US009533053B2
`
`(12) United States Patent
`US 9,533,053 B2
`(10) Patent No.:
`Gamache et al.
`(45) Date of Patent:
`*Jan. 3, 2017
`
`(54) HIGH CONCENTRATION OLOPATADINE
`OPHTHALMIC COMPOSITION
`
`USPC ................................. 514/449, 450, 777, 778
`See application file for complete search history.
`
`(71) Applicant: Alcon Research, Ltd., Fort Worth, TX
`(US)
`
`(56)
`
`(72)
`
`Inventors: Daniel A. Gamache, Arlington, TX
`(US); Laman Alani, Fort Worth, TX
`(US); Malay Ghosh, Fort Worth, TX
`(US); Francisco Javier Galan, Teia
`(ES); Nuria Carreras Perdiguer,
`Barcelona (ES); Onkar N. Singh,
`Arlington, TX (US)
`
`(73) Assignee: Alcon Research, Ltd., Fort Worth, TX
`(US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 117 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 14/304,124
`
`(22)
`
`Filed:
`
`Jun. 13, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2014/0296328 A1
`
`Oct. 2, 2014
`
`Related US. Application Data
`
`(63) Continuation of application No. 13/475,607, filed on
`May 18, 2012, now Pat. No. 8,791,154.
`
`(60) Provisional application No. 61/548,957, filed on Oct.
`19, 2011, provisional application No. 61/487,789,
`filed on May 19, 2011.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2011.01)
`
`Int. Cl.
`A61K 31/335
`A01N 43/02
`A61K 47/00
`A61K 47/40
`A61K 9/00
`A61K 47/32
`A61K 9/08
`A61K 47/48
`C083 37/16
`C08L 5/16
`A61K 47/10
`B82Y 5/00
`(52) us. Cl.
`CPC ............. A61K 47/40 (2013.01); A61K 9/0048
`(2013.01); A61K 9/08 (2013.01); A61K 31/335
`(2013.01); A61K 47/10 (2013.01); A61K 47/32
`(2013.01); A61K 47/48969 (2013.01); BSZY
`5/00 (2013.01); C083 37/0015 (2013.01);
`C08L 5/16 (2013.01)
`
`(58) Field of Classification Search
`CPC .......... A61K 47/40; A61K 47/10; A61K 9/08;
`A61K 47/48969; A61K 47/32; A61K
`31/335; A61K 9/0048; B82Y 5/00; C08L
`5/16; C08B 37/0015
`
`References Cited
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`James I. McGill, “A review of the use of olopatadine in allergic
`conjunctivitis”, 2004,
`International Ophthalmology, 25(3):171-
`179.*
`
`(Continued)
`
`Primary Examiner 7 My-Chau T Tran
`
`(74) Attorney, Agent, or Firm 7 Scott A. Chapple
`
`(57)
`
`ABSTRACT
`
`The present invention is an ophthalmic composition con-
`taining a relatively high concentration of olopatadine. The
`composition is typically an ophthalmic aqueous solution
`containing relatively high concentrations of olopatadine
`solubilized within the solution. The composition is prefer-
`ably capable of providing enhanced relief from symptoms of
`ocular allergic conjunctivitis, particularly late phase symp-
`toms of ocular allergic conjunctivitis.
`
`13 Claims, 5 Drawing Sheets
`
`Ayla Pharma LLC (IPR2020-00295) EX. 1002 p. 001
`
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`
`

`

`US 9,533,053 B2
`
`Page 2
`
`(56)
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`
`* cited by examiner
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`

`

`U.S. Patent
`
`Jan. 3, 2017
`
`Sheet 1 of 5
`
`US 9,533,053 B2
`
`Regimes-gs
`I‘VIeanC3aniluictival
`
`T
`
`S
`
`9
`
`ID
`
`11
`
`13
`
`1'3.
`
`14
`
`‘13
`
`16
`
`1?
`
`15
`
`1'9
`
`3'3
`
`Past-SAC Time {Minutes}
`
`FIG. 1
`
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`

`U.S. Patent
`
`Jan. 3, 2017
`
`Sheet 2 of 5
`
`US 9,533,053 B2
`
`I m Olapatadineflm'h
`*""‘* Olupatadine [102%
`9’ G'OVBhiClE
`
`Rednesss;
`
`18.182111Canilmetival
`
`Post-CA6 Time (Minutes)
`
`FIG. 2
`
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`

`

`U.S. Patent
`
`Jan. 3, 2017
`
`Sheet 3 of 5
`
`US 9,533,053 B2
`
`' mfllepatadinefifim
`*‘H Glepatadine filth:
`
`9' H‘Jehicle
`
`
`
`
`
`hieanTatalRednegs
`
`
`
`Past-GAG Time fit-finutes}
`
`FIG. 3
`
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`

`U.S. Patent
`
`Jan. 3, 2017
`
`Sheet 4 of 5
`
`US 9,533,053 B2
`
`4.21
`
`m Olapatadine (Mm
`3:3 *""‘* Olupatadine 0,2911:
`9’ H Vehicle
`
` 5
`
`
`
`
`
`hiemlC3culm‘Itching
`
`Past-GAG Time (Minutes)
`
`FIG. 4
`
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`

`US. Patent
`
`Jan. 3, 2017
`
`Sheet 5 of 5
`
`US 9,533,053 132
`
`I m Olapatadine 0,17%
`*""‘* Olupatadine [102%
`9’ G'OVBhiClE
`
`Rednesss;
`
`18.182111Canilmetival
`
`Post-CA6 Time (Minutes)
`
`FIG. 5
`
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`

`US 9,533,053 B2
`
`1
`HIGH CONCENTRATION OLOPATADINE
`OPHTHALMIC COMPOSITION
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application is a continuation application of US.
`Utility patent application Ser. No. 13/475,607 filed May 18,
`2012 (now allowed), which claims priority based on US.
`Provisional Patent Application Ser. No. 61/487,789 filed
`May 19, 2011 and US. Provisional Patent Application Ser.
`No. 61/548,957 filed Oct. 19, 2011.
`
`TECHNICAL FIELD OF THE INVENTION
`
`The present invention relates to an ophthalmic composi-
`tion containing a relatively high concentration of olopata-
`dine. More particularly, the present invention relates to an
`ophthalmic aqueous solution containing a relatively high
`concentration of solubilized olopatadine wherein the solu-
`tion is capable of providing enhanced relief from symptoms
`of ocular allergic disorders (e.g., conjunctivitis) in the early
`phase, the late phase or preferably both phases.
`
`BACKGROUND OF THE INVENTION
`
`Individuals suffering from allergic conjunctivitis experi-
`ence symptoms such as ocular irritation, itchiness, redness
`and the like. It has been found that these symptoms are
`significantly reduced using topical ophthalmic solutions
`containing olopatadine. Such solutions are sold under the
`tradenames PATANOL® and PATADAY®, which are both
`commercially available from Alcon Laboratories, Inc., Fort
`Worth, Tex.
`These marketed solutions were generally believed to be
`the most efficacious products known for addressing symp-
`toms of allergic conjunctivitis. Surprisingly, and as dis-
`cussed further below, it has been discovered that relatively
`high concentration solutions of olopatadine provide signifi-
`cantly improved reduction of late phase ocular allergic
`conjunctivitis symptoms in addition to relief from early
`phase symptoms. Even more surprising, it has been discov-
`ered that such high concentrations of olopatadine also pro-
`vide significantly improved reduction of redness in the early
`phase. Further, it has been discovered that enhanced relief
`from these early and late phase symptoms can be achieved
`through once a day dosing of relatively high concentration
`olopatadine solution as opposed to greater dosing frequen-
`c1es.
`
`The discovery of improved reduction of early and late
`phase symptoms is quite significant and desirable for indi-
`viduals suffering from allergic conjunctivitis. Generally,
`these discoveries can provide patients greater relief from
`itching and provide better aesthetic appearance to the eye.
`Further, avoiding more frequent dosing is more convenient
`for patients and helps assure better compliance. Further yet,
`improved early prevention and/or reduction of redness is
`particularly desirable since patients generally have a desire
`to keep as much redness out of their eyes as possible.
`The discovery that relatively high concentration solutions
`of olopatadine can relieve late phase ocular allergic con-
`junctivitis symptoms provides hope to sufferers of ocular
`allergic conjunctivitis that a single dose of olopatadine per
`day could provide a substantial degree of full day relief from
`their symptoms. However, the development of a multi-dose
`ophthalmic solution that includes high concentrations of
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`olopatadine necessary to achieve desired levels of efficacy is
`extremely difficult and complex.
`Solubilizing high concentrations of olopatadine in a stable
`manner has proven difficult by itself. Olopatadine, by itself,
`is only soluble in water (pH about 7.0) at room temperature
`up to a concentration of about 0.18 w/v %. However, it is
`desirable to achieve solubilization of much higher concen-
`trations of olopatadine in an effort to treat late phase allergic
`conjunctivitis.
`Solubilizing such higher concentrations of olopatadine
`has proven difficult. As one example, excipients such as
`polyethylene glycol (PEG) 400 and polyvinylpyrrolidone
`(PVP), when used at reasonably desirable concentrations,
`have proven incapable, alone or in combination, of solubi-
`lizing sufficient concentrations of olopatadine in composi-
`tions having approximately neutral pH. Thus, innovation is
`required to solubilize a sufficient concentration of olopata-
`dine.
`
`In the process of such innovation, is has been discovered
`that higher molecular weight PEGs such as PEG 6000 can
`significantly enhance solubility of olopatadine. However,
`such PEGs cause risk of discomfort when administered to
`
`humans. It has also been discovered that cyclodextrins, such
`as hydroxypropyl-y-cyclodextrin, hydroxypropyl-B-cyclo-
`dextrin and sulfoalkyl ether-B-cyclodextrin, have the ability
`to solubilize significantly higher concentrations of olopata-
`dine. However, use of undesirably high concentrations of
`cyclodextrins has been found to reduce olopatadine efficacy
`and/or preservation efficacy of solutions. As such, still
`further innovation was needed to create a desirable olopa-
`tadine formulation that not only solubilized sufficient
`amounts of olopatadine, but also allowed the formulation to
`achieve other desirable pharmaceutical characteristics.
`Thus, the present invention is directed at an ophthalmic
`composition that can provide high concentrations of olopa-
`tadine topically to the eye. Further, the present invention is
`directed to such a composition wherein the olopatadine is
`solubilized in solution in a stable manner, the composition
`exhibits consistent efficacy against late phase symptoms of
`allergic conjunctivitis, the composition exhibits sufficient
`antimicrobial activity to provide desired levels of preserva-
`tion efficacy or any combination thereof
`
`SUMMARY OF THE INVENTION
`
`The present invention is directed to an ophthalmic com-
`position for treatment of allergic conjunctivitis. The com-
`position will
`include a relatively high concentration of
`olopatadine, preferably at least 0.67 w/v % olopatadine,
`preferably dissolved in solution. The composition will typi-
`cally include a cyclodextrin, and more particularly, a y-cy-
`clodextrin derivative and/or a B-cyclodextrin derivative to
`aid in solubilizing the olopatadine. The cyclodextrin deriva-
`tive is preferably hydroxypropyl-y-cyclodextrin (HP-y-CD),
`hydroxypropyl-B-cyclodextrin (HP-B-CD), sulfoalkyl ether
`B-cyclodextrin (SAE-B-CD)(e.g., sulfobutyl ether B-cyclo-
`dextrin (SBE-B-CD)), or a combination thereof. The com-
`position will typically include a lactam polymer (e.g., poly-
`vinylpyrrolidone (PVP)) to aid in the solubilization of the
`olopatadine. The composition will also typically include a
`polyether (e.g., polyethylene glycol (PEG)) for enhancing
`solubility and/or aiding in achieving the desired tonicity. It
`is generally desirable for the composition to be disposed in
`an eyedropper, have a pH of 5.5 to 8.0, to have an osmolality
`of 200 to 450, to have a viscosity of 10 to 200 cps or any
`combination thereof. The composition will also typically
`include a preservative to allow the composition to achieve
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`US 9,533,053 B2
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`3
`United States and/or European Pharmacopeia preservation
`standards. Preferred preservatives include a polymeric qua-
`ternary ammonium compound, such as polyquaternium-1,
`and benzalkonium chloride. The composition also typically
`includes borate and/or polyol to aid in achieving desired
`preservation.
`The present invention also contemplates a method of
`treating ocular allergy symptoms. The method will include
`topically applying a composition having a defined combi-
`nation of the characteristics described above to an eye of a
`human. This step of topically applying the composition
`preferably includes dispensing an eyedrop from an eyedrop-
`per.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 is a graph of mean conjunctival redness determined
`by a conjunctival allergen challenge (CAC) at 27 minutes.
`FIG. 2 is a graph of mean conjunctival redness determined
`by a conjunctival allergen challenge (CAC) at 16 hours.
`FIG. 3 is a graph of mean total redness determined by a
`conjunctival allergen challenge (CAC) at 24 hours.
`FIG. 4 is a graph of mean ocular itching determined by a
`conjunctival allergen challenge (CAC) at 24 hours.
`FIG. 5 is a graph of mean conjunctival redness determine
`by a conjunctival allergen challenge (CAC) at 24 hours.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The present invention is predicated upon the provision of
`an ophthalmic composition for treatment of allergic con-
`junctivitis. The ophthalmic composition is preferably an
`aqueous solution. The ophthalmic composition includes a
`relatively high concentration of olopatadine solubilized in
`aqueous solution. The ophthalmic composition also includes
`a unique set of excipients for solubilizing the olopatadine
`while maintaining comfort of the composition and/or effi-
`cacy of the composition in treating symptoms associate with
`allergic conjunctivitis, particularly symptoms associated
`with late phase allergic conjunctivitis. Preferably, the com-
`position exhibits improved late phase efiicacy in reducing
`ocular itching, ocular redness or both. The composition also
`preferably exhibits improved early phase efficacy in reduc-
`ing ocular redness relative to vehicle and/or relative to lower
`concentrations of olopatadine. In a preferred embodiment,
`the ophthalmic composition is a multi-dose ophthalmic
`composition that also exhibits a required degree of preser-
`vation efficacy.
`Unless indicated otherwise, all component amounts (i.e.,
`concentrations) are presented on a weight volume percent
`(w/v %) basis and all references to concentrations of olo-
`patadine are to olopatadine free base.
`Olopatadine is a known compound that can be obtained
`by the methods disclosed in US. Pat. No. 5,116,863, the
`entire contents of which are hereby incorporated by refer-
`ence in the present specification for all purposes. The
`formulation of the present invention contains at least 0.50%,
`more typically at least 0.55%, more typically at least 0.6%
`or 0.65%, even more typically at least 0.67% or 0.68%, still
`more typically at least 0.7%, possibly at least 0.75% and
`even possibly at least 0.85% but typically no greater than
`1.5% more typically no greater than 1.0%, still more typi-
`cally no greater than 0.8%, possibly no greater than 0.75%
`and even possibly no greater than 0.72% of olopatadine
`where concentrations of olopatadine typically represent con-
`centrations of olopatadine in free base form if the olopata-
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`dine is added to the composition as a salt. These lower limits
`of concentrations of olopatadine are particularly important
`since it has been found that efficacy of olopatadine in
`aqueous ophthalmic solutions in reducing late phase allergy
`symptoms and enhanced reduction of early phase redness
`begins to show improvement at concentrations greater than
`0.5 w/v % of olopatadine and begins to show statistically
`significant
`improvements in reducing late phase allergy
`symptoms at concentrations of about 0.7 w/v % olopatadine
`and above (e.g., at least 0.65 w/v %, at least 0.67 w/v % or
`at least 0.68 w/v %). Most preferably, the concentration of
`the olopatadine in the composition is 0.7 w/v %.
`Generally, olopatadine will be added in the form of a
`pharmaceutically acceptable salt. Examples of the pharma-
`ceutically acceptable salts of olopatadine include inorganic
`acid salts such as hydrochloride, hydrobromide, sulfate and
`phosphate; organic acid salts such as acetate, maleate,
`fumarate,
`tartrate and citrate; alkali metal salts such as
`sodium salt and potassium salt; alkaline earth metal salts
`such as magnesium salt and calcium salt; metal salts such as
`aluminum salt and zinc salt; and organic amine addition salts
`such as triethylamine addition salt (also known as trometh-
`amine), morpholine addition salt and piperidine addition
`salt. The most preferred form of olopatadine for use in the
`solution compositions of the present invention is the hydro-
`chloride salt of (Z)-11-(3-dimethylaminopropylidene)-6,11-
`dihydro-dibenZ-[b,e]oxepin—2-acetic acid. When olopata-
`dine is added to the compositions of the present invention in
`this salt form, 0.77% olopatadine hydrochloride is equiva-
`lent
`to 0.7% olopatadine free base, 0.88% olopatadine
`hydrochloride is equivalent to 0.8% olopatadine free base,
`and 0.99% olopatadine hydrochloride is equivalent to 0.9%
`olopatadine free base.
`Generally, it is preferred that the entire concentration of
`olopatadine is dissolved in the composition as a water based
`or aqueous solution. However, it is contemplated that olo-
`patadine could be only partially dissolved. For example, a
`portion of the olopatadine could be in solution with the
`remainder being in suspension.
`The composition of the present invention also preferably
`includes cyclodextrin derivative and more preferably B-cy-
`clodextrin derivative, y-cyclodextrin derivative or both to
`aid in solubilizing the olopatadine (i.e., as a solubilizer). The
`B-cyclodextrin derivative, y-cyclodextrin derivative or com-
`bination thereof is typically present in the composition at a
`concentration that is at least 0.5% w/v, more typically at
`least 1.0% w/v and even possibly at least 1.3% w/v, but is
`typically no greater than 4.0% w/v, typically no greater than
`3.2% w/v and even possibly no greater than 2.8% w/v.
`Preferably, the total concentration of cyclodextrin is from
`0.9 w/v % to 3.2 w/v %.
`
`The specific amount of B-cyclodextrin derivative, y-cy-
`clodextrin derivative or combination thereof in a particular
`composition will typically depend upon the type or combi-
`nation of types of derivatives used. One particularly desir-
`able B-cyclodextrin derivative is a hydroxy alkyl-B-cyclo-
`dextrin such as hydroxypropyl-B-cyclodextrin (HP-B-CD).
`One particularly desirable y-cyclodextrin derivative is a
`hydroxy alkyl-y-cyclodextrin such as hydroxypropyl-y-cy-
`clodextrin (HP-y-CD). Another particularly desirable B-cy-
`clodextrin derivative is
`sulfoalkyl ether-B-cyclodextrin
`(SAE-B-CD), particularly sulfobutyl ether-B-cyclodextrin
`(SBE-B-CD).
`It
`is contemplated that a combination of
`hydroxypropyl-B-cyclodextrin, hydroxypropyl-y-cyclodex-
`trin and/or sulfoalkyl ether-B-cyclodextrin derivative may be
`employed in a single composition, but it is typically desir-
`able to use only one of the three as the sole or substantially
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`US 9,533,053 B2
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`5
`the sole (i.e., at least 90% by weight of the cyclodextrin
`component) cyclodextrin derivative.
`When HP-B-CD is employed as the sole or substantially
`sole B-cyclodextrin derivative, it is typically present in the
`composition at a concentration that is at least 0.5% w/v,
`more typically at least 1.0% w/v and even more typically at
`least 1.3% w/v, but is typically no greater than 3.0% w/v,
`typically no greater than 2.2% w/v and is typically no greater
`than 1.7% w/v. When HP-y-CD is employed as the sole or
`substantially sole y-cyclodextrin derivative,
`it is typically
`present in the composition at a concentration that is at least
`0.5% w/v, more typically at least 1.0% w/v and even more
`typically at least 1.3% w/v, but is typically no greater than
`3.0% w/v, typically no greater than 2.2% w/v and is typically
`no greater than 1.7% w/v. When SAE-B-CD is employed as
`the sole or substantially sole B-cyclodextrin derivative, it is
`typically present in the composition at a concentration that
`is at least 0.3% w/v, more typically at least 0.7% w/v and
`even more typically at least 0.9% w/v, but is typically no
`greater than 2.4% w/v, typically no greater than 1.5% w/v
`and is typically no greater than 1.1% w/v.
`HP-B-CD is a commodity product and pharmaceutical
`grades of HP-B-CD can be purchased from a variety of
`sources, for example, from SIGMA ALDRICH, which has
`its corporate headquarters in St. Louis, Mo. or ASHLAND
`SPECIALTY INGREDIENTS, headquartered in Wayne,
`N.J. HP-y-CD is a commodity product and pharmaceutical
`grades of HP-y-CD can be purchased from a variety of
`sources, for example, from SIGMA ALDRICH, which has
`its corporate headquarters in St. Louis, Mo. or ASHLAND
`SPECIALTY INGREDIENTS, headquartered in Wayne,
`N.J. SAE-B-CD can be formed based upon the teachings of
`US. Pat. Nos. 5,134,127 and 5,376,645, which are incor-
`porated herein by reference for all purposes. It is generally
`preferred, however,
`to use purified SAE-B-CD. Purified
`SAE-B-CD is preferably formed in accordance with the
`teachings of US. Pat. Nos. 6,153,746 and 7,635,773. Puri-
`fied SAE-B-CD is commercially available under the trade-
`name CAPTISOL® from CyDex Pharmaceuticals,
`Inc.,
`Lenexa, Kans.
`With regard to y-cyclodextrin derivative and B-cyclodex-
`trin derivative in the composition of the present invention, it
`has been found that undesirably high concentrations of
`y-cyclodextrin derivative and/or B-cyclodextrin derivative
`can significantly interfere with preservation efficacy of the
`compositions, particularly when benzalkonium chloride
`and/or polymeric quaternary ammonium compound are
`employed as preservation agents. Thus, lower concentra-
`tions of y-cyclodextrin derivative and/or B-cyclodextrin
`derivative are typically preferred. Advantageously,
`it has
`also been found, however, that the ability of the y-cyclo-
`dextrin derivative and B-cyclodextrin derivatives in solubi-
`lizing olopatadine is very strong and relatively low concen-
`trations of y-cyclodextrin derivative and/or B-cyclodextrin
`derivative can solubilize significant concentrations of olo-
`patadine in aqueous solution. As such, more desirable and
`reasonable concentrations of additional solubilizing agent
`can be used to aid in s