorolac tromethamine.
[0028] 12) The topical aqueous solution of paragraphs 1, 2, 3, 4,
5, 8, 9, 10 and 11 wherein the keterolac tromethamine is present in
a mixture of crystal forms.
[0029] 13) The topical aqueous solution of paragraph 4 wherein the
viscosity is from 10 to 30 cps.
[0030] 14) The topical aqueous solution of paragraphs 3, 4, 6 and 8
wherein the carboxymethylcellulose is present in the amount of 0.5%
percent by weight.
[0031] 15) The topical aqueous solution of paragraphs 4 and 9
wherein the solution may be administered at least once a day before
or after eye surgery to promote healing of epithelial cell growth
of the cornea.
[0032] 16) The topical aqueous solution of paragraph 1, 2, 3, 4, 9,
10 and 13 wherein administration of the solution to the eye
accelerates corneal wound healing of the eye after surgery to a
greater degree than keterolac solutions containing no carboxymethyl
cellulose.
[0033] 17) A method of accelerating the healing of corneal
epithelial tissues in a patient after eye surgery by administering
a composition comprising 0.45% w/v ketorolac and carboxymethyl
cellulose wherein the healing of corneal epithelial tissues in the
patient progresses more rapidly than it would without
administration of a ketorolac and carboxymethyl cellulose
composition.
[0034] 18) The method of paragraph 17 wherein the composition is a
topical aqueous solution and wherein the topical aqueous solution
is instilled at least twice daily to the patient's eyes.
[0035] 19) The method of paragraph 17 wherein the carboxymethyl
cellulose is a combination of medium and high viscosity
carboxymethyl cellulose.
[0036] 20) The method of paragraph 17 wherein the eye surgery is
selected from the group consisting of laser eye surgery, cataract
surgery, glaucoma surgery, refractive surgery, corneal surgery,
vitreoretinal surgery, eye muscle surgery, oculoplastic surgery,
surgery involving the lacrimal apparatus, and photorefractive
surgery.
[0037] 20) The method of paragraph 17 further comprising a mixture
of medium and high viscosity sodium carboxymethyl cellulose, sodium
chloride, sodium citrate dehydrate, sodium hydroxide, hydrochloric
acid and purified water.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] FIG. 1 shows the ocular pharmacokinetics of the results in
Example 7 of the increased and prolonged keterolac exposure in the
aqueous humor of the 0.45% w/v keterolac solution in comparison to
ACULAR LS.RTM.;
[0039] FIG. 2 shows the results of FIG. 1 in table form of Cmax,
AUC and percent relative bioavailability of the ocular
pharmacokinetics in Example 7 of the aqueous humor relative
bioavailability of 0.45% w/v keterolac solution in comparison to
ACULAR LS.RTM.;
[0040] FIG. 3 shows the ocular pharmacokinetics of the results in
Example 7 of the increased and prolonged keterolac exposure in the
iris-ciliary body of 0.45% w/v keterolac solution in comparison to
ACULAR LS.RTM.;
[0041] FIG. 4 shows the results of FIG. 3 in table form of Cmax,
AUC and percent relative bioavailability of the increased and
prolonged exposure in the iris ciliary body of 0.45% w/v keterolac
solution in comparison to ACULAR LS.RTM.;
[0042] FIG. 5 shows a multiple dose simulation of Example 7 of
0.45% keterolac BID in comparison to ACULAR LS.RTM. QID in the iris
ciliary body;
[0043] FIG. 6 shows safety and tolerability results in human
clinical trials of 0.45% w/v keterolac solution vs. ACULAR LS;
[0044] FIG. 7 shows representative images of corneas with original
wound and those following treatment with Triton X-100 1%;
[0045] FIG. 8 shows representative images of corneas treated with
ketorolac 0.5%, 0.4%, and 0.45% (a) and corresponding intensity of
the wound area staining (b) are shown; and
[0046] FIG. 9 shows remaining epithelial wound area in corneas
treated with nepafenac 0.1%, Bromfenac 0.09%, and Ketorolac
0.45%.
DETAILED DESCRIPTION OF THE INVENTION
[0047] During the reformulation of Allergan's marketed Acular
LS.RTM. product (0.40% w/v keterolac) it was surprisingly found
that a test formulation containing 0.45% ketorolac tromethamine and
sodium carboxymethylcellulose (NaCMC) exhibited significantly
better ocular absorption in rabbits than did the currently marketed
product, i.e. Acular LS.RTM.. It has also been surprisingly
discovered that certain formulations of ketorolac aid in corneal
epithelial wound healing.
[0048] Since the viscosities of the two test solutions were
virtually identical, the mechanism for achieving increased ocular
penetration compared to the control formulation cannot be accounted
for only by the viscosity of the test solutions. In fact, a
comparison of two identical carboxymethyl cellulose-containing
solutions which differ only in having viscosity of 11 and 22 cps
shows similar absorption of ketorolac into the aqueous humor. While
not wishing to be bound by theory, it is believed that there is a
functional relationship between the sodium carboxymethyl cellulose
and either the ketorolac or some component of the ocular surface
that facilitates absorption of ketorolac.
[0049] All of the aqueous topical ophthalmic solutions of this
invention are contemplated for use in treating or preventing ocular
pain. Preferably, all of the solutions of this invention are
contemplated for use when said ocular pain is a result of
photorefractive keratectomy surgery (PRK) or cataract surgery.
[0050] One important aspect of this invention is that the solutions
of the present invention have a concentration of ketorolac
tromethamine which is optimized to reduce side effects, while
maintaining clinical efficacy in treating ocular pain. As such, the
concentration of ketorolac tromethamine in compositions related to
this invention is preferably from 0.35% to 0.45%, most preferably
the concentration of ketorolac tromethamine in the aqueous topical
ophthalmic solution of this invention is 0.45% ketorolac
tromethamine, by weight/volume.
[0051] Carboxymethyl cellulose (CMC) is a carboxymethyl derivative
of cellulose formed by the reaction of cellulose with alkali and
chloroacetic acid. As a result of said reaction, carboxymethyl
groups are bound to some of the hydroxyl groups of the
glucopyranose units that make up the backbone of cellulose. The
degree of substitution of carboxymethyl varies from about 0.6 to
0.95 per glucopyranose unit. CMC is used in aqueous solutions
usually as the sodium salt to increase viscosity.
[0052] Carboxymethyl cellulose is available in various molecular
weights. Low molecular weight carboxymethyl cellulose has an
average Mw of about 90,000 and a 2% solution thereof will have a
viscosity of about 1.1 cP at 25.degree. C. Medium weight
carboxymethyl cellulose has an average Mw of about 250,000. High
molecular weight carboxymethylcellulose has an average Mw of about
700,000 and a 2% solution will have a viscosity of about 12 cP at
25.degree. C.
[0053] For the purpose of the present invention, it is desirable to
use a mixture of medium and high molecular weight sodium
carboxymethyl cellulose. For example, from 25/75 to 75/25
carboxymethyl cellulose, preferably from 30/70 to 70/30 and most
preferably about 35/65 medium/high molecular weight sodium
carboxymethyl cellulose.
[0054] The fact that the concentration of ketorolac tromethamine in
compositions related to this invention achieves greater or equal
absorption of ketorolac into the aqueous humor of the eye and
includes carboxymethyl cellulose, allows the solutions of the
present invention to be prepared with no preservative, surfactant
and chelating agent. This is a significant advantage over prior art
keterolac formulations as preservatives, surfactants and chelating
agents can cause irritation to the eye resulting in less patient
compliance and less effectiveness of prior art keterolac
formulations.
[0055] The term preservative has the meaning commonly understood in
the ophthalmic art. Preservatives are used to prevent bacterial
contamination in multiple-use ophthalmic preparations, and, while
not intending to be limiting, examples include benzalkonium
chloride, stabilized oxychloro complexes (otherwise known as
Purite.RTM.), phenylmercuric acetate, chlorobutanol, benzyl
alcohol, parabens, and thimerosal. Preferably, the keterolac
solution of the present invention is preservative free.
[0056] The term surfactant used in this invention has the meaning
commonly understood in the art. Surfactants are used to help
solubilize the therapeutically active agent or other insoluble
components of the composition. Anionic, cationic, amphoteric,
zwitterionic, and nonionic surfactants may all be used in this
invention. If a surfactant is included in the solutions of this
invention, preferably, a nonionic surfactant is used. While not
intending to limit the scope of the invention, some examples of
useful nonionic surfactants are polysorbates, poloxamers, alcohol
ethoxylates, ethylene glycol-propylene glycol block copolymers,
fatty acid amides, and alkylphenol ethoxylates, and phospholipids.
Most preferably, the surfactant is an octylphenol ethoxylate with
an average of 40 ethoxylate groups. This type of surfactant, also
known as octoxynol-40 or Igepal CA-897.RTM., can be purchased under
the Igepal CA-897.RTM. tradename from Rhone-Poulenc. Preferably,
the keterolac solution of the present invention is surfactant
free.
[0057] The term chelating agent refers to a compound that is
capable of complexing a metal, as understood by those of ordinary
skill in the chemical art. Chelating agents are used in ophthalmic
compositions to enhance preservative effectiveness. While not
intending to be limiting, some useful chelating agents for the
purposes of this invention are edetate salts like edetate disodium,
edetate calcium disodium, edetate sodium, edetate trisodium, and
edetate dipotassium. Preferably, the keterolac solution of the
present invention is chelator free.
[0058] In addition to surfactants, preservatives, and chelating
agents, tonicity agents and other excipients are often used in
ophthalmic compositions. Tonicity agents are often used in
ophthalmic compositions to adjust the concentration of dissolved
material to the desired isotonic range. Tonicity agents are known
to those skilled in the ophthalmic art, and, while not intending to
be limiting, some examples include glycerin, mannitol, sorbitol,
sodium chloride, and other electrolytes. Preferably, the tonicity
agent is sodium chloride.
[0059] One preferred embodiment of this invention relates to an
aqueous topical ophthalmic composition comprising 0.4% ketorolac
tromethamine, from 0.2 to 2.0%, by weight/volume, sodium
carboxymethyl cellulose.
[0060] The most preferred embodiment of this invention relates to
an aqueous topical ophthalmic composition consisting of 0.45% (w/v)
of ketorolac tromethamine, 0.5% w/v of carboxymethylcellulose
sodium, e.g. a mixture of medium and high viscosity sodium
carboxymethyl cellulose, sodium chloride, sodium citrate dehydrate,
sodium hydroxide, hydrochloric acid and purified water.
Example 1
[0061] Unless otherwise specified, all steps in this procedure were
carried out at room temperature. The following procedure was
followed in accordance with the amounts listed in Table 1 below.
Purified water was charged into the main batch vessel. Mixing was
initiated to produce a vortex sufficient to disperse and/or
dissolve all product ingredients without excessive aeration or foam
formation. The following components were added directly into the
vortex in order, allowing each to dissolve before adding the next:
sodium chloride, calcium chloride, dihydrate magnesium chloride,
hexahydrate, boric acid, sodium borate, sodium carboxymethyl
cellulose as a an percent aqueous solution comprising including a
mixture of 65% medium molecular weight and 35% high molecular
weight carboxymethyl cellulose. The solution was mixed for no
longer than 15 minutes. A specified amount of 1N sodium hydroxide,
was then added. The pH was checked and, if needed, was adjusted to
7.3 with 1N sodium hydroxide or 1N hydrochloric acid. Ketorolac
tromethamine was then added based on "as is" assay and mixed until
completely dissolved based on visual inspection. When dissolved,
the solution pH was again checked and if needed adjusted to pH
7.3-7.5 (final target pH is 7.4) with 1N sodium hydroxide or 1N
hydrochloric acid. Purified water was then added to bring the bulk
solution to final volume and allowed to mix for at least 15 minutes
to ensure uniformity. The solution was then sterile filtered for
use.
TABLE-US-00001 TABLE 1 0.4% Ketorolac Tromethamine Ophthalmic
Solution of the Invention Keterolac Tromethamine 0.4% CMC, Med
Visc. 0.65% CMC Low Visc. 0.35% Potassium chloride 0.14% Calcium
chloride, dihydrate 0.060% Magnesium chloride, hexahydrate 0.060%
Boric acid .060% Sodium borate .1225%
Example 2
[0062] Unless otherwise specified, all steps in this procedure were
carried out at room temperature. The following procedure was
followed in accordance with the amounts listed in Table 2 below.
Purified water at 90% of batch size was charged into the main batch
vessel. Mixing was initiated to produce a vortex sufficient to
disperse and/or dissolve all product ingredients without excessive
aeration or foam formation. The following components were added
directly into the vortex in order, allowing each to dissolve before
adding the next: sodium chloride, edetate disodium, octoxynol-40
(as a 70% stock solution) and benzalkoniurn chloride (as a 10%
stock solution). The amount of benzalkonium chloride added took
into account the assay of the stock solution used. The solution was
mixed for no longer than 15 minutes. A specified amount of 1N
sodium hydroxide, 1.85 mL per liter of final bulk product, was then
added. The pH was checked and if needed was adjusted to 10.7-11.0
with 1N sodium hydroxide or 1N hydrochloric acid. Ketorolac
tromethamine was then added based on "as is" assay and mixed until
completely dissolved based on visual inspection. When dissolved,
the solution pH was again checked and if needed adjusted to pH
7.3-7.5 (final target pH is 7.4) with 1N sodium hydroxide or 1N
hydrochloric acid. Purified water was then added to bring the bulk
solution to final volume and allowed to mix for at least 15 minutes
to ensure uniformity. The solution was then sterile filtered for
use.
TABLE-US-00002 TABLE 2 0.4% Ketorolac Tromethamine Ophthalmic
Solution (Comparative) Ketorolac Tromethamine 0.4% Edetate Disodium
0.015% NaCl 0.79% Benzalkonium Chloride 0.006% Octoxynol-40 0.003%
Ph 7.4
Example 3
[0063] This example was prepared according to the procedure of
Example 1, except that hydroxypropyl cellulose was used in place of
the sodium carboxymethyl cellulose in an amount sufficient to
provide a viscosity equivalent to the viscosity of the composition
of Example 1.
Example 4
[0064] The following composition was manufactured on a volume basis
at ambient temperates from two principal parts. Each part is
manufactured separately and then combined under controlled
sequences to form a sterile bulk product: the first part (Part 1)
involves the dissolution of carboxymethylcellulose sodium in water
followed by bulk heat sterilization, and the second part (Part 2)
involves dissolution of keterolac tromethamine and salts in water
sterile filtration throng a 0.2 micron membrane into a sterile
pressure vessel. The sterile bulk solution is then clarity filtered
through a 20 micron polypropylene membrane filter into the filling
machine reservoir.
[0065] The sterile post-clarity filtered solution is then filled by
a UD filling machine via blow-fill-seal process into UD vials using
virgin LDPE resin without colorant. The filling is done in an ISO
Class 5 environment. The nominal fill is 0.4 mL into 0.9 mL
capacity vials.
TABLE-US-00003 TABLE 3 0.45% w/v Keterolac Tromethamine Ophthalmic
Solution Concentration Ingredient Function (% w/v) Keterolac
tromethamine Active 0.45% Carboxymethycellulose Thickening Agent
0.325% Sodium (Med. Viscosity) Carboxymethycellulose Thickening
Agent 0.175% Sodium (High Viscosity) NaCl Tonicity Agent 0.7%
Sodium Citrate Buffer 0.2% Dihydrate Sodium Hydroxide (1N) pH
adjustment Adjust to pH 6.8 Hydrochloric Acid (1N) pH adjustment
Adjust to pH 6.8 Purified Water Vehicle Q.S.
Example 5
[0066] Comparison of Aqueous Humor Ketorolac Pharmacokinetics
Following a Single Ocular Instillation of 0.45% Ketorolac
Tromethamine Formulations with Varying pH to Acular LS.RTM. in New
Zealand White Rabbits.
[0067] Study Objectives:
1) To compare aqueous humor ketorolac pharmacokinetics following a
single ocular instillation of 0.45% ketorolac tromethamine
formulations with varying pH and Acular LS.RTM. to New Zealand
White rabbits; 2) This Example was designed to determine whether
decreasing the pH of the composition would increase the absorption
of ketorolac into the eye; and, 3) In addition, one arm of this
trial was designed to test the effect of decreasing viscosity of
the composition from 22 cps to 11 cps.
[0068] The specifics of this study are as follows:
Rabbit Aqueous Humor Ketorolac Concentrations Following
Administration of Three 0.45% Ketorolac Tromethamine Formulations
and Acular LS
TABLE-US-00004 [0069] TABLE 4 Treatment Groups 0.45% Ketorolac
Tromethamine 22 cps pH = 7.4 0.45% Ketorolac Tromethamine 22 cps pH
= 7.2 0.45% Ketorolac Tromethamine 22 cps pH = 7.0 0.45% Ketorolac
Tromethamine 11 cps pH = 7.0 0.45% Ketorolac Tromethamine 22 cps pH
= 6.8 Acular LS pH = 7.4 Dosing Route: Topical ocular Animal
Gender: NZW Rabbits/Female Dosing Regimen Single dose, bilateral
Timepoints: 1, 2 and 4 hrs post-dose # Rabbits: 3 rabbits/timepoint
+ 1 rabbit blank Total = 39 rabbits Tissues/Matrices: Aqueous Humor
Bioanalysis: LC-MS/MS Data analysis: AUC.sub.0-t, C.sub.max
[0070] The results of the study are reported in Table 5, below.
TABLE-US-00005 TABLE 5 PK Parameters AUC.sub.0-4 .+-. SE C.sub.max
.+-. SD Formulation (ng h/ml) (ng/ml) Relative % F* 0.45% CMC 22
cps 627 .+-. 51 265 .+-. 71 135 pH 7.4 w.o "outlier" 0.45% CMC 22
cps 713 .+-. 96 322 .+-. 153 153 pH 7.4 0.45% CMC 22 cps 620 .+-.
50 240 .+-. 84 133 pH 7.2 0.45% CMC 22 cps 658 .+-. 73 268 .+-. 125
142 pH 7.0 0.45% CMC 22 cps 939 .+-. 163 389 .+-. 258 202 pH 6.8
0.45% CMC 11 cps 649 .+-. 74 347 .+-. 218 139 pH 7.0 Acular LS
.RTM. 465 .+-. 65 211 .+-. 106 100
Summary of the Results
[0071] The sodium carboxymethyl cellulose-containing formulations
perform better than Acular LS.RTM. with a relative bioavailability
ranging from 133% (0.45% Keto 22 cps pH 7.2) to 202% (0.45% Keto 22
cps pH 6.8). However, there is not a clear pH effect-because the
0.45% Keto 22 cps pH 7.4 has a relative bioavailability of 153%,
although one anomalous result may be driving this observation.
Nevertheless, the solution having a pH of 6.8 shows the best
bioavailability.
Example 6
[0072] A multicenter, randomized, double-masked, parallel-group
study is carried out using the 0.4% ketorolac tromethamine
formulations of Examples 2 and 3. The study subjects consisted of
157 patients (78-79/group) undergoing unilateral PRK surgery. The
key inclusion criteria for the study is that each subject a) is a
candidate for unilateral photorefractive keratectomy surgery (PRK)
within 7 days after the initial visit, b) have best-corrected ETDRS
visual acuity of 20/100 or better, and c) is capable of wearing a
soft bandage contact lens. Key exclusion criteria are a history of
refractive ocular surgery and sensitivity to study medication or
its vehicle, Tylenol #3.RTM., or Ocuflox.RTM.. The patient
demographics are shown in Table 6. A total of 157 patients are
enrolled with an age range of 20-66 years. There are no significant
demographic differences between treatment groups.
TABLE-US-00006 TABLE 6 Patient Demographics n % Gender Female 91 58
Male 66 42 Age, mean .+-. SD 39 .+-. 10 Race Caucasian 148 94 Black
5 3 Hispanic 2 1 Asian 1 1 Other 1 1
[0073] Each subject receives the Ocuflox.RTM. 5 min prior to study
medication. The study subjects then receive ketorolac tromethamine
0.4% ophthalmic solution of Example 2 or Example 3, 1 drop QID for
up to 4 days. Then all subjects are then instructed to take Tylenol
#3.RTM. as needed for intolerable pain (escape medication).
Patients use electronic diaries with date and time stamp to record
the ocular pain they experience as one of the following: no pain,
mild, moderate, severe, intolerable.
[0074] The pain intensity is less for the subjects who receive the
solution of Example 2 during the first 12 hours post-PRK compared
to those who receive the solution of Example 3. In particular,
during the first 12 hours post-PRK, the group that receive the
solution of Example 2 had fewer patients with severe or intolerable
pain compared with the receive the solution of Example 3. In
particular, the median pain intensity reported by the group which
receive the solution of Example 2 was 1 grade less than with the
group which receive the solution of Example 3 (moderate vs. severe
on a 5-point scale of 0=no pain to 4=intolerable pain).
Additionally, pain intensity is also less for the group which
receive compared with the group which receive the solution of
Example 3.
[0075] This clinical study shows that the solution of invention
provides a greater degree of absorption of ketorolac as compared to
the solution without sodium carboxymethylcellulose despite the fact
that the solutions have the same concentration of ketorolac and are
at the same viscosity.
[0076] In summary, the 0.4% ketorolac formulation is clinically
effective in treating post PRK ocular pain. In patients treated
with 0.4 ketorolac tromethamine--the patients treated with the
solution comprising sodium carboxymethyl cellulose experienced
significantly greater and faster pain relief, and used less escape
medication compared to the patients treated with the solution
comprising hydroxypropylcellulose.
Example 7
[0077] Rabbit Ocular Pharmacokinetic Evaluation of Keterolac
Tromethamine 0.45%
NZW Rabbits/Female
[0078] Dosing Regimen: Single ocular dose, bilateral Timepoints:
0.5, 1, 2, 4, 8, 10 and 24 hrs post-dose Tissues/Matrices: Aqueous
Humor and Iris-ciliary body
Bioanalysis: LC-MS/MS
[0079] Data Analysis: Pharmacokinetic analyses and simulation
Conclusions
[0080] 1) Increase in relative bioavailability of keterolac as
compared to Acular LS.RTM.; 2) Increased ketorolac concentrations
are maintained longer post-dose; and 3) Together these data support
a reduction in dosing frequency from 4.times./day to
2.times./day.
TABLE-US-00007 TABLE 12 Safety and Tolerability Results Ketorolac
ACULAR LS Variable 0.45% 0.40% Ocular AEs-Irritation 10.0% (2/20)
15.4% (6/39) Symptoms-Burning/stinging 10.0% (2/20) 12.8% (5/39)
(.gtoreq.1 grade increase) Bulbar hyperemia 10.0% (2/20) 23.1%
(9/39) (.gtoreq.trace) Ocular comfort 90-100% 84-100%
(.gtoreq.comfortable)
Conclusions
[0081] Acular 0.45% is safe and well-tolerated when given 5 times
over a half-day and compares very favorably to ACULAR LS. The
present invention is not to be limited in scope by the exemplified
embodiments, which are only intended as illustrations of specific
aspects of the invention. Various modifications of the invention,
in addition to those disclosed herein, will be apparent to those
skilled in the art by a careful reading of the specification,
including the claims, as originally filed. It is intended that all
such modifications will fall within the scope of the appended
claims.
Example 8
Corneal Wound Healing
[0082] Studies have reported that the corneal toxicity of topical
NSAIDS may result from an upregulation of matrix metalloproteinases
(MMPs), endopeptidases involved in the remodeling of the corneal
extracellular matrix. The addition of topical ketorolac, as well as
several other topical NSAIDS, has been shown in animal models to
stimulate the production of MMP-1 (collagenase), MMP-2
(gelatinase), and MMP-8 (collagenase) in both intact and epithelial
debrided corneas. As topical NSAIDs are commonly used in the
perioperative setting, it is critical to develop formulations that
do not inhibit epithelial healing.
[0083] Ophthalmic bromfenac 0.09% (Xibrom.RTM.; ISTA
Pharmaceuticals, Irvine, Calif.).sup.6 and nepafenac 0.01%
(Nevanac.RTM.; Alcon Laboratories, Inc., Fort Worth, Tex.).sup.7
are other preserved topical NSAIDs. It was 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 and compared to bromfenac
and nepafenac. This hypothesis was tested using a porcine-derived,
corneal organ culture model.
[0084] A porcine corneal model of wound healing was developed which
has previously been used to assess the role of growth factors in
corneal reepithelialization. Given the changes in the formulation
of ketorolac, the present study was designed to compare the impact
on wound healing of the new formulation of ketorolac 0.45% to prior
generations of ketorolac (0.4% and 0.5%) as well as to bromfenac
0.09% and nepafenac 0.1%.
TABLE-US-00008 Ophthalmic Study Drug Formulations Active Ketorolac
Ketorolac Ketorolac Napafenac Ingredient 0.45%.sup.3 0.5%.sup.4
0.4%.sup.5 Bromfenac0.09%.sup.6 0.1%.sup.7 Brand Name Acuvail
Acular Acular LS Xibrom Nevanac Inactive CMC, Na EDTA, EDTA, EDTA,
boric acid, EDTA, ingredients citrate octoxynol octoxynol Na
borate, Na mannitol, sulfite, povidone, carbomer polysorbate 80
947P, NaCl, tyloxapol Preservative No BAK BAK BAK (0.005%) BAK
preservative (0.01%) (0.006%) (0.005%) pH 6.8 7.4 7.4 8.3 7.4 CMC =
carboxymethylcellulose. BAK = benzalkonium chloride. EDTA =
ethylenediaminetetraacetic acid (sodium edetate).
[0085] In this Example, epithelial debrided porcine corneas were
exposed to different formulations of the ketorolac molecule, namely
ketorolac 0.45% (Acuvail.RTM., Allergan, Inc), ketorolac 0.4%
(Acular LS.RTM.; Allergan, Inc.) and ketorolac 0.5% (Acular.RTM.,
Allergan, Inc). In brief, porcine eyes were obtained from a local
abattoir, transported to the laboratory on ice in a moist chamber,
and processed for corneal culture on the same day. An epithelial
wound was made by demarcating an area on the central cornea with a
5-mm trephine and then removing the epithelium within the circle
with a small scalpel, leaving an intact basement membrane.
Corneal-scleral rims, with approximately 4 mm of the limbal
conjunctiva present, were excised and rinsed in sterilized
phosphate-buffered saline. The excised corneas were placed
epithelial-side down into a sterile cup.
[0086] The endothelial corneal concavity was then filled with
Minimum Essential Medium (MEM) containing 1% agarose and 1 mg/ml
rat tail tendon collagen maintained at 42.degree. C. This mixture
was allowed to gel. The cornea, along with its supporting gel, was
inverted (endothelial side down) and then transferred to a 35-mm
dish. The culture medium (.about.2 ml) was added drop-wise to the
surface of central cornea until the limbal conjunctiva was covered,
leaving the epithelium exposed to the air. The corneas were then
cultured in a humidified 5% CO.sub.2 incubator at 37.degree. C. in
MEM for 24 hours to ensure initial wound recovery. The basic steps
were carried out as follows: [0087] 5 mm central epithelial wound
made in freshly isolated porcine cornea with a trephine. [0088]
After 24 hours, corneas were incubated for 10 minutes in either:
[0089] 50 .mu.L Minimum Essential Medium (MEM) (negative control)
[0090] Triton X-100 (positive control) [0091] NSAID (ketorolac
0.45%, ketorolac 0.4%, or ketorolac 0.5%) [0092] Corneas rinsed
twice with 3 mL PBS, and 2 mL fresh MEM was added. [0093] Corneas
allowed to heal for another 24 hours prior to staining with
Richardson's staining solutions. [0094] Remaining wound area was
photographed and the intensity of staining was quantified using
Adobe.RTM. Photoshop.RTM. and expressed as area in pixels.
[0095] After 24 hours, a 50-.mu.L volume of MEM, Triton X-100 (1%;
Dow Chemical Company, Midland, Mich.), or study drugs (ketorolac
0.45%, ketorolac 0.4%, ketorolac 0.5%, nepafanc 0.01%, or bromfenac
0.09%) was applied to the epithelial wound surface for 10 minutes.
MEM alone was used as a negative control, and Triton X-100 was used
as a positive control. Corneas were rinsed twice with 3 mL of
phosphate-buffered saline and incubated in 2 mL of fresh MEM for an
additional 24 hours prior to staining. The remaining wound area was
then stained with Richardson staining solution and
photographed..sup.20 The staining area was quantified (in pixels)
using Adobe Photoshop.RTM. (Adobe Systems, Inc., San Jose, Calif.)
as previously described. A total of five corneas was used in each
treatment group.
[0096] Data were presented as the mean of remaining wound
area.+-.standard deviation (SD). One way analysis of variance
(ANOVA) with a Newman-Keuls posttest was used for statistical
comparison among groups. A P-value of <0.05 was considered
statistically significant.
[0097] The mean (SD) original wound area induced by the 5 mm
trephine was 200,506.+-.4,363 pixels. At 48 hours, corneas treated
with Triton X-100 1% had a mean (SD) remaining wound area of
59,509.+-.4,850 pixels (FIG. 7). The mean (SD) remaining wound
areas at 48 hours following treatment with MEM control, ketorolac
0.45%, ketorolac 0.4%, and ketorolac 0.5% were 2,969.+-.1633
pixels, 586.+-.299 pixels, 10,228.+-.7,541 pixels, and
50,674.+-.33,409 pixels, respectively (FIG. 8). Corneas treated
with ketorolac 0.45% had a significantly smaller mean remaining
wound area than did corneas treated with MEM control, ketorolac
0.4%, and ketorolac 0.5% (P<0.05). In contrast, the mean
remaining wound area of corneas treated with ketorolac 0.5% was not
statistically different than those treated with Triton X-100
1%.
[0098] The results as shown in FIGS. 7 and 8 demonstrate that
ketorolac 0.45%-treated corneas demonstrated superior wound closure
than the MEM negative control (no drug) (P<0.05). Ketorolac
0.45%-treated corneas showed greater wound closure than the Triton
X-100 positive control and prior ketorolac formulations
(Acular.RTM., Acular LS.RTM.) (P<0.05).
[0099] FIG. 8 shows corneal wound area was significantly reduced in
the ketorolac 0.45% group compared to eyes that received no drug
(P<0.05).
Wound area was also significantly reduced in the ketorolac 0.45%
group compared to previous formulations (P<0.05).
Example 9
Corneal Wound Healing
[0100] In this example, two parallel-group comparison studies were
performed in series to evaluate epithelial wound closure in ex vivo
porcine corneas treated with unpreserved ketorolac 0.45% compared
with preserved ketorolac 0.4% and ketorolac 0.5% and ketorolac
0.45% compared with bromfenac 0.09% and nepafenac 0.1%. The basic
steps were carried out as follows: [0101] A 5-mm central epithelial
wound was made by demarcating an area on freshly isolated central
porcine corneas with a trephine (n=3-5 per group). [0102] Corneas
were incubated in Minimum Essential Medium (MEM) in an air-lifted
format for 24 hours to ensure initial wound recovery. [0103] A
50-.mu.L volume of MEM, Triton.TM. X-100 detergent, or study drug
was applied to the epithelial wound surface for 10 minutes. MEM
alone was used as a negative control, and Triton X-100 was used as
a positive control. [0104] Corneas were rinsed twice with 3 mL
phosphate-buffered saline (PBS) and incubated in 2 mL of fresh MEM
for an additional 24 hours prior to staining. [0105] The remaining
wound area was then stained with Richardson staining solution and
photographed. [0106] The intensity of the staining was quantified
using Adobe Photoshop.RTM. (Adobe Systems, Inc.; San Jose, Calif.)
and expressed as area in pixels.
[0107] The results demonstrate that ketorolac 0.45% leads to more
rapid wound healing than prior formulations of ketorolac and both
bromfenac and nepafenac in an animal model. Ketorolac 0.45%-treated
corneas had similar or significantly greater wound closure than the
MEM negative control (no drug). In this model, the enhanced wound
closure in corneas exposed to ketorolac 0.45% compared to other
agents may be attributed to the addition of carboxymethyl cellulose
("CMC") and the absence of BAK in its formulation. CMC is a
commonly used viscosity-enhancing agent. In cell culture, CMC
increases epithelial cell migration and cell proliferation.
[0108] In Example 9, corneas treated with MEM control, ketorolac
0.45%, bromfenac 0.09%, and nepafenac 0.1% had mean (SD) remaining
wound areas at 48 hours of 565.+-.1,263 pixels, 322.+-.229 pixels,
29,093.+-.14,295 pixels, and 47,322.+-.13,736 pixels, respectively
(FIG. 9). The remaining wound areas were significantly smaller in
corneas treated with ketorolac 0.45% as compared to those treated
with bromfenac 0.09% or nepafenac 0.1% (P<0.01). Corneas treated
with nepafenac 0.1% had a significantly larger mean remaining wound
area than those treated with bromfenac 0.09% (P<0.01). The mean
remaining wound area of corneas treated with nepafenac 0.1% was not
statistically different from that of corneas treated with Triton
X-100 1%.
[0109] As shown in FIG. 9, the mean remaining wound area was
significantly reduced in corneas exposed to ketorolac 0.45%
compared with corneas exposed to bromfenac, nepafenac, or Triton
X-100 (P<0.01). Compared to the MEM control (no drug), the
remaining wound area in bromfenac-, nepafenac-, and Triton
X-100-treated corneas was significantly greater (P<0.001). The
remaining wound area in corneas exposed to bromfenac compared with
corneas exposed to nepafenac and Triton X-100 was significantly
reduced (P<0.01). No statistical difference was detected between
the remaining wound areas of nepafenac- and Triton X-100-treated
eyes.
CONCLUSION
[0110] Compared with other NSAIDs and previous ketorolac
formulations, ketorolac 0.45% provided more rapid epithelial 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%.
The 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%.
* * * * *