(12) PATENT ABRIDGMENT (11) Document No. AU-B-22042/88
`(12) PATENT ABRIDGMENT
`(11) Document No. AU·B-22042/88
`(10) Acceptance No. 626798
`(10) Acceptance No. 626798
`(19) AUSTRALIAN PATENT OFFICE
`(19) AUSTRALIAN PATENT OFFICE (cid:9)
`
`(54) Title
`(54) Title
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`International Patent Classification(s)
`International Patent Classification(s)
`A61K 031/13 (cid:9)
`(51)4 A61K 031 /40 (cid:9)
`(51) 4 A.61 K 031/40
`A61 K 031/13
`A61K 031/405
`A61K 031/405
`A61K 047/18
`(51)5 A61K 047/10
`A61K 047/18
`(51)5 A61K 047/10 (cid:9)
`(21) Application No. : 22042/88 (cid:9)
`(21) Application No. : 22042/88
`
`A61K 031/19 (cid:9)
`A61 K 031/1 9
`
`A61K 031/195
`A61 K 031/195
`
`(22) Application Date : 09.09.88
`(22) Application Date : 09.09.88
`
`(33) Country
`(33) Country
`US UNITED STATES OF AMERICA
`US UNITED STATES OF AMERICA
`
`(30) Priority Data
`(30) Priority Data
`(31) Number
`(32) Date
`(31) Number (32) Date (cid:9)
`096173
`11.09.87
`11.09.87 (cid:9)
`096173 (cid:9)
`( 43) Publication Date : 16.03.89
`(43) Publication Date 16.03.89
`(44) Publication Date of Accepted Application : 13.08.92
`(44) Publication Date of Accepted ApplicJation: 13.08.92
`(71) Applicant(s)
`(71) Applicant(s)
`SYNTEX (U.S.A.) INC.
`SYNT·EX (U.S.A.) INC.
`lnventor(s)
`Inventor(s)
`CHERNG-CHYI ROGER FU; DEBORAH M. LIDGATE
`CHERNG-CHYI ROGER FU; DEBORAH M. LIDGATE
`
`( 72)
`(72)
`
`(74) Attorney or Agent
`,
`(74) Attorney or Agent
`WATERMARK PATENT & TRADEMARK ATTORNEYS , Locked Bag 5, HAWTHORNiVIC 3122
`WATERMARK PATENT & TRADEMARK ATTORNEYS, Locked Bag 5, HAWTHORN VIC 3122
`
`{57) Claim
`(57) Claim
`1. (cid:9)
`An ophthalmic NSAID formulation comprising:
`l.
`An ophthalmic NSAID formulation comprising:
`a NSAID in an effective amount for ophthalmic treatme~t,
`a NSAID in an effective amount for ophthalmic treatment,
`a quater.nary ammonium preservative, a stabilizing amount
`a quaternary ammonium preservative, a stabilizing amount
`of a nonionic ethoxylated octylphenol surfactant, and an
`of a nonionic ethoxylated octylphenol surfactant, and an
`aqueous vehicle.
`aqueous vehicle.
`
`22. (cid:9)
`22.
`
`An antimicrobially effective ophthalmologically acceptable preservative system
`An antimicrobially effective ophthalmologicaily acceptable preservative system
`
`for ophthalmologically acceptable, carboxyl grou_p .. containing druqs, said preservative
`for ophthalmologically acceptable, carboxyl groupcontaining drugs, said preservative
`system comprising a quaternary ammonium preservative and a stabilizing amount of a
`system comprising a qt~aternary ammonium preservative and a stabilizing amount of a
`nonionic ethoxylated octylphenol surfactant.
`nonionic ethoxylated octylphenol surfactant.
`
`----~~·--~--------------------------------------------·
`
`Innopharma EX1011, Page 1
`
`

`
`COMMONWEALTH OF AUSTRALIA
`COMMONWEALTH OF AUSTRALIA
`
`PATENTS ACT 1852-69
`PATENTS ACT 1952·69
`
`Form 10
`Form 10
`
`COMPLETE SPECIFICATION
`COMPLETE SPECIFICATION
`
`(ORIGINAL' 626798
`(ORIGINAL! 626798
`
`Class
`Class (cid:9)
`
`Int. Class
`Int. Class
`
`Application Number:
`Application Number:
`Lodged:
`Lodged:
`
`Complete Specification Lodged:
`Complete Specification Lodged:
`Accepted:
`Accepted:
`Published:
`Published:
`
`SYNTEX (U.S.A.) INC .
`SYNTEX (U.S.A.) INC.
`
`3401 Hillview Avenue, Palo Alto, California 94304, United
`3401 Hiliview Avenue, Palo Alto, California 94304, United
`States of America
`States of America
`
`CHERNG-CHYI ROGER FU and DEBORAH M. LIDGATE
`CHERNG-CHYI ROGER FU and DEBORAH, M. LIDGATE.
`
`.. .
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`Actual Inventor:
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`• • • • ·~ame of Applicant:
`„*„ • *Warne of Applicant :
`• ••
`
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`
`Address of Applicant :
`Address of Applicant :
`•• •
`•••• (cid:9)
`••
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`111 •
`
`•
`
`Address for Service :
`Address for service:
`
`EDWD. WATERS & SONS,
`EDWD. WATERS & SONS,
`50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
`50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
`
`Complete Speeification for the inventi.on entitled:
`Complete Specification for the invention entitled:
`
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`The following statement is a full description of this invention, including the best method of performing it k m to (cid:9)
`The foUowing statement is a full description of this invention, including the best method of performing it 'k"A~n 't'' ; ..
`
`us
`US
`
`-'~'1.......--------
`
`Innopharma EX1011, Page 2
`
`

`
`(cid:9) (cid:9)
`
`•
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`5
`5
`
`10
`10
`
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`
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`PRESERVATIVE SYSTEM FOR OPHTHALMIC FORMULATIONS
`
`•
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`15
`
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`The present invention relates to improved ophthalmic
`The present invention relates to improved ophthalmic
`formulations, particularly to ophthalmic formulations for
`formulations, particularly to ophthalmic formulations for
`anti-inflammatory drugs, and specifically to ~n improved
`anti-inflammatory drugs, and specifically to an improved
`preservative system for ophthalmic formulations of
`preservative system for ophthalmic formulations of
`carboxyl ("-COOH") group-containing drugs, especially
`carboxyl ("-CO-OH") group-containing drugs, especially
`non-steroidal anti-inflammatory drugs ("NSAIDs").
`non-steroidal anti-inflammatory drugs ("NSAIDs").
`The invention also relates to methods of using these
`The invention also relates to methods of using these
`formulations for treating diseases that are either caused
`20
`20 formulations for treating diseases that are either caused
`by, associated with or accompanied by inflammatory
`by, associated with or accompanied- by inflammatory
`processes, including, among others, glaucoma, cystoid
`processes, including, among others, glaucoma, cystoid
`macular edema, uveitis, diabetic ret~nopathy, and
`macular edema, uveitis, diabetic retinopathy, and
`conjunctiviti~, or any ttauma caused by eye surgery or
`conjunctivitis, or any trauma caused by eye surgery or
`eye injury •
`25
`25 eye injury.
`The topical use of NSAIDs~ particularly pyrrolo
`The topical use of NSAIDs, particularly pyrrolo
`py~roles, in the treatment of ophthalmic diseases was
`pyrroles i in the treatment of ophthalmic diseaset was
`first taught in u.s. Patent No. 4,454,151, where NSAID
`first taught in U.S. Patent No. 4,454,151, where NSAID
`compounds (such as those described in U.Sw Patents
`compounds (Such as those described in U.S. 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
`30
`30 4,089,969; 4,232,038;. 4,087539 and 4,097,579) were
`exemplified in formulation with NaH2Po 4 ·H 2o,
`exemplified in, formulation with NaH2PO4 •1-1 20,,
`Na2 HP04 ~ 2 o, NaCl, benzalkonium chloride ("BAG")
`Na2HPO4 *H 20, NaCI, benzaIkonium chloride ("BAC")
`and st~rilized water. While the formulations described
`and sterilized water. While the formulations described
`
`35
`35
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`Innopharma EX1011, Page 3
`
`

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`-
`
`--- -~----------------------------~---~------
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`in the '151 patent were efficacious, an insoluble complex
`in the '151 patent were efficacious, an insoluble complex
`was found to form between the NSAID and the SAC. The
`was found to form between the NSAID and the BAC. The
`formulations became cloudy or turbid and did not,
`formulations became cloudy or turbid and did not,
`therefore, have the stability desired for shelf life in
`therefore, have the stability desired for shelf life in
`commercial applications. A reasonable minimum shelf life
`5
`5 commercial applications. A reasonable minimum shelf life
`(that is, the time during which a solution remains clear
`(that is, the time during which a solution remains clear
`and retains its pharmaceutical activity) is at least
`and retains its pharmaceutical activity) is at least
`about one year, representing sufficient time to package,
`about one year, representing sufficient time to package,
`ship, and store a formulation without having to replace
`ship, and store a formulation without having to replace
`10 expired stock too frequently. The solutions of the
`10 expired stock too frequently. The solutions of the
`present invention have shown a shelf life of at least one
`present invention have shown a shelf life of at least one
`year. Thus, the present invention entails an improvement
`year. Thus, the present invention entails an improvement
`over the formulations described in the '151 patent.
`over the formulations described in the '151 patent.
`rn general, an ophthalmic formulation contains an
`In general, an ophthalmic formulation contains an
`15 active compound and various ophthalmologically acceptable
`15 active compound and various ophthalmologically acceptable
`excipients, in the form of a solution,. an ointment, a
`excipients,, in the form of a solution,, an ointment, a
`suspension, etc. An excipient is ophthalmologically
`suspension, etc. An excipient is ophthalmologically
`acceptable if it is non-irritating to the eye and if its
`acceptable if it is non-irritating to the eye and if its
`active ingredient penetrates the blood-aqueous barrier
`active ingredient penetrates the blood-aqueous barrier
`20 and/or diffuses through the various ocular substructures
`20 and/or diffuses through the various ocular substructures
`to the site where it is pharmacologically active. The
`to the site where it is pharmacologically active. The
`excipisnts can include a tonicifier, a preservative, a
`excipients can include a tonicifier, a preservative, a
`surfactant, a buffering system, a chelating agent~ a
`surfactant, a buffering system, a chelating agent, a
`viscosity agent as well as other stabilizing agents~
`viscosity agent as well as other stabilizing agents.
`25 Ophthalmic formulations must be ~terile, and if intended
`25 Ophthalmic formulations must, be sterile, and if intended
`for multiple dosing regimens, must be preserved with an
`for multiple dosing regimens, must be preserved with an
`effective anti-microbial agent.
`effective anti-microbial agent.
`Organo-mercurials (e.g., thimerosal, phenylmercuric
`Organo-mercurials (e.g., thimerosal, phenylmercuric
`acetate and phenylmercuric nitrate) have been used
`acetate and phenylmercuric nitrate) have been used
`30 extensively as the preservative in ophthalmic solutions.
`3G extensively as the preservative in ophthalmic solutions.
`These compounds, however, pose difficulties due to
`These compounds, however, pose difficulties due to
`potential mercury toxicity as well as poor chemical
`potential mercury toxicity as well as poor chemical
`stability. Benzalkonium chloride, a quaternary ammonium
`stability. Benzalkonium chloride, a quaternary ammonium
`compound, has been widely used in ophthalmic solutions,
`compound, has been widely used in ophthalmic solutions,
`35 and is considered to be the preservative of choice.
`35 and is considered to be the preservative of choice.
`
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`Innopharma EX1011, Page 4
`
`(cid:9)
`

`
`-3-
`-3-
`
`However~ BAC has typically been considered to be
`However, BAC has typically been considered to be
`incompatible with anionic drugs (e.g., salicylates or
`incompatible with anionic drugs (e.g., salicylates or
`nitrates, etc.), forming insoluble complexes which cause
`nitrates, etc.), forming insoluble complexes which cause
`the solution to become cloudy or turbid. Such a complex
`the solution to become cloudy or turbid. Such a complex
`5 between the anionic drug and benzalkonium chloride can
`5 between the anionic drug and benzalkonium chloride can
`cause a decrease in the pharmaceutical activity of the
`cause a decrease in the pharmaceutical activity of the
`anionic drug.
`anionic drug.
`Many NSAIDs (such as ketorolac, indomethacin,
`Many NSAIDs (such as ketorolac, indomethacin,
`flurbiprofen and diclofenac) are being developed for
`flurbiprofen and diclofenac) are being developed for
`10 ocular use because of their activity as anti-inflammatory
`10 ocular use becauSe of their activity as anti-inflammatory
`agents including their ability to prevent cystoid macular
`agents including their ability to prevent cystoid macular
`edema.
`edeMa.
`In the past, as in the case with other ophthalmic
`In the past, as in the case with other ophthalmic
`drugs that contain a -COOH group, antiinflammatory
`drugs that contain a -COOH group, antiinflammatory
`15 solutions of NSAIDs for occular use have proven to be
`15 solutions of NSAIDs for occular use have proven to be
`incompatible with quaternary ammonium compounds such as
`incompatible with quaternary ammonium compounds such as
`BAG. This incompatibility is due to the fact that the
`BAC. This incompatibility is due to the fact that the
`-GOOH group can form a complex with the quaternary
`-COON group can form a complex with the quaternary
`ammonium compounds, rendering the preservative less
`ammonium compounds, rendering the preservative less
`available to serve its function, and reducing the
`20
`20 available to serve its function, and reducing the
`activity of the active ingredient.
`Indomethacin
`activity of the active ingredient. Indomethacin
`ophthalmic formulations have been prepared, however,
`ophthalmic formulations have been prepared, however,
`these are suspensions, not solUtions. Ocufen Ophthalmic
`these are suspensions, not solutions. Ocufen Ophthalmic
`solution, an NSAID (flurbiprofen) approved by the FDA for
`solution, an NSAID (flurbiprofen) approved by the FDA for
`ophthalmic use, incorporates thimerosal (with EDTA) as
`25 ophthalmic use, incorporates thimerosal (with EDTA) as
`25
`In u.s. patent 4,454,151 there
`its preservative system.
`its preservative system'. In U.S. patent 4,454,151 there
`is a disclosure of an ophthalmic formulation using
`is a disclosure of an ophthalmic formulation using
`ketQrolac, benzalkonium chlOride (as the preservative)
`ketorolac, benzalkonium chlOride (as the preservative)
`and polysorbate 80, however the solution became cloudy or
`and polysorbate 80, however the solution became cloudy or
`30 turbid after a short period of time~
`30 turbid after a short period of time.
`It has remained desired to provide a stable, clear,
`It has remained desired to provide a stable, clear,
`antimicrobially effective ophthalmic formulation with a
`antimicrobially effective ophthalmic formulation with a
`prolong~d shelf life for
`-GOOH group containing
`prolonged shelf life for -COOH group containing
`ophthalmic drugs, especially NSAIDs, using BAG as the
`ophthalmic drugs, especially NSAIDs, using BAC as the
`35 preservative.
`35 preservative.
`
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`Innopharma EX1011, Page 5
`
`

`
`-4-
`-4-
`
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`It has now been discovered that stable, clear and
`It has now been discovered that stable, clear and
`antimicrobially effective, NSAID-containing ophthalmic
`antimicrobially effective, NSAID-containing ophthalmic
`formulations can be prepared which include a quaternary
`formulations can be prepared which include a quaternary
`ammonium preservative. These solutions have an improved
`5
`5 ammonium preservative. These solutions have an improved
`shelf life, exhibiting no cloudiness or turbidity oveF
`shelf life, exhibiting no cloudiness or turbidity over
`extended periods.
`extended periods.
`In one aspect of the invention, these compositions
`In one aspect of the invention, these compositions
`include an ophthalmologically effective amount of a
`include an ophthalmologically effective amount of a
`10 NSAID, a quaternary ammonium preservative and a
`10 NSAID, a quaternary ammonium preservative and a
`stabilizing amount of an ethoxylated octylphenol as a
`stabilizing amount of an ethoxylated octylphenol as a
`nonionic surfactant,. all in an aqueous vehicle •
`nonionic surfactant, all in an aqueous vehicle.
`Another aspect is an ophthalmic composition
`Another aspect is an ophthalmic composition
`including an ophth~lmologically effettive amount of a
`including an ophthalmologically effective amount of a
`NSAID, a quaternary ammonium preservate and q stabilizing
`15
`15 NSAID, a quaternary ammonium preservate and a stabilizing
`amount of an ethoxylated octylphenol as a nonionic
`amount of an ethoxylated octylphenol as a nonionic
`surfactant .
`surfactant.
`Another aspect is an ophthalmic composition
`Another aspect is an ophthalmic composition
`including an ophthalmologically effective amount of a
`including an ophthalmologically effective amount of a
`NSAID, benzalkonium chloride as a preservative and a
`20 NSAID, benzalkonium chloride as a preservative and a
`20
`stabilizing amount of an ethoxylated octylphenol as a
`stabilizing amount of an ethoxylated octylphenol as a
`nonionic surfactant •
`nonionic surfactant.
`Another aspect is an ophthalmic compositio,n
`Another aspect is an ophthalthic compotitioth
`including an ophthalmologically effettive amount of a
`including an ophthalmologically effeOtive amount of a
`25 NSAID, benzalkonium chloride as a preservative a~d a
`25 NSAID, benzalkonium chloride as a preservative and a
`stabilizing amount of Octoxynol 40 as a nonionic
`stabilizing amount of Octoxynol 40 as a nonionic
`surfactant.
`Surfactant.
`Another aspect is an ophthalmic composition
`Another aspect is an ophthalmic composition
`including an ophthaimologically effective amount of
`including an ophthalmologically effective amount of
`JO ketorolac or an isomer, an ester, oF a pharmaceutically
`30 ketorolac or an isomer, an ester, or a pharmaceutically
`acceptable salt thereof, benzalk.onium chloride as a
`acceptable salt thereof, benzalkonium chloride as a
`preservative and a stabilizing amount of Octoxynol 40 as.
`preservative and a stabiliZing amount of Octoxynol 40 as
`a nonionic surfactant.
`a nonionic surfactant.
`
`35
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`Metrics EX1011, Page 6
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`...• (cid:9)
`• • •
`.. •
`.....
`• . •
`
`• • •
`.. •
`••
`•
`
`00.4 (cid:9)
`
`-
`
`-5-
`-5-
`
`In another aspect of the invention, methods for
`In another aspect of the invention, methods for
`treating ophthalmic diseases in mammals using the
`treating ophthalmic diseases in mammals using the
`ophthalmic pharmaceutical formulations of the invention
`ophthalmic pharmaceutical formulations of the invention
`are also disclosed. These diseases are those that are
`are also disclosed. These diseases are those that are
`5 either caused by, associated with or accompanied by
`5 either caused by, associate~ with or accompanied by
`inflammatory processes, including, among others,
`inflammatory processes, including, among others,
`glaucoma, cystoid macular edema, uveitis, diabetic
`glaucoma, cystoid macular edema, uveitis, diabetic
`retinopathy and conjunctivitis, or any trauma caused by
`retinopathy and conjunctivitis, or any trauma caused by
`eye surgery or eye injury.
`eye surgery or eye injury.
`
`10
`10
`
`15
`15
`
`20
`20
`
`25 (cid:9)
`25
`
`30
`30
`
`DETAILED DESCRIPTIGN OF THE PREFERRED EMBODIMENTS
`DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
`Definitions
`Definitions
`As used herein. the term "NSAID" means an
`As used herein, the term "NSAID" means an
`ophthalmologically acceptable non-steroidal
`ophthalmologically acceptable non-steroidal
`anti-inflammatory drug. The NSAid's includej for
`anti-inflammatory 'drug. The NSAID's include, for
`example, flurbiprofen, ketorolac, diclofenac,
`example, flurbiprofen, ketorOlac, diclofenac,
`indomethacin, Snd the isomers, ~sters, and
`indomethacin, and the isomers, 'esters, and
`pharmaceutically acceptable salts thereof.
`pharmaceutically acceptable salts thereof.
`As usecl herein, the term "q.s." means adding a
`As used herein, the term "q.s." means adding a
`quantity sufficient to achie~e a stated function, e.g.,
`quantity sufficient to achieVe a stated function, e.g.,
`to bring a solution to the desired volume (i.e., 100%) •
`to bring a solution to the desired volume (i.e., 100%).
`As used herein, the term "treatment" or "treating"
`As used herein, the term "treatment" or "treating"
`means any treatment of a disease in a mammal~ including:
`means any treatment of a disease in a mammal, including:
`(i) preventing the disease~ that is, causing the
`(i) preventing the disease; that is, causing the
`clinical symptoms of the disease not ~o develop;
`cliniCal symptoms Of the disease not t0 develOp;
`(ii)
`inhibiting the disease, that is, arresting the
`(ii) inhibiting the disease, that is, arresting the
`developm~nt of clinical symptoms; and/or
`development of clinical symptoms; and/or
`(iii)
`relieving the disease, that is~ causing the
`(iii) relieving the disease, that is, causing the
`regression of clinical symptoms.
`regression Of clinical symptoms.
`As used herein, the term "effective amount" means a
`A8 used herein, the term "effective amount" means a
`dosage sufficient to provide treatment for the disease
`dosage sufficient to provide treatment for the disease
`state being treated. This will vary depending on the
`state being treated. This will vary depending on the
`patient, the disease and the treatment being effected.
`patient, the disease and the treatment being effected.
`
`35
`35
`
`8408Y
`8408Y (cid:9)
`
`26280-FF
`26280-FF
`
`Innopharma EX1011, Page 7
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`(cid:9) (cid:9)
`
`l I
`
`l
`
`•
`
`•
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`• n• (cid:9) .
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`
`-6-
`... 6-
`
`As used herein, the term "antimicrobially effective"
`As used herein, the term "antimicrobially effective"
`means ability to withstand the U.S. Pharmacopia
`means ability to withstand the U.S. Pharmacopia
`antimicrobial challenge.
`antimicrobial challenge.
`As used herein, the term "surfactant" me~ns a
`As used herein, the term "surfactant" means a
`5 nonionic surfactant, preferably ethoxylated octylphenol
`5 nonionic surfactant, preferably ethoxylated octylphenol
`compounds as described below.
`compounds as described below.
`As used herein, the term "quaternary ammonium
`As used herein, the term "quaternary ammonium
`preservative" means a quaternary ammonium compound such
`preservative" means a quaternary ammonium compound such
`as described below.
`as described below.
`As used herein, the term "stabilizing" means keeping
`As used herein, the term "stabilizing" means keeping
`a formulation clear and antimicrobially effective for its
`a formulation clear and antimicrobially effective for its
`minimum reasonable shelf life, e.g., at least one Jear.
`minimum reasonable shelf life, e.g., at least one year.
`
`10
`10
`
`15
`15 (cid:9)
`
`Formulations
`Formulations
`The formulations of tha present invention include an
`The formulations of the present invention include an
`NSAID active agent in an effective amount for ophthalmic
`NSAID active agent in an effective amount for ophthalmic
`treatment, a quaternary ammonium preservative, a
`treatment, a quaternary ammonium preservative, a
`stabilizing amount of an ethoxylated ootylphenol as a
`stabilizing amount of an ethoxylated octylphenol as a
`nonionic surfactant, optionally including other
`nonionic surfactant, optionally including other
`excipients such as a chelating agent, a tonicifier, a
`20
`20 excipients such as a chelating agent, a tonicifier, a
`buffering systam, a viscosity agent as well as other
`buffering system, a viscosity agent as well as other
`stabilizing agents. Gphthalmic solutions and suspensions
`stabilizing agents. Ophthalmic solutions and suspensions
`typically contain an aqueous vehicle rather than an oily
`typically contain an aqueous vehicle rather than an oily
`vehicle. Ophthalmic formulations must be sterile, and if
`vehicle. Ophthalmic formulations must be sterile, and if
`intended for multiple dosing reg.imen.s, must be
`25 intended for multiple dosing regimens, must be
`25
`antimicroblally effective for their minimum reasonable
`antimicrobially effective for their minimum reasonable
`shelf life, e.g~, at least one yearr and preferably two
`shelf life, e.gi, at least one year, and preferably two
`to three years or more. The ingredients used in the
`to three years or more. The ingredients used in the
`formulations of the p.resent invention are typically
`formulations of the present invention are typically
`30 commercially available or can be made by methods readily
`30 commercially available or can be made, by methods readily
`known to those skilled in the art.
`known to those skilled in the art.
`Pharmaceutical ophthalmic formulations typically
`PharMaceutical ophthalmic fortulations typically
`contain an effective amount, e.g., o.OQl% to 10% wt/vol.,
`contain an effective amount, e.g., 0.001% to 10% wt/vol.,
`preferably 0.002% to 5% wt/vol, most preferably 0.005% to
`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
`35 1% wt/vol of an active ingredient (e.g., the NSAID of the
`
`8408Y
`8408Y
`
`26280-FF
`26280-FF
`
`Innopharma EX1011, Page 8
`
`

`
`-7-
`-7-
`
`present invention). The amount of active ingredient will
`present invention). The amount of active ingredient will
`vary with the particular formulation and the disease
`vary with the particular formulation and the disease
`state for which it is intended. The total concentration
`state for which it is intended. The total concentration
`of solutes should be such that, if possible, the
`of solutes should be such that, if possible, the
`resulting solution is isotonic with the lacrimal fluid
`5
`5 resulting solution is isotonic with the lacrimal fluid
`(though this is not absolutely necessary) and has a pH in
`(though this is not absolutely necessary) and has a pH in
`the range of 6 to 8.
`the range of 6 to 8.
`The formulations of the present invention are
`The formulations of the present invention are
`prepared as solutions incorporating the above-described
`prepared as solutions incorporating the above-described
`ingredients within the following approximate ranges:
`10
`10 ingredients within the following approximate ranges:
`Amount
`Ingredient
`Amount
`Ingredient (cid:9)
`Active Agent
`0.001% to 10.0% wt/vol.;
`Active Agent (cid:9)
`0.001% to 10.0% wt/vol.;
`0.001% to 1.0% wt/vol.;
`Preservative
`0.001% to 1.0% wt/vol.;
`Preservative (cid:9)
`Surfactant
`0.001% to 1.0% wt/vol.;
`Surfactant (cid:9)
`0.001% to 1.0% wt/vol.;
`0% to 10.0% Wt/vol.; and
`Other Excipients
`0% to 10.0% wt/vol.; and
`Other Excipients (cid:9)
`q.s. to 100% •
`Purified Water
`Purified Water (cid:9)
`q.s. to 100%.
`Optional other exc!pients, such as a chelating agent and
`Optional other excipients, such as a chelating agent and
`a tonicifier, are Used in the following approximate
`a tonicifier, are used in the following approximate
`proportions:
`proportions:
`Ingredient
`Ingredient (cid:9)
`Chelating agent
`Chelating agent (cid:9)
`Tonicifier
`Tonicifier (cid:9)
`
`15
`15 (cid:9)
`
`20
`20 (cid:9)
`
`Amount
`Amount
`0.01% to l.O%wt/vol.;
`0.01% to 1.0%wt/vol.;
`q.s. to achieve
`q.s. to achieve
`isotonicity with
`isotonicity with
`lacrimal fluid; and
`lacrimal fluid; and
`q.s. to adjust pH to
`q.s. to adjust pH to
`6.0 to 8.0 •
`6.0 to 8.0.
`
`25
`25 (cid:9)
`
`lN NaOH or lN HC1
`1N NaOH or 1N HC1 (cid:9)
`
`30
`30
`
`35
`35
`
`8408Y
`8408Y
`
`26280-FF
`26280-FF
`
`•• (cid:9)
`
`•
`
`•
`
`Ik•
`
`***0
`
`*000
`
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`•
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`41b 4
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`
`•
`
`00' 0
`• •
`•
`
`50
`
`•• •
`
`l
`
`I ' I
`
`Innopharma EX1011, Page 9
`
`

`
`• 41 (cid:9)
`
`•
`
`•
`• •
`••
`
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`
`-8-
`-8-
`
`In a preferred ophthalmic NSAID solution, the
`In a preferred ophthalmic NSAID solution, the
`ingredients are combined in the following proportions:
`ingredients are combined in the following proportions:
`Ingredient
`Amount
`Amount
`Ingredient (cid:9)
`NSAID
`0.002%
`to 5.0% wt/vol.;
`NSAID (cid:9)
`0.002% to 5.0% wt/vol.;
`BAC
`0.002% to 1.0% wt/vol.;
`0.002% to 1.0% wt/vol.;
`BAC (cid:9)
`(50% aq. soln.)
`(50% aq. soln.)
`Octoxynol 40
`0.001% to 1.0% wt/vol.;
`0.001% to 1.0% wt/vol.;
`Octoxynol 40 (cid:9)
`(70% aq. soln.)
`(70% aq. soln.)
`0.01% to 1.0% wt/vol.;
`EDTA Na2
`0.01% to 1.0% wt/vol.;
`EDTA Na2 (cid:9)
`NaCl
`q,s. for isotonicity with
`NaC1 (cid:9)
`q.s. for isotonicity with
`lacrimal fluid;
`lacrimal fluid;
`lN NaOH or lN HCl q.s. to adjust pH to
`IN NaOH or 1N HC1 q.s. to adjust pH to
`7. 4 ±0. 4; and
`7.4±0.4; and
`q. s. t 0 100%.
`q.s. to 100%.
`
`Purified Water
`Purified Water (cid:9)
`
`In another preferred ophthalmic NSAID solution 1
`the
`In another preferred ophthalmic NSAID solution, the
`ingredients are combined in the following proportions:
`ingredients are combined in the following proportions:
`Amount
`Ingredient
`Amount
`Ingredient (cid:9)
`NSAID
`0.005%
`to 1.0% wt/vol.;
`NSAID (cid:9)
`0.005% to 1.0% wt/vol.;
`0.002% to 1~0% wt/vol.;
`SAC
`0.002% to 1.0% wt/vol.;
`BAC (cid:9)
`(50% aq. soln.)
`(50% aq. soln.)
`0.001% to 1.0% wt/vol.;
`Octoxynol 40
`0.001% to 1.0% wt/vol.;
`Octoxynol 40 (cid:9)
`(70% aq. soln.)
`(70% aq. soln.)
`0.01% to 1.0% wt/vol.;
`EDTA Na2
`0.01% to 1.0% wt/vol.;
`EDTA Na2 (cid:9)
`NaCl
`q.s. for isotonicity with
`NaC1 (cid:9)
`q.s. for isotonicity with
`lacrimal fluid;
`lacrimal fluid;
`lN NaOH or lN HCl q.s. to adjust pH to
`1N NaOH or 1N HC1 q.s. to adjust pH to
`7.4±0.4; and
`7.4.4; and
`q.s. to 100%.
`q.s. to 100%.
`
`Purified Water
`Purified Water (cid:9)
`
`5 (cid:9)
`5
`
`10
`10 (cid:9)
`
`15
`15
`
`20 (cid:9)
`20
`
`25
`25 (cid:9)
`
`30
`30
`
`35
`35
`
`•• •
`• • •
`
`•
`
`•
`••••
`••••
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`• • •
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`
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`
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`.. •
`
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`
`••••
`•
`• 4
`•• •
`
`••••
`••••
`• • •
`. • •
`••
`•
`•• •
`
`8408Y
`8408Y (cid:9)
`
`26280-FF
`26280-FF
`
`-- --- -------- -- ------~~~~- --- -~---------------------
`
`Innopharma EX1011, Page 10
`
`

`
`-
`
`- --- - ~-------------------
`
`In a more preferred ophthalmic NSAID solution, the ingredients are combined in
`In a more preferred ophthalmic NSAID solution, the ingredie