United States Patent
`
`19
`
`Cherng-Chyi et al
`
`ii44i4iiiýiiiýtiiitiyiýý44ý4ýtiti4iii4ti4ii4ii44iii44i4i444ti4ii4tiii4i4i4ýtii44i
`
`U S005110493A
`Patent Number
`
`Date of Patent
`
`it
`
`45
`
`5110493
`May 5 1992
`
`Pseudomo-751
`Antibacte-73
`Non-51
`Sup-plement
`Toi-doned.
`
`830864
`
`3/1960
`
`United Kingdom
`
`OTHER PUBLICATIONS
`
`v 42 pp.
`
`Fraser-Smith et at. Effect of Ketorolac on
`3. Ocular Pharmacol.
`nas aeruginosa ..
`101-109 1988.
`Influence of Ethoxys Octyl Phenol on the
`rial Properties of Preservatives M. T. Nadir et al.
`Journal of Pharmacy and Pharmacology
`vol. 29
`Dec. 1977 p. 67P.
`Ocufen flurbiprofen sodium 0.03% Liquifilm sterile
`ophthalmic
`solution Allergan product
`description
`sheet one page.
`CTFA Cosmetic Ingredient Dictionary Cosmetic
`letry and Fragrance Association Inc. pp. 187-188.
`Schmolka Irving R. The Synergistic Effects of
`ionic Surfactants Upon Cationic Germicidal Agents J.
`Soc. Cosmet. Chem. 24 577-592 Aug. 9 1973.
`The Condensed Chemical Dictionary
`Seventh Ed.
`Reinhold Publishing Co. N.Y. p. 985.
`McCutcheons Emulsifiers
`Detergents North
`American Edition 1982 p. 154.
`
`54 OPHTHALMIC NS AID FORMULATIONS
`CONTAINING A QUATERNARY
`AMMONIUM PRESERVATIVE
`NONIONIC SURFACTANT
`
`AND A
`
`Inventors Roger F. Cherng-Chyi Deborah M.
`Lidgate both of Los Altos Calif.
`
`Assignee
`
`Syntex U.S.A. Inc. Palo Alto Calif.
`21 Appl. No. 624027
`22 Filed
`Dec. 7 1990
`
`Related U.S. Application Data
`
`63
`
`Continuation
`
`of Ser. No. 96.173 Sep. 11 1987 aban-
`
`Int. CI.S .............................................
`52 U.S. Cl....................................
`
`58 Field of Search
`
`......................
`
`A61K 31/40
`514/413 252/106
`514/912 514/914
`514/413 912 914
`252/106
`
`56
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4087538
`4.087.539
`
`4.089.969
`
`4336.152
`
`4474751
`4474811
`4500538
`4.559.343 12/1985
`
`4.607038
`
`8/1986
`
`Portnoff
`2/1978
`2/1978 Muchowski
`3/1978 Muchowski
`5/1978 Muchowski
`4.097.579
`et at ...............
`4230.724
`10/1980 Cooper et al ......................
`4.232.038 10/1980 Kluee et at
`3/1982
`Like et al ...........................
`3/1982
`Like et a1
`2/1984 Waterbury .........................
`10/1984 Haslam et al ......................
`10/1984 Masuda et al ......................
`2/1985 Woltersdorf
`Han et at
`Ogata et al
`PATENT DOCUMENTS
`
`.............................
`
`et al ...............
`
`et al ...............
`
`........................
`
`...........................
`
`.......................
`
`............................
`
`..............
`
`514/914
`
`424/274
`
`424/274
`
`424/274
`
`514/912
`
`424/274
`
`252/106
`
`252/106
`
`424/274
`
`514/912
`
`514/912
`
`514/367
`
`514/264
`
`514/291
`
`Primary Examiner-A. Lionel Clingman
`Assistant Examiner-Mary C. DiNunzio
`Attorney Agent or Firm-Derek P. Freyberg Karl
`Bozicevic
`
`57
`
`ABSTRACT
`
`ophthalmic
`
`ophthalmologically
`
`effective
`
`Stable clear antimicrobially effective
`an
`mutations
`include
`amount of a drug especially a -COOH
`a NSAID and
`ing drug or
`a preservative
`system
`formed of a quaternary ammonium preservative and a
`vehicle. These
`nonionic
`in an aqueous
`surfactant
`formulations are useful
`that are
`for treating diseases
`either caused by associated with or accompanied by
`inflammatory processes including among others
`coma cystoid macular edema uveitis diabetic
`pathy and conjunctivitis or any trauma caused by eye
`surgery or eye injury.
`
`all
`
`for-4336.151
`group-contain-4454.151
`glau-FOREIGN
`retino-0038698
`
`3026402
`
`23318
`8504106
`
`10/1981
`
`Pat. Off..
`European
`Fed. Rep. of Germany
`2/1982
`2/1985 -Japan
`PCT Intl Appl..
`9/1985
`
`16 Claims No Drawings
`
`EXHIBIT
`
`2InnoPharma
`
`EX1063
`
`IPR2015-00902
`
`IPR2015-00903
`
`ýý-v
`
`ed
`
`

`
`1
`
`5110493
`
`OPHTHALMIC NSAID FORMULATIONS
`AMMONIUM
`CONTAINING A QUATERNARY
`AND A NONIONIC
`PRESERVATIVE
`
`5
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`abandoned.
`
`especially
`
`non-steroidal
`
`anti-inflammatory
`
`drugs
`
`BACKGROUND OF THE INVENTION
`The present
`invention relates to improved ophthal-
`mic formulations particularly to ophthalmic
`formula-
`tions for anti-inflammatory drugs and specifically to an
`improved preservative system for ophthalmic
`formula-
`of carboxyl -COOH group-containing drugs
`NSAIDs.
`The invention also relates to methods of using these
`for treating diseases that are either caused
`associated with or accompanied by inflammatory
`processes including among others glaucoma cystoid
`macular edema uveitis diabetic retinopathy
`and
`or any trauma caused by eye surgery or eye
`
`con-junctivitis.
`
`injury.
`
`use of NSAIDs particularly pyrrolo
`topical
`diseases was
`pyrroles in the treatment of ophthalmic
`in U.S. Pat. No. 4454151 where NSAID
`taught
`first
`compounds such as those described in U.S. Pat. Nos.
`4089969 4232038 4087539 and 4097579 were ex-
`emplified in formulation with NaH2PO4.H2O Na2H-
`
`P04.H20 NaCl. benzalkonium chloride BAC and
`
`life is at
`
`it
`
`ac-
`
`a
`
`ophthalmic
`
`15
`
`20
`
`taining ophthalmic drugs.
`
`25
`
`It has now been discovered that stable i.e. clear and
`antimicrobially effective NSAID-containing
`mic formulations can be prepared that do not
`
`include an
`
`all
`
`in an
`
`preservative.
`30 organo-mercurial
`In one aspect of the invention these
`compositions
`effective amount of a
`include an ophthalmologically
`NSAID a quaternary ammonium preservative
`and a
`amount of a nonionic
`surfactant
`stabilizing
`vehicle.
`35 aqueous
`Another aspect
`is an antimicrobially effective
`drugs having a -COOH
`vative system for ophthalmic
`group including a quaternary ammonium preservative
`and a stabilizing amount of a nonionic surfactant.
`In a third aspect of the invention methods for
`diseases in mammals using the
`ing ophthalmic
`mic pharmaceutical
`formulations of the invention
`are
`also disclosed. These diseases are those that are either
`caused by associated with or accompanied by
`45 matory processes including among others glaucoma
`cystoid macular edema uveitis diabetic retinopathy
`and conjunctivitis or any trauma caused by eye surgery
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`DEFINITIONS
`As used herein the term NSAID. means an
`non-steroidal
`thalmologically acceptable
`
`2
`to be incompatible with anionic drugs e.g. salicylates
`or nitrates. etc. and can be inactivated by surfactants.
`Many NSAIDs such as ketorolac
`indometlacin
`flurbiprofen and suprofen are being developed for
`lar use because of their activity as anti-inflammatory
`agents as well as their ability to prevent cystoid macular
`edema.
`These NSAIDs have proven to be incompatible with
`as BAC
`quaternary ammonium compounds
`such
`This application is a continuation of our copending
`filed Sep. 11 1987 now ýý cause they can form a complex with them rendering the
`Ser. No. 07/096173
`preservative less available to serve its function as is the
`contain
`drugs that
`case with other
`a
`-COOH group. Thus less preferred
`preservatives
`formulations. For
`have been used in such ophthalmic
`example Ocufen Ophthalmic solution the first NSAIID
`flurbiprofen approved by the FDA for ophthalmic
`use incorporates thimerosal with EDTA as its
`vative system.
`It has
`remained desired to provide a stable clear
`formulation for
`antimicrobially effective
`ophthalmic
`NSAIDs using BAC as the preservative
`and an
`proved preservative system for -COOH group
`
`ocu-SURFACrANT
`be-application
`preser-tions
`con-by
`im-formulations
`ophthal-The
`preser-151
`treat-mum
`ophthal-sufficient
`inflam-over
`oint-ment
`oph-surfactant
`anti-inflamma-cosity
`quan-multiple
`includ-extensively
`regres-choice.
`
`sterilized water. While the formulations described in the
`patent were efficacious.
`a complex was found to
`form between the NSAID and the BAC. The formula-
`therefore have
`tions did not
`the stability desired for
`shelf life in commercial applications. A reasonable mini- 40
`least about one year representing
`shelf
`time to package ship and store a formulation
`without having to replace expired stock too frequently.
`Thus the present
`entails an improvement
`invention
`the formulations described in the 151 patent.
`formulation contains an
`In general
`an ophthalmic
`and various ophthalmologically
`active compound
`in the form of a solution an
`ceptable excipients
`a suspension etc. An excipient
`ophthalmologi-cally
`is
`is non-irritating to the eye and if its 50
`acceptable
`if
`active ingredient penetrates the blood-aqueous barrier
`and/or difuses through the various ocular substructures
`active. The
`to the site where it
`is pharmacologically
`excipients can include a tonicifier
`a preservative
`a buffering system a chelating agent a vis- 55
`agent as well as other stabilizing agents. Ophthal-
`mic formulations must be sterile and if
`intended for
`dosing regimens must be preserved with an
`effective anti-microbial agent.
`Organo-mercurials e.g. thimerosal phenylmercuric
`been used
`nitrate have
`and phenylmercuric
`acetate
`as the preservative in ophthalmic solutions.
`due to
`These
`however
`compounds
`pose difficulties
`potential mercury toxicity as well as poor chemical
`-arar ammo-
`chloride a qa.mpaterný
`stability Benzalkonismt
`a
`compound
`has been widely used in ophthalmic
`and is considered to be the preservative of
`solutions
`However BAC has typically been considered
`
`ý-nium
`
`60
`
`_ GS
`
`Tory drug.
`As used herein the term q.s. means adding a
`tity sufficient
`to achieve 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
`ing
`i preventing the disease that
`is causing the clinical
`to develop
`symptoms of the disease not
`t disease
`is arresting the de.dev.e1
`
`the diseasethatthat
`inhibia
`opment of clinical symptoms and/or
`relieving the disease that
`is causing the
`sion of clinical symptoms.
`
`ii
`
`iii
`
`is
`
`Page 2
`
`

`
`3
`As used herein the term effective amount means a
`for the disease
`to provide treatment
`sufficient
`dosage
`vary depending on the
`state being treated. This will
`the disease and the treatment being effected.
`patient
`As used herein the term antimicrobialiv effective
`means ability to withstand the U.S. Pharmacopia anti-
`microbial challenge.
`As used herein the term stabilizing means keeping
`a formulation clear and antimicrobially effective for its
`minimum reasonable shelf
`least one year.
`g. at
`FORMULATIONS
`
`life e.
`
`5110493
`
`4
`
`-continued
`
`ingredient
`
`BAC
`50% aq solo.
`Ocioxynol 40
`705 aq. soln.
`EDTA Nat
`NaCl
`
`IN NaOH or IN HC1
`
`5
`
`10
`
`Amount
`
`0.02% wvvol.
`
`0.01% wt/%-ol.
`
`0.10% wt/vol..
`
`for isotonicity with
`q.s.
`lacrimal fluid
`q.s. to adjust pH to
`7.4
`0.4. and
`
`Purified water
`
`q.s.
`
`to. 10017c.
`
`ac-stabilizing
`in-pensions
`
`20
`
`The formulations of the present
`invention include a
`NSAID active agent
`in an effective amount
`for ophthal-
`mac tctats5tm a sýuatessasy amines
`a 15
`sr psestscattivt
`amount of a nonionic surfactant optionally
`including other excipients such as a chelating agent
`a
`tonicifier a buffering system a viscosity agent as well as
`solutions and sus-
`other stabilizing agents. Ophthalmic
`typically contain an aqueous
`vehicle rather
`formulations must be
`than an oily vehicle. Ophthalmic
`sterile and if
`intended for multiple dosing regimens
`their minimum
`must be antimicrobially effective for
`reasonable shelf life e.g. at least one year and prefera-
`bly two to three years or more. The ingredients used in 25
`the formulations of the present
`invention are typically
`be made by methods
`available or can
`commercially
`readily known to those skilled in the art.
`ophthalmic
`Pharmaceutical
`formulations
`0.001 % to 10%
`an effective amount e.g.
`0.005% to 1% of an active
`wt/vol. most preferably
`ingredient e.g. the NSAID of the present
`invention
`The amount of active ingredient will vary with the
`formulation and the disease state for which it
`particular
`is intended. The total concentration of solutes should be
`such that
`if possible the resulting solution is isotonic
`the lacrimal
`fluid though this is not absolutely
`and has a pH in the range of 6-8.
`formulations of the present
`are pre-
`invention
`pared as solutions incorporating the above-described
`ingredients within the following approximate ranges
`
`typically
`
`30
`
`35
`
`The invention relates primarily to formulations hav.
`ing as the active agent ophthalmologically acceptable
`drugs including the esters and pharmaceutically
`ceptable salts thereof that can form a complex with a
`ammonium
`compound
`quaternary
`particularly
`NSAIDs and drugs with a carboxyl group.
`NSAIDs useful
`in the practice of this invention
`diode for example ketorolac and the other compounds
`described as being ophthalmological y effective in U.S.
`Pat. No. 4454151 to Waterbury issued Jun. 12 1984
`the pertinent portions of which are incorporated herein
`by reference indomethacin
`flurbiprofen sodium and
`suprofen
`the esters and pharmaceutically
`including
`acceptable salts thereof.
`Preservatives useful
`in the formulations of the present
`include quaternary ammonium compounds
`as cetyltrimethylammonium bromide
`such
`dinium chloride and preferably benzalkonium chloride.
`The nonionic surfactants useful
`in the formulations of
`the present
`invention are preferably
`surfactants
`
`invention
`
`polyoxyethylated
`
`hydrogenated
`including
`polyoxyethylene
`60 hydrogenated
`vegetable oils such as polyethylene
`and sold by Kao Corp. of
`castor oil manufactured
`Japan under the trade name Emanon CH-60 and
`such as
`compounds
`ably ethoxylated octylphenol
`toxynol 10 and most preferably Octoxynol 40
`40 tured 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
`sulfate citric acid and
`clude 8-hydroxyquinoline
`45 erably disodium edetate. Under certain conditions
`agent may also enhance
`the anti-microbial
`chelating
`effect due to its
`ability to render essential metal
`unavailable to the microbes.
`in the
`systems optionally useful
`Buffering
`tions of the present invention are based on for example
`citrate borate orphosphate.
`Tonicifiets optionally useful
`the present invention include dextrose potassium
`and/or
`sodium chloride preferably sodium
`
`cetylpyri-contain
`prefer-with
`Oc-necessary
`manufac-The
`in-Ingredient
`pref-Active
`formula-5o
`chlo-55
`chlo-ride
`deriva-Tonicifier
`
`the
`
`ions
`
`in the formulations of
`
`Agent
`Preservative
`
`Surfactant
`
`Other Excipients
`Purified water
`
`Amount
`
`0.001rl
`
`to 10.01-f wt/vol.
`0.001 %c to 1.0% wt/vol.
`0.001% to 1.09 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 pro-
`portions
`
`Ingredient
`
`Amount
`
`Chelating agent
`
`IN NaOH or IN HCI
`
`0.01% to 1.0% wt/vol.
`q.s. to achieve
`isotonicity with
`lacrimal fluid and
`q.s to adjust pH to
`6.0 to 8.0.
`
`ride.
`
`60
`
`in the. formulations
`
`Viscosity agents optionally useful
`invention
`include the cellulose
`of the present
`tives such as hydroxypropylmethyl cellulose sodium
`and hydroxyethylcellulose.
`carboxymethylcellulose
`Other optional excipients useful
`in the formulations of
`the present
`invention include stabilizing agents such as
`and ascorbic
`e.g. sodium metabisulfate
`antioxidants
`acid depending on the NSAID used.
`These formulations
`are prepared by dissolving the
`65 solutes e.g. the NSAID the preservative
`the
`the chelating agent and the buffering agent
`in a
`suitable quantity of wirer adjusting the pH to about
`6-8 preferably 6.8-8.0 and most preferably 7.4 making
`
`In a preferred ophthalmic NSAID solution the ingredi-
`ents are combined in the following proportions
`
`Ingredient
`
`NSAID
`
`Amount
`
`0.50% wt/vol.
`
`surfac-tant
`
`Page 3
`
`

`
`con-It
`Rem-10
`formu-PREFERRED
`stabil-amountally
`per-preservative
`ap-disodium
`sur-NSAID
`de-scribed
`con-IN
`represen-to
`Trome-UTILITY
`ad-Ketorolac.Tromethamine.
`
`15
`
`25
`
`30
`
`5
`to 100% with additional
`a final volume adjustment
`water and sterilizing the preparation using any suitable
`method known to those in the art.
`
`formulations
`
`has been discovered that ophthalmic
`incorporating the preservative system of the invention
`are physically stable i.e. remain clear and functionally
`for at
`stable i.e. remain antimicrobialy effective
`the minimum reasonable shelf life of such products.
`FORMULATIONS
`
`least
`
`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 inven-
`tion includes a NSAID active agent
`in an effective
`treatment and an antimicrobi-
`for ophthalmic
`effective amount of the above-described preferred
`
`system.
`The preferred preservative of the invention is benzal
`konium chloride.
`The preferred surfactant of the invention is Octox-
`ynol 40 especially when combined with benzalkonium
`chloride.
`The preferred chelating
`agent of the invention
`is
`edetate especially when combined with benz-
`alkonium chloride and Octoxynol
`40.
`The preferred ophthalmic
`solutions of the invention
`include a NSAID benzalkonium chloride Octoxynol
`40 and disodium edetate.
`A preferred ophthalmic NSAID solution has
`following formulation
`
`the
`
`Ingredient
`
`14AC
`50% aq. solo.
`Octoxynol 40
`70% aq. sotn.
`EDTA Nat
`NaCI
`
`NaOH or IN HCI
`
`Purified Water
`
`Amount
`
`0.50% wt/vol.
`0.02% wt/vol.
`
`0.01% wt/vol.
`
`0.10% wt/vot.
`
`for isotonicity
`q.s.
`with lacrimal nuid
`q.s. to adjust pH to
`7.4
`0.4
`q.s to 100%
`
`Most preferred is the ophthalmic
`solution according
`the NSAID is
`above
`formulation wherein
`the
`
`AND ADMINISTRATION
`to NSAID ophthalmic
`This invention
`is directed
`formulations and a method useful for treating ophthal-
`in mammals. These diseases are either
`mic diseases
`caused by associated with or accompanied by inflam-
`matory processes including among others glaucoma
`cystoid macular edema ueitis diabetic retinopathy
`and conjunctivitis or any trauma caused by eye surgery
`or eye injury.
`is both curative and
`The method of this invention
`preventative. here applied for example pre-surgi-
`cally or immediately post-traumatically i.e. before in-
`it prevents development of in-
`flammation develops
`flammation. When applied directly to the eye suffering
`from any of the named opthalmic diseases it supresses
`already developed inflammatory processes.
`Opthalmic formulations are typically administered by
`into
`topical application to the eyelids or for instillation
`the space cul-de-sac between the eyeball and the eye-
`
`5110493
`
`6
`
`5
`
`solutions suspen.
`
`lids by topically applied ophthalmic
`sions or ointments or by subconjunctival
`injection.
`The dosage level will. of course depend on the
`centration of the drops the condition of the subject and
`the individual magnitude of responses to treatment.
`However
`ranges might be about 2-10
`typical dosage
`drops of 0.1 cle solution of active ingredient per day.
`For a more detailed discussion of ophthalmic
`lations their preparation and administration see
`15th Ed.
`Pharmaceutical
`Sciences
`ingtons
`1489-1504 1975.
`
`pages
`
`TESTING
`
`formulations
`
`such as the solutions of the
`
`both
`
`its
`
`limits.
`
`Ophthalmic
`present invention are typically tested for physical
`ity chemical stability and preservative
`efficacy
`when they are first manufactured and after a fixed
`two years. They are generally
`e.g. after
`iod of time
`20 considered to be safe and clinically acceptable if proven
`to be well tolerated in the eye.
`is determined by observation of a
`Physical stability
`solution after expiration of a fixed period of time. A
`solution is considered to be physically
`stable if
`pearance e.g. color and clarity does not change and if
`the pH remains
`constant within acceptable
`Chemical stability involves a routine chemical analysis
`of the solution to be sure that
`and
`its active ingredient
`the excipients have not changed
`after a fixed period of
`time.
`
`Preservative efficacy is tested by the procedure
`Compendiary
`the U.S.
`Pharmacopia
`whereby a solution is challenged with a microbe and a
`the microbe
`determination is made as to whether
`
`in
`
`vives in it.
`
`EXAMPLES
`
`The following examples are given to enable
`those
`to more clearly understand and to
`y
`skilled in the art
`practice the present invention. They should not be
`sidered as a limitation on the scope of the invention but
`and representative thereof.
`merely as being illustrative
`EXAMPLE 1
`
`This example illustrates the preparation of a
`formulation for ophthalmic
`tative pharmaceutical
`ministration containing the NSAID Ketorolac
`thamine.
`
`35
`
`40
`
`45
`
`50
`
`55
`
`Ingredient
`
`Ketorolac Troniethamine
`BAC
`50% sq. sotn.
`cýý o
`70% sq. soln.
`EDTA Nat
`NaCI
`
`Amount
`
`0.50% wt/vol.
`0.02% wt/vol.
`
`0.01% wi/vol
`
`0.10% wt/vol.
`0.79% wt/vol.
`
`6u
`
`The above
`ingredients are mixed adding purified
`the pH is adjusted to
`water until
`they are dissolved
`7.40.4 and the balance of the formulation is made up
`with purified water adding a quantity
`sufficient
`to
`65 make 100% volume. The solution is then sterilized.
`Other NSAIDs such as those described above can
`be used as the active compound in the preparation of the
`formulation of this example.
`
`Page 4
`
`

`
`5110493
`
`7
`
`EXAMPLE 2
`
`This example illustrates the preparation of a represen-
`ad-
`formulation for ophthalmic
`tative pharmaceutical
`ministration containing the NSAID Ketorolac Trome- 5
`thamine.
`
`8
`with purified water adding a quantity
`sufficient
`make 100% volume. The solution is then sterilized.
`drugs and NSAIDs such as those
`Other ophthalmic
`described above can be used as the active compound in
`the preparation of the formulation of this example.
`EXAMPLE 5
`
`to
`
`Physical stability of the formulations of the present
`invention is measured by preparing clear formulations
`10 e.g. according to the foregoing Examples sealing them
`and observing the clarity of the
`in sterilized containers
`solution after a period of one month and again after five
`remain clear are considered
`months. Solutions that
`
`ble in this procedure.
`have
`The
`the present
`formulations
`of
`invention
`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.
`
`EXAMPLE 6
`
`15
`
`20
`
`30
`
`Ingredient
`
`Tromethamine
`
`Ketorolac
`SAC
`50% sq. solo.
`Octoxynol 40
`70%i sq. soln.
`Na2
`
`NaCI
`
`Amount
`
`0.50% wt/vol.
`
`0.01% wt/vol.
`
`0.02% wt/vol.
`
`0.20% wt/vol.
`0.79% wt/vol.
`
`The above
`
`ingredients
`
`are mixed adding purified
`the pH is adjusted to
`water until
`they are dissolved
`7.40.4 and the balance of the formulation is made up
`with purified water adding a quantity
`to
`sufficient
`make 100% volume. The solution is then sterilized.
`NSAIDs such as those described above can
`be used as the active compound in the preparation of the
`formulation of this example.
`
`3
`
`This example illustrates the preparation of a represen-
`ad-
`formulation for ophthalmic
`pharmaceutical
`the NSAID Ketorolac Trome-
`ministration containing
`thamine.
`
`Ingredient
`
`Tromethamine
`
`BAC
`50%% sq. solo.
`40
`70% sq. soln.
`EDTA Nat
`NaCl
`
`Amount
`
`0.10re. wt/vol.
`
`o.oo.ic wt/vol.
`
`0.004% wn/vol.
`
`0.05-c wt/vol.
`0.88% wt/vol.
`
`The above
`
`ingredients
`
`sta-EDTA
`pres-Other
`subject-25
`chal-EXAMPLE
`demon-tative
`substi-Ketorolac
`com-Octoxynol
`anti-with
`be-Other
`antimi-formulation
`
`Preservative efficacy of the formulations of the
`is measured by preparing formulations
`ent
`invention
`e.g. according to the foregoing Examples and
`ing them to the U.S. Pharmacopia antimicrobial
`lenge.
`The formulations
`invention
`of the present
`strate preservative efficacy when tested in accordance
`with the above procedure.
`While the present invention has been described with
`reference to the specific embodiments thereof
`it should
`be understood by those skilled in the art
`that various
`changes may be made and equivalents may be
`tuted without departing from the true spirit and scope
`In addition many modifications may
`35 of the invention.
`be made to adapt
`a particular situation material
`position of matter process process step or steps to the
`objective spirit and scope of the present invention. All
`are intended to be within the scope
`such modifications
`40 of the claims appended hereto.
`What
`is claimed is
`1. An ophthalmologically acceptable
`non-steroidal
`anti-inflammatory drug formulation comprising
`non-steroidal
`an ophthalmologically acceptable
`drug in
`inflammatory carboxyl
`group-containing
`an effective amount
`treatment
`for ophthalmic
`tween 0.001% and 10.0% wt/vol
`a quaternary ammonium preservative
`in an
`amount between 0.001% and
`crobially effective
`1.0% wt/vol
`that conforms generally
`an ethoxylated alkyl phenol
`to the formula CSH17C6H.tOCH2CH2nOH
`where
`n has an average value of 40 in a stabilizing amount
`between 0.001% and 1.0% wt/vol
`and an aqueous
`to 100%.
`vehicle q.s.
`2. The ophthalmologically acceptable
`non-steroidal
`anti-inflammatory drug formulation of claim 1 wherein
`said quaternary ammonium preservative
`nium chloride.
`3. The ophthalmologically acceptable
`non-steroidal
`anti-inflammatory drug formulation of claim 2 wherein
`said ophthalmologically acceptable non-steroidal
`drug is
`group-containing
`inflammatory carboxyl
`from ketorolac
`lected from the group selected
`methacin flurbiprofen and suprofen.
`4. The ophthalmologically acceptable non-steroidal
`anti-inflammatory drug formulation of claim 3 wherein
`non-steroidal anti-
`said ophthalmologically acceptable
`
`are mixed adding purified
`the pH is adjusted to
`water until
`they are dissolved.
`7.40.4 and the balance of the formulation is made up
`purified water adding a quantity
`sufficient
`to 45
`make 100% volume. The solution is then sterilized.
`NSAIDs such as those described above can
`be used as the active compound in the preparation of the
`of this example.
`EXAMPLE 4
`
`5a
`
`This example illustrates the preparation of a represen-
`ad-
`formulation for ophthalmic
`the NSAID flurbiprofen so-
`
`ministration
`
`containing
`
`tative pharmaceutical
`
`dium.
`
`55
`
`sc-NaCI
`benzalko-Flurbiprofen
`anti-EDTA
`indo-65
`
`Ingredient
`
`Sodium
`
`BAC
`50% sq. Coln.
`Octoxynol 40
`70% sq. soin.
`Nat
`
`Amount
`
`0.03% wi/vol.
`0.02% wt/vol.
`
`0.01% wt/vol.
`
`0.30c wt/vol.
`0.90% wt/vol.
`
`The above
`are mixed adding purified
`the pH is adjusted to
`they are dissolved
`water until
`7.40.4 and the balance of the formulation is made up
`
`ingredients
`
`60
`
`is
`
`Page 5
`
`

`
`9
`
`5110493
`
`lU
`10. The method of claim 9 wherein said
`
`non-steroidal
`
`logically acceptable
`
`anti-inflammatory
`from the
`drug is selected
`group-containing
`carboxyl
`indomethacin
`group selected from ketorolac.
`5. profen and suprofen.
`11. The method of claim 10 wherein said
`
`inflammatory
`
`carboxyl
`
`group-containing
`
`drug
`
`is
`
`tromethamine.
`
`5. The ophthalmologically acceptable
`non-steroidal
`drug formulation of claim 1 further
`anti-inflammatory
`
`a chelating agent
`wt/vol
`
`in an amount between
`
`0.01% and
`
`a tonicifier
`
`q.s.
`
`to achieve isotonicity with lacrimal
`
`carboxyl group-containing
`
`drug is ketorolac
`
`ophthalmo-ketorolac
`flurbi-comprising
`ophthalmo-1.O%k
`trometha-fluid
`
`logically acceptable
`
`non-steroidal
`
`anti-inflammatory
`
`mine.
`12. The method of claim 8 wherein the formulation
`further comprises
`a chelating agent in an amount between 0.01% and
`1.0% wt/vol
`a tonicifier q.s.
`fluid and
`IN NaOH or IN HCI q.s.
`to adjust pH to 7.40.4.
`13. The method of claim 8 wherein the formulation
`comprises
`
`to achieve
`
`isotonicity with lacrimal
`
`and
`IN NaOH or IN HCl q.s.
`to adjust pH to 7.40.4.
`6. The ophthalmologically acceptable
`non-steroidal
`drug formulation of claim 1 compris-
`
`anti-inflammatory
`ing
`
`10
`
`ophthalmologically acceptable
`
`0.50% wi/vol
`
`non-steroidal
`
`phenol
`
`anti-inflammatory
`carboxyl group-containing drug
`BAC
`50% aq. soln.
`an ethoxylated
`alkyl
`that conforms
`to the formula
`generally
`C8H17C5H4OCH2CH2OH
`where n has an
`average value of 40
`70% sq. soln
`Na2EDTA
`NaCI
`
`IN NaOH or IN HCJ
`purified water
`
`0.02% wt/vol.
`
`0.01% wt/vol
`
`0.107c art/vol
`
`for isotonicity with
`q.s.
`lacrimal fluid
`q.s. to pH 7.4
`q.s..to 100x.
`
`0.4 and
`
`7. The ophthalmologically acceptable
`anti-inflammatory drug formulation of claim 6 compris-
`ing
`
`non-steroidal
`
`tromethamine
`
`ketorolac
`BAC
`50% sq. soln.
`alkyl phenol
`an ethoxylated
`that conforms generally
`to the formula
`CSH17C6H4OCH2CH2OH
`where n has an average
`value of 40
`
`707c
`aq. soln.
`Na2EDTA
`NaCI
`IN NaOH or IN HCI
`purified water
`
`0.50% wt/vol
`0.02% wt/vol
`
`0.01% wt/vol
`
`0.10% wi/vol
`0.79% wt/vol
`q.s. to pH 7.4
`q.s. to 100%.
`
`0.4 and
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`8. A method of treating an ophthalmic disease caused
`by associated with or accompanied by inflammatory 50
`administering to a mammal
`processes comprising
`therefrom a formulation comprising
`an ophthalmologically acceptable non-steroidal anti-
`drug in
`carboxyl group-containing
`effective amount
`treatment be- 55
`for ophthalmic
`tween 0.001% and 10.0% wt/vol
`quaternary ammonium preservative in an antimi-
`amount between
`0.001% and
`crobially effective
`1.0% wt/vol
`
`that conforms generally
`an ethoxylated alkyl phenol
`to the formula C5H17C6HdOCH2CH2nOH
`where
`n has an average value of 40 in a stabilizing amount
`0.001 % and 1.0% wt/vol and an aqueous
`10001S
`vehicle q.s.
`9. The method of claim 8 wherein said quaternary
`ammonium preservative is benzalkonium chloride.
`
`t
`
`60
`
`65
`
`ophthalmogically acceptable
`
`0.50% wt/vol
`
`non-steroidal
`
`anti-inflammatory
`drug
`
`carboxyl group-containing
`BAC
`50% sq. sotn.
`an ethoxyated alkyl phenyl
`that conforms generally
`to the formula
`CgH17C6H4OCH2CH2OH
`where n has an average
`value of 40
`70% aq. soln.
`Na2EDTA
`NaCI
`
`IN NaOH or IN HCl
`purified water
`
`0.02% wt/vol
`
`0.011-t wt/vol
`
`0.30% wt/vol
`for
`
`icily with
`
`q.s.
`fluid
`lacrimal fluid
`q.s to pH 7.4 -- 0.4 and
`to 100%.
`
`q.s.
`
`14. The method of claim 13 wherein the formulation
`
`comprises
`
`0.50% wt/vol
`0.02% wt/vol
`
`0.01% wt/vol
`
`tromethamine
`
`ketorolac
`BAC
`50% aq. soln.
`an ethoxylated
`alkyl phenol
`that conforms generally
`to the formula
`CgHI7C6H4OCH2CH2OH
`where n has an
`average value of 40
`
`70cic
`sq. soln.
`Na2EDTA
`NaCl
`IN NaOH or IN HCI
`purified water
`
`0.10% wt/vol
`0.79% wt/vol.
`to pH 7.4
`g.s..to 100%.
`
`q.s.
`
`0.4 and
`
`15. An antimicrobially effective preservative
`system
`for an ophthalmologically
`acceptable non-steroidal
`drug
`
`ti-inflammatory carboxyl group-containing
`lation comprising
`a quaternary ammonium preservative
`in an
`amount. between 0.001% and
`crobially effective
`1.0% wt/vol of the formulation and
`that conforms generally
`an ethoxylated alkyl phenol
`to the formula CSHI7C6H4OCH2CH2OH where
`n has an average value of 40 in a stabilizing amount
`between 0.001% and 1.0% wt/vol of the
`
`tion.
`
`au. a i e preservative system of claim 15 wherein said
`preservative is benzalkonium chloride.
`
`forrlu-an
`suf-fering
`antimi-a
`an-inflammatory
`formula-between
`
`Page 6
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`
`DATED
`
`INVENTORS
`
`5110 4.93
`May 5 1992
`
`Cherng-Chyi Roger Fu and Deborah M. Lidgate
`
`It
`
`is certified that error appears in the above-indentified
`
`patent and that said Letters Patent
`
`is hereby
`
`corrected as shown below
`
`On the title page under
`--Fu -
`therefor
`
`item 19 delete Cherng-Chyi and. insert
`
`Item 75 Inventors
`--Cherng-Chyi R. Fu -
`
`delete Roger F. Cherng-Chyi
`
`and insert therefor
`
`Signed and Sealed this
`
`Twentyourth Day of August 1993
`
`Attest
`
`Attesting Officer
`
`Commissioner of Patents and Trademarks
`
`BRUCE LEHMAN
`
`Page 7