123
`
`Ophthalmic Solution Following Topical Instillation into the Eyes of New Zealand White Rabbits
`
`Bakla yan G.A.
`Bausch & Lomb Inc.
`
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`Bromfenac,
`like most of the NSAIDs, are weakly acidic
`drugs, which ionize at the pH of the lachrymal fluid and
`therefore have limited permeability through the anIonIc
`cornea, which has an isoelectric point
`(pI) of 3.2.
`Reducing the pH of
`the formulation Increases the
`unionized
`fraction
`of
`the
`drug which
`enhances
`permeatIon. 4
`solution) 0.09%,
`Xibrom""
`(bromfenac ophthalmic
`administered twice daily, was approved by the Food and
`Drug Administration (FDA) on March 24, 2005 for the
`treatment
`of
`patients with
`post—cataract
`ocular
`Inflammatlon, and In January 2006 for the treatment of
`ocular pain following cataract surgely 5
`Bromdaym (bromfenac ophthalmic solution) 0.09%
`administered once daily, was approved by the FDA on
`October 16, 2010 for the treatment of postoperative
`inflammation and reduction of ocular paln Ir patlents
`who have undergone cataract extraction. 6
`An advanced formulation of bromfenac (PROLENSATM
`[bromfenac ophthalmic solution] 0.07%) has been
`developed which contalns a lower pH (7.8) compared to
`earlier formulations. The lower pH facilitates corneal
`penetration. PROLENSA also has a lower concentration
`compared
`to
`other
`available
`formulations
`of
`bromfenac.7
`
`
`14C-labeled bromfenac 0.07% was analyzed to verify the
`radIoactive purity prior to its use in the study.
`3rior to treatment, 18 animals were weighed and randomly
`asslgned to 6 treatment groups.
`A physical examlnatlon was performed on each animal
`including a pre—treatment ophthalmic examination (slit lamp
`anc
`indirect ophthalmoscopy). Acceptance
`crIterIa
`for
`olacement on study were as follows:
`+ Scores of S 1 for conjunctival swelling
`VJ Scores of 0 for all other observation variables
`Each rabbit received topical ocular doses of a 50pL test agent
`dose into the conjunctival sac using a calibrated pipette and
`he eyelid was held closed for 5-10 seconds following the
`dose.
`
`3 rabbits (both eyes) were assessed per time point over a 24
`wour period
`Animals were euthanized at the following 6 tIme poInts:1 hr
`:t 5 mIn, 2 hrs :l: 15 min, 4 hrs :l: 15 min, 8 hrs :l: 15 min, 12
`'Irs :l: 15 mln, or 24 hrs :l: 15 mln following dosing.
`The irIs/ciliary body,
`lens, vltreous, retlna, choroid, sclera,
`conjunctiva, and cornea were collected from each eye and
`weighed.
`bromfenac
`14C—labeled
`of
`The
`ocular pharmacokinetics
`0.07°/o, pH=7.8 was assessed at 6 time points over a 24
`hour tIme interval.
`
`
`10.0000 I
`
`< queous Humor
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`mo ‘I000
`E‘
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`3-
`
`0,0100
`
`(10010 .
`
`0,0002 ‘
`
`
`
`
`
` -r '.:3.”!'F1¢'Ji
`
`?".5E’§i=.f¢f9*.';'-C To evaluate the 24-hour ocular distribution
`and concentratIons of 14C-Iabeled low-concentratlon,
`modified bromfenac ophthalmic solution following topical
`instillation In New Zealand White rabbit eyes.
`.
`Eighteen New Zealand whlte rabbits were
`randomly assigned to 6 treatment groups (3 animals per
`treatment group). A single dose of 50pL of the dosing
`solution was topically administered Into the conjunctival
`sac of both eyes
`of each animal. Animals were
`euthanized and the aqueous humor was collected at 1
`hour :l: 5 mlnutes, 2 hours i 15 mlnutes, 4 hours :I: 15
`minutes, 8 hours :I: 15 minutes, 12 hours :l: 15 minutes,
`or 24 hours
`:l:
`15 mlnutes
`following dosing. The
`iris/clliary body,
`lens, vitreous, retina, choroid, sclera,
`conjunctlva,
`and cornea
`(target
`tissues) were also
`collected from each eye for analysis. Dosing solutions
`were
`analyzed
`to
`confirm radiochemical
`purlty;
`radioactlve concentratlon of
`the dosing solutions was
`calculated uslng liquid scintillation countlng (LSC).
`:
`“J:
`Radioactive
`residues
`of
`1“C—Iabeled
`bromfenac, expressed as mean parts per million [(ppm)
`pg/g] was seen In all target tIssues of the eyes, with the
`highest concentrations found in the cornea, conjunctiva,
`and sclera. The concentratlons In the tIssues diminished
`to varying degrees over the 24 hour study period, with
`the exceptlon of the lens, which increased insIgnIficantly
`from the 1 hour time point. The levels detected in the
`lens
`and vltreous humor were
`low and close
`to
`background levels.
`€,‘.£.‘v;r’:.’;3¢.'I:’-,'E1)3’:.'
`SIgnIfIcant penetratIon and measurable
`amounts of “C-labeled bromfenac were detected in most
`ocular target tIssues over 24 hours, with highest levels
`In the cornea, conjunctlva, and sclera. The 14C—low
`concentration bromfenac residues in ocular tissues were
`sImIlar to those prevIously reported wIth 0.09% 14C-
`bromfenac,
`the currently available concentration of
`bromfenac formulation.
`"'
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`
`Page 1 of 1
`
`inflammatory drug
`Bromfenac is a non—steroidal anti
`(NSAID) with an extenslve history of cllnical efficacy; It
`acts by blocking prostaglandin synthesis by inhibiting
`cyclooxygenase
`1
`and 2
`In
`the arachidonIc
`acId
`pathway.
`a
`contains
`of bromfenac
`structure
`The
`chemical
`bromine atom at
`the C4 posItIon, which Imparts
`dIstinguishing characterlstics from other ophthalmic
`NSAIDs
`including improved potency and enhanced
`lipophillcity
`molecule,
`of
`the
`which
`facilitates
`
`Animal use for this study was approved by the facility's In
`tutional Anlmal Care and Use Committee (IACUC) and conformed to the ARVO “Statement on the Use of Animals in Ophthalmlc and Visual Research.
`Presented at the 2013 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; May 5-9, 2013; Seattle, WA
`
`v=¢~sIrI‘s/CiIiery Body
`-.«:4:4.4-Lens
`
`-1-Retina
`~ ~Chnroicl
`
`an:-:»~Sclera
`
`'/oi’-'-C0l'l1ea
`
`-Conjunctiva
`
`Hours
`
`
`pg/g of drug-derived radioactivity following
`The mean
`adminIstration of 1“C—bromfenac was seen in all tissues of
`the eyes at
`low levels, with the highest ooncentratIons
`found In the cornea, COl'l]Ul’lCtlVa, and sclera (Flgure 1).
`The concentrations in the tissues diminished to varying
`degrees over the 24 hour study period. Levels In the lens
`were very low and remained essentially unchanged. The
`radIoactivity detected by LSC In both the lens and the
`vitreous humor was very low and close to background
`values.
`
`
`The bromfenac 0.07°/o formulation has been shown to
`Improve the
`penetratIon Into ocular
`tIssues thereby
`allowing for a lower concentration with comparable tissue
`concentratIons to those seen with BROMDAY.
`
`BRUMLJAY,
`to XIBRUM and
`SImIlar
`formulation of bromfenac 0.07% provIdes
`concentratlons throughout ocular t|SSU$ for 24 hours
`which allows for once daily dosing.
`PROLENSA (bromfenac ophthalmic solution) 0.07% was
`FDA approved on April 5“, 2013 for once daily dosing for
`the treatment of postoperative inflammation and reduction
`of ocular paln In patIents who have undergone cataract
`surgery.
`
`
`Significant penetration and measurable amounts of
`14C-labeled bromfenac were detected in most ocular
`target tissues over 24 hours, with highest levels in the
`cornea, conjunctiva, and sclera. The 0.07% 14C-
`bromfenac residues in ocular tissues were similar to
`those previously reported with 0.09% ”C—bromfenac.
`
`
`1.
`Baklayari GA, Patterson HM, Song CK, Gow JA, McNamara TR.
`Pharmacol Ther2008;24(4):392-398.
`2. Donnenfeld, E.D., Holland, 5.1., Stewart, R.H., et.a|. Ophthalmology.
`2007; 114:l653-1662.
`3.
`Kim, s.J., Flach, A.J., Jampol,
`l_.M. Surv Ophthalmol.
`133.
`Ahuja M, Dhake AS, Sharma SK. Majumdar DK. AAPS J 2008;10:229-41.
`XIBROMW Pracribing Information. ISTA Pharmaceuticals, Inc. 2010
`BROMDAYW Prescribing Information. Bauscri and Lomb, Inc. 2011.
`\lo\U1-b
`PROLENSAW Pr$Cribing Information, Bausch and Lomb, Inc. 2013
`Financial support: Bausch & Lomb Inc., In/Ine, CA, USA
`Financial disclosura: GA Baklayan is an employee of Bausch & Lomb, Inc
`George A Baklayan, Ph D
`Pharrnaceutlcal Development, Bausch & Lornb, Inc
`50 Technology Dr 1nIne,cA 92618
`Phone (949)788—5314
`george baklayan@bausch corn
`
`SENJU EXHIBIT 2223
`
`LUPIN V. SENJU
`
`IPR2015-01099
`PROLO280755
`
`Page 1 of 1
`
`SENJU EXHIBIT 2223
`LUPIN v. SENJU
`IPR2015-01099