(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`22 November 2012 (22.11.2012)
`
`9’
`WIPOI PCT
`
`(10) International Publication Number
`
`WO 2012/159064 A1
`
`(51)
`
`International Patent Classification:
`
`A61K 31/335 (2006.01)
`A61K 9/00 (2006.01)
`
`A61P 27/14 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/US2012/038663
`
`Malay [US/US]; 4221 Kirkland Court, Fort Worth, Texas
`76109 (US). GALAN, Francisco Javier [ES/ES]; c/ Dels
`Pins,
`19, E-08329 Teia (ES). PERDIGUER, N1'1ria
`[ES/ES]; Ametller, 9, E-08140 Calades de Montbui (ES).
`SINGH, Onkar [US/US]; 5606 Rachel Court, Arlington,
`Texas 76017 (US).
`
`Agents: SCOTT A. CHAPPLE et al.; Alco11 Research,
`Ltd., IP Legal, Mail Code TB4-8, 6201 South Freeway,
`l-'ort Woith, Texas 76134-2099 (US).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG. MK. MN. MW. MX, MY, MZ, NA, NG, NI, NO, NZ,
`OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`
`[Continued on nextpage]
`
`(22)
`
`International Filing Date:
`
`(25)
`
`Filing Language:
`
`Publication Language:
`
`(26)
`
`(30)
`
`18 May 2012 (18.05.2012)
`
`English
`
`English
`
`Priority Data:
`61/487,789
`61/548,957
`
`19 May 2011 (19.05.2011)
`19 October 2011 (19.10.2011)
`
`US
`US
`
`Applicant 0’or all designated States except US): ALCON
`RESEARCH, LTD. [US/US]; 6201 South Freeway, Mail
`Code TB4-8, Fort Worth, Texas 76134-2099
`
`Inventors; and
`Inventors/Applicants for US only): GAMACHE, Daniel
`A.
`[US/US]; 5610 Hunterwood Lane, Arlington, Texas
`76017 (US). ALANI, Laman [US/US]; 6809 Shadow
`Creek Court, Fort Worth, Texas 76132 (US). GHOSH,
`
`(54) Title: HIGH CONCENTRATION OLOPATADINE OPHTHALMIC COMPOSITION
`
`I *+*Olopatadine0.77%
`.
`*‘*‘*Olopatadix1e0.2% i
`99'9Vehic1e
`’
`
`
`
`
`
`lvfeanColljunctivalRedness
`
`(57) Abstract: The present invention is
`an ophthalmic composition containing a
`relatively high concentration of olo-
`patadine. The composition is typically
`an ophthalmic aqueous solution contain-
`ing relatively high concent1'ations of
`olopatadine solubilized Within the solu-
`tion. The composition is preferably cap-
`able of providing enhanced relief from
`symptoms of ocular allergic conjunctiv-
`itis, particularly late phase symptoms of
`ocular allergic conjunctivitis.
`
`ARGENTUM PHARM. 1019
`
`01f' .w.r.,,.,...r,..,,.
`7
`‘
`9
`10
`ll
`13
`13
`14
`15
`16
`
`18
`
`Post-CAC Time (Minutes)
`
`V-1
`
`<fl
`<1-
`\o
`c:
`ax
`In
`V-1E
`
`NV
`
`-1
`
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`
`ARGENTUM PHARM. 1019
`
`000001
`
`

`
`WO 2012/159064 A1 ||||||||||||||||||||||||||||||||||||||||||ll|||||||||||||||||||||||||||||||||||||||||||||||||||
`
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GM, KE, LR, LS, MW, MZ, NA, Rw, SD, SL, sz, TZ,
`GW, ML, MR, NE, SN, TD, TG).
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, P hr h d.
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`“ ‘S " -
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, — with international Search report (Art. 21(3))
`
`000002
`
`000002
`
`

`
`WO 2012/159064
`
`PCT/US2012/038663
`
`HIGH CONCENTRATION OLOPATADINE
`
`OPHTHALMIC COMPOSITION
`
`Cross-Reference to Related Application
`
`The present application claims priority based on U.S. Provisional Patent
`
`Application Serial No. 61/487,789 filed May 19, 2011 and U.S. Provisional Patent
`
`Application Serial No. 61/548,957 filed October 19, 2011.
`
`Technical Field of the Invention
`
`The present
`
`invention relates to an ophthalmic composition containing a
`
`relatively high concentration of olopatadine. More particularly,
`
`the present
`
`invention relates to an ophthalmic aqueous solution containing a relatively high
`
`concentration of solubilized olopatadine wherein the solution 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 experience 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, TX.
`
`These marketed solutions were generally believed to be the most efficacious
`
`products known for addressing symptoms of allergic conjunctivitis. Surprisingly,
`
`and as discussed further below,
`
`it has been discovered that
`
`relatively high
`
`concentration solutions of olopatadine provide significantly improved reduction of
`
`late phase ocular allergic conjunctivitis symptoms in addition to relief from early
`
`phase symptoms. Even more surprising,
`
`it has been discovered that such high
`
`concentrations of olopatadine also provide 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
`
`-1-
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`WO 2012/159064
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`PCT/US2012/038663
`
`dosing of relatively high concentration olopatadine solution as opposed to greater
`
`dosing frequencies.
`
`The discovery of improved reduction of early and late phase symptoms is
`
`quite significant and desirable for individuals 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 conjunctivitis 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 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 concentrations 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 solubizing sufficient
`
`concentrations of olopatadine in compositions having approximately neutral pH.
`
`Thus, innovation is required to solubilize a sufficient concentration of olopatadine.
`
`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-
`
`-2-
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`WO 2012/159064
`
`PCT/US2012/038663
`
`cyclodextrin, hydroxypropyl-B-cyclodextrin and sulfoalkyl ether-B-cyclodextrin,
`
`have the ability to solubilize significantly higher concentrations of olopatadine.
`
`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 olopatadine 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 olopatadine 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 preservation efficacy or any
`
`combination thereof.
`
`Summary of the Invention
`
`The present invention is directed to an ophthalmic composition for treatment
`
`of allergic conjunctivitis.
`
`The composition will
`
`include a relatively high
`
`concentration of olopatadine, preferably at least 0.67 w/v % olopatadine, preferably
`
`dissolved in solution. The composition will typically include a cyclodextrin, and
`
`more particularly, a y-cyclodextrin derivative and/or a B—cyclodextrin derivative to
`
`aid in solubilizing the olopatadine. The cyclodextrin derivative is preferably
`
`hydroxypropyl-y-cyclodextrin (HP-y-CD), hydroxypropyl- B~cyclodextrin (HP- [3-
`
`CD),
`
`sulfoalkyl ether B—cyclodextrin (SAE— B-CD)(e.g.,
`
`sulfobutyl ether B-
`
`cyclodextrin (SBE-B~CD)), or a combination thereof.
`
`The composition will
`
`typically include a lactam polymer (e.g., polyvinylpyrrolidone (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 United States and/or European Pharmacopeia preservation standards.
`
`Preferred preservatives include a polymeric quaternary ammonium compound, such
`
`000005
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`
`WO 2012/159064
`
`PCT/US2012/038663
`
`as polyquaternium—l, 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 combination 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 eyedropper.
`
`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) atl6 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 conjunctivitis. 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 efficacy of the composition in
`
`treating symptoms associate with allergic conjunctivitis, particularly symptoms
`
`associated with late phase allergic conjunctivitis.
`
`Preferably,
`
`the composition
`
`_ 4 _
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`WO 2012/159064
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`PCT/US2012/038663
`
`exhibits improved late phase efficacy in reducing ocular itching, ocular redness or
`
`both. The composition also preferably exhibits improved early phase efficacy in
`
`reducing 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 preservation
`
`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 olopatadine are to olopatadine free base.
`
`Olopatadine is a known compound that can be obtained by the methods
`
`disclosed in U.S. Pat. No. 5,116,863,
`
`the entire contents of which are hereby
`
`incorporated by reference 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 typically 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 concentrations of olopatadine in free base form if
`
`the olopatadine 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 pharmaceutically 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
`
`-5-
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`WO 2012/159064
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`PCT/US2012/038663
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`zinc salt; and organic amine addition salts such as triethylamine addition salt (also
`
`known as tromethamine), 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
`
`hydrochloride
`
`salt
`
`of
`
`(Z)—l 1-(3 -
`
`dimethylaminopropylidene)-6,l1—dihydro-dibenz-[b,e ]oxepin-2-acetic acid. When
`
`olopatadine is added to the compositions of the present invention in this salt form,
`
`0.77% olopatadine hydrochloride is equivalent 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 olopatadine 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-cyclodextrin
`
`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
`
`combination 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-cyclodextrin derivative
`
`or combination thereof in a particular composition will typically depend upon the
`
`type or combination of types of derivatives used. One particularly desirable
`
`B-cyclodextrin derivative is a hydroxy alkyl-B—cyclodextrin such as hydroxypropyl-
`
`B-cyclodextrin (HP-B-CD). One particularly desirable y-cyclodextrin derivative is a
`
`hydroxy alkyl-y-cyclodextrin such as hydroxypropyl—y—cyclodextrin (HP-y-CD).
`
`Another particularly desirable B-cyclodextrin derivative is sulfoalkyl ether-[3-
`
`cyclodextrin (SAE-B-CD), particularly sulfobutyl ether—[3—cyclodextrin (SBE-B-
`
`CD).
`
`It
`
`is contemplated that a combination of hydroxypropyl—[3—cyclodextrin,
`
`hydroxypropyl— y —cyclodextrin and/or sulfoalkyl ether—B-cyclodextrin derivative
`
`may be employed in a single composition, but it is typically desirable to use only
`
`-6-
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`WO 2012/159064
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`one of the three as the sole or substantially 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, Missouri or ASHLAND
`
`SPECIALTY INGREDIENTS, headquartered in Wayne, New Jersey. 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, Missouri or ASHLAND SPECIALTY
`
`INGREDIENTS, headquartered in Wayne, New Jersey. SAE-B-CD can be formed
`
`based upon the teachings of U.S. Patent Nos. 5,134,127 and 5,376,645, which are
`
`incorporated herein by reference for all purposes.
`
`It
`
`is generally preferred,
`
`however, to use purified SAE~B-CD. Purified SAE-[3-CD is preferably formed in
`
`accordance with the teachings of U.S. Patent Nos. 6,153,746 and 7,635,773.
`
`Purified SAE-B-CD is commercially available under the tradename CAPTISOL®
`
`from CyDex Pharmaceuticals, Inc., Lenexa, KS.
`
`With regard to 'y—cyclodextrin derivative and B-cyclodextrin 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
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`PCT/US2012/038663
`
`when benzalkonium chloride and/or polymeric quaternary ammonium compound
`
`are employed as preservation agents. Thus, lower concentrations 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-
`
`cyclodextrin derivative and B-cyclodextrin derivatives in solubilizing olopatadine is
`
`very strong and relatively low concentrations of y-cyelodextrin derivative and/or [3-
`
`cyclodextrin derivative can solubilize significant concentrations of olopatadine in
`
`aqueous solution. As such, more desirable and reasonable concentrations of
`
`additional solubilizing agent can be used to aid in solubilizing the desired amounts
`
`of olopatadine.
`
`Further, it has been found that a composition formed using a combination of
`
`solubilizing agents such as polyvinylpyrrolidone, tyloxapol, polyethylene glycol
`
`and others to solubilize relatively high concentrations of olopatadine in the absence
`
`of y-cyclodextrin derivative and/or B-cyclodextrin derivative will typically lack
`
`long term stability or shelf life.
`
`It has been found that such a composition will
`
`typically begin to precipitate after undesirably short periods of time. Thus,
`
`it is
`
`important to employ the y-cyclodextrin derivative and/or B—cyclodextrin derivative
`
`in combination with one or more additional solubilizers.
`
`As such, the ophthalmic composition of the present invention includes at
`
`least one solubilizing agent (i.e., solubilizer), but possibly two or more solubilizing
`
`agents, in addition to cyclodextrin. The additional solubilizing agents can include
`
`surfactants such as castor oil, polysorbate or others. Preferably, the additional
`
`solubilizing agent[s] includes one or more polymers. One preferred polymer for
`
`aiding in solubilizing the olopatadine is la.ctam polymer. Another preferred
`
`polymer for aiding in solubilizing the olopatadine is polyether.
`
`As used herein, the phrase “lactam polymer” refers to any polymer formed
`
`from more than one lactam monomer. The lactam polymer is typically present in
`
`the composition at a concentration that is at least 1.0% w/v, more typically at least
`
`3.0% w/v and even more typically at least 3.7 % w/v, but is typically no greater
`
`than 8.0% w/v, typically no greater than 5.0% w/v and is typically no greater than
`
`4.3% w/v. Polyvinylpyrrolidone (PVP) is the most preferred lactam polymer and
`
`can be the only or substantially the only lactam polymer. Thus,
`
`in a preferred
`
`embodiment, the lactam polymer consists or consists essentially of only PVP. The
`
`average molecular weight of the lactam polymer, particularly when it is PVP, is at
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`least 20,000, more typically at least 46,000 and even more typically at least 54,000
`
`but is typically no greater than 90,000, more typically no greater than 70,000 and
`
`still more typically no greater than 62,000. One preferred PVP is sold under the
`
`tradenames PLASDONE® K29/32 or K30, which have an average molecular
`
`weight of approximately 50,000 and are commercially available from ASHLAND
`
`SPECIALTY INGREDIENTS, headquartered in Wayne, NJ, USA.
`
`The polyether can aid in the solubility of olopatadine in the composition
`
`and/or can provide tonicity to the composition (i.e., act as a tonicity agent). The
`
`polyether is typically present in the composition at a concentration that is at least
`
`1.0% w/v, more typically at least 3.0% w/V and even more typically at least 3.7 %
`
`w/v, but is typically no greater than 8.0% w/v, typically no greater than 5.0% w/v
`
`and is typically no greater than 4.3% w/v. Polyethylene glycol (PEG) is the most
`
`preferred polyether and can be the only or substantially the only polyether polymer.
`
`Thus in a preferred embodiment, the polyether consists or consist essentially of
`
`only PEG. The average molecular weight of the PEG will typically depend upon
`
`the particular solubility and particular tonicity desired for the composition.
`
`In a
`
`preferred embodiment, the average molecular weight of the polyether, particularly
`
`when it is PEG, is at least 200, more typically at least 320 and even more typically
`
`at least 380 but is typically no greater than 800, more typically no greater than 580
`
`and still more typically no greater than 420. One preferred PEG is PEG400.
`
`It may also be desirable for the ophthalmic composition of the present
`
`invention to include a viscosity enhancing agent in order to enhance residence time
`
`of the composition upon the cornea when the composition is topically administered.
`
`Examples of potentially suitable viscosity enhancing agent
`
`include, without
`
`limitation, carboxyvinyl polymer, galactomannan, hyaluronic acid, cellulosic
`
`polymer, any combination thereof or the like.
`
`In a prel’erred embodiment,
`
`the
`
`ophthalmic
`
`composition
`
`includes
`
`hydroxyethyl
`
`cellulose
`
`(HEC),
`
`hydroxylpropylmethyl cellulose (HPMC) or both. One preferred HEC is sold under
`
`the tradename NASTROSOL® ZSOHX, which is commercially available from
`
`Hercules Incorporated, Aqualon Division, Argyle, TX. One preferred HPMC is
`
`sold under the tradename E4M 2910 and is commercially available from Dow
`
`Chemical, Midland, MI.
`
`The amounts and molecular weights of HPMC and/or I-"IEC used in the
`
`composition will depend upon the viscosity, osmolality and other attributes to be
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`achieved for the composition. As used herein, viscosity is measured by a
`
`Brookfield viscometer (LVDVI+, CP-42, 12 RPM and a temperature of25 °C).
`
`In
`
`a preferred embodiment, the viscosity of the composition is at least 2.0 centipoise
`
`(cps), more typically at least 15 cps, even more typically at least 21 cps and even
`
`possibly at least 27 cps, but is typically no greater than 65 cps, typically no greater
`
`than 40 cps, more typically nor greater than 33 cps and even possibly no greater
`
`than 30 cps. Advantageously, and as further discussed below, viscosity within
`
`these ranges has been discovered to be more desirable for producing desired droplet
`
`sizes when the composition of the present invention is topically delivered from an
`
`eye dropper.
`
`The preferred average molecular weight of HEC, when used, is typically in
`
`the range of 90,000 to 1,300,000 (e.g., approximately 1,000,000). The preferred
`
`average molecular weight of HPMC is typically in the range of 10,000 to 1,500,000
`
`and more typically in the range of 189,000 to 688,000).
`
`When HPMC is used alone,
`
`it
`
`is typically present
`
`in composition at a
`
`concentration that is at least 0.15% w/v, more typically at least 0.3% w/v and even
`
`more typically at
`
`least 0.5% w/v, but
`
`is typically no greater than 1.5% w/v,
`
`typically no greater than 1.0% w/v and is typically no greater than 0.7% w/v.
`
`When HEC is used alone,
`
`it
`
`is
`
`typically present
`
`in the composition at a
`
`concentration that is at least 0.1% w/v, more typically at least 0.25% w/v and even
`
`more typically at
`
`least 0.45% w/v, but
`
`is typically no greater than 1.4% w/v,
`
`typically no greater than 0.9% w/v and is typically no greater than 0.65% w/v.
`
`Advantageously, when HPMC and HEC are used to together, they may produce a
`
`synergistic viscosity effect which allows the use of low concentrations of these
`
`excipients to produce the desired viscosity of the compositions. When HPMC and
`
`HEC are used in combination, HPMC is typically present in composition at a
`
`concentration that is at least 0.05% w/v, more typically at least 0.1% w/v and even
`
`more typically at
`
`least 0.2% w/v, but
`
`is typically no greater than 1.0% w/v,
`
`typically no greater than 0.55% w/v and is typically no greater than 0.4% w/v.
`
`When HPMC and HEC are used in combination, HEC is typically present
`
`in
`
`composition at a concentration that is at least 0.02% w/v, more typically at least
`
`0.06% w/v and even more typically at least 0.09% w/v, but is typically no greater
`
`than 0.6% w/v, typically no greater than 0.3% w/v and is typically no greater than
`
`0.17% w/v. Notably,
`
`in at
`
`least some embodiments of the present invention,
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`HPMC is a preferred viscosity enhancing agent since, as the data present below
`
`shows, it can also aid in solubilizing the olopatadinc.
`
`The composition can also include buffering agents and/or tonicity agents.
`
`Suitable tonieity-adjusting agents and/or buffering agents include, but are not
`
`limited to, mannitol, sodium chloride, glycerin, sorbitol, phosphates, borates,
`
`acetates and the like.
`
`Borate is a highly preferred buffering agent and will typically be included in
`
`the composition of the present invention. As used herein, the term "borate" shall
`
`refer to boric acid, salts of boric acid, borate derivatives and other pharmaceutieally
`
`acceptable borates, or combinations thereof. Most suitable are: boric acid, sodium
`
`borate, potassium borate, calcium borate, magnesium borate, manganese borate,
`
`and other such borate salts. Typically, when used, the borate is at least about 0.05
`
`w/v %, more typically at least about 0.18 w/v % and even possibly at least about
`
`0.27 w/v % of the ophthalmic composition and is typically less than about 1.0 w/v
`
`%, more typically less than about 0.75 w/v % and still more typically less than
`
`about 0.4 w/v %, and even possibly less than about 0.35 w/v % of the ophthalmic
`
`composition.
`
`The composition of the present invention can also include polyol. As used
`
`herein,
`
`the term “polyol” includes any compound having at
`
`least one hydroxyl
`
`group on each of two adjacent carbon atoms that are not in trans configuration
`
`relative to each other.
`
`The polyol can be linear or cyclic, substituted or
`
`unsubstituted, or mixtures thereof, so long as the resultant complex is water soluble
`
`and pharmaceutieally acceptable. Examples of such compounds include:
`
`sugars,
`
`sugar alcohols, sugar acids and uronie acids. Preferred polyols are sugars, sugar
`
`alcohols and sugar acids, including, but not limited to: mannitol, glycerin, xylitol,
`
`sorbitol and propylene glycol.
`
`It is contemplated that the polyol may be comprised
`
`of two or more different polyols.
`
`When both borate and polyol are present in the composition, borate typically
`
`interacts with polyol, such as glycerol, propylene glycol, sorbitol and mannitol, or
`
`any combination thereof to form borate polyol complexes. The type and ratio of
`
`such complexes depends on the number of OH groups of a polyol on adjacent
`
`carbon atoms that are not in trans configuration relative to each other.
`
`It shall be
`
`understood that weight/volume percentages of the ingredients polyol and borate
`
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`include those amounts whether as part of a complex or not. Advantageously, the
`
`borate and polyol can act as buffers and/or tonieity agents and can also aid in
`
`enhancing preservation efficacy of the composition.
`
`In a preferred embodiment of the invention,
`
`the composition includes
`
`propylene glycol, glycerine or both.
`
`It has been found that y—eyelodextrin
`
`derivatives and/or B—cyclodextrin derivatives tend to inhibit preservation efficacy
`
`within the formulations of the present invention, however, propylene glycol in the
`
`presence of borate appears to significantly limit this inhibition. Moreover, it has
`
`been found that glycerine often acts in a manner very similar to propylene glycol
`
`when used for aiding preservation. When used, propylene glycol, glycerine or a
`
`combination thereof is typically present in the composition at a concentration that is
`
`at least 0.4 w/v%, more typically at least 0.65 w/v% and even possibly at least 0.85
`
`w/v% but is typically no greater than 5.0 w/v%, more typically no greater than 2.2
`
`w/v% and even more typically no greater than 1.7 w/v%.
`
`In a same or alternative preferred embodiment of the invention,
`
`the
`
`composition includes mannitol,
`
`sorbitol or both. Mannitol may also aid
`
`preservation of the composition of the present invention when used in the presence
`
`of borate. Moreover, it has been found that sorbitol often acts in a manner very
`
`similar to mannitol when used for aiding preservation