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`
`(11) Document No. AU-B-22042/88
`(12) PATENT ABRIDGMENT
`(10) Acceptance No. 626798
`(19) AUSTRALIAN PATENT OFFICE
`
`(54)
`
`(31)
`
`(72)
`
`INC.
`
`A61K 031/19
`
`A61K031/195
`
`(22) Application Date 09.09.88
`
`(33) Country
`US UNITED STATES OF AMERICA
`
`Title
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`International Patent Classification(s)
`(51) 4 A61K031/40
`A61K 031/13
`A61K 031/405
`(51) 5 A61K047/10
`A61K 047/18
`Application No. 22042/88
`(21)
`Priority Data
`(32) Date
`Number
`11.09.87
`096173
`Publication Date: 16.03.89
`(43)
`(44) Publication Date of Accepted Application 13.08.92
`(71)
`Applicant(s)
`SYNTEX
`Inventor(s)
`CHERNG-CHYI ROGER FU; DEBORAH M. LIDGATE
`(74) Attorney or Agent
`WATERMARK PATENT
`(57) Claim
`1.
`An ophthalmic NSAID formulation comprising:
`a NSAID
`in an effective amount for ophthalmic treatment,
`a quaternary ammonium preservative, a stabilizing amount
`of a nonionic ethoxylated octylphenol surfactant, and an
`aqueous vehicle.
`
`I
`
`TRADEMARK ATTORNEYS, Locked Bag 5, HAWTHORN VIC 3122
`
`22.
`An antimicrobially effective ophthalmologically acceptable preservative system
`for ophthalmologically acceptable, carboxyl group-containing drugs, said preservative
`system comprising a quaternary ammonium preservative and a stabilizing amount of a
`nonionic ethoxylated octylphenol surfactant.
`
`LUPIN EX1011, Page 1
`
`

`
`i
`
`i
`
`i;
`
`i
`
`-II~
`
`COMMONWEALTH OF AUSTRALIA
`
`PATENTS ACT 1952-69
`
`Form
`
`COMPLETE SPECIFICATION
`
`9
`
`6267
`
`626798
`
`Class
`
`Int. Class
`
`(ORIGINAL)
`
`Application Number:
`Lodged:
`
`Complete Specification Lodged:
`Accepted:
`Published:
`
`*Priority
`0000
`
`Related Art:
`
`0
`
`00
`
`0*
`
`'lame of Applicant:
`
`SYNTEX
`
`INC.
`
`Address of Applicant:
`
`3401 Hillview Avenue,
`States of America
`
`*0
`
`0
`
`Palo Alto, California 94304, United
`
`Actual Inventor:
`
`CHERNG-CHYI ROGER FU and DEBORAH M. LIDGATE
`
`Address for Service:
`
`SONS,
`EDWD. WATERS
`50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
`
`Complete Specification for the invention entitled:
`
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`The following statement is a full description of this invention, including the best method of performing it known to
`
`US
`
`1.
`
`LUPIN EX1011, Page 2
`
`

`
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`15
`
`20
`
`BACKGROUND OF THE INVENTION
`The present invention relates to improved ophthalmic
`formulations, particularly to ophthalmic formulations for
`anti-inflammatory drugs, and specifically to an improved
`
`preservative system for ophthalmic formulations of
`carboxyl
`group-containing drugs, especially
`non-steroidal anti-inflammatory drugs ("NSAIDs").
`The invention also relates to methods of using these
`formulations for treating diseases that are either caused
`by, associated with or accompanied by inflammatory
`processes, including, among others, glaucoma, cystoid
`macular edema, uveitis, diabetic retinopathy, and
`conjunctivitis, or any trauma caused by eye surgery or
`
`eye injury.
`
`The topical use of NSAIDs, particularly pyrrolo
`
`pyrroles, in the treatment of ophthalmic d.seases was
`
`first taught in U.S. Patent No. 4,454,151, where NSAID
`
`compounds (such as those described in U.S. Patents
`4,089,969; 4,232,038; 4,087,539 and 4,097,579) were
`exemplified in formulation with NaH 2 PO 4 "H2 0
`Na 2 HPO 4 H 2 0
`NaC1, benzalkonium chloride ("BAC")
`and sterilized water. While the formulations described
`
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`LUPIN EX1011, Page 3
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`

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`-2-
`
`in the '151 patent were efficacious, an insoluble complex
`was found to form between the NSAID and the BAC. The
`formulations became cloudy or turbid and did not,
`therefore, have the stability desired for shelf life in
`commercial applications. A reasonable minimum shelf life
`(that is, the time during which a solution remains clear
`and retains its pharmaceutical activity) is at least
`about one year, representing sufficient time to package,
`ship, and store a formulation without having to replace
`
`expired stock too frequently. The solutions of the
`present invention have shown a shelf life of at least one
`year. Thus, the present invention entails an improvement
`
`Sover
`
`the formulations described in the '151 patent.
`
`In general, an ophthalmic formulation contains an
`active compound and various ophthalmologically acceptable
`
`excipients, in the form of a solution, an ointment, a
`
`suspension, etc. An excipient is ophthalmologically
`acceptable if it is non-irritating to the eye and if its
`active ingredient penetrates the blood-aqueous barrier
`
`and/or diffuses through the various ocular substructures
`to the site where it is pharmacologically active. The
`excipients can include a tonicifier, a preservative, a
`surfactant, a buffering system, a chelating agent, a
`viscosity agent as well as other stabilizing agents.
`Ophthalmic formulations must be sterile, and if intended
`for multiple dosing regimens, must be preserved with an
`effective anti-microbial agent.
`Organo-mercurials
`
`thimerosal, phenylmercuric
`
`acetate and phenylmercuric nitrate) have been used
`
`extensively as the preservative in ophthalmic solutions.
`These compounds, however, pose difficulties due to
`potential mercury toxicity as well as poor chemical
`
`stability. Benzalkonium chloride, a quaternary ammonium
`compound, has been widely used in ophthalmic solutions,
`
`and is considered to be the preservative of choice.
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`

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`o
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`*e
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`-3-
`
`However, BAC has typically been considered to be
`salicylates or
`incompatible with anionic drugs
`nitrates, etc.), forming insoluble complexes which cause
`the solution to become cloudy or turbid. Such a complex
`between the anionic drug and benzalkonium chloride can
`
`cause a decrease in the pharmaceutical activity of the
`
`anionic drug.
`
`Many NSAIDs (such as ketorolac, indomethacin,
`flurbiprofen and diclofenac) are being developed for
`ocular use because of their activity as anti-inflammatory
`agents including their ability to prevent cystoid macular
`edema.
`
`In the past, as in the case with other ophthalmic
`
`drugs that contain a -COOH group, antiinflammatory
`
`solutions of NSAIDs for occular use have proven to be
`incompatible with quaternary ammonium compounds such as
`BAC. This incompatibility is due to the fact that the
`
`-COOH group can form a complex with the quaternary
`ammonium compounds, rendering the preservative less
`
`available to serve its function, and reducing the
`
`activity of the active ingredient. Indomethacin
`ophthalmic formulations have been prepared, however,
`these are suspensions, not solutions. Ocufen Ophthalmic
`solution, an NSAID (flurbiprofen) approved by the FDA for
`
`ophthalmic use, incorporates thimerosal (with EDTA) as
`its preservative system. In U.S. patent 4,454,151 there
`
`is a disclosure of an ophthalmic formulation using
`
`ketorolac, benzalkonium chloride (as the preservative)
`and polysorbate 80, however the solution became cloudy or
`turbid after a short period of time.
`It has remained desired to provide a stable, clear,
`antimicrobially effective ophthalmic formulation with a
`prolonged shelf life for -COOH group containing
`ophthalmic drugs, especially NSAIDs, using BAC as the
`
`preservative.
`
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`

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`_I
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`II"U -4iI
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`I""
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`-4-
`
`SUMMARY OF THE INVENTION
`
`It has now been discovered that stable, clear and
`antimicrobially effective, NSAID-containing ophthalmic
`formulations can be prepared which include a quaternary
`ammonium preservative. These solutions have an improved
`shelf life, exhibiting no cloudiness or turbidity over
`
`extended periods.
`
`In one aspect of the invention, these compositions
`
`include an ophthalmologically effective amount of a
`
`NSAID, a quaternary ammonium preservative and a
`stabilizing amount of an ethoxylated octylphenol as a
`
`nonionic surfactant, all in an aqueous vehicle.
`
`.Another
`
`aspect is an ophthalmic composition
`
`including an ophthalmologically effective amount of a
`15 NSAID, a quaternary ammonium preservate and a stabilizing
`
`amount of an ethoxylated octylphenol as a nonionic
`
`surfactant.
`Another aspect is an ophthalmic composition
`including an ophthalmologically effective amount of a
`
`20 NSAID, benzalkonium chloride as a preservative and a
`stabilizing amount of an ethoxylated octylphenol as a
`nonionic surfactant.
`
`Another aspect is an ophthalmic composition
`including an ophthalmologically effective amount of a
`
`NSAID, benzalkonium chloride as a preservative and a
`stabilizing amount of Octoxynol 40 as a nonionic
`surfactant.
`
`Another aspect is an ophthalmic composition
`including an ophthalmologically effective amount of
`
`ketorolac or an isomer, an ester, or a pharmaceutically
`acceptable salt thereof, benzalkonium chloride as a
`preservative and a stabilizing amount of Octoxynol 40 as
`a nonionic surfactant.
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`LUPIN EX1011, Page 6
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`

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`I~
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`V
`
`In another aspect of the invention, methods for
`treating ophthalmic diseases in mammals using the
`ophthalmic pharmaceutical formulations of the invention
`are also disclosed. These diseases are those that are
`either caused by, associated with or accompanied by
`
`inflammatory processes, including, among others,
`glaucoma, cystoid macular edema, uveitis, diabetic
`retinopathy and conjunctivitis, or any trauma caused by
`
`eye surgery or eye injury.
`
`DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
`
`Definitions
`
`As used herein, the term "NSAID" means an
`
`ophthalmologically acceptable non-steroidal
`15 anti-inflammatory drug. The NSAID's include, for
`
`example, flurbiprofen, ketorolac, diclofenac,
`
`indomethacin, and the isomers, esters, and
`
`pharmaceutically acceptable salts thereof.
`
`As used herein, the term
`quantity sufficient to achieve a stated function, e.g.,
`
`means adding a
`
`to bring a solution to the desired volume
`
`100%).
`
`As used herein, the term "treatment" or "treating"
`
`means any treatment of a disease in a mammal, including:
`
`preventing the disease, that is, causing the
`clinical symptoms of the disease not to develop;
`(it) inhibiting the disease, that is, arresting the
`development of clinical symptoms; and/or
`(iii) relieving the disease, that is, causing the
`
`regression of clinical symptoms.
`As used herein, the term "effective amount" means a
`dosage sufficient to provide treatment for the disease
`state being treated. This will vary depending on the
`patient, the disease and the treatment being effected.
`
`0
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`LUPIN EX1011, Page 7
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`

`
`v
`
`1
`
`-6-
`
`As used herein, the term "antimicrobially effective"
`means ability to withstand the U.S. Pharmacopia
`
`antimicrobial challenge.
`
`As used herein, the term "surfactant" means a
`nonionic surfactant, preferably ethoxylated octylphenol
`
`compounds as described below.
`
`As used herein, the term "quaternary ammonium
`
`preservative" means a quaternary ammonium compound such
`
`as described below.
`
`As used herein, the term "stabilizing" means keeping
`a formulation clear and antimicrobially effective for its
`
`minimum reasonable shelf life,
`
`at least one year.
`
`Formulations
`
`15
`
`The formulations of the present invention include an
`
`active agent in an effective amount for ophthalmic
`SNSAID
`Streatment,
`a quaternary ammonium preservative, a
`stabilizing amount of an ethoxylated octylphenol as a
`
`nonionic surfactant, optionally including other
`20 excipients such as a chelating agent, a tonicifier, a
`buffering system, a viscosity agent as well as other
`S'**stabilizing agents. Ophthalmic solutions and suspensions
`
`typically contain an aqueous vehicle rather than an oily
`vehicle. Ophthalmic formulations must be sterile, and if
`
`intended for multiple dosing regimens, must be
`antimicrobially effective for their minimum reasonable
`shelf life,
`at least one year, and preferably two
`to three years or more. The ingredients used in the
`formulations of the present invention are typically
`commercially available or can be made by methods readily
`known to those skilled in
`the art.
`Pharmaceutical ophthalmic formulations typically
`contain an effective amount,
`0.00.1% to 10% wt/vol.,
`preferably 0.002% to 5% wt/vol, most preferably 0.005% to
`
`1% wt/vol of an active ingredient
`
`the NSAID of the
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`

`
`v
`
`-7-
`
`present invention). The amount of active ingredient will
`vary with the particular formulation and the disease
`state for which it is intended. The total concentration
`
`of solutes should be such that, if possible, the
`resulting solution is isotonic with the lacrimal fluid
`
`(though this is not absolutely necessary) and has a pH in
`
`the range of 6 to 8.
`
`The formulations of the present invention are
`prepared as solutions incorporating the above-described
`ingredients within the following approximate ranges:
`
`Ingredient
`Active Agent
`
`Preservative
`Surfactant
`
`Amount
`
`0.001% to 10.0% wt/vol.;
`
`0.001% to 1.0% wt/vol.;
`
`0.001% to 1.0% wt/vol.;
`
`15
`
`Other Excipients
`
`0% to 10.0% wt/vol.; and
`
`0"
`
`S,
`
`20
`
`Purified Water
`q.s. to 100%.
`Optional other excipients, such as a chelating agent and
`a tonicifier, are used in the following approximate
`
`proportions:
`
`Ingredient
`Chelating agent
`
`Amount
`0.01% to
`
`Tonicifier
`
`q.s. to achieve
`
`IN NaOH or lN HC1
`
`isotonicity with
`lacrimal fluid; and
`
`q.s. to adjust pH to
`6.0 to
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`LUPIN EX1011, Page 9
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`

`
`27
`
`-8-
`
`In a preferred ophthalmic NSPAID solution, the
`ingredients are combined in the following proportions:
`Amount
`Ingredient
`0.002% to 5.0% wt/vol.;
`NSAID
`BAC
`0.002% to 1.0% wt/vol.;
`
`aq. soin.)
`Octoxynol 40
`aq. soln.)
`E0TPA Na2
`NaCl
`
`1N NaOH or 1N HCl
`
`Purified Water
`
`0.001% to 1.0% wt/vol.;
`
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity with
`lacrimal fluid;
`q.s. to adjust pH to
`7.4±0.4; and
`q.s. to 100%.
`
`In another preferred ophthalmic NSAID solution, the
`ingredients are combined in the following proportions:
`Amount
`Ingredient
`NSAID
`0.005% to 1.0% wt/vol.,
`BAC
`0.002% to 1.0% wt/vol.;
`
`aq. soln.)
`Octoxynol. 40
`(70% aq. soln.)
`EDTA Na2
`NaCl
`
`1N NaOH or 1N HCl
`
`Purified Water
`
`0.001% to 1.0% wt/vol.;
`
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity with
`lacrimal fluid;
`q.s. to adjust pH to
`7.4±0.4; and
`q.s. to 100%.
`
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`LUPIN EX1011, Page 10
`
`

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`In a more preferred ophthalmic NSAID
`
`solution, the ingredients are combined in
`
`the following proportions:
`
`Ingredient
`NSAID
`
`BAC
`
`Octoxynol 40
`
`EDTA Na2
`NaCI
`
`aq. soln.)
`
`aq. soln.)
`
`1N NaOH or 1N HCI
`
`Purified Water
`
`Amount
`0.50% wt/vol.;
`
`0.02% wt/vol.;
`
`0.01% wt/vol.;
`
`0.10% wt/vol.;
`
`q.s. for isotonicity with lacrimal
`
`fluid;
`q.s. to adjust pH to 7.4 0.4; and
`
`q.s. to 100%.
`
`The invention relates primarily to formulations having as the active agent
`or
`ophthalmologically acceptable drugs [including the isomers (as either the
`isomer) esters and pharmaceutically acceptable salts thereof) that can form a complex
`with a quaternary ammonium compound, particularly NSAIDs and drugs with a carboxyl
`
`group.
`
`NSAIDs useful in the practice of this invention include, for example, ketorolac
`
`(and the other compounds described as being ophthalmologically effective in U.S. Patent
`to Waterbury, issued June 12, 1984, the pertinent portions of which
`
`No. 4,454,151
`
`incorporated herein by reference),
`are
`diclofenac, including the isomers, esters and pharmaceutically acceptable salts thereof.
`invention
`include
`
`indomethacin,
`
`flurbiprofen sodium, and
`
`Preservatives useful
`
`in the formulations of the present
`
`quaternary ammonium compounds, such as cetyltrimethylammonium bromide,
`
`cetylpyridinium chloride and benzalkonium chloride, preferably, benzalkonium chloride.
`
`LUPIN EX1011, Page 11
`
`

`
`I_
`
`I~
`
`The nonionic surfactants useful in the formulations
`of the present invention are preferably ethoxylated
`octylphenol compounds, such as octylphenoxypoly-
`(ethyleneoxy)ethanols, more preferably, a homologous
`series of surfactants sold under the trade name Igepal CA
`with a numerical suffix indicating the mole ratio of
`ethylene oxide to octylphenol, the ratio being 3 to
`Examples include Octoxynol 9, Octoxynol 12, Octoxynol 13,
`and Octoxynol 40, and most preferably Octoxynol
`manufactured and sold by GAF under the trade name Igepal
`CA897 (a 70% aqueous solution of Octoxynol
`Among the optional excipients, the chelating agents
`useful in the formulations of the present invention
`include 8-hydroxyquinoline sulfate, citric acid, and
`preferably disodium edetate. Under certain conditions,
`the chelating agent may also enhance the anti-microbial
`effect due to its ability to render essential metal ions
`unavailable to the microbes.
`Buffering systems optionally useful in the
`20 formulations of the present invention are based on, for
`example, citrate, borate, or phosphate.
`Tonicifiers optionally useful in the formulations of
`the present invention include dextrose, potassium
`chloride and/or sodium chloride, preferably sodium
`25 chloride.
`Viscosity agents optionally useful in the
`formulations of the present invention include the
`cellulose derivatives such as hydroxypropylmethyl
`cellulose, sodium carboxymethylcellulose, and
`
`hydroxyethylcellulose.
`Other optional excipients useful in the formulations
`of the present invention include stabilizing agents such
`as antioxidants,
`sodium metabisulfate and ascorbic
`acid, depending on the NSAID used.
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`LUPIN EX1011, Page 12
`
`

`
`-11-
`
`These formulations are prepared by dissolving the
`solutes
`the NSAID, the preservative, the
`surfactant, the chelating agent, and the buffering agent)
`in a suitable quantity of water, adjusting the pH to
`about 6 to 8, preferably 6.8 to 8.0 and most preferably
`7.4, making a final volume adjustment to 100% with
`additional water, and sterilizing the preparation using
`any suitable method known to those in the art.
`It has been discovered that ophthalmic formulations
`incorporating the preservative system of the invention are
`physically stable
`remain clear) and functionally
`remain antimicrobially effective) for at
`least the minimum reasonable shelf life of such products.
`
`stable
`
`S.
`
`15 Preferred Formulations
`
`The preferred preservative system of the invention
`includes a quaternary ammonium preservative and a
`stabilizing amount of a nonionic surfactant.
`The preferred ophthalmic formulation of the
`invention includes a NSAID active agent in an effective
`amount for ophthalmic treatment and an antimicrobially
`effective amount of the above-described preferred
`preservative system.
`The preferred preservative of the invention is
`benzalkonium chloride.
`
`The preferred surfactant of the invention is
`Octoxynol 40, especially when combined with benzalkonium
`chloride as the preservative.
`
`The preferred chelating agent of the invention is
`disodium edetate, especially when combined with
`benzalkonium chloride as the preservative and
`Octoxynol 40 as the nonionic surfactant.
`The preferred ophthalmic solutions, of the invention
`include a NSAID, benzalkonium chloride, Octoxynol 40 and
`disodium edetate.
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`

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`V
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`-12-
`
`A preferred ophthalmic NSAIO solution, the
`ingredients are combined in the following proportions:
`
`Ingredient
`NSAID
`BAG
`
`aq. soin.)
`Octoxynol 40
`aq. soln.)
`EDTA Na 2
`N aC 1
`
`1N NaOH or 1N HCl
`
`Purified Water
`
`Amount
`0.002% to 5.0% wt/vol.;
`0.002% to 1.0% wt/vol.;
`
`0.001% to 1.0% wt/vol.;
`
`0.1% to 1.0% wt/vol.;
`q.s. for isotonicity
`with lacrimal fluid;
`q.s. to adjust pH to
`and
`q.s. to 100%.
`
`Another preferred ophthalmic NSAID solution, the
`ingredients are combined in the following proportions:
`Ingredient
`Amount
`NSAID
`0.005% to 1.0% wt/vol.;
`BAG
`0.002% to 1.0% wt/vol.;
`(50% aq. soin.)
`Octoxynol 40
`(70% aq. soln.)
`EOTA Na 2
`NaG 1
`
`0.001% to 1.0% wt/vol.;
`
`1N NaOH or 1N HCl
`
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity
`with lacrimal fluid;
`q.s. to adjust pH to
`7.4±0.4; and
`
`Purified Water
`
`q.s. to 100%.
`
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`S.
`
`6e
`
`0
`
`0@
`OS
`
`0O
`
`*6
`9
`
`*5
`
`0S
`
`0*
`
`0e
`
`S
`
`6
`
`@6.0
`05
`
`S.
`
`S
`
`0650
`0*
`
`*e
`
`0
`
`Li
`
`LUPIN EX1011, Page 14
`
`

`
`-13-
`
`A preferred ophthalmic NSAID solution has the
`following formulation:
`
`Ingredient
`
`Amount
`
`NSAID
`BAC
`
`0.50% wt/vol.
`0.02% wt/vol.
`
`aq. soln.)
`
`Octoxynol 40
`
`0.01% wt/vol.
`
`aq. soln.)
`
`EDTA Na 2
`NaCl
`
`0.10% wt/vol.
`q.s. for isotonicity
`
`with lacrimal fluid
`
`1N NaOH or 1N HC1
`
`q.s. to adjust pH to
`
`Purified Water
`
`q.s. to 100%
`
`7.4±0.4
`
`*1
`
`Most preferred is the ophthalmic solution according
`to the above formulation wherein the NSAID is Ketorolac
`Tromethamine or an isomer thereof.
`
`20 Utility and Administration
`
`This invention is directed to NSAID ophthalmic
`formulations and a method useful for treating ophthalmic
`diseases in mammals.
`These diseases are either caused
`by, associated with or accompanied by inflammatory
`
`processes, including, among others, glaucoma, cystoid
`macular edema, uveitis, diabetic retinopathy and
`conjunctivitis, or any trauma caused by eye surgery or
`eye injury.
`The method of this invention is both curative and
`
`preventative. Where applied, for example, pre-surgically
`or immediately post-traumatically, i.e. before
`inflammation develops, it prevents development of
`inflammation. When applied directly tothe eye suffering
`
`from any of the named ophthalmic diseases, it supresses
`
`already developed inflammatory processes.
`
`8408Y
`
`26280-FF
`
`LUPIN EX1011, Page 15
`
`

`
`-14-
`
`Ophthalmic formulations are typically administered
`by topical application to the eyelids or for instillation
`into the space (cul-de-sac) between the eyeball and the
`
`eyelids, of topically applied ophthalmic solutions,
`suspensions or ointments, or by subconjunctival injection.
`
`The dosage level will, of course, depend on the
`concentration of the drops, the condition of the subject
`and the individual magnitude of responses to treatment.
`However, typical dosage ranges might be about 2 to
`
`drops of 0.5% solution of active ingredient per day.
`
`For a more detailed discussion of ophthalmic
`
`formulations, their preparation and administration, see
`
`Remington's Pharmaceutical Sciences, 15th Ed., pages
`
`1489-1504, (1975).
`
`gong
`
`S.
`
`Testing
`Ophthalmic formulations such as the solutions of the
`present invention are typically tested for physical
`stability, chemical stability, and preservative efficacy,
`
`both when they are first manufactured and after a fixed
`period of time
`after two years). They are
`generally considered to be safe and clinically acceptable
`
`if proven to be well tolerated in the eye.
`
`*Physical
`
`stability is determined by observation of a
`
`solution after expiration of a fixed period of time. A
`
`solution is considered to be physically stable if its
`'appearance
`color and clarity) does not change and
`if the pH remains constant, within acceptable limits.
`Chemical stability involves a routine chemical analysis
`
`of the solution, to be sure that its active ingredient
`and the excipients have not changed after a fixed period
`of time.
`
`Preservative efficacy is tested by, the procedure
`described in the U.S. Pharmacopia Compendiary, whereby a
`
`8408Y
`
`26280-FF
`
`i
`
`LUPIN EX1011, Page 16
`
`

`
`I
`
`L-
`
`-I
`
`solution is challenged with a microbe and a determination
`is made as to whether the microbe survives in it.
`
`EXAMPLES
`
`The following examples are given to enable those
`skilled in the art to more clearly understand and to
`practice the present invention. They should not be
`considered as a limitation on the scope of the invention,
`but merely as being illustrative and representative
`
`thereof.
`
`EXAMPLE 1
`
`This example illustrates the preparation of a
`representative pharmaceutical formulation for ophthalmic
`administration containing the NSAID Ketorolac
`Tromethamine.
`
`Ingredient
`Ketorolac Tromethamine
`BAC
`
`Amount
`0.50% wt/vol.
`0.02% wt/vol.
`
`(50% aq. soln.)
`Octoxynol 40
`
`(70% aq. soln.)
`EDTA Na 2
`NaCl
`
`0.01% wt/vol.
`
`0.10% wt/vol.
`
`0.79% wt/vol.
`
`The above ingredients are mixed, adding purified
`water until they are dissolved, the pH is adjusted to
`7.4±0.4 and the balance of the formulation is made up
`with purified water, adding a quantity sufficient to make
`100% volume. The solution is then sterilized.
`Other NSAIDs or their isomers, salts or esters, such
`as those described above, can be used as the active
`
`15
`
`20
`
`S*
`
`'m
`
`8408Y
`
`26280-FF
`
`LUPIN EX1011, Page 17
`
`

`
`A
`
`-16-
`
`compound in the preparation of the formulation of this
`example.
`
`EXAMPLE 2
`
`This example illustrates the preparation of a
`representative pharmaceutical formulation for ophthalmic
`
`administration containing the NSAID Ketorolac
`
`Tromethamine.
`
`Ingredient
`Amount
`Ketorolac Tromethamine 0.50% wt/vol.
`0.02% wt/vol.
`
`BAC
`(50% aq. soln.)
`
`15
`
`Octoxynol 40
`
`0.02% wt/vol.
`
`(70% aq. soln.)
`EDTA Na 2
`NaCl
`
`0.20% wt/vol.
`0.79% wt/vol.
`
`The above ingredients are mixed, adding purified
`water until they are dissolved, the pH is adjusted to
`7.4±0.4 and the balance of the formulation is made up
`with purified water, adding a quantity sufficient to make
`100% volume. The solution is then sterilized.
`
`Other NSAIDs or their isomers, salts or esters, such
`as those described above, can be used as the active
`compound in the preparation of the formulation of this
`example.
`
`EXAMPLE 3
`
`This example illustrates the preparation of a
`representative pharmaceutical formulation for ophthalmic
`
`8408Y
`
`26280-FF
`
`LUPIN EX1011, Page 18
`
`

`
`-17-
`
`administration containing the NSAID Ketorolac
`
`Tromethamine.
`
`Ingredient
`Ketorolac Tromethamine
`BAC
`
`Amount
`
`0.10% wt/vol.
`
`0.004% wt/vol.
`
`aq. soln.)
`Octoxynol 40
`aq. soln.)
`EDTA Na 2
`NaCl
`
`0.004% wt/vol.
`
`0.05% wt/vol.
`
`0.88% wt/vol.
`
`The above ingredients are mixed, adding purified
`water until they are dissolved, the pH is adjusted to
`
`7.4±0.4 and the balance of the formulation is made up
`with purified water, adding a quantity sufficient to make
`
`15
`
`100% volume. The solution is then sterilized.
`Other NSAIDs their isomers, salts or esters, such as
`those described above, can be used as the active compound
`in the preparation of the formulation of this example.
`
`EXAMPLE 4
`
`This example illustrates the preparation of a
`
`representative pharmaceutical formulation for ophthalmic
`25 administration containing the NSAID flurbiprofen sodium.
`
`t
`
`0*
`
`S.
`
`0
`
`I
`
`S
`
`5e
`
`0*
`
`Ingredient
`
`Amount
`
`Flurbiprofen Sodium
`
`0.03% wt/vol.
`
`BAC
`
`0.02% wt/vol.
`
`aq. soln.)
`
`Octoxynol 40
`
`0.01% wt/vol.
`
`aq. soln.)
`EDTA Na 2
`NaCl
`
`0.10% wt/vol.
`
`0.90% wt/vol.
`
`The above ingredients are mixed, adding purified
`
`8408Y
`
`26280-FF
`
`LUPIN EX1011, Page 19
`
`

`
`r
`
`-18-
`
`water until
`they are dissolved,
`the pH is adjusted to
`7.4±0.4 and the balance of the formulation is made up
`with purified water, adding a quantity sufficient to make
`100% volume. The solution is then sterilized.
`Other ophthalmic drugs and NSAIDs, such as those
`described above, can be used as the active compound in
`
`the preparation of the formulation of this example.
`
`EXAMPLE
`
`Physical stability of the formulations of the
`present invention is measured by preparing clear
`
`formulations, in the concentrations shown in the table
`below, sealing them in sterilized containers, and
`of the solution after a period of
`15 observing the clarity
`one month and again after five months. Solutions that
`remain clear are considered stable in
`this procedure.
`
`S.
`
`The formulations of the present invention have
`proven to be stable when tested in accordance with the
`above procedure. Formulations using surfactants other
`than the nonionic surfactants of the invention did not
`remain clear and were not stable.
`Three surfactants were evaluated for their ability
`to dissolve the ketorolac
`benzalkonium chloride complex
`and maintain a physically clear solution over an extended
`period of time.
`The three surfactants tested were:
`40; Polysorbate 80 (Tween 80); and Myrj 52.
`
`*Octoxynol
`
`Two concentrations of each surfactant were incorporated
`
`into the ophthalmic formulation, and these were placed at
`
`various temperatures for future visual observations.
`
`8408Y
`
`26280-FF
`
`LUPIN EX1011, Page 20
`
`

`
`i
`
`-19-
`
`Octoxynol 40
`
`Tween 80
`
`0.004% 0.02%
`
`0.0035% 0.01%
`
`Myrj 52
`0.0015% 0.01%
`
`1 month
`60 0 C
`0 C
`
`clear clear
`
`clear
`
`clear
`
`clear clear
`
`very
`
`very
`
`clear
`turbid
`
`clear
`turbid
`
`turbid turbid
`
`RT
`4-400C
`
`clear clear
`clear clear
`
`turbid turbid
`
`clear
`
`turbid turbid
`
`clear
`
`clear
`
`clear
`
`month
`
`6000C
`
`clear clear
`
`clear
`
`clear
`
`clear
`
`4000C
`
`clear clear
`
`turbid turbid
`
`turbid
`
`RT
`
`clear clear
`
`turbid turbid
`
`turbid
`
`clear
`turbid
`
`turbid
`
`At the 5 month time period it was apparent that
`the Octoxynol 40 surfactant was superior to the other two
`surfactants. At 5 months, Tween 80 and Myrj 52 displayed
`turbidity when stored at RT. The presence of turbidity
`
`20 suggested the inability to solubilize a precipitate
`formation between the Ketorolac moiety and benzalkonium
`
`chloride.
`
`A further study has shown a 2 year shelf life
`for the ophthalmic formulation. Precipitate formation
`
`and turbidity are not a problem with this formulation.
`Preservative efficacy is maintained throughout the 2 year
`shelf life.
`
`0*
`
`S
`
`06
`
`S.
`
`50S0
`
`S.
`
`S
`
`S
`
`S.
`
`0
`
`SO
`
`*5
`
`S
`
`S
`
`@0
`
`5
`
`OS
`
`5
`
`0*
`
`5
`
`EXAMPLE 6
`
`Preservative efficacy of the formulations of the
`present invention is measured by preparing formulations,
`according to the foregoing Examples, and subjecting
`
`them to the U.S. Pharmacopia antimicrobial challenge.
`
`8408Y
`
`26280-FF
`
`LUPIN EX1011, Page 21
`
`

`
`V
`
`The formulations of the present invention
`demonstrate preservative efficacy when tested in
`accordance with the above procedure.
`
`EXAMPLE 7
`
`The objective of this clinical efficacy study was to
`compare the effectiveness and safety of ketorolac with a
`Scontrol solution in reducing inflammation following
`cataract removal and intraocular lens implantation. All
`patients underwent an extracapsular cataract extraction
`with intraocular lens implantation 1 day following
`initiation of treatment.
`
`I
`
`Ophthalmic examinations were performed
`15 preoperatively (within 3 weeks of surgery) and during the
`first week (postoperative days 1 to
`second week
`
`S*
`
`*0
`
`*(postoperative
`days 4 through 12), and third week
`(postoperative days 15 through 27) of treatment.
`Particular attention was given to signs and symptoms
`20 consistent with inflammation. Among the ocular
`characteristics assessed on a scale of none, mild,
`moderate, or severe were: lid edema, corneal edema,
`conjunctival injections, ciliary flush, and the presence
`of cells and flare in the anterior chamber.
`Fluorophotometry: Anterior segment inflammation
`iritis, cyclitis, iridocyclitis) is by definition
`a disruption of the blood-aqueous barrier. When
`inflammation is present, a careful slit lamp examination
`will reveal cells and flare within the anterior chamber
`of the eye. The clinical grading of cells and flare is a
`measure of degree of anterior segment inflammation; but
`consistent grading of these observations is difficult,
`even by experts.
`Ocular fluorophotometry is based on the fact that
`the blood-aqueous barrier becomes permeable to
`
`8408Y
`
`26280-FF
`
`i-J
`
`LUPIN EX1011, Page 22
`
`

`
`-21-
`
`intravascular cells and proteinaceous fluid (explaining
`the observed cells and flare) and also to intravascular
`fluorescein. Furthermore, the appearance of fluorescein
`
`within the anterior chamber is a more sensitive
`indication of the breakdown of the blood-aqueous barrier
`
`than the gross observation of cells and flare, and is
`consistently quantifiable. For these reasons, a
`
`Flurortron* Master (Coherent, Sunnyvale, California),
`
`complete with software modifications designed for this
`study was used. Following oral administration of
`fluorescein, the fluorophotometer was used to determine
`
`the integrity of the aqueous barrier by measuring the
`concentration of fluorescein in the anterior chamber.
`The fluorophotometry data were analyzed using the
`15 Wilcoxon Rank Sum Test or analysis of variance (ANOVA) of
`m" :rank-transformed data by calculating the percentage
`difference in fluorescein coiientration between the
`patient's two eyes, according to the formula:
`Percent difference
`[(fluorescein concentration of
`
`fluorescein concentration of
`operated eye
`unoperated eye)/fluorescein concentration of
`eye] x 100.
`
`S~unoperated
`
`Sinterpatient
`
`This calculation allowed and corrected for any
`variation in the timing and concentration of
`
`fluorescein administered.
`
`e.129
`
`m
`
`patients began treatment for 21 days with either
`ketorolac or vehicle. In this study, the ketorolac
`
`formulation used was that illustrated in Example 1
`above. During the first week 118 patients and during the
`
`second week 110 patients were evaluated for postoperative
`inflammation with ophthalmic examinations and
`fluorophotometry. During the third week, 83 patients
`
`were evaluated with ophthalmic examinations alone. At 2
`
`weeks ketorolac pr

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