U.S. patent application number 12/953622 was filed with the patent office on 2011-06-30 for ketorolac tromethamine compositions for treating or preventing ocular pain.
This patent application is currently assigned to ALLERGAN, INC.. Invention is credited to Mayssa Attar, Chin-Ming Chang, Eldon Q. Farnes, Richard S. Graham, Rhett M. Schiffman, Devin F. Welty.
Application Number | 20110160271 12/953622 |
Document ID | / |
Family ID | 40852460 |
Filed Date | 2011-06-30 |
United States Patent
Application |
20110160271 |
Kind Code |
A1 |
Farnes; Eldon Q. ; et
al. |
June 30, 2011 |
KETOROLAC TROMETHAMINE COMPOSITIONS FOR TREATING OR PREVENTING
OCULAR PAIN
Abstract
The present invention provides an aqueous ophthalmic solution
comprising an effective amount of ketorolac which comprises
carboxymethyl cellulose in an aqueous solution wherein said
concentration of carboxymethyl cellulose is selected to provide an
increased absorption of ketorolac in the eye of a patient that is
at least 130% greater than the absorption of a comparative aqueous
ketorolac ophthalmic solution having the same concentration of
ketorolac.
Inventors: |
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.: |
12/953622 |
Filed: |
November 24, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12396131 |
Mar 2, 2009 |
7842714 |
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12953622 |
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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 31/407 20130101;
A61K 47/12 20130101; A61P 27/02 20180101; A61K 47/02 20130101; A61K
47/186 20130101; A61K 47/10 20130101; A61P 29/00 20180101; A61K
47/38 20130101; A61K 9/0048 20130101; A61K 31/14 20130101 |
Class at
Publication: |
514/413 |
International
Class: |
A61K 31/407 20060101
A61K031/407; A61P 29/00 20060101 A61P029/00; A61P 27/02 20060101
A61P027/02 |
Claims
1. A topical aqueous ophthalmic solution comprising keterolac
tromethamine, carboxymethyl cellulose and no preservative.
2. The topical aqueous ophthalmic solution of claim 1 wherein the
keterolac tromethamine is present in a concentration of
approximately 0.40-0.45 percent by weight/volume.
3. The topical aqueous ophthalmic solution of claim 1 wherein the
carboxymethyl cellulose is a combination of medium and high
viscosity carboxymethyl cellulose.
4. The topical aqueous ophthalmic solution of claim 1 wherein the
keterolac tromethamine is present in a concentration of 0.45
percent by weight/volume.
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 5 wherein the
concentration of carboxymethylcellulose 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 8 for use in treatment of
ocular pain associated with postoperative photorefractive
keratectomy.
10. The topical aqueous solution of claim 4 further comprising a
mixture of medium and high molecular weight sodium carboxymethyl
cellulose.
11. 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.
12. The topical aqueous solution of claim 10 wherein the
combination of carboxymethyl cellulose and keterolac increases the
absorption in the eye of a patient more than a solution of
keterolac alone.
13. The topical aqueous solution of claim 1 wherein the keterolac
tromethamine is present as a racemic mixture of R-(+) and
S-(-)-ketorolac tromethamine.
14. The topical aqueous solution of claim 1 wherein the keterolac
tromethamine is present in a mixture of crystal forms.
15. The topical aqueous solution of claim 5 wherein the viscosity
is from 10 to 30 cps.
16. The topical aqueous solution of claim 6 wherein the
carboxymethylcellulose is present in the amount of 0.5% percent by
weight.
17. The topical aqueous solution of claim 4 wherein the solution
may be administered before or after eye surgery to prevent ocular
pain.
18. The topical aqueous solution of claim 4 wherein the solution
increases healing time of the eye after surgery in comparison to
keterolac solutions containing a preservative.
19. The topical aqueous solution of claim 4 wherein the topical
aqueous solution is instilled twice daily to achieve proper
efficacy.
20. The topical aqueous solution of claim 4 wherein the aqueous
solution is surfactant free.
Description
RELATED APPLICATION
[0001] This application is a Continuation of U.S. patent
application Ser. No. 12/396,131, filed Mar. 2, 2009, which claims
the benefit of U.S. Provisional Application Ser. No. 61/067,925,
filed Mar. 3, 2008; Ser. No. 61/096,096 filed Sep. 11, 2008; and
Ser. No. 61/111,919 filed Nov. 6, 2008, the disclosures of which
are hereby incorporated in their entirety herein by reference.
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 treating or
preventing ocular pain.
DESCRIPTION OF THE RELATED ART
[0003] Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are
used to control pain and postoperative inflammation. All drugs are
associated with some adverse effects. With the use of NSAIDS in
topical ophthalmic treatment of patients, surface toxicity has been
a concern, and incidents of keratitis, corneal subepithelial
infiltrates, ulceration, and corneal melts have been reported
(Guidera et al, Ophthalmology, 2001, 108 (5), pp. 936-944; Solomon
et al, J Cataract Refract Surg, 2001, 27 (8), pp. 1232-1237; Teal
et al, J Cataract Refract Surg, 1995, 21(5), pp. 516-518). Further,
patients often report burning or stinging on instillation (Jaanus
et al, Antiinflammatory Drugs. Clinical Ocular Pharmacology,
Bartlet, J. D. and Jaanus, S. D., Ed., Boston: Heineman, 2001, pp.
265-298). The burning or stinging could be related to the
concentration of the active component of the formulation.
[0004] Ketorolac tromethamine 0.5% (w/v) ophthalmic solution,
available from Allergan, Inc., under the tradeneme ACULAR.RTM., is
a safe and effective NSAID with proven analgesic and
anti-inflammatory activity. The most common adverse event
associated with the use of the 0.5% ketorolac formulation is ocular
irritation, primarily burning and stinging upon instillation.
Keterolac tromethamine 0.4% (w/v) ophthalmic solution, under the
tradename ACULAR LS.RTM., has shown improved bioavailability and
less stinging on instillation than ACULAR.RTM., but there remains a
need for an improved keterolac tromethamine formulation with
greater bioavailability and greater tolerability, minimized ocular
surface toxicity, improved patient comfort, increased retention
time of the active ingredient and improved wound healing
capabilities during use.
[0005] It is one object of this invention to provide a keterolac
formulation for instillation in the eye to eliminate or reduce
ocular irritation, to improve tolerability, compliance, duration
and effect of keterolac, to allow for dosing from four times daily
to twice daily, and to increase the effectiveness of treatment by
being free of benzalkonium chloride or other preservatives.
[0006] It is another object of the invention to improve
bioavailability and increase the ocular absorption of ketorolac yet
provide an aqueous solution having an optimized concentration of
ketorolac.
[0007] It is another object of the invention to extend the effects
of keterolac and allow for a decrease in required daily dosage.
[0008] It is another object of the invention to provide reduction
of inflammation associated with cataract surgery and reduction of
pain associated with cataract surgery in comparison to other
keterolac formulations.
[0009] It is another object of the invention to create a keterolac
formulation with improved wound healing capabilities.
[0010] Other objects of this invention will become apparent from a
reading of the present specification.
BRIEF DESCRIPTION OF DRAWINGS
[0011] 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.;
[0012] 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.;
[0013] 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.;
[0014] 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.;
[0015] 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; and,
[0016] FIG. 6 shows safety and tolerability results in human
clinical trials of 0.45% w/v keterolac solution vs. ACULAR LS.
SUMMARY OF THE INVENTION
[0017] 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 only 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.
[0018] 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.
[0019] More preferably, the aqueous ophthalmic solution of the
present invention has a concentration of carboxymethyl cellulose of
from about 0.2 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.
[0020] Even more preferably, the aqueous ophthalmic solution of the
present invention comprises a mixture of medium viscosity and high
viscosity sodium carboxymethyl cellulose.
[0021] 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.
[0022] More preferably, the aqueous ophthalmic solution of the
invention has a viscosity of from 5 to 50 cps, preferably from 10
to 30 cps.
[0023] 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.
[0024] 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% by weight and most preferably
about 0.45% ketorolac tromethamine by weight/volume. The present
invention also contains from 0.2 to 2 percent by weight, more
preferably from 0.5 to 1.5 percent by weight and most preferably
about 0.5% w/v percent 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
comprising topically administering to said patient a sterile
composition comprising from 0.25 to 0.50 percent, by weight, more
particularly from 0.35% to 0.45% by weight, or about 0.45% w/v
ketorolac tromethamine in combination with from 0.2 to 2 percent,
by weight, preferably from 0.5 to 1.5 percent by weight, and most
preferably 0.5% percent by weight/volume, sodium carboxymethyl
cellulose and mixtures thereof.
[0025] 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 which improves
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.
[0026] 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.
DETAILED DESCRIPTION OF THE INVENTION
[0027] 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..
[0028] 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.
[0029] 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).
[0030] 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.
[0031] 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.
[0032] Carboxymethyl cellulose is available in various molecular
weights. Low molecular weight carboxymethyl cellulose has a 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 a Mw of about 250,000. High molecular weight
carboxymethylcellulose has a Mw of about 700,000 and a 2% solution
will have a viscosity of about 12 cP at 25.degree. C.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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.
[0039] 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, sodium carboxymethyl
cellulose.
[0040] 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
[0041] 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
[0042] 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 benzalkonium 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
[0043] 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
[0044] 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.
[0045] 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
[0046] 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.
[0047] Study Objectives: [0048] 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; [0049] 2) This Example
was designed to determine whether decreasing the pH of the
composition would increase the absorption of ketorolac into the
eye; and, [0050] 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.
[0051] 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 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
[0052] 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
[0053] 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 maybe driving this observation.
Nevertheless, the solution having a pH of 6.8 shows the best
bioavailability.
Example 6
[0054] 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
[0055] 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 .RTM.
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; and intolerable.
[0056] 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 receives 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.
[0057] 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.
[0058] 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
[0059] Rabbit Ocular Pharmacokinetic Evaluation of Keterolac
Tromethamine 0.45%
[0060] NZW Rabbits/Female
[0061] Dosing Regimen Single ocular dose, bilateral
[0062] Timepoints: 0.5, 1, 2, 4, 8, 10 and 24 hrs post-dose
[0063] Tissues/Matrices: Aqueous Humor and Iris-ciliary body
[0064] Bioanalysis: LC-MS/MS
[0065] Data Analysis: Pharmacokinetic analyses and simulation
Conclusions
[0066] As shown in FIGS. 1-5, Example 7 shows there is an: [0067]
1) Increase in relative bioavailability of keterolac as compared to
Acular LS.RTM.; [0068] 2) Increased ketorolac concentrations are
maintained longer post-dose; and [0069] 3) Together these data
support a reduction in dosing frequency from 4.times./day to
2.times./day.
Conclusion
[0070] As shown in FIG. 6, Acular 0.45% is safe and well-tolerated
among human patients when given 5 times over a half-day and
compares very favorably to ACULAR LS.
[0071] 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.
* * * * *