Europaisches Patentamt
`
`s
`
`D
`
`European Patent Office
`
`Publication number
`
`Office europden des brevets
`
`0 306 984
`Al
`
`h
`
`EUROPEAN PATENT APPLICATION
`
`21
`
`Application number 88114804.3
`
`Q Date of filing 09.09.88
`
`Q Priority 11.09.87 US 96173
`
`a3 Date of publication of application
`
`15.03.89 Bulletin 89/11
`
`Q Designated Contracting States
`AT BE CH DE FR GB IT LI LU NL SE
`
`51
`
`Int. 01.4 A61 K 9/06
`
`A61 K 47/00
`
`Applicant SYNTEX U.S.A.
`3401 Hillview Avenue
`Palo Alto California 94304US
`
`INC.
`
`Q Inventor Roger Fu Cherng-Chyi
`14050 Shadow Oaks Way
`Saratoga California 95070US
`Inventor Lidgate Deborah M.
`325 Arboleda Drive
`Los Altos California 94022US
`
`7d Representative Barz Peter Dr. et al
`Patentanwaite Or. V. Schmied-Kowarzik
`Dipl.-Ing. G. Dannenberg Dr. P. Weinhold Dr.
`D. Gudel Dipl.-Ing. S. Schubert Dr. P. Barz
`Slegfriedstrasse 8
`D-8000 MUnchen 40DE
`
`Q Preservative system forophthalmic formulations.
`
`@ stable clear antimicrobially
`effective
`formulations
`include
`effective
`an ophthalmologically
`ophthalmic
`amount of a drug especially a -000H group-containing drug or a NSAID and a preservative system formed of a
`quaternary ammonium preservative and a nonionic surfactant
`in an aqueous vehicle. These formulations are
`that are either caused by associated with or accompanied
`useful
`by inflammatory
`cystoid macular edema uveitis
`and
`among others glaucoma
`diabetic
`including
`or any trauma caused by eye surgery or eye injury.
`
`all
`
`retinopathy
`
`for
`
`treating
`
`diseases
`
`processes
`
`conjunctivitis
`
`EXHIBIT
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`1
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`PA to
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`Xerox Copy Centre
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`InnoPharma EX1062
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`IPR2015-00902
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`IPR2015-00903
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`co
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`MOM0 L
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`LW
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`

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`EP 0 306 984 Al
`
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`formula-tions
`glau-coma
`
`The present
`
`for anti-inflammatory
`
`formulations
`
`particularly to ophthalmic
`
`to
`
`preservative
`
`system for ophthalmic
`
`invention relates to improved ophthalmic
`an improved
`drugs and specifically
`-COOH group-containing
`drugs especially
`
`formulations
`of carboxyl
`drugs NSAIDs.
`The invention also relates to methods of using these formulations for treating diseases that are either
`processes
`among others
`caused by associated with or accompanied
`by inflammatory
`including
`and conjunctivitis
`or any trauma caused by eye
`cystoid macular edema uveitis diabetic retinopathy
`
`non-steroidal
`
`anti-inflammatory
`
`life
`
`to package
`
`therefore
`
`life
`
`time
`
`invention
`
`surgery or eye injury.
`The topical use of NSAIDs particularly pyrrolo pyrroles in the treatment of ophthalmic diseases was
`in U.S. Patent No. 4454151 where NSAID compounds such as those described in U.S. Patents
`taught
`first
`in formulation with NaHZPO4H2O
`4087539 and 4097579 were exemplified
`4089969 4232038
`Na2HPO4H2O NaCl benzalkonium chloride BAC and sterilized water. While the formulations described
`an insoluble complex was found to form between the NSAIO and the
`in the 151 patent were efficacious
`have the stability desired for shelf
`SAC. The formulations became cloudy or turbid and did not
`in commercial applications. A reasonable minimum shelf
`is the time during which a solution
`that
`least about one year representing sufficient
`remains clear and retains its pharmaceutical activity is at
`too frequently. The
`ship and store a formulation without having to replace expired stock
`least one year. Thus the present
`invention have shown a shelf
`life of at
`solutions of
`the present
`entails an improvement over the formulations described in the 151 patent.
`formulation contains an active compound
`an opthalmic
`an ointment a suspension
`in the form of a solution
`is non-irritating to the eye and if
`acceptable if
`diffuses through the various ocular substructures
`
`s
`
`To
`
`1s
`
`20
`
`3o
`
`35
`
`40
`
`45
`
`50
`
`blood-aqueous
`pharmaco-2s
`ophthal-mologically
`
`In general
`
`acceptable excipients
`
`barrier and/or
`
`it
`
`and various ophthalmologically
`etc. An excipient
`
`is
`
`its active
`
`ingredient penetrates the
`to the site where it
`
`is
`
`logically
`
`a preservative
`
`a surfactant
`
`a buffering system a
`formulations must be
`
`active. The excipients can include a tonicifier
`a viscosity agent as well as other stabilizing agents. Ophthalmic
`chelating agent
`be preserved with an effective anti-microbial
`intended for multiple dosing regimens must
`sterile and
`
`if
`
`agent.
`
`acetate
`
`been
`
`to
`
`nitrate have
`and phenylmercuric
`thimerosal phenylmercuric
`e.g.
`Organo-mercurials
`however pose difficulties
`used extensively as the preservative in ophthalmic solutions. These compounds
`due to potential mercury toxicity as well as poor chemical stability. Benzalkonium chloride a quaternary
`be the
`solutions and
`ammonium compound
`has been widely used in ophthalmic
`is considered
`preservative of choice. However BAC has typically been considered to be incompatible with anionic drugs
`forming insoluble complexes which cause the solution to become cloudy
`e.g. salicylates or nitrates etc.
`turbid. Such a complex between the anionic drug and benzalkonium chloride can cause a decrease in
`or
`the pharmaceutical activity of the anionic drug.
`indomethacin
`Many NSAIDs such as ketorolac
`ocular use because of
`their activity as anti-inflammatory
`
`flurbiprofen
`
`and diclofenac
`
`are being developed for
`
`agents including their ability to prevent cystoid
`
`macular edema.
`
`as in the case with other ophthalmic drugs that contain a -COOH group antiinflammatory
`In the past
`solutions of NSAIDs for occular use have proven to be incompatible with quaternary ammonium compounds
`the -COOH group can form a complex with the
`is due to the fact
`that
`such as BAC. This incompatibility
`and
`quaternary ammonium compounds
`less available to serve its
`function
`rendering the preservative
`formulations have been prepared
`indomethacin
`the active
`ophthalmic
`reducing the activity of
`ingredient.
`solution an NSAID flurbiprofen
`solutions. Ocufen Ophthalmic
`these are suspensions
`however
`approved by the FDA for ophthalmic use incorporates th irnerosal with EDTA as its preservative system.
`benzalkonium
`formulation using ketorolac
`U.S. patent 4454151
`there is a disclosure of an ophthalmic
`the solution became cloudy or turbid after a
`and polysorbate 80 however
`chloride as the preservative
`
`not
`
`in
`
`short period of time.
`effective ophthalmic formulation with a
`It has remained desired to provide a stable clear antimicrobiaily
`-COOH group containing ophthalmic drugs especially NSAIDs using SAC as the
`
`prolonged shelf
`
`life for
`
`preservative.
`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.
`
`2
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`Page 2
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`

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`EP 0 306 984 Al
`
`include an ophthalmologically
`In one aspect of the invention these compositions
`NSAID a quaternary ammonium preservative and a stabilizing amount of an ethoxylated octylphenol
`in an aqueous vehicle.
`nonionic surfactant
`
`all
`
`as a
`
`effective amount of a
`
`amount of a
`effective
`including an ophthalmologically
`is an ophthalmic
`composition
`Another aspect
`NSAID a quaternary ammonium preservative and a stabilizing amount of an ethoxylated octyiphenol
`nonionic surfactant.
`
`as a
`
`amount of a
`effective
`including an ophthalmologically
`is an ophthalmic
`Another aspect
`composition
`NSAID benzalkonium chloride as a preservative and a stabilizing amount of an ethoxylated octylphenol as a
`nonionic surfactant.
`
`is an ophthalmic
`including an ophthalmologically
`composition
`Another aspect
`NSAIO benzalkonium chloride as a preservative and a stabilizing amount of Octoxynol
`surfactant.
`
`effective
`
`amount of a
`40 as a nonionic
`
`Another aspect
`
`is an ophthalmic
`
`composition
`
`effective
`
`amount of
`
`an ophthalmologically
`including
`acceptable salt thereof benzalkonium chloride as a
`ketorolac or an isomer an ester or a pharmaceutically
`preservative and a stabilizing amount of Octoxynol 40 as a nonionic surfactant.
`treating ophthalmic diseases in mammals using the
`the invention methods for
`In another aspect of
`the invention are also disclosed. These diseases are those that
`
`ophthalmic pharmaceutical
`are either caused by associated with or accompanied by inflammatory processes
`glaucoma cystoid macular edema uveitis diabetic retinopathy and conjunctivitis
`
`formulations of
`
`among others
`including
`or any trauma caused by
`
`20
`
`eye surgery or eye injury.
`
`Definitions
`
`s
`
`10
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`anti-inflam-matory
`
`indomethacin
`
`and the
`
`acceptable non-steroidal
`
`As used herein the term NSAID means an ophthalmologically
`drug. The NSAIDs
`include for example flurbiprofen ketorolac diclofenac
`isomers esters and pharmaceutically acceptable salts thereof.
`As used herein the term q.s. means adding a quantity sufficient
`bring a solution to the desired volume i.e. 100%.
`As used herein the term treatment or treating means any treatment of a disease in a mammal
`
`to achieve
`
`a state function e.g. to
`
`including
`i preventing the disease that is causing the clinical symptoms of the disease not to develop
`Inhibiting the disease that is arresting the development of clinical symptoms and/or
`ii
`relieving the disease that is causing the regression of clinical symptoms.
`
`Iii
`
`As used herein the term effective
`
`disease state being treated. This will vary depending
`
`amount means a dosage sufficient
`the disease and the treatment being
`on the patient
`
`to provide treatment
`
`for the
`
`effected.
`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.
`the term quaternary ammonium preservative
`As used herein
`compound such as described below.
`As used herein the term stabilizing means keeping a formulation clear and antimicrobially
`for its minimum reasonable shelf life e.g. at least one year.
`
`means a quaternary
`
`ammonium
`
`effective
`
`Formulations
`
`octyl-phenol
`
`amount
`
`for
`
`in an effective
`invention include an NSAID active
`The formulations of
`agent
`the present
`a quaternary ammonium preservative
`a stabilizing amount of an ethoxylated
`treatment
`ophthalmic
`as a nonionic surfactant optionally including other excipients such as a chelating agent a tonicifier
`and
`stabilizing agents. Ophthalmic
`solutions
`agent as well as other
`a buffering system a viscosity
`than an oily vehicle. Ophthalmic formulations must
`suspensions typically contain an aqueous vehicle rather
`intended for multiple dosing regimens must be antimicrobially effective for their minimum
`be sterile and if
`least one year and preferably two to three years or more. The ingredients
`commerically available or can be made by
`invention are typically
`the present
`
`reasonable shelf
`
`life e.g. at
`
`used in the formulations
`
`of
`
`3
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`Page 3
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`

`
`EP 0 306 984 Al
`
`methods readily known to those skilled in the art
`
`Pharmaceutical ophthalmic
`
`formulations
`
`typically
`
`wt/vol.
`
`to 10 %%
`
`if
`
`contain an effective amount e.g. 0.001 %a
`preferably 0.002% to 5% wt/vol most preferably 0.005% to 1 % wt/vol of an active ingredient e.g.
`invention. The amount of active
`the NSAID of the present
`ingredient will vary with the particular formulation
`of solutes should be such that
`and the disease state for which it
`is intended. The total concentration
`fluid though this is not absolutely necessary
`possible the resulting solution is isotonic with the lacrimal
`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
`
`Amount
`
`Active Agent
`
`Preservative
`
`Surfactant
`
`Other Excipients
`
`Purified Water
`
`0.001 % to 10.0% wt/vol.
`0.001% to 1.0% wt/vol.
`
`0.001% to 1.0% wt/vol.
`0% to 10.0% wt/vol. and
`q.s. to 100%.
`
`Optional other excipients
`
`such as a chelating agent and a tonicifier are used in the following approximate
`
`proportions
`
`Ingredient
`
`Amount
`
`chelating agent
`
`Tonicifier
`1 N NaOH or 1 N HCI
`
`0.01% to 1.0%wt/voi.
`isotonicity with lacrimal fluid and
`
`q.s. to achieve
`
`q.s. to adjust pH to 6.0 to 8.0.
`
`In a preferred ophthalmic NSAID solution the ingredients are combined in the following proportions
`
`Ingredient
`
`Amount
`
`NSAID
`BAC 50% aq. soln.
`Octoxynol 40 70% aq. soln.
`EDTA Nat
`
`0.002% to 5.0% wt/vol.
`
`0.002% to 1.0% wt/vol.
`0.001% to 1.0% wt/vol.
`0.01% to 1.0% wt/vol.
`
`NaCl
`1 N NaOH or 1 N HCI
`Purified Water
`
`q.s. for isotonicity with lacrimal
`q.s. to adjust pH to 7.410.4 and
`q.s. to 100%.
`
`fluid
`
`propor-tions
`
`In another preferred ophthalmic NSAID solution the ingredients are combined in the following
`
`Ingredient
`
`Amount
`
`NSAID
`BAC 50% aq. soln.
`Octoxynol 40 70% aq. soln.
`EDTA Nat
`NaCl
`1 N NaOH or 1 N HCI
`Purified Water
`
`0.005% to 1.0% wt/vol.
`
`0.002% to 1.0% wt/vol.
`
`0.001% to 1.0% wt/vol.
`
`0.01% to 1.0% wt/vol.
`
`q.s. for isotonicity with lacrimal
`q.s. to adjust pH to 7.410.4 and
`q.s. to 100%.
`
`fluid
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`5
`
`55
`
`In
`
`a more preferred
`
`ophthalmic
`
`NSAID
`
`solution
`
`the ingredients
`
`are combined
`
`in the
`
`following
`
`proportions
`
`4
`
`Page 4
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`

`
`EP 0 306 984 Al
`
`Ingredient
`
`NSAID
`BAC 50% aq. soln.
`Octoxynol 40 70% aq. soln.
`EDTA Nat
`NaCI
`1N NaOH or 1N HCI
`
`Purified Water
`
`Amount
`
`0.50% wt/vol.
`
`0.02% wt/vol.
`
`0.01% wt/vol.
`
`0.10% wt/vol.
`for isotonicity with lacrimal
`to adjust pH to 7.40.4 and
`to 100%.
`
`q.s.
`
`q.s.
`
`q.s.
`
`fluid
`
`The invention relates primarily to formulations having as the active agent ophthalmologically
`drugs including the isomers esters and pharmaceutically acceptable salts thereof that can form a complex
`with a quaternary ammonium compound particularly NSAIDs and drugs with a carboxyl group.
`for example ketorolac and the other
`this invention include
`NSAIDs useful
`in the practice of
`effective in U.S. Patent No. 4454151
`to Waterbury
`pounds described as being ophthalmologically
`herein by reference
`June
`12 1984 the pertinent portions of which are incorporated
`including the isomers esters and pharmaceutically
`flurbiprofen sodium and diclofenac
`thereof.
`
`issued
`
`indomethacin
`
`acceptable salts
`
`acceptable
`
`com-pounds
`com-pounds
`
`Preservatives useful
`
`in the formulations
`
`such
`
`pounds
`preferably benzalkonium chloride.
`
`as cetyltrimethylammonium
`
`invention include quaternary ammonium
`of
`the present
`bromide cetylpyridinium chloride and benzalkonium chloride
`
`in the formulations
`
`of the present
`
`invention are preferably ethoxylated
`The nonionic surfactants useful
`more preferably a homologous
`compounds
`such
`as octylphenoxypoly-ethyleneoxyethanols
`octylphenol
`series of surfactants sold under the trade name Igepal CA with a numerical suffix indicating the mole ratio of
`include Octoxynol 9 Octoxynol 12
`ratio being 3 to 40. Examples
`the
`ethylene oxide to octylphenol
`Octoxynol 13 and Octoxynol 40 and most preferably Octoxynol 40 manufactured and sold by GAF under
`the trade name igepal CA897 a 70% aqueous solution of Octoxynol 40.
`in the formulations
`of the present
`the chelating agents useful
`Among the optional excipients
`sulfate citric acid and preferably disodium edetate. Under certain conditions
`include 8-hydroxyquinoline
`the anti-microbial effect due to its ability to render essential metal
`the chelating agent may also enhance
`ions unavailable to the microbes.
`
`invention
`
`Buffering
`
`in the formulations
`
`of
`
`the present
`
`invention
`
`are based on for
`
`of
`
`invention include dextrose potassium
`
`Viscosity agents optionally
`
`derivatives such
`
`as hydroxypropylmethyl
`
`cellulose
`
`hydroxyethylcel-lulose.
`
`invention include stabilizing agents
`the present
`in the formulations
`Other optional exciplents useful
`such as antioxidants e.g. sodium metabisulfate and ascorbic acid depending on the NSAID used.
`the NSAID the preservative
`the solutes e.g.
`These formulations
`are prepared by dissolving
`in a suitable quantity of water adjusting the pH to
`the chelating agent and the buffering agent
`surfactant
`to 100% with
`about 6 to 8 preferably 6.8 to 8.0 and most preferably 7.4 making a final volume adjustment
`additional water and sterilizing the preparation using any suitable method known to those in the art.
`system of
`the preservative
`It has been discovered
`formulations
`incorporating
`that ophthalmic
`remain antimicrobially
`
`of
`
`the
`
`the
`
`invention
`
`are physically
`
`stable i.e.
`
`remain clear
`
`and
`
`functionally
`
`stable i.e.
`
`effective
`
`for at
`
`least the minimum reasonable shelf life of such products.
`
`Preferred Formulations
`
`The preferred preservative system of the invention includes a quaternary ammonium preservative and a
`stabilizing amount of a nonionic surfactant.
`
`the invention includes a NSAID active
`agent
`The preferred ophthalmic
`formulation of
`treatment and an antimicrobially effective amount of the above-described
`amount
`
`for ophthalmic
`
`in an effective
`
`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
`
`5
`
`systems optionally useful
`example citrate borate or phosphate.
`the present
`in the formulations
`Tonicifiers optionally useful
`chloride and/or sodium chloride preferably sodium chloride.
`useful
`in the formulations
`
`of
`
`the present
`sodium carboxymethylcellulose
`
`invention include the cellulose
`
`and
`
`5
`
`10
`
`25
`
`so
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`ss
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`50
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`Page 5
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`

`
`EP 0 306 984 Al
`
`chloride as the preservative.
`
`the invention is disodium edetate especially when combined with
`The preferred chelating agent of
`benzalkonium chloride as the preservative and Octoxynol 40 as the nonionic surfactant.
`the invention include a NSAID benzalkonium chloride Octoxynol
`
`The preferred ophthalmic solutions of
`40 and disodium edetate.
`A preferred ophthalmic NSAID solution the ingredients are combined in the following proportions
`
`Ingredient
`
`Amount
`
`NSAID
`BAC 50% aq. soln.
`Octoxynol 40 70% aq. soln.
`EDTA Nat
`NaCl
`1 N NaOH or 1 N HCI
`Purified Water
`
`0.002% to 5.0% wt/vol.
`0.002% to 1.0% wt/vol.
`0.001 % to 1.0% wt/vol.
`0.01% to 1.0% wt/vol.
`
`q.s.
`
`for isotonicity with lacrimal
`q.s. to adjust pH to 7.420.4 and
`to 100%.
`
`q.s.
`
`fluid
`
`Another preferred ophthalmic NSAID solution the ingredients are combined in the following proportions
`
`Ingredient
`
`Amount
`
`NSAID
`BAC 50% aq. soln.
`Octoxynol 40 70% aq. soln.
`EDTA Nat
`
`0.005% to 1.0% wt/vol.
`
`0.002% to 1.0% wt/vol.
`
`0.001% to 1.0% wt/vol.
`
`0.01% to 1.0% wt/vol.
`
`NaCl
`1 N NaOH or 1 N HCI
`Purified Water
`
`q.s.
`
`q.s.
`
`q.s.
`
`for isotonicity with lacrimal
`to adjust pH to 7.40.4 and
`to 100%.
`
`fluid
`
`A preferred ophthalmic NSAID solution has the following formulation
`
`Ingredient
`
`NSAID
`BAC 50% aq. soln.
`Octoxynol 40 70% eq. soln.
`EDTA Nat
`NaCl
`1 N NaOH or 1 N 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
`q.s. to adjust pH to 7.40.4
`to 100%
`
`q.s.
`
`fluid
`
`Most preferred is the ophthalmic
`Ketorolac Tromethamine or an isomer
`
`solution according to the above
`
`formulation wherein the NSAID is
`
`thereof.
`
`Utility and Administration
`
`processes
`
`of
`
`inflam-iiiatory
`pre-surgically
`
`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
`including. among others glaucoma cystoid macular edema uveitis diabetic re inopathy
`or any trauma caused by eye surgery or eye injury.
`and conjunctivitis
`this invention is both curative and preventative. Where applied for example
`The method of
`it prevents develpment
`i.e. before inflammation develops
`or immediately
`post-traumatically
`the named ophthalmic diseases it
`inflammation. When applied directly to the eye suffering from any of
`supresses already developed inflammatory processes.
`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
`
`5
`
`10
`
`15
`
`20
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`25
`
`30
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`
`40
`
`45
`
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`
`55
`
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`EP 0 306 984 Al
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`suspensions or ointments or by subconjunctival
`The dosage level will of course depend on the concentration of the drops the condition of the subject
`typical dosage ranges might be about 2
`and the individual magnitude of responses to treatment. However
`to 10 drops of 0.5% solution of active
`
`Ingredient per day.
`
`injection.
`
`5
`
`their preparation and administration
`For a more detailed discussion of ophthalmic
`formulations
`15th Ed. pages 1489-1504 1975.
`Remingtons Pharmaceutical Sciences
`
`see
`
`Testing
`
`10
`
`stability
`
`chemical
`
`stability
`
`the present
`both when
`
`two years. They are generally
`
`invention are typically tested for physical
`they are first manufactured and after a
`considered to be
`safe and clinically
`
`Ophthalmic formulations such as the solutions of
`and preservative efficacy
`time e.g. after
`fixed period of
`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
`its appearance e.g. color and clarity does not change and
`solution is considered to be physically stable if
`the pH remain constant within acceptable limits. Chemical stability involves a routine chemical analysis of
`its active ingredient and the excipients have not changed after a fixed period of
`the solution to be sure that
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`5o
`
`55
`
`f
`
`if
`
`time.
`
`described in the U.S. Pharmacopia Compendiary
`is tested by the procedure
`Preservative efficacy
`whereby a solution is challenged with a microbe and a determination is made as to whether
`
`the microbe
`
`survives in it.
`The following examples are given to enable those skilled in the art to more clearly understand and to
`invention. They should not be considered as a limitation on the scope of
`the invention
`practice the present
`but merely as being illustrative and representative thereof.
`
`EXAMPLE I
`
`This example illustrates the preparation of a representative pharmaceutical
`administration containing the NSAID Ketorolac Tromethamine.
`
`formulation for ophthalmic
`
`Ingredient
`
`Ketorolac Tromethamine
`BAC 50% aq. soln.
`Octoxynol 40 70% aq. soln.
`EDTA Nat
`NaCl
`
`Amount
`
`0.50% wt/vol.
`
`0.02% wt/vol.
`0.01 % wt/vol.
`0.10% wt/vol.
`
`0.79% wt/vol.
`
`The above
`
`active
`
`their
`
`ingredients are mixed adding purified water until
`they are dissolved
`the formulation is made up with purified water
`7.40.4 and the balance of
`make 100% volume. The solution is then sterilized.
`Other NSAIDs or
`isomers salts or esters such as those described above can
`compound in the preparation of the formulation of this example.
`
`the pH is adjusted to
`
`adding a quantity sufficient
`
`to
`
`be used as the
`
`EXAMPLE 2
`
`This example illustrates the preparation of a representative pharmaceutical
`administration containing the NSAID Ketorolac Tromethamine.
`
`formulation for ophthalmic
`
`7
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`Page 7
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`
`EP 0306984 Al
`
`ingredient
`
`Ketorolac Tromethamine
`BAC 50% aq. soln.
`Octoxynol 40 70% aq. soln.
`EDTA Nat
`NaCI
`
`Amount
`
`0.50% wt/vol.
`
`0.02% wt/vol.
`
`0.02% wt/vol.
`
`0.20% wt/vol
`
`0.79% wt/vol.
`
`The above
`
`their
`
`they are dissolved the pH is adjusted to
`ingredients are mixed adding purified water until
`the formulation is made up with purified water adding a quantity sufficient
`7.4-0.4 and the balance of
`make 100% volume. The solution is then sterilized.
`isomers salts or esters such as those described above
`Other NSAIDs or
`active compound in the preparation of the formulation of this example.
`
`to
`
`can be used as the
`
`EXAMPLE 3
`
`This example illustrates the preparation of a representative pharmaceutical
`administration containing the NSAID Ketorolac Tromethamine.
`
`formulation for ophthalmic
`
`Ingredient
`
`Ketorolac Tromethamine
`SAC 50% aq. soln.
`Octoxynol 40 70% aq. soln.
`EDTA Nat
`NaCl
`
`Amount
`
`0.10% wt/vol.
`
`0.004% wt/vol.
`
`0.004% wt/vol.
`
`0.05% wt/vol.
`
`0.88% wt/vol.
`
`they are dissolved the pH is adjusted to
`The above ingredients are mixed adding purified water until
`7.410.4 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 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
`administration containing the NSAID flurbiprofen sodium.
`
`formulation for ophthalmic
`
`Ingredient
`
`Flurbiprofen Sodium
`BAC 50% aq. soin.
`Octoxynol 40 70% aq. soin.
`EDTA Nat
`NaCl
`
`Amount
`
`0.03% wt/vol.
`
`0.02% wtivoi.
`0.01 % wt/vol.
`0.10./ wtjvol.
`
`0.90% wt/vol.
`
`the pH is adjusted to.
`they are dissolved
`ingredients are mixed adding purified water until
`the formulation is made up with purified water adding a quantity sufficient
`7.410.4 and the balance of
`make 100% volume. The solution is then sterilized.
`drugs and NSAIDs
`such
`Other ophthalmic
`compound in the preparation of the formulation of
`
`The above
`
`to
`
`as those described above can
`
`be used as the active
`
`this example.
`
`8
`
`5
`
`0
`
`75
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`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
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`Page 8
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`

`
`formula-s
`
`Physical stability of
`
`invention is measured by preparing clear
`the present
`the formulations of
`and observing
`shown in the table below sealing them in sterilized containers
`tions in the concentrations
`five months. Solutions that remain
`the solution after a period of one month and again after
`
`EP 0 306 984 Al
`
`EXAMPLE 5
`
`the clarity of
`
`io
`
`15
`
`20
`
`25
`
`so
`
`ss
`
`40
`
`45
`
`50
`
`55
`
`clear are considered stable in this procedure.
`invention have proven to be stable when tested in accordance with the
`The formulations of
`the present
`the invention did not
`above procedure. Formulations using surfactants other than the nonionic surfactants of
`remain clear and were not stable.
`
`their ability to dissolve the ketorolac - benzalkonium chloride
`Three surfactants were evaluated for
`time. The three surfactants
`complex and maintain a physically clear solution over an extended period of
`tested were Octoxynol 40 Polysorbate 80 Tween 80 and Myrj 52. Two concentrations of each surfactant
`and these were placed at various temperatures for future
`were incorporated into the ophthalmic formulation
`visual observations.
`
`Octoxynol 40
`
`Tween
`
`80
`
`Myrj 52
`
`0.004%
`
`0.02%
`
`0.0035%
`
`0.01%
`
`0.0015%
`
`0.01%
`
`1 month
`
`60
`
`a C
`40 C
`RT
`4.40 C
`
`5 month
`
`C
`
`C
`60
`40 C
`RT
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`clear
`
`very turbid
`
`very turbid
`
`turbid
`
`turbid
`
`clear
`
`turbid
`
`turbid
`
`turbid
`
`turbid
`
`clear
`
`turbid
`
`turbid
`
`clear
`
`turbid
`
`clear
`
`clear
`
`clear
`
`turbid
`
`turbid
`
`clear
`
`turbid
`
`clear
`
`clear
`
`clear
`
`turbid
`
`turbid
`
`of
`
`40 surfactant was superior
`to the other
`the 5 month time period it was apparent
`that
`the Octoxynol
`At
`80 and Myrj 52 displayed turbidity when stored at RT. The presence
`two surfactants. At 5 months Tween
`turbidity suggested the inability to solubilize a precipitate formation between the Ketorolac moiety and
`benzalkonium chloride.
`A further study has shown
`a 2 year shelf
`for the ophthalmic
`turbidity are not a problem with this formulation. Preservative efficacy is maintained throughout
`
`life
`
`formulation. Precipitate formation and
`
`the 2 year
`
`shelf
`
`life.
`
`EXAMPLE 6
`
`invention is measured by preparing formulations
`Preservative efficacy of the formulations of the present
`and subjecting them to the U.S. Pharmacopla antimicrobial
`e.g. according to the foregoing Examples
`
`challenge.
`The formulations of the present
`
`with the above procedure.
`
`invention demonstrate preservative efficacy when tested in accordance
`
`EXAMPLE 7
`
`this clinical efficacy study was to compare the effectiveness
`The objective of
`removal and intraocular
`with a control solution in reducing inflammation following cataract
`All patients underwent an extracapsular cataract extraction with intraocular
`treatment.
`
`and safety of ketorolac
`
`lens implantation.
`
`lens implantation 1 day following
`
`initiation of
`
`Ophthalmic examinations were performed preoperatively within 3 weeks of surgery and during the first
`
`9
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`EP 0 306 984 Al
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`week
`
`to 3 second week postoperative
`days 4 through 12 and
`third week
`days 1
`postoperative
`treatment. Particular attention was given to signs and symptoms
`days 15 through 27 or
`postoperative
`a scale of none mild
`assessed on
`consistent with inflammation. Among
`the ocular characteristics
`ciliary flush and the presence
`moderate or severe were lid edema corneal edema conjunctival
`of cells and flare in the anterior chamber.
`
`injections
`
`cyclitis iridocyclitis is by definition
`segment
`Anterior
`inflammation
`i.e.
`Fluorophotometry
`the blood-aqueous barrier. When inflammation is present a careful
`lamp examination will
`disruption of
`the eye. The clinical grading of cells and flare is a
`reveal cells and flare within the anterior chamber of
`these observations
`inflammation but consistent grading of
`measure of degree of anterior segment
`even by experts.
`
`iritis
`
`slit
`
`a
`
`is
`
`difficult
`
`5
`
`ro
`
`Ocular fluorophotometry
`
`intravascular cells and proteinaceous
`
`fluorescein. Furthermore
`
`the appearance of
`the breakdown of the blood-aqueous
`
`indication of
`
`15
`
`is consistently
`
`quantifiable. For
`
`these reasons
`
`to
`
`of
`
`fluorescein concentration of unoperated
`
`in
`
`the blood-aqueous barrier becomes permeable
`is based on the fact
`that
`fluid explaining the observed cells and flare and also to intravascular
`is a more sensitive
`fluorescein within the anterior chamber
`barrier than the gross observation of cells and flare and
`a Flurortrone Master Coherent Sunnyvale California
`this study was used. Following oral administration
`designed for
`software modifications
`complete with
`the aqueous barrier by measuring
`the fluorophotometer was used to determine the integrity of
`fluorescein
`the concentration of fluorescein in the anterior chamber.
`data were analyzed using the Wilcoxon Rank Sum Test or analysis of variance
`The fluorophotometry
`data by calculating the percentage difference in fluorescein concentration
`20 ANOVA of rank-transformed
`between the patients two eyes according to the formula
`of operated eye -
`fluorescein concentration
`Percent difference
`concentration of unoperated eye x 100.
`eye/fluorescein
`This calculation allowed and corrected for any interpatient variation in the timing and concentration of
`fluorescein administered.
`In this study the ketorolac
`for 21 days with either ketorolac or vehicle.
`129 patients began
`treatment
`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
`activity than the vehicle as measured by
`2 weeks ketorolac provide significantly greater anti-inflammatory
`than 40% difference
`fluorophotometry p
`0.019. When
`patients were excluded who
`had greater
`fluorescein concentration between eyes at baseline the p-value during week
`In addition the
`2 rose to 0.06.
`lamp examination e.g. eyelid edema p
`inflammation seen on slit
`vehicle-treated patients had more ocular
`folds p
`injection p
`0.001 and Descemet
`0.002 than did the ketorolac-treated
`0.001 conjunctival
`patients. Finally there were significantly more complaints p
`0.01 and more sever complaints consistent
`in the vehicle-treated
`group than in the
`inflammation photophobia iritis
`conjunctival
`injection
`
`with ocular
`
`ketorolac-treated group.
`In summary ketorolac solutions
`by patients having fewer
`lamp examination
`by routine slit
`inflammation as quantitated by fluorophotometry
`and milder adverse events and by infrequent need of additional corticosteroid therapy to control
`
`proved significantly
`
`superior
`
`inflamma-tion.
`
`to vehicle
`
`in treating postoperative
`
`EXAMPLE 8
`
`25
`
`so
`
`is
`
`40
`
`45
`
`so
`
`parallel comparison with vehicle to evaluate the efficacy of ketorolac 0.50
`This was a double-blind
`ophthalmic solution in reducing signs and symptoms of allergic conjunctivitis. Ketorolac 0.5% solution or a
`the same pH and tonicity were instilled four times daily into the eyes of patients with
`vehicle solution of
`allergic conjunctivitis ocular itching with and without eosinophils seen in conjunctival scrapings for 7 days.
`participated in the study. Following admission to the study
`Thirty patients with allergic conjunctivitis
`and final one-week examinations. At each
`for baseline mid-week
`patients reported to the investigator
`visual acuity external eye exam
`these visits patients received ophthalmic
`using s
`examinations
`biomicroscopy measurement
`examination.
`intraocular pressure and undilated ophthalmoscopic
`tory tests included a conjunctival scraping performed at baseline and the final exam.
`All patients completed the study. There were no adverse events
`or toxicities in patie