`(12) PATENT ABRIDGMENT
`(10) Acceptance No. 626798
`(19) AUSTRALIAN PATENT OFFICE
`
`(54) Title
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`International Patent Classification(s)
`(51) 4 A.61 K 031/40
`A61 K 031/13
`A61K 031/405
`(51)5 A61K 047/10
`(21) Application No. : 22042/88
`
`A61K 047/18
`
`A61 K 031/1 9
`
`A61 K 031/195
`
`(22) Application Date : 09.09.88
`
`(30) Priority Data
`(31) Number
`096173
`
`(32) Date
`11.09.87
`
`(33) Country
`US UNITED STATES OF AMERICA
`
`( 43) Publication Date : 16.03.89
`(44) Publication Date of Accepted ApplicJation: 13.08.92
`
`(71) Applicant(s)
`SYNT·EX (U.S.A.) INC.
`lnventor(s)
`CHERNG-CHYI ROGER FU; DEBORAH M. LIDGATE
`
`( 72)
`
`,
`(74) Attorney or Agent
`WATERMARK PATENT & TRADEMARK ATTORNEYS, Locked Bag 5, HAWTHORN VIC 3122
`
`{57) Claim
`An ophthalmic NSAID formulation comprising:
`l.
`a NSAID in an effective amount for ophthalmic treatme~t,
`a quater.nary ammonium preservative, a stabilizing amount
`of a nonionic ethoxylated octylphenol surfactant, and an
`aqueous vehicle.
`
`22.
`
`An antimicrobially effective ophthalmologicaily acceptable preservative system
`
`for ophthalmologically acceptable, carboxyl grou_p .. containing druqs, said preservative
`
`system comprising a qt~aternary ammonium preservative and a stabilizing amount of a
`nonionic ethoxylated octylphenol surfactant.
`
`----~~·--~--------------------------------------------·
`
`Metrics EX1011, Page 1
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`
`
`COMMONWEALTH OF AUSTRALIA
`
`PATENTS ACT 1952·69
`
`Form 10
`
`COMPLETE SPECIFICATION
`
`(ORIGINAL! 626798
`
`Class
`
`Int. Class
`
`Application Number:
`Lodged:
`
`Complete Specification Lodged:
`Accepted:
`Published:
`
`• • • •~riority:
`
`SYNTEX (U.S.A.) INC .
`
`3401 Hillview Avenue, Palo Alto, California 94304, United
`States of America
`
`CHERNG-CHYI ROGER FU and DEBORAH M. LIDGATE
`
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`Actual Inventor:
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`• • • • ·~ame of Applicant:
`
`Address of Applicant :
`•
`
`••
`
`Address for Service :
`
`EDWD. WATERS & SONS,
`50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
`
`Complete Speeification for the inventi.on entitled:
`
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`The foUowing statement is a full description of this invention, including the best method of performing it 'k"A~n 't'' ; ..
`
`us
`
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`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
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`BACKGROUND OF THE INVENTION
`The present invention relates to improved ophthalmic
`formulations, particularly to ophthalmic formulations for
`anti-inflammatory drugs, and specifically to ~n improved
`preservative system for ophthalmic formulations of
`carboxyl ("-COOH") 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 ret~nopathy, and
`conjunctiviti~, or any ttauma caused by eye surgery or
`eye injury •
`The topical use of NSAIDs~ particularly pyrrolo
`py~roles, in the treatment of ophthalmic diseases was
`first taught in u.s. Patent No. 4,454,151, where NSAID
`compounds (such as those described in U.Sw Patents
`4 , 0 8 9 , 9 6 9 ; 4 , 2 3 2 , 0 3 8 ; 4 , 0 8 7 ,53 9 and 4 , 09 7 , .57 9 ) were
`exemplified in formulation with NaH2Po 4 ·H 2o,
`Na2 HP04 ~ 2 o, NaCl, benzalkonium chloride ("BAG")
`and st~rilized water. While the formulations described
`
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`Metrics EX1011, Page 3
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`in the '151 patent were efficacious, an insoluble complex
`was found to form between the NSAID and the SAC. 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
`10 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
`over the formulations described in the '151 patent.
`rn general, an ophthalmic formulation contains an
`15 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
`20 and/or diffuses through the various ocular substructures
`to the site where it is pharmacologically active. The
`excipisnts can include a tonicifier, a preservative, a
`surfactant, a buffering system, a chelating agent~ a
`viscosity agent as well as other stabilizing agents~
`25 Ophthalmic formulations must be ~terile, and if intended
`for multiple dosing regimens, must be preserved with an
`effective anti-microbial agent.
`Organo-mercurials (e.g., thimerosal, phenylmercuric
`acetate and phenylmercuric nitrate) have been used
`30 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,
`35 and is considered to be the preservative of choice.
`
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`Metrics EX1011, Page 4
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`However~ BAC has typically been considered to be
`incompatible with anionic drugs (e.g., salicylates or
`nitrates, etc.), forming insoluble complexes which cause
`the solution to become cloudy or turbid. Such a complex
`5 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
`10 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
`15 solutions of NSAIDs for occular use have proven to be
`incompatible with quaternary ammonium compounds such as
`BAG. This incompatibility is due to the fact that the
`-GOOH 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
`In u.s. patent 4,454,151 there
`its preservative system.
`is a disclosure of an ophthalmic formulation using
`ketQrolac, benzalkonium chlOride (as the preservative)
`and polysorbate 80, however the solution became cloudy or
`30 turbid after a short period of time~
`It has remained desired to provide a stable, clear,
`antimicrobially effective ophthalmic formulation with a
`prolong~d shelf life for
`-GOOH group containing
`ophthalmic drugs, especially NSAIDs, using BAG as the
`35 preservative.
`
`25
`
`20
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`Metrics EX1011, Page 5
`
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`-4-
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`5
`
`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 oveF
`extended periods.
`In one aspect of the invention, these compositions
`include an ophthalmologically effective amount of a
`10 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 ophth~lmologically effettive amount of a
`NSAID, a quaternary ammonium preservate and q 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 an ethoxylated octylphenol as a
`nonionic surfactant •
`Another aspect is an ophthalmic compositio,n
`including an ophthalmologically effettive amount of a
`25 NSAID, benzalkonium chloride as a preservative a~d a
`stabilizing amount of Octoxynol 40 as a nonionic
`surfactant.
`Another aspect is an ophthalmic composition
`including an ophthaimologically effective amount of
`JO ketorolac or an isomer, an ester, oF a pharmaceutically
`acceptable salt thereof, benzalk.onium chloride as a
`preservative and a stabilizing amount of Octoxynol 40 as.
`a nonionic surfactant.
`
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`-5-
`
`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
`5 either caused by, associate~ 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 DESCRIPTIGN OF THE PREFERRED EMBODIMENTS
`Definitions
`As used herein. the term "NSAID" means an
`ophthalmologically acceptable non-steroidal
`anti-inflammatory drug. The NSAid's includej for
`example, flurbiprofen, ketorolac, diclofenac,
`indomethacin, Snd the isomers, ~sters, and
`pharmaceutically acceptable salts thereof.
`As usecl herein, the term "q.s." means adding a
`quantity sufficient to achie~e a stated function, e.g.,
`to 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~ including:
`(i) preventing the disease~ that is, causing the
`clinical symptoms of the disease not ~o develop;
`(ii)
`inhibiting the disease, that is, arresting the
`developm~nt 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.
`
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`As used herein, the term "antimicrobially effective"
`means ability to withstand the U.S. Pharmacopia
`antimicrobial challenge.
`As used herein, the term "surfactant" me~ns a
`5 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, e.g., at least one Jear.
`
`10
`
`15
`
`20
`
`Formulations
`The formulations of tha present invention include an
`NSAID active agent in an effective amount for ophthalmic
`treatment, a quaternary ammonium preservative, a
`stabilizing amount of an ethoxylated ootylphenol as a
`nonionic surfactant, optionally including other
`excipients such as a chelating agent, a tonicifier, a
`buffering systam, a viscosity agent as well as other
`stabilizing agents. Gphthalmic solutions and suspensions
`typically contain an aqueous vehicle rather than an oily
`vehicle. Ophthalmic formulations must be sterile, and if
`intended for multiple dosing reg.imen.s, must be
`antimicroblally effective for their minimum reasonable
`shelf life, e.g~, at least one yearr and preferably two
`to three years or more. The ingredients used in the
`formulations of the p.resent invention are typically
`30 commercially available or can be made by methods readily
`known to those skilled in the art.
`Pharmaceutical ophthalmic formulations typically
`contain an effective amount, e.g., o.OQl% to 10% wt/vol.,
`preferably 0.002% to 5% wt/vol, most preferably 0.005% to
`35 1% wt/vol of an active ingredient (e.g., the NSAID of the
`
`25
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`8408Y
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`26280-FF
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`Metrics EX1011, Page 8
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`
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`-7-
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`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:
`Amount
`Ingredient
`Active Agent
`0.001% to 10.0% wt/vol.;
`0.001% to 1.0% wt/vol.;
`Preservative
`Surfactant
`0.001% to 1.0% wt/vol.;
`0% to 10.0% Wt/vol.; and
`Other Excipients
`q.s. to 100% •
`Purified Water
`Optional other exc!pients, such as a chelating agent and
`a tonicifier, are Used in the following approximate
`proportions:
`Ingredient
`Chelating agent
`Tonicifier
`
`5
`
`10
`
`15
`
`20
`
`Amount
`0.01% to l.O%wt/vol.;
`q.s. to achieve
`isotonicity with
`lacrimal fluid; and
`q.s. to adjust pH to
`6.0 to 8.0 •
`
`25
`
`lN NaOH or lN HC1
`
`30
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`In a preferred ophthalmic NSAID solution, the
`ingredients are combined in the following proportions:
`Ingredient
`Amount
`to 5.0% wt/vol.;
`NSAID
`0.002%
`BAC
`0.002% to 1.0% wt/vol.;
`(50% aq. soln.)
`Octoxynol 40
`(70% aq. soln.)
`EDTA Na2
`NaCl
`
`0.001% to 1.0% wt/vol.;
`
`0.01% to 1.0% wt/vol.;
`q,s. for isotonicity with
`lacrimal fluid;
`lN NaOH or lN HCl q.s. to adjust pH to
`7. 4 ±0. 4; and
`q. s. t 0 100%.
`
`Purified Water
`
`the
`In another preferred ophthalmic NSAID solution 1
`ingredients are combined in the following proportions:
`Amount
`Ingredient
`NSAID
`to 1.0% wt/vol.;
`0.005%
`0.002% to 1~0% wt/vol.;
`SAC
`(50% aq. soln.)
`Octoxynol 40
`(70% aq. soln.)
`EDTA Na2
`NaCl
`
`0.001% to 1.0% wt/vol.;
`
`0.01% to 1.0% wt/vol.;
`q.s. for isotonicity with
`lacrimal fluid;
`lN NaOH or lN HCl q.s. to adjust pH to
`7.4±0.4; and
`q.s. to 100%.
`
`Purified Water
`
`5
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`10
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`15
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`20
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`Metrics EX1011, Page 10
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`-
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`- --- - ~-------------------
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`In a more preferred ophthalmic NSAID solution, the ingredients are combined in
`
`9
`
`the following proportions:
`lngredjent
`
`5
`
`NSAID
`Bf\C
`
`(50% aq. soln.)
`
`Octoxynol 40
`(70% aq. soln.)
`EDTANa2
`
`Amount
`
`0.50% wtlvol.;
`
`0.02% wtlvol.;
`
`0.01% wt/vol.;
`
`0.10% wt/vol.;
`
`1 0
`
`NaCI
`
`1N NaOH or 1N HCI
`
`Purified Water
`
`q.s. for isotonicity with lacrimal
`
`fluid;
`q.s. to adjust pH to 7.4 ± 0.4; and
`q.s. to 1 00%.
`
`1 5
`
`The invention relates primarily to formulations having as the active agent
`ophthalmologically acceptable drugs [including the isomers (as either the (d)- or (1 )-
`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.
`
`2 0
`
`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
`No. 4,454,151 to Waterbury, issued June 12, 1984, the pertinent portions of which
`are
`incorporated herein by reference),
`indometnacin,
`flurbiprofen sodium, and
`
`diclofenac, including t_he isomers, esters and pharmaceutically acceptable salts thereof.
`Preservatives useful in the formulations of the present invention include
`
`2 5
`
`quaternary ammonium compounds, such as cetyltl'imethylammonium bromide,
`cetylpyridinium chloride and benzalkonium chloride, preferably, benzalkonium chloride.
`
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`The nonionic surfactants useful in the formulations
`of the present invention are preferably ethoxylated
`octylphenol compounds, such as octylphenoxypoly(cid:173)
`(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 40.
`Examples include Octoxynol 9, Octoxynol 12, Octoxynol 13,
`and Octoxynol 40, and most preferably Octoxynol 40,
`10 manufactured and sold by GAF under the trade name Igepal
`CA897 (a 70% aqueous solution of Octoxynol 40).
`Among the optional excipients, the chelating agents
`useful in the formulations of the present invention
`include a-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
`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
`chloride.
`Viscosity agents optionally useful in the
`formulations of the present invention include the
`cellulose derivatives such as hydroxypropylmethyl
`cellulosej sodium carboxymethylcellulose, and
`30 hydroxyethy !cellulose.
`Other optional excipients useful in the formulations
`of the present invention include stabilizing agents such
`as antioxidants, e.g. 1 sodium metabisulfate and ascorbic
`acid, depending on the NSAID used.
`
`15
`
`20
`
`25
`
`35
`
`8408Y
`
`26280-FF
`
`Metrics EX1011, Page 12
`
`
`
`These formulations are prepared by dissolving the
`solutes (e.g., 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 (i.e.~ remain clear) and functionally
`stable (i.e., remain antimicrobially effective) for at
`least the minimum reasonable shelf life of such products.
`
`5
`
`10
`
`2(}
`
`15 Preferred Formulations
`The preferred presetvative 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 amnunt 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
`30 disodium edetate, es~ecially 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
`35 disodium edetate.
`
`25
`
`840SY
`
`2628Q ... f~
`
`•• •
`• • •
`• • •
`••••
`•
`••••
`•
`•
`••
`•
`•• •
`
`....
`....
`. . .
`. ..
`. . .
`. ..
`. • •
`
`• ••
`• ••
`• ••
`• • •
`• ••
`••••
`
`• • .
`.. •
`.....
`• . •
`
`••
`
`•
`
`Metrics EX1011, Page 13
`
`
`
`-12-
`
`•• •
`• • •
`
`•
`
`. .. .
`.... •
`.... ....
`....
`.. •
`•
`. • •
`. ..
`. • •
`
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`•
`
`.. • •
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`. • •
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`
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`••
`•
`
`. -
`
`••••
`• •
`•• •
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`A preferred ophthalmic NSAID solution, the
`ingredients are combined in the following proportions:
`Ingredient
`Amount
`to 5.0% wt/vol.;
`NSAID
`0.002%
`BAC
`0.002% to 1.0% wt/vol.;
`(50% aq. so ln.)
`Octoxynol 40
`(70% aq. soln.)
`EDTA Na 2
`NaCl
`
`0.001% to 1.0% wt/vol.;
`
`lN NaOH or lN HCl
`
`Purified Water
`
`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% •
`
`Another preferred ophthalmic NSAID solution, the
`ingredients are combined in the following proportions:
`Ingredient
`Amount
`to 1.0% wt/vol.;
`NSAID
`0.005%
`BAC
`0.002% to 1.0% wt/vol.;
`(50% aq. soln.)
`Octoxynol 40
`(70% aq. soln.)
`EDTA Na 2
`NaCl
`
`0.001% to 1.0% wt/vo1.;
`
`lN NaOH or lN HCl
`
`Purified Water
`
`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%.
`
`8408Y
`
`26280-FF
`
`Metrics EX1011, Page 14
`
`
`
`,
`
`-13-
`
`A preferred ophthalmic NSAID solution has the
`following formulation:
`Ingredient
`NSAID
`BAC
`(50% aq. soln.)
`Octoxynol 40
`(70% aq. soln.)
`EDTA Na2
`NaCl
`
`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
`q.s • to 100%
`
`lN NaOH or lN HCl
`
`P L.r if i e d Water
`
`5
`
`10
`
`15
`
`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 iA mammals. These diseases are either caused
`by, associated with or accompanied by inflammatory
`25 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 inventio,n is both curative and
`30 preventative. Where ~pplied, for example, pre-surgically
`or immediately post-traumatically, i.e. before
`inflammation develops, it prevents develop·ment of
`inflammation. When applied dir.ectly to. the eye suffering
`from any of the n~med ophthalmic diseases, it supresses
`35 already developed inflammatory processes.
`
`8408Y
`
`26280-FF
`
`l
`
`••
`•
`••••
`••••
`•••-o
`•• •
`• • •
`•• •
`•
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`
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`. .
`. . ..
`. . . . -..: .. , ..
`.. . ..
`....
`-. . -.
`••••
`•• •
`
`•••
`
`••••
`• • •
`•• •
`
`~
`,_ --'--'*
`•
`
`Metrics EX1011, Page 15
`
`
`
`1
`
`~ '
`
`•• •
`• • •
`• • •
`••••
`•
`••••
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`••••
`•• •
`
`-14-
`
`5
`
`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 josage ranges might be about 2 to 10
`10 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., pa.ges
`1489-1504, (1975) •
`
`15
`
`20
`
`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 ate first Manufactured and after a fixed
`period of time (e.g., after twD years). They ar9
`generally considered ta be safe and clinically acceptable
`if proven to be well t1)lerated 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 (e.g., color and clarity) does not change and
`1 f the pH rem~lins constant, within acceptable limits.
`Chemical s-tability involves a routine chem.ical analysis
`30 of the solution, t:o be sure that its active ingredient
`and the excipients have not changed after a fixed period
`of time.
`Preservative eff ica·cy is testad by. the procedure
`described Ln the u.s. Pharmacopia Compendiary, whereby a
`
`25
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`35
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`8408Y
`
`26280-FF
`
`Metrics EX1011, Page 16
`
`
`
`••
`•
`• • •
`• • •
`••••
`•
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`•
`···~
`•
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`..
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`
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`.....
`
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`
`lj>o
`
`-1.5-
`
`solution is challenged with a microbe and a determination
`is made as to whether the microbe survives in it.
`
`5
`
`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,
`10 but merely as b.eing i llust rat i ve and representative
`thereof.
`
`15
`
`20
`
`25
`
`EXAMPLE 1
`
`This example illustrates the preparation of a
`repres-entative pharmaceutical formu.lation for ophthalmic
`administration containing the NSAID Keto~olac
`Tromethamine.
`
`Ingredient
`Ketoro,lac Tromethamine
`BAC
`(50% aq • soln.)
`Octoxynol 40
`(70% aq. soln.)
`EDTA Na 2
`NaCl
`
`Amount
`0 . .50% wt /val.
`0.02% wt/vol.
`
`O.Dl% wt/vol.
`
`0.10% wt/vol.
`0.79% wt/vol.
`
`The above in9redients are mixed, adding purified
`30 water until they are dissolved, the pH is adjusted to
`7.4±0.4 and the balance of the formulation is made up
`with ~urified water, adding a quantity sufficient to make
`lGO% volume. The solution is then sterilized.
`Other NSAIDs or their isomers, salts or esters, such
`35 as those described above, can be used a~ the active
`
`8408Y
`
`26280-FF
`
`t
`
`I
`
`Metrics EX1011, Page 17
`
`
`
`t
`
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`• • •
`• • •
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`•
`••••
`·-···
`•
`•
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`
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`
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`
`.....
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`.....
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`
`-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.
`
`Amount
`Ingredient
`Ketorolac Tromethamine 0.50% wt/vol.
`BAC
`0.02% wt/vol •
`(50% aq. soln.)
`Octoxynol 40
`00% aq. soln.)
`EDTA Na 2
`NaCl
`
`0.20% wt/vol.
`.0. 79% wt/v"ol.
`
`0. 02% wt./vol.
`
`The above ingredients are mixed, adding purified
`water until they are dissolvedi the pH is adjusted to
`7~4:!:0.4 and the balance of the formulation is made up
`with purified water, adding a. quantity suffieient to make
`100% volume. The solution is then sterilizedr
`Other NSAIDs or their isom·ers, salts or esters, such
`as those described above, can be used as the active
`compound in the preparation of the formulati~n of this
`example.
`
`EXAMPLE 3
`
`This example illustrates the preparation of a
`repres~ntative pharmaceutical formulation for ophthalmic
`
`840.8Y
`
`26280-FF
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Metrics EX1011, Page 18
`
`
`
`-17-
`
`administration containing the NSAID Ketorolac
`Tramethamin'9.
`
`Amount
`0.10% wt/vol.
`0.004% wt/vol.
`
`0.-004% wt/vol.
`
`5
`
`10
`
`Ingredient
`Ketarolac Tramethamine
`SAC
`(SO% aq. saln.)
`Octoxynol 40
`(70% aq. soln.)
`0.05% wt/vol.
`EDTA Na2
`0. 88% wt/vol.
`NaCl
`The above ingredients are mixed, adding purified
`water until they are dissolved, the pH is adjusted to
`7.4~.4 _and the balance of the formulation is made up
`15 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.
`
`20
`
`EXAMPLE 4
`
`This example illustrate~ the preparation of a
`representative pharmaceutical formulatio1'1 for ophthalmic
`25 administratiQn containing the NSAID f lurbiprofen sodium •
`
`Amount
`().03% wtlvol.
`0. 02% wt/vol.
`
`~ngredient
`Flurbiprofen Sodium
`BAC
`(50% aq. soln.)
`Octoxynol 40
`(70% aq. soln.)
`EDTA Na2
`0.10% wt/vol.
`NaCl
`Q.90% wt/vol.
`The above ingredients are mixed, adding purified
`
`O.OHl wt/vol.
`
`30
`
`35
`
`8408Y
`
`26280-FF
`
`l
`
`1
`
`. .. .
`•• •
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`••••
`•
`•
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`• ••
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`• ••
`
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`•••
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`•• •
`
`••••
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`•
`
`L-~----
`
`Metrics EX1011, Page 19
`
`
`
`- -- --~----~----------------
`
`'
`
`-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 NSA!Ds, such as those
`described above, can be used as the active compound in
`the preparation of the formulation of this example.
`
`EXAMPLE 5
`
`5
`
`10
`
`••
`•
`• • •
`•••• .
`• • •
`••••
`. •
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`••••
`••
`•
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`. • •
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`. • •
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`-· ••
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`••••
`••
`•
`....
`• . •
`
`••
`
`•
`
`• I
`
`15
`
`20
`
`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 tont~iners, and
`observing the clarity of the solution after a period of
`one month and again after five months, Solutions that
`remain clear are considered stable in this procedure .
`The formulations of the present invention have
`proven to be stable when tested in accordance with the
`above procedure.. Formwlations using surfactants other
`than the nonionic surfactant;s of t.he invention did not
`remain clear and were not ~table •
`Three surfactants were evaluated for their ability
`to dissolve the ketorolac - benzalkonium chloride complex
`and maintain a physically tlear solution over an extended
`period of tim.e. The three surfactants tested w·ere:
`Octoxynol 40; Polysorbate 80 (Tween 80); and Myrj 52 .
`Two concentrations of each surfactant were incorporated
`into the ophthalmic formulation, and these were placed at
`30 variGus temperatures fGr ·future visual Gbservations.
`
`25
`
`35
`
`8408Y
`
`26280-FF
`
`Metrics EX1011, Page 20
`
`
`
`----------------------------------------·
`
`-19-
`
`Octoxynol 40
`0.004% 0.02%
`
`Tween 80
`0.0035% 0.01%
`
`Myrj 52
`0.0015% 0.01%
`
`5
`
`1 month
`60°C
`40°C
`
`clear clear
`clear clear
`
`RT
`4-40°C
`
`clear clear
`clear